The Publication of the British Society for Cardiovascular Research Vol

The Publication of The British Society for Cardiovascular Research Vol. 12 No. 2

Registered Charity Number: J 011141 The Bulletin The Publication of The British Society for Cardiovascular Research

Editors Dr. James Mockridge and Dr. Harold Raat Dr. Adrian Brady Department of Cardiology Department of Medical Cardiology The Rayne Institute, St. Thomas' Hospital Royal Infirmary London SE17EH 16 Alexandra Parade Tel.:0171-9289292ext.l818 GlasgowG312ER Fax.:0171-9605659 TeL:0141-2114727 E-mail: j [email protected] Fax.:0141-2111171 E-mail: [email protected] Dr. Michael Marber Department of Cardiology Chairman The Rayne Institute, St. Thomas' Hospital London SE17EH Prof Gianni Angelini Tel.:0171-9228191 Bristol Heart Institute Fax.:0171-9605659 Bristol Royal Infirmary E-mail: [email protected] Bristol BS28HW Tel.:0117-9283145 Dr. Barbara McDermott Fax.: Oil 7-9283871 Department of Therapeutics and Pharmacology The Queen's University of Belfast Whitla Medical Builiding Secretary 97 Lisbum Road Dr. Gary F.Baxter BelfastBT97BL The Hatter Institute for Cardiovascular Studies Tel.: 01232-272242/335770 University College Hospital Fax.:01232-*38346 Grafton Way E-mail: [email protected] London WC1E6DB Tel.:0171-3809888/9881 Dr. Kathryn O. Ryder Fax.:0171-3885095 P.O. Box 6779, E-mail: [email protected] Dundee DDI IWN. Tel.:01382-223189 Fax.:01382-221571 Treasurer Dr. Michael J. Curtis Dr. M.-Saadeh Suleiman Pharmacology Group Bristol Heart Institute Kings College London University of Bristol Rayne Institute, St. Thomas' Hospital Bristol Royal Infirmary London SE17EH Marlborough Street Tel.:0171-9289292 ext. 2230 Bristol BS2 8HW TeL:0117-9283519 Fax.:0171-9280658 Fax.:0117-9283581 E-mail: [email protected] E-mail: m. s. suleiman@bri stol.ac.uk

Committee Dr. Ian Zachary Department of Medicine and Wolfson Institute for Dr. PaulJ.R. Barton Biomedical Research Imperial College School of Medicine f University College London National Heart and Lung Institute 5 University Street Dovehouse Street London WC1E6JJ London SW3 6LY Tel.: 0171-2096620 Tel.:01713518184 Fax.: 0171-2096612 Fax.:0171-3763442 E-mail: [email protected] E-mail: [email protected]

2 Contents

Editorial 3 Review Article: Getting to the heart of the matter: how can we study the modem historyofcardiovascularresearchandpracticebyDrT.Tansey 4 Secretary's Column 7 Review Article: Cationic amino acid transporters: characteristics, function and role in nitric oxide biosynthesis by Dr A.Baydoun 8 Cardiovascular related meetings 14 BSCR Bulletin BookReview: Renin-Angiotensin 15 British Heart Foundation Grants 17 Cardiovascular Related Wellcome Trust Grants 19 BSCR Autumn Meeting: Myocardial Responses to Sub-Lethallschaemia: preconditioning, stunning and hibemation 20 Editorial Welcome to the Spring issue of The Bulletin. Therefore, if any of you would like to suggest a Sorry for a slightly slimmer issue than you're used to colleague's lab or their own or someone who has made but unfortunately one of the contributors failed to meet a significant contribution to cardiovascular research, here the deadline and therefore could not be included. or abroad, it would be great to hearfrom you. See the Hopefully, the next issue will make up for it! opposite page for our contact details. Nevertheless, we do have two review articles; one from As we mentioned in our Editorial in the last issue, Dr Tillie Tansey from the Welcome Institute for the we have been giving some thought to adding a new History of Medicine writing about the key figures in feature aimed primarily at PhD students who have just the early history of heart transpantation and the other finished, or are about tofinish, thei r studies. The aim of from Dr Anwar Baydoun describing cationic this feature is to give an opportunity for students to write transporters and their role in nitric oxide biosynthesis. a short summary (1 -2 pages of A4) describing not only This issue's book review is an overseas contribution the work done, but also to share their experiences during from Prof Jos Smits from University of Maastricht. their studentship. In addition, it would also be a way to Thanks to all our contributors. 'advertise' their skills and research interests throughout As we mentioned last time, we are keen to the cardiovascular research arena. If you're a PhD maintain the 'flavour' of the Bulletin by highlighting student and would be interested in writing such an article different topics in cardiovascular research rather than please get in contact with us and we will give you fiirther solely providing information about grants and details. We look forward to hearing from you. forthcoming meetings. However, in order to achieve this we need your contributions. In particular, we are James Mockridge & Harold Raat in need of people to write 'Laboratory Profiles' and 'Careers in Cardiovascular Research' articles.

Cover artwork copyright Anthony Wright, 1997 Cover design copyright Sidn Rees and Anthony Wright, 1997 3 Getting to the heart of the matter: how can we study the modern history of cardiovascular research and practice? Dr Tillie M Tansey Twentieth Century Medicine Group, Wellcome Institute for the History of Medicine, 183 Euston Road, London NWl 2BE Many scientists moan, with some justification, immunologist and Nobel Laureate Sir Peter Medawar about the proliferation of published material in their once suggested, in a famous article entitled, 'Is the disciplines, and the impossibility of 'keeping up with scientific paper a fi^ud', that therigid, formal structure the literature'. George Lundberg, until recently the editor of scientific papers meant that much literature of JAMA, has estimated that 2 million biomedical 'misrepresents the processes of thought that accompa• articles appear each year. He suggested two strategies nied or gave rise to the work that is described ...', for the reader keen to keep abreast of all this literature: allowing for little individual expression or amplification. one was that the active researcher should read two Tuming to unpublished archives for elucidation, as articles per day throughout the year - unfortunately historians do, can introduce additional difficulties: in by the end of the year that still left 60-centuries worth the United Kingdom public records, which includes of reading to be done. An alternative, Lundberg hospital records and those of Govemment fiinded proposed, somewhat tongue-in-cheek, was that the bodies such as the MRC, are subject to a restriction busy scientist should read 6000 articles every day! By that keeps papers hidden for at least thirty years; in the judiciously reading/scanning the core joumals of their case of clinical and other records the period of closure disciplines, taking a regular look at an indexing/ is 100 years. Equally, specialist archives can present abstracting source such as Current Contents or problems: the survival of personal papers can be erratic, Medline, and by attending meetings and talking with many are lost during the lifetime of an individual, as colleagues, the busy researcher has the possibility of space constraints or relocation demand the jettisoning keeping up with the main developments in his field. of material without proper regard for its significance. But what hope has the poor historian of modem Probably even more papers are wrongly discarded as medicine, who not only has to make sense of this mass worthless and uninteresting by their owners, or by of published data, but is also expected to scour archives relatives acting immediately after a bereavement. for additional unpublished accounts and illuminating Thus historians of contemporary medicine are details? And paradoxically these records might not be increasingly tuming, or returning, to the traditional enough. In this era of telephone, fax and e-mail technique of oral history to supplement, or extend, communication, and when national and international existing records, and to create new resources. meetings are occurring all over the globe, all the time, Recognising that many of the principal sources of what survives of these interactions? How can historians contemporary medical history are still walking around, attempt to understand, reconstmct, and convey to often on increasingly elderly andfragile legs , historians others, the stories of the recent past and their are attempting to hear, and record, the accounts of the significance? Should contemporary researchers historical actors themselves. Aparticularly specialised acknowledge that a part of their current intellectual form of oral history is the Witness Seminar, and to date, responsibility is to present and future historians? the Wellcome Tmst's History of Twentieth Century The extensive published record of modem Medicine Group has arranged almost twenty such medicine and medical science raises particular problems meetings in medicine and the biomedical sciences. A for historians: it is often presented in a piecemeal but Witness Seminar as a workshop where several people formal fashion, sometimes seemingly designed to associated with a specific set of circumstances, or a conceal rather than reveal the processes by which discovery, are invited to meet together to discuss, scientific medicine is conducted. The distinguished debate, and even disagree about the events to which

4 they were common witnesses. The entire proceedings President of the Royal College of Surgeons, he had of such a meeting are recorded and transcribed, and applied for a British Heart Foundation grant, for then edited for publication, and all or part offifteen hav e preliminary experiments on heart transplants in dogs, been, or are about to be, published on behalf of The 'and we were told that the roars of laughter could be Wellcome Trust. heard two or three blocks away. In late 1963, we got The early history of heart transplantation in the a grant £6 000, which in those days was a very large UK was one such meeting, co-organised and chaired sum of money and I rented a laboratory in the Royal by Professor Tom Treasure, Professor of Cardio- Veterinary College for six old pence a year, and we set thoracic Surgery at St. George's Hospital Medical about what we thought was a very scientific approach School in London. Several early pioneers of heart and we were also supported by the Wellcome [Trust]'. transplantation in the UK discussed the early events Amongst visitors to the lab was Christiaan Bamard, leading to thefirst UK heart transplant, and the sequelae and the entire team for the first British transplant, who that have shaped modem heart transplant programmes. carried out thefiill experimental procedure twice. Participants included surgeons, anaesthetists and Sir Keith Ross, the third surgical member of the cardiologists involved in the early transplants in the UK. team, also recalled his experiences of thatfirst huma n The surgeons involved in the veryfirst transplant , operation. In the late 1950s he had worked in Mr Donald Ross, Sir Keith Ross and Professor Donald Shumway's lab, gaining considerable experience in Longmore all described events surrounding their valve surgery, and in September 1967 was appointed involvements in that operation, peribrmed on the 3rd a Consultant at the National Heart Hospital. On May of May 1968 at the National Heart Hospital, London. 3rd 1968 he had the responsibility of taking out the This followed the world's first ever human heart donor heart, whilst Donald Ross took responsibility transplant performed by Christiaan Bamard on Louis for the recipient patient. Sir Keith recalled 'one was Washkansky at the Groote Schuur Hospital, Cape aware, very much I think, while this was going on, that Town, South Afiica, on 3 December 1967. As Donald this was a historic moment and slightly unreal in the Ross reminded the audience though,' it was the father relative calm of the operating theatre at the National figures in this area, Messrs Shumway and Lower of Heart Hospital.' Palo Alto, California, near San Francisco, who had That historic moment was almost immediately been scientifically working on transplantation of the picked up by the press, and all the witnesses of the heart in animals. We were all playing around with it first UK heart transplant recalled their naivety towards technically, excited about this sewing in of the heart, the media at the time, with little or no consideration which is in fact when you come to think about it, is given towards public relations following such the event, quite a simple plumbing job.' Bamard, like other heart either by the individuals themselves or the National surgeons, went to Stanford University in Palo Alto, saw Heart Hospital. Another general consensus was the lack the technical advances that Norman Shumway and his of bureaucracy and constraints, which allowed the team were achieving, and decided to perform the event to take place. No special arrangements were operation in a human subject. Ross continued' within made to fund the operation, and there was no a couple of months he did it. He had the courage to do involvement of any ethical committee. With no legal it, but the background knowledge comes from precedent, this later proved to be a problem, and Shumway, there's no doubt about that.' Almost Donald Longmore vividly recalled his appearance at immediately after the pioneering work in South Afiica, the Coroners Court to justify the removal of the there was a rush around the world, as national pride functioning donor heart, and being asked for his seemingly demanded at least one heart transplant each definition of death. Similar problems for Shumway's country could call their own. Dr Renee Fox, a medical team in Califomia had resulted in the threat of being sociologist from the University of Pennsylvania, indicted for murder, and the meeting heard from commented that during 1968,105 cardiac transplants Professor John Bunker, who had been the anaesthetist were performed around the world, 60 of them over for Shumway'sfirst donor. Bunker recalled 'The local the course of September to November of that year. coroner [in Palo Alto] was not pleased that the heart Another member of thefirst British surgical team, was removed before he could carry out an autopsy. Professor Donald Longmore, recalled a sUghtly earlier He said, afterwards, 'When I do an autopsy, I don't period, when, with Sir Thomas Holmes Sellors, later want anyone fiddling with my bodies.' Shumway was

5 Participants in the Wellcome Trust's Witness Seminar on Early UK Heart Transplants

Figure 1 Professor Tom Treasure Figure 2 Mr Donald Ross

Figure 3 Professor Donald Longmore Figure 4 Sir Terence English

All photographs courtesy of the Wellcome Trust Medical Photographic Library not deterred by the possibility that he might be indicted therapeutic innovations, which proceed along a for murder, nor was I. So we went ahead, willy nilly, pathway of exhilaration, criticism, review, and finally and fortunately the district attorney for the State of partial or complete acceptance. Califomia took a much more realistic view of the The final section of the seminar contained matter'. These events highlighted the need for a legal contributionsfrom Si r Terence English who commented definition of clinical death, and which culminated in our on the later work of Norman Shumway, who present criteria of brain stem death. continued to operate and persisted during the seventies It was generally agreed that the poor success of in researching and using anti-rejectionfreatments, suc h the early heart transplants in Britain was due to a lack as ATG. Shumway also assessed the impact of of experience and in particular the lack of ability to cyclosporin,first used clinically by Sir Roy Calne in treat or even recognise immunological rejection. The 1978 in kidney transplantations, and it was used in "medicine by committee approach" which evolved Stanford for heart transplantation in 1980 when Mr could not work in the midst of disputes between John Wallwork first had experience of it. Cyclosporin surgeons, physicians and other hospital personnel. The was introduced into Sir Terence's transplant unacceptably poor results led to a voluntary clinical programme at Papworth Hospital in March 1982. Sir moratorium and Dr Renee Fox discussed the Terence also discussed in particular the formal moratorium in the light of the history of a wide range of establishment of a heart transplant programme in Britain.

6 The Department of Health and Social Security established a Transplant Advisory Panel advised the Chief Medical Officer on criteria to be met by any Secretary's Column centre before a cardiac transplant programme could At the time of writing, the BSCR can look forward to be approved. Sir Terence descibed how, after working three main meetings (two this year and another in with Shumway at Stanft)rd and later with Professor Autumn 2000), a workshop in April and a joint session Roy Calne at Addenbrookes Hospital in Cambridge, at the British Cardiac Society in May. I would stress he set about establishing a specialist heart transplant the importance of early planning for such events. It is centre at Papworth. The encouraging results in not too early to submit proposals for meetings, Cambridge and also at Sir Magdi Yacoub's unit at workshops or British Cardiac Society symposia in 2000 Harefield enabled both centres to receive supra and beyond. As I mentioned in my last letter, the regional funding with additional centres being Committee will be pleased to consider all suggestions. established at the end of the eighties and early nineties. Further details of the support available for meetings and The seminar lasted for over ft^ur hours and workshops are available from me and I would urge all provided a fascinating insight into many historical events members to at least consider areas of interest that should which have shaped the field of heart transplantation be covered by future meetings. Even if you are not as described by the principal sources of this prepared to organise a meeting yourself, contact me contemporary medical history. It will be published in and give me the name of someone who might be cajoled September 1999, and suggests one mechanism into doing it. whereby medical scientists and practitioners of today Since the last Bulletin mailing, it is clear that there are can assist the medical historian of tomorrow. several subscribing members of the Society whose addresses are unknown to us. 1 think it unlikely that these people are "of no fixed abode" but rather that having moved on to pastures new, they have failed to notify us of their new addresses. I attach a list of Dr Tansey is Historian of Modern Medical members for whom we do not have a current address History/Convenor of the Twentieth Century and would ask readers who know of the whereabouts Medicine Group, Wellcome Institutefor the History of these members to contact me so that I can update of Medicine our records accordingly. If the Bulletin you are holding now has been redirected to you from a previous or incorrect address, I would ask you to drop me a line with your correct address. Submission Of Abstracts WHERE ARE THEY NOW? Dr AAhmed, previously of the University of Dundee To The Bulletin Dr P Brooksby, address unknown Abstracts presented at BSCR meetings, such as the Dr R A J Challiss, address unknown; recent Signal Transduction and Growth Control Dr S Herbsthofer, previously of Vienna; in the Cardiovascular System at University College Mr C Marston, address unknown; London, can be published in The Bulletin. It is a Dr A L Rothaul, previously of British Biotech; good forum to present preliminary data, for students Dr D D Sandeman, address unknown; to develop presentation skills and for more senior Dr AG Violaris, address unknown; authors to give us a snapshot of work they will Dr D R Wheeldon, previously of Papworth Hospital; present elsewhere. Please send your abstract on disk Dr E Winslow, address unknown. saved as a PC-compatible file, preferably as a Word document, accompanied by a hard copy. Please ensure disks are free of viruses as infected disks Gary Baxter cannot be read. Send to the Editors or to the meeting organisers marked for our attention.

7 Cationic amino acid transporters: characteristics, function and role in nitric oxide biosynthesis Dr Anwar R Baydoun Biosciences Department, University of Hertfordshire, Hatfield, Herts, ALIO 9BA The discovery in 1987 that endothelium- pathways [reviewed in 4 and 5]. derived relaxing factor is nitric oxide (NO) [ 1 ] was Both the endothelial and neuronal NOS are followed a year later with reports that the cationic constitutively expressed, dependent upon Ca^^ and amino acid L-arginine is the physiological precursor calmodulin for activation, and produce picomolar for nitric oxide [2]. It has since been established that amounts of NO over short periods of time following the terminal guanidinium nitrogen of L-arginine is agonist stimulation. Under normal physiological metabolised via a series of oxidation reactions conditions, NO produced via the constitutive endothelial resulting in NO production, with citmUine being formed L-arginine-nitric oxide pathway appears to be a key as a co-product. These novelfindings stimulated new physiological regulator of vascular tone, maintaining the interest in amino acid transport with several groups, vasculature in a constant state of vasodilatation [6,7]. including ours, focusing in understanding the In contrast, synthesis of NO via the inducible characteristics, fiinction and regulation of L-arginine pathway involves induction of a Ca^^/calmodulin- transports. Considerable attention is also being given insensitive NO synthase (iNOS) previously identified in to identifying the role of L-arginine transporters in NO macrophages and now known to be induced in a wide synthesis, with a view to exploiting these systems as variety of cell types including the endothelium, vascular potential targets for novel pharmacological and/or smooth muscle cells and cardiac myocytes. Expression molecular interventions. In this review I will give an of this enzyme is time-dependent and involves de novo overview of the physiological and molecular protein synthesis, which can be inhibited by the protein characteristics,fianction and regulation of L-arginine synthesis inhibitor cycloheximide and also by the transporters. I will also discuss data that point to a glucocorticoid dexamethasone [see 3-5]. Once induced critical role for L-arginine transport in the regulation the activity of the enzyme is sustained over prolonged of NO synthesis. I will start however by giving a periods and generates quantitatively more NO compared summary of the pathways associated with NO to its constitutive isoforms. biosynthesis. This will only be dealt with in brief since other articles, published in recent issues of this Bulletin, Source of substrate for NO synthesis have already discussed this topic in more detail. The source of L-arginine for NO synthesis appears to depend on the physiological state and L-arginine-nitric oxide pathways biosynthetic pathway being activated. L-arginine on it Nitric oxide is a free radical that has gained own has no significant effect on blood pressure in vivo recognition as a ubiquitous biological mediator with a [6,7], on coronary perfusion pressure in vitro [8,9], or multitude of physiological and pathophysiological on the tension developed by isolated aortic rings [10], functions [reviewed in 3]. This highly labile molecule suggesting that basal NO synthesis is not limited by is synthesisedfrom th e cationic amino acid L-arginine subsfrate availability. This is perhaps predictable since following oxidation of the terminal guanidino-nitrogen L-arginine is present in high concentrations in endothelial by a family of enzymes referred to as NO synthases cells (-0.8 mM) [11]. The K„ of eNOS for L-arginine (NOS). At present three distinct isoforms, endothelial is <0.01 mM, with maximal stimulation occurring in the (eNOS), neuronal (nNOS) and inducible (iNOS), presence of 0.03-0.1 mM L-arginine [11-13]. Thus the have been identified and are known to be derived from availability of L-arginine may not be rate limiting for the separate genes and regulated by diverse signalling relatively small quantities of NO released under basal

8 ©

Cytokines L-arg

Figure 1. Schematic illustration of possible relationship between L-arginine transport and nitric oxide synthesis in cultured vascular cells. Stimulation of cells (endothelial) with agonist elevates intracellular Ca^* and activates both eNOS and Ca^*- activated K" channels. The latter results in hyperpolarization of cell membrane, increasing and thus L-arginine entry into cells. With the induced model, activation of cells with pro-inflammatory mediators such as LPS and/or cytokines stimulates signalling mechanisms (yet to be identified) which results in induction of new carrier proteins. These proteins are thought to supply L-arginine for NO synthesis by iNOS- see review for discussion.

conditions. The same appears to be true for transient arginine [18,19], and is inhibited following blockade of stimulation of NO production by various agonists, L-arginine entry into cells [19]. including bradykinin and acetylcholine. However, when Taken together, these fmdings strongly support a stimulus is applied repeatedly over prolonged periods, the notion that availability and transport of extracellular endogenous substrate becomes rate limiting. Under these L-arginine can limit NO production under both conditions the availability and entry of exogenous L- physiological and pathophysiological conditions. arginine restores responses previously rendered tolerant by repeated or prolonged agonist administration Influence of increased NO synthesis on L-arginine [ 10,14]. In the same context, several studies in cultured transport endothelial cells [2], perfused hearts [8], animals [7] The critical role of exogenous L-arginine in and man [15] have shown that exogenous L-arginine regulating NO production begs the question of whether can reverse inhibition of eNOS by inhibitor analogues stimulation ofNO synthesis facilitates entry of L-arginine of L-arginine itself and enhance or sustain agonist- into cells. In this regard, it is interesting to note that induced release of NOfrom the endothelium. fransport of L-arginine is significantly elevated in cells The dependence of NO production on expressing iNOS [ 19,20] and transiently increased in exogenous L-arginine is perhaps more apparent with endothelial cells stimulated with NO releasing agonists iNOS, a high output system that generates nanomolar such as bradykinin or ATP [21,22]. At present there is quantities of NO over prolonged periods. Release of very little evidence to suggest that the two pathways NO by this enzyme is not only dependent on the may be directly coupled. Enhanced L-arginine transport presence of extracellular arginine [16-19], but also in iNOS expressing cells is due to de novo protein directly related to the rate of transport of exogenous synthesis [19,20] (see below) and that in endothelial

9 Table 1. Characteristics of cationic amino acid transporters

CAT-1 CAT-2A CAT-2B CAT-3

Km (mM) 0.1-0.2 2.1-5.2 0.04-0.3 0.1-0.15 Na^-independent yes yes yes yes Amino acids 622 657 658 619 MW (kDa) 67 72 72 67 N-glycosylation yes yes yes yes Expression constitutive constitutive inducible constitutive Key cell type ubiquitous liver, muscle T-cells brain except liver skin macrophages cells may be a consequence of the hyperpolarsing Transport proteins (CAT), CAT-1 [26,27], CAT-2A actions of the agonists used (see figure 1). Nevertheless [27], CAT-2B [28] and CAT-3 [29] have been it is not unreasonable to postulate that the increase in identified [reviewed in 25,30]. Some of the key transporter activity provides a mechanism for sustaining characteristics of these proteins are discussed below L-arginine supply during enhanced utilization of this and summarised in Table 1.1 have placed little emphasis substrate for the generation of NO. on CAT-3, since this transporter is expressed predominantly in the brain [29] and thus of little relevance Transport systems for L-arginine to the cardiovascular system. L-arginine is predominantly transported across cell membranes via specific sodium-independent Molecular identification and structure of CATs transporter(s) selective for cationic amino acids. This Of the four proteins, CAT-1, a high-affinity pathway was originally termed system y^ [23, see 24 electrogenic transporter, was the first to be for a comprehensive review]. Although other systems, characterised at the molecular level. This protein was including the b^, b"-^, B°'^ and y^L, have been identified cloned, albeit serendipitously, by a group searching for as transporters of cationic amino acids, these carriers the ecotropic murine leukemia virus receptor (ecoR) also accept a wider range of substrates, including neutral [31]. The deduced amino acid sequence of the cloned amino acids [reviewed in 25]. Thus the only truly cDNA revealed a 622 amino acid glycoprotein of about selective cationic transporter expressed in vascular cells 67 kDa with 12 to 14 transmembrane spanning domains still remains system y+. (Figure 2). Approximately two years after cloning ecoR, System y+ was initially thought of in terms of a it was demonstrated that expression of this protein in "one-protein-one transport activity" paradigm. Xenopus oocytes mediated cationic amino acid However, the evolution of recombinant DNA transport [32,33]. It is worth noting that the human technology and the development of new kinetic homologue of this gene has also been cloned and experimental approaches have unveiled a more complex mapped to chromosome 13ql2-ql3. Its cDNA picture. It is now evident that transport of L-arginine, sequence, like that of the murine gene, predicts a 68 and indeed other cationic amino acids, involves several kDa protein with 12-14 membrane spanning domains distinct proteins which are distinguishable by their of629 amino acids, and shares 88% homology with structure, distribution and affinity for cationic amino the mouse sequence [34]. acids. A truncated C AT-2 gene was cloned shortly At least four different Cationic Amino acid after CAT-1 and initially named Tea (T-cell early

10 Figure 2. Predicted model of CAT-1 with 14 transmembrane spanning domains (TMs). Dashed loop on TM Vand VI contains ecoR and the forked region is the predicted N-glycosylation site. The dashed loop on TM VIII and IX represents the domain that determines CAT properties. This figure is adapted form Closs [30]. activation receptor) because of its induction early in Unlike CAT-1 and C AT-2 A, CAT-2B is an the response of normal T cells to mitogens [35]. The inducible protein (at least in macrophages) with a high full length cDNA which encode a 658 amino acid affmity for L-arginine (k^: 0.04 - 0.3- mM) comparable protein (CAT-2B) was subsequently isolated by Closs to that of CAT-1, despite its high sequence identity with et al. [21 ] and shown to have a 61 % homology with CAT-2A [27,36,37]. This strongly indicates that the CAT-1 (see Table 1) and 98 % homology with CAT- divergent domain in the predicted fourth loop of CAT- 2A. It is now known that CAT-2A and CAT-2B are 2 may be critical for substrate recognition and/or the product of differentially spliced mRNAs. The translocation. Indeed, substitution of the protein domain deduced sequence of these two proteins differ by only in the fourth loop of CAT-2B with that of CAT-2A 20 amino acids within a stretch of 41 amino acids in an resulted in a chimeric protein that had a low affinity for alternatively spliced region in the predicted fourth L-arginine- ie exhibited transport properties similar to extracellular loop (Figure 3). that of CAT-2A. Similarly, substituting this domain in CAT-2A with that of CAT-1 or CAT-2B resulted in a Tissue distribution and function of CATs transporter with high affinity for L-arginine comparable CATs are expressed in a tissue-specific manner to that of CAT-1 andCAT-2B [27]. (see Table 1). The general consensus is that CAT-1 is The inducible nature of CAT-2B has lead to the ubiquitously expressed except in liver, and mediate high suggestion that this protein may be the patho• affinity (K^: 0.1 -0.2 mM) transport of L-arginine under physiological transporter, mediating the enhanced normal physiological conditions [28,32,33,36]. In uptake of L-arginine in cells activated with a variety of contrast, CAT-2A has a restricted expression pattern. extemal stimuli, including bacterial lipopolysaccharide This transporter is found predominantly in liver and (LPS) [26,38], cytokines [39,40], mitogens [25], insulin mediates low (K^: 2.1 -5.2 mM) affinity uptake of L- [39] and angiotensin II [40,41]. This notion may arginine [28,37]. CAT-2A therefore only functions however be a little premature and should be viewed adequately at high extracellular substrate concentrations, with caution. In preliminary studies, using isoform- and presumably acts as a kinetic barrier between hepatic specific probes in RNase protection analyses, we have urea cycle and extracellular arginine. Moreover, it is identified transcripts for CAT-1, CAT-2A and CAT- plausible that C AT-2 A contributes only very little to the 2B which are constitutively expressed in primary total influx of L-arginine into cells at physiological cultures of rat aortic smooth muscle cells. Moreover, arginine concentrations in plasma. we could detect significant elevations in mRNA for all

11 CAT-2A: 277 - I FPMPRVIYAM AEDGLLFKCL AQINSKTKTP VIATLSSGA VA - 318

** -k-k -k k kr-k k-k -k -k-k -k k: * * *

CAT-2B: 277- M FPLPRILFAM ARDGLLFRFL ARV-SKRQSP VAATMTAGV IS - 318

Figure 3. Deduced amino acid sequence of the alternative spliced region in the predicted fourth extracellular loop of murine CAT-2Aand CAT-2B. Asterisks identifies sequence identity and dots indicate conservative substitutions between CAT-2A and CAT-2B. three CAT isoforms following activation of cells with as atherosclerosis [42]. Moreover, supply of L-arginine LPS and interferon-y (unpublished observations). This in this disease appears crucial for the production ofNO induction pattem is consistent with one other study in by eNOS. Acute administration of L-arginine restores rat cardiac myocytes, where increases in transcripts of endothelium-dependent vasodilatation in hypercho- CAT-1, -2A and -2B have been observed following lesterolemic patients [43,44], with both acute and treatment with IL-1 (3 and IFN-y [39]. These fmdings chronic administration normalising impaired have now lead to the realization that transport of L- endothelium-dependent relaxation of vessels isolated arginine may be more complex than the initial "one- from cholesterol-fed rabbits [45-48]. The specific protein-one transport activity" paradigm, and raise the regulation of individual CATS in diseases such as question of the specific contribution of each CAT to atherosclerosis now remain to be addressed. total arginine transport under both physiological and pathophysiological conditions. Specific knockouts and/ REFERENCES or antisense strategies are clearly required to address this issue. Using the same approach we should be able [I] Palmer, R.M.J., Ferrige, A.G. and Moncada, S. (1987). to shed light on the critical regulation of NO synthesis Nature, 327, 524-526. [2] Palmer, R.M.J., Ashton, D.S. and Moncada, S. by CATs and identify key CAT or CATs associated (1988) . NaUire, 333, 664-666. with this process. [3] Moncada, S., Palmer, R.M.J, and Higgs, E.A. (1991). Pharmacol. Rev, 43, 109-142. Conclusions [4] Knowles, R.G. and Moncada, S. (1994). Biochem.J., An attempt has been made in this review to 298,249-258. highlight what is emerging as a potentially crucial [5] Sessa, W.C. (1994). J.Vasc.Res. 31, 131-143. regulatory step in the synthesis ofNO. The identification [6] Rees, D.D., Palmer, R.M.J, and Moncada, S. (1989). Proc. Nati. Acad. Sci. USA. 86, 3375-3378. of several distinct proteins that can transport L-arginine [7] Aisaka, K., Gross, S., Griffith, O.W. and Levi, R. has been a significant breakthrough. A better (1989) . Biochem. Biophys. Res. Commun., 163, 710- understanding of these systems is now critical. Future 717. emphases in this field, I believe, would be placed in [8] Amezcua, J.L., Palmer, R.M.J., de Souza, B.M. and understanding the function, regulation of expression and Moncada, S. (1989). Br. J. Pharmacol. 97, 1119-1124. compartmentalization of individual CATs. Elucidation [9] Baydoun, A.R. and Woodward, B. (1991). Br. J. of the three-dimensional structure of each CAT and the Pharmacol., 103,1829-1833. mechanism of substrate translocation through the cell [10] Gold, M.E., Bush, RA. and Ignarro, L.J. (1989). membrane would also be invaluable. As fiirther progress Biochem. Biophys. Res. Commun. 164, 714-721. is made in these areas we envisage being able to design [II] Baydoun, A.R., Emery, P.W., Pearson, J.D. and specific probes that could be used to selectively Mann, G.E. (1990). Biochem. Biophys. Res. Commun. manipulate the expression and/or fiinction of select 173,940-948. CATs. This would undoubtedly allow for the [12] Palmer, R.M.J, and Moncada,S. (1989). Biophys. Res. Commun. 158, 348-352. physiological role of these proteins and their involvement [13] Mayer, B., Schmidt, K., Humbert, P. and Bohme, in various diseases to be established. Indeed there are E. (1989). Biophys. Res. Commun. 164, 678-685. indications that altered arginine transport may contribute [14] Malinski, T., Radomski, M.W., Taha, z. and Moncada, to the pathophysiology of cardiovascular disorders such S. (1993). Biochem. Biophys. Res. Commun. 194, 960-

12 965. 271,24017-24022. [15] Vallance, P., Collier, J. and Moncada, S. (1989). [39] Simmons, W. W., Closs, E. I., Cunningham, J. M., Lancet, 2,997-1000. Smith, T. W., and Kelly, R. A. (1996). J. Biol. Chem., [16] Drapier, J-C. and Hibbs, J.B. Jr. (1988). J. Immunol., 271,11694-11702. 140,2829-2838. [40] Gill, D. J., Low, B. C, and Grigor, M. R. (1996) J [17] Granger, D.L., Hibbs, J.B. Jr., Perfect, J.R. and Biol Chem271,11280-11283 Durack, D.T. (1990). J. Clin. Invest., 85, 264-273. [41] Low, B. C, and Girgor, M. R. (1995) J Biol Chem [18] Assreuy, J. and Moncada, S. (1992). Br. J. 270,27577-27583. Pharmacol., 107,317-321. [42] Chen, L.Y, Mehta, P & Mehta, J.L. (1996). [19] Bogle, R.G., Baydoun, A.R., Moncada, S., Pearson, Circulation, 93,1740-1746. J.D. and Mann, G.E. (1992). Biochem. J. 284, 15-18. [43] Drexler, H. & Zeiher, A.M. (1991). Hypertension, [20] Wileman, S.M., Mann, G.E. and Baydoun, A.R. 18,1190-1199. (1995). Br. J. Pharmacol., 116, 3243-3250. [44] Creager, M.A., Gallagher, S.J., Girerd, X.J., [21] Bogle, R.G., Coade, S.B., Pearson, J.D., Moncada, Coleman, S.M., Dzau, V.J. & Cooke, J.R (1992). J. Clin. S. and Mann, G.E. (1991). Biochem. Biophys. Res. Invest., 90, 1248-1253. Commun. 180,926-932. [45] Girerd, X.J., Hirsch, A.T., Cooke, J.P, Dzau, V.J. [22] Bogle, R.G., Baydoun, A.R., Pearson, J.D. and & Creager, M.A. (1990). Circ.Res., 67, 1301-1308. Mann, G.E. (1996). J. Physiol., 490,229-241. [46] Cooke, J.P, Andon, N.A., Girerd, X.L., Hirsch, A.T. [23] Christensen, H.N. (1969). J.Biol.Chem., 244,1497- & Creager, M.A. (1991). Circulation, 83, 1057-1062. 1504. [47] Cooke, J.R, Singer, A.H., Tsao, R, Zera, P, Rowan, [24] White, M. F. (1985). Biochim. Biophys. Acta, 822 R.A. & Billingham, M.E. (1992). J. Clin. Invest., 90, 355-374. 1168-1172. [25] Deves, R. and Boyd, C.A.R. (1998). Physiol. Rev, [48] Boger, R.H., Bode-Boger., S.M., Mugge, A., 78,487-545 Kienke, S., Brandes, R., Dwenger, A. & Frolich, J.C. [26] Closs, E. I., Borel Rinkes, I. H. M., Bader, A., (1995). Atherosclerosis, 117,273-284 Yarmush, M. L., and Cunningham, J. M. (1993). J. Virol., [49] Jeremy, R.W., McCarron, H. & Sullivan, D. (1996). 67,2097-2102. Circulation. 94,498-506. [27] Closs, E. I., Lyons, C. R., Kelly, C, and Cunningham, J. M. (1993). J. Biol. Chem., 268, 20796-20800. [28] Closs, E. I., Albritton, L. M., Kim, J. W., and Cunningham, J. M. (1993). J.Biol. Chem., 268, 7538- Dr Baydoun is a lecturer at the University of 7544. Hertfordshire. The British Heart Foundation [29] Hosokawa, H., Sawamura, T., Kobayashi, S., is gratefully acknowledged for the support of Ninomiya, H., Miwa, S., and Masaki, T. (1997). J. Biol. the author's work cited in this review. Chem., 272,8717-8722. [30] Closs. E.I. (1996). Amino Acids, 11, 193-208. [31] Albritton, A.L., Rseng, L., Scadden, D. and Cunningham, J.M. (1989). Cell, 57,659-666. [32] Kim, J. W., Closs, E. I., Albritton, L. M. and Cunningham, J. M. (1991). Nature, 352, 725-728. [33] Wang, H., Kavanaugh, M. P, North, R. A. and Kabat, D. (1991). Nature, 352, 729-731. Travel Reports for the [34] Yoshimoto, T., Yoshimoto, E. and Meruelo. D. (1991).Virology 185,10-17. Bulletin [35] MacLeod, C.L., Finley, K., Kakuda, D., Kozak, C.A. The Bulletin regularly publishes travel reports written and Wilkinson, M.F. (1990). Mol. Cell. Biol., 10, 3663- by members. These are up to 3 pages in length includ• 3674. ing photographs, and can be on any conference, course [36] Kakuda, D. K., Finley, K. D., Dionne, V. E., and or laboratory visit of interest to other members. If you MacLeod, C. L. (1993). Transgene 1, 91-101. [37] Kavanaugh, M. R, Wang, H., Zhang, Z., Zhang, are planning to travel to a meeting and would like to W., and Wu, Y. N. (1994). J. Biol. Chem., 269, 15445- write a report for the Bulletin, please contact the edi• 15450. tors. A bursary of £100 is available towards the cost of [38] Stevens, B. R., Kakuda, D. K., Yu, K., Waters, M., your visit, and this will be provided on receipt of the Vo, C. B., and Raizada, M. K. (1996). J. Biol. Chem., report. Bon voyage!

13 Cardiovascular related meetings British Cardiac Society. Manchester, UK, May 24-27. For further information see the BCS website: httpiWwww.cardiac.org.ulc 1st Oslo Conference on Molecular Cardiology and Myocardial Function, Oslo, Norway, May 24-26,1999. Havard Attramadal and Geir Christensen, organizers. For more information contact Congex at mcm©[email protected]. Tel +47-2256 1930, Fax: +47-2256 0541. Heart Failure '99 - European Society of Cardiology Working Group on Heart Failure, Goteborg, Sweden, June 5-8,1999. For more information, please contact by E-mail: [email protected] or by telephone : +44 (0) 1235 537780; Fax: +44 (0) 1235 537782 or contact the CBC Oxford web site at: www.cbcoxf com. 20th Annual Meeting of the ISHR - European Section, Maastricht, The Netherlands, June 23-26,1999. Enquiries: Contact Dr. L.H. Snoeckx, Cardiovascular Research Institute Maastricht, Department of Physiology, Maastricht University, RO.Box 616,6200 MD Maastricht, The Netherlands. Fax: +31-43-367-1028 E-mail: [email protected]. XXIst Congress of the European Society of Cardiology, Barcelona, Spain, August 28-September 1,1999. For more information contact ECOR at Tel: +33 (0)4 92 94 76 00, Fax: +33-(0)4 92 94 76 01 Sophia Antipolis, Cedex France. BSCR Autumn Meeting 1999. Myocardial responses to sub-lethal ischaemia: preconditioning, stunning and hibernation University College London. September 20-21,1999. Enquires to Dr G.F Baxter, The Hatter Institute, Division of Cardiology, UCL Hospital & Medical School, Grafton Way, London WC 1E 6DB. Telephone 0171 380 9888; Fax: 0171 388 5095; E-mail [email protected].

BSCR/BCS Joint Symposium: 25 May 1999 The unstable atherosclerotic plaque: clinical significance, mechanisms and prevention Chairs: Prof Giani Angelini (Bristol) and D Grossman (Sheffield) Speakers: Dr Michael Davis (St Geroges, London): Pathology and clinical significance Dr Peter Libby (Boston, USA; to be confirmed): Cellular and molecular basis Prof Peter Weissberg (Cambridge): Insights from clinical trials Erof Andrew Newby (Bristol): Future possibilities for prevention: drugs, genes or screens

14 BSCR Bulletin Book Review Renin-Angiotensin. Ed. H.R.Ulfendahl and M.Aurell ISBN 1 85578 128X , Portland Press Ltd 1998, £75, pp324 A century ago, in 1897, Robert Tigerstedt observed the categories it is apparent that there is a heavy accent that saline-extracts of the renal cortex elevated blood on the kidney and the role of the renin-angiotensin pressure in recipient rabbits when they were injected system in the control of renal function. That can be with it. The active component in the extract, renin, and justified, because of its importance from a historical its associated cascade resulting in the formation of point of view. And not having kept up with details of angiotensin II and other active metabolites have been developments in this area, I have actually enjoyed these subject of extensive studies ever since, with an explosive parts and appreciate them as good and comprehensive growth after the successfiil introduction of drugs that reviews by such expert authors like DiBona, Blantz, interfere with the system into the clinic. One hundred Kirchheim, Arendshorst, Schnermann, and Navar, to years of research were commemorated in a sympo• name a few. But newer insights that deal with local sium in 1997 in Stockholm, the town where the original renin-angiotensin systems and their possible roles in discovery was made. The book is based on the cardiovascular homeostasis and disease are scarcely proceedings of that symposium. All authors may be mentioned. In this respect, the chapter by Horiuchi and considered as leaders in their specific fields of research. co-workers does provide detailed information on The cover of the book states that it is considered recent experiments from the Boston laboratory on the "essential reading for all clinical and research scientists mechanisms that control tissue-specific expression of working with and interested in the renin-angiotensin renin, but they fail to put their observations into some system and specifically its role in hypertension and physiological perspective. Also, reviews on the trophic cardiovascular diseases". and mitogenic effects of angiotensins are missing, As probably all symposium proceedings, the book whereas some of the most important recent contains a mix of historical reviews as well as state-of- developments in our insights into the role of the renin- the-art reviews with different depths, where the former angiotensin system in the long-term control of the seem to aim at a different group of readers than the circulation have been achieved in this very area. latter. This is nicely demonstrated in comparing the last Appropriately, the subject is part of the paper by Dzau three chapters of the book. The final chapter is a and co-workers, but it is, in my view, not adequately beautifiil account by Laragh and Sealey that deals with discussed in a book that claims to discuss "the most the historical developments of insights into the role of recent advances in this important field of research". the renin-angiotensin system in cardiovascular disease Thus, the book poses a dilemma: with very few and the undisputed role that their group has played in exceptions all chapters cover what they claim to cover, this. The preceding chapter by Gavras and Gavras is and do so in a more than adequate way. But the sum of rather superficial, although it does address effects the the parts does not constitute a review of "the" most renin-angiotensin system that have recently draw or recent advances. Therefore, the qualification "essential redrawn attention, such as effects on the coagulation- reading" seems to be an over-qualification. fibrinolytic system and the cardiac conduction system. The chapter before that, by Bianchi and TorieUi, focuses on adducin: it reviews the evidence for the hypothesis that genetic abnormalities in this protein contribute to the development of essential hypertension, rather than Prof Jos KM. Smits is from the Department of on the renin-angiotensin system. Pharmacology, Cardiovascular Research Institute The content of the book is categorized into 5 Maastricht (CARIM), University of Maastricht, areas: molecular bases, integrative aspects, renal The Netherlands physiology, juxtaglomerular apparatus and cardio• vascular system, where the latter should have been more appropriately named cardiovascular disease. But fi-om

15 Position offered: Submission Deadlines for The Post-doctoral fellow Bulletin: A position is immediately available for a motivated post• doctoral fellow to investigate the relationship between Volume Date Deadline the Na+ and Ca^+ gradients and energetics. The project 12(3) July 1999 June 1" will study this relationship in the isolated heart using a 12(4) Oct. 1999 Sept. P' combination of techniques: biochemistry, physiology, 13(1) Jan. 2000 Dec. ]" NMR measurements of Na^ and energetics, and 13(2) April 2000 March 1" aequorin measurements of Ca^^. The academic appointment will be as a Postdoctoral Fellow at Harvard Medical School. Candidates must have a Ph.D. degree in chemistry, biochemistry, biomedical engineering, physiology, or a related field. Experience Book reviewers with the isolation and perfiasion of hearts is desirable required but not necessary. Applicants should send a letter of We have requested/received a number of books for interest, curriculum vitae, and the names of three the Book Review feature in The Bulletin. If you references to: would like to review any of thetides Uste d here, please contact the Editors. James A. Balschi, Ph.D. NMR Laboratory for Physiological Chemistry • Apoptosis Genes (Wilson, Booth & Potter eds) 221 LongwoodAve, Rm. 247 ISBN 0-412-83860-5 Boston, MA 02115. • Reactive Oxygen Species in Biological Systems USA (Colton & Gilbert eds) ISBN 0-30604575603 E-mail [email protected] Phone (617)732-6996 • Delayed Preconditioning and Adaptive Fax (617) 732-6990 Cardioprotection (Baxter & Yellon eds) ISBN 0- 7923-52599 Why Not Organise A BSCR Meeting Or Workshop? The most recent meetings oftheBSCRwcre Genetic Manipulation of the Cardiovascular System in Guy's Hospital London, April 1998 and Signal Transduction Pathways Controlling Cardiac Growth ana f/yp

16 BRITISH HEART FOUNDATION GRANTS Project Grants Committee, December 1998 Dr V Ellis, Thrombosis Research Inst, London. "Characterisation of Deferred applications awarded a novel tPA receptor on vascular smooth muscle cells" (3 years) Drs C A Graham & D P Nicholls, Belfast City Hospital "The genetic £117,493. basis of familial hypercholesterolaemia - families without LDLR/ Drs P G Nugent & G Kemball-Cook, Hammersmith Hospital, Lon• FDB point mutations" (3 years) £87,137. don. "Isolation and structural characterisation of the procoagulant Dr V Zammit, Hannah Research Institute, Ayr, "Partitioning of and inhibited higher-order protein complexes of factor Vila and tis• diacylglycerol as a determinant of triacylglycerol secretion by the sue factor" (3 years) £101,924. liver" (3 years) £106,307. Drs J Nourooz-Zadeh & J Hothersall, University College London. Dr S O'Dell et afUniversity of Southampton. "Genetic variation in "Potential formation of nitroprostanes during simultaneous the IGF2 region of Chromosome 11: Relationship with overweight in nitrosative and oxidative stress" (1 year) £51,993. the Northwick Park Heart Study" (2 years) £140,297. Drs J H McVey & E Bachli, Hammersmith Hospital, London. "The Prof J Scott et al. Hammersmith Hospital, London. "Genes in famil• identification and characterisation of DNA sequences and trans-act• ial combined hyperlipidemia" (2 years) £180,024. ing factors binding to regulatory elements within the 5'UTR of the human tissue factor gene" (2 years) £80,014. Dr G Derrick et al, Royal Brompton Hospital, London. "Right (sys• temic) ventricular fimction late after atrial diversion operations: an New Applications Awarded assessment of the response to inotropic stimulation, exercise per• Drs J Vandenberg & A Trezise, University of Cambridge. "Regula• formance and angiotensin converting enzyme inhibition" (2 years) tion of erg potassium channel expression in the heart" (3 years) £107,621. £130,297. Profs N J Severs & C H Fry, National Heart & Lung Inst, London. Dr M Gosling et al.. Charing Cross Hospital, London. "Molecular "Relating connexin expression and connexon structure to conduction and electrophysiological analysis of shear activated potassium chan• properties in the heart: an in vitro transfected cell model" (3 years) nels in saphenous vein endothelium" (2 years) £117,302. £171,900. Dr M Walker et al.. University of Newcastle upon Tyne. "Investiga• Dr F W Flitney & Prof R T Hay, University of St Andrew's. "Tran• tion of the genetic basis of abdominal obesity" (2° years) £111,264. scriptional activation of endothelial flow-responsive genes by NF- Dr L M Williams et al., Rowett Research Inst, Aberdeen. "Leptin kB" (3 years) £133,866. receptor function" (3 years) £166,798. Drs L J Partridge & P N Monk, University of Sheffield. "The pro• Dr S P Watson, University of Oxford. "Regulation of functions of duction of inhibitors of tetraspanin activity" (3 years) £130,614. MAP-kinases and SAP-kinases in platelets" (3 years) £129,974. Prof E R Maher et al., University of Birmingham. "Molecular inves• Prof D W Johnston et al.. University of St Andrew's. "Predicting tigation of phaeochromocytoma: isolation of a chromosome" (3 years) adherence to treatment and re-admission to hospital in patients with £104,816. congestive heart failure (CHF): behavioural, cognitive, social, emo• Prof T W Evans & Dr C P Winlove, Royal Brompton Hospital, tional, clinical and demographic predictors" (3 years) £19,710. London. "Redox balance and vascular control in sepsis" (3 years) Drs M F Scully & M A M Gebska., Thrombosis Research Inst, £127,458 London. "Characterization of high affinity binding of heparin to Dr G B Nash et al.. University of Birmingham. "Molecular mecha• leukocytes following treatment with cholesterol oxide" (2 years) nism by which endothelial CD31 regulates migration of neutrophils" £66,508. (3 years) £131,157. Dr S Ye et al., Southampton University Hospital. "Genetic influence on progression and severity of coronary heart disease and restenosis Dr A A Grace et al.. University of Cambridge. "Molecular characteri• after angioplasty: the Southampton atherosclerosis study (SAS)" (3 sation of the human (4-adrenergic receptor" (2 years) £107,366. years) £147,633. Prof A H Weston, University of Manchester. "Interactions between Drs J Ohanian & V Ohanian, Manchester Royal Infirmary. "Vaso• endothelial and smooth muscle cells in the vasculature" (3 years) constrictor induced sphingomyelin hydrolysis and ceramide pro• £297,335. duction: a role in arachidonic acid generation in intact small arteries" Prof F A Lai, University of Wales College of Med, Cardiff. "Charac• (3 years) £119,903. terisation and expression of novel splice variants of the human car• Drs P J Talmud & S E Humphries, University College London. "In diac ryanodine receptor gene" (3 years) £168,543. vitro characterisation of LPL D9N variant to determine the basis of Dr S A Stansfeld et al.. University College London. "Psychological the in vivo interaction with smoking that leads to increased risk of morbidity and the risk of mortality in the midspan study" (1 year 9 IHD" (3 years) £131,602. months) £50,429. Prof N J Samani, Glenfield Hospital, Leicester. "Characterisation of Profs DA Wood & M J Davies, National Heart & Lung Inst, London. early molecular changes in pressure-induced left ventricular hyper• "Sudden Adult Death Syndrome (SADS)" (8 months) £40,196. trophy" (2 years) £99,418.

77 Prof A J Camm, St George's Hospital Med Sch, London. "A detailed Dr D G Mackenzie & Dr M Denvir, Western General Hospital, study of the electrophysiological mechanisms in human atrial fibril• Edinburgh. "Regression of left ventricular hypertrophy and fibrosis: lation" (1° years) £102,410. a detailed echocardiographic and biochemical study using radio- Drs M J Mitchinson & P J Coussons, University of Cambridge. frequency back-scatter analysis, Doppler tissue imaging and collagen "The role of anti-oxidant enzymes and antibodies in the develop• metabolism enzymes" (2 years) £75,180. ment of human atherosclerosis" (2 years) £73,241. Dr R Mansfield & Dr J McEwan, Middlesex Hospital, London. "Photodynamic therapy: prevention of angioplasty and stent induced Drs S Jeffery & A Crosby, St George's Hospital Med Sch, London. intimal hyperplasia" (2 years) £95,553 "Search for the gene for Noonan syndrome and cardiac expressed genes on chromosome 12q24" (3 years) £128,920. Dr V Markides & Dr N S Peters, St Mary's Hospital, London. "Characterisation of focal ectopy causing human atrial fibrillation: A Dr S Ye & Prof I N M Day, Southampton University Hospitals. strategy for identification and cure of patients" (2 years) £87,025 "Variation in the stromelysin (matrix metalloproteinase-3) gene in relation to coronary heart disease" (3 years) £113,403. Dr I S Malik & Prof D Haskard, Hammersmith Hospital, London. "Development of an anti-E-selectin single chain antibody (sFv) for Dr J Gurm et al.. Northern General Hospital, Sheffield. "Is active clinical imaging of vascular inflammation" (2 years) £ 115,346 TGF a legitimate target for anti-restenosis therapy?" (1° years) £68,659. Dr A J Chase & Prof A Newby, Bristol Royal Infirmary. "Inhibition of transcription factor NF-kB. A potential strategy to inhibit Drs P J R Barton & N J Brand, National Heart & Lung Inst, London. macrophage-derived metalloproteinase secretion and stabilise "Functional analysis of the human cardiac troponin I gene promoter" atherosclerotic plaques" (2 years) £84,874 (2 years) £143,346. Drs M Wilkins & D Lefroy, Hammersmith Hospital, London. "Role of natriuretic peptides in recovery from myocardial infarction" (2 PhD Studentships years) £84,806. Unnamed, University College London, Supervisor; Prof D S Prof K J Wood, John Radcliflfe Hospital, Oxford. "Role of CD40 Latchman. "Role of the co-activators CBP and p300 in the response mediated costimulation in the initiation and evolution of cardiac allo• of cardiac cells to stressful, protective and hypertrophic stimuli" (3 graft atherosclerosis and chronic rejection" (3 years) £ 191,607. years) £59,999. Drs M Avkiran & R S Haworth, St Thomas' Hospital, London. Unnamed, St Thomas' Hospital, London, Supervisor; Dr H Snieder. "Myocyte signalling via protein kinase D, a novel regulator of the "A twin study of thrombotic aspects of insulin resistance syndrome: Na+/H+ exchanger" (3 years)£I49,924. Determination of genetic and environmental contribution to thrombotic risk" (3 years) £50,694. Dr A R Ness et al.. University of Bristol. "Assessment of the long term effects of dietary advice on diet and mortality in a randomised Mr A Mathewson, University of Strathclyde, Supervisor; Prof R M trial of men following myocardial infarction" (1° years) £17,603. Wadsworth "Modulation of nitrergic cerebral vasodilation by inducible nitric oxide synthase" (3 years) £56,710. Drs D J Chambers & R L Featherstone, St Thomas' Hospital, Lon• don. "Pharmacologic preconditioning before storage and phosphodi• Miss H Goddard, University of Oxford, Supervisor; Dr D Terrar esterase inhibition during reperfusion as interventions to improve "Influence of fentanyl, morphine and related substances on recovery long term preservation of the lung" (3 years) £145,020. of cardiac muscle following transient ischaemia; pharmacological and Dr R C Saumarez, Papworth Hospital, Cambridge. "Three dimen• cellular mechanisms" (3 years) £63,635. sional location of electrodes and mapping of electrogram fractionation Unnamed, University of Oxford, Supervisor; Dr S P Watson, "Cross• in the diseased human right ventricle" (3 years) £19,527. talk between tyrosine kinase-linked and G protein-coupled receptors in platelets" (3 years). £60,600. Unnamed, Royal Free Hospital, London, Supervisor; Dr J S Owen Fellowships Committee, January 1998 "Recombinant apoE (E2, E3 and E4 isoforms) and lecithin-cholesterol transferase (LCAT), individually and in combination, as tools to Intermediate Research Fellowship study anti-atherogenic actions of HDL" (3 years) £59,694. Dr R E Simmonds & Prof D A Lane, Charing Cross Hospital, London. "Regulation andfiinction of the endothelial cell protein C/activated protein C receptor (EPCR) gene and protein" (3 years) £124,204 PhD Studentships (Clinical) Dr J M M Kabir, University College London, Supervisor; Dr I C Junior Research Fellowships Zachary "The role of focal adhesion kinase in the regulation of vascular endothelial cell apoptosis" (3 years) £131,442. Mr S Ghosh, & Mr M Galinanes, Glenfield Hospital, Leicester. Dr C E Head, University of Cambridge, Supervisor; Dr A Grace. "The role of protein kinase C (PKC) and mitogen-activated protein "Development and characterisation of a gene-targetted mouse model kinase (MAPK) systems as a second messenger of ischaemic of the Brugada syndrome" (3 years) £148,727. preconditioning in the human heart" (1 year) £43,803 Dr R R Chaturvedi, King's College London, Supervisor; Prof R Dr R J Johnson & Prof M P Frenneaux, University of Wales College Simmons "Passive stiffhess of ventricular myocardium from children of Medicine, Cardiff "Intracellular signalling pathways activated with diastolic dysfiinction" (3 years) £168,526. during coxsackievirus B3 infection of cardiac myocytes" (2 years) £57,091

18 Cardiovascular Related Wellcome Trust Grants November 1998 to March 1999

Project Grants Programme Grant Dr G Laing, Liverpool School of Tropical Medi• Dr C J Garland, Department of Pharmacology, cine, University of Liverpool: £184,917 for 36 School of Medical Sciences, University of Bris• months. "Toxins as tools for studying the inflam• tol: £912,140 for 60 months. "An investigation matory response to local tissue damage." of the cellular and molecular mechanisms which underlie diameter change in small resistance ar• Dr M S Marber, Department of Cardiology, teries and arterioles." UMDS, St Thomas' Hospital London: £218,695 for 36 months. "The use of protein kinase C de• ficient mice to investigate ischaemic precondition- mg. Senior Research Fellowships In Basic Biomedi• cal Science Prof M Malik, Department of Cardiological Sciences, St George's Hospital Medical School, Dr Cecile Julier, Nuffield Department of Clini• London: £127,845 for 24 months. "Automatic cal Medicine, John Radcliffe Hospital, Level 7, intracardiac detection of myocardial ischaemia." University of Oxford: £827,712 for 60 months. "Mapping and identification of genes involved in Dr Margaret R Maclean, Division of Neuro- type I diabetes and its complications, and hyper• science & Biomedical Sys, Institute Biomedical tension." & Life Science, University of Glasgow: £ 121,046 for 24 months. "5-Hydroxytryptamine IB receptors: role in pulmonary hypertension." Research Career Development Fellowships In Dr A M Evans, Department of Pharmacology, Basic Biomedical Science University of Oxford: £127,566 for 36 months. "The regulation of calcium release from the sar• Dr S D R Harridge, Department of Geriatric coplasmic reticulum of pulmonary artery smooth Medicine, Royal Free Hospital School of Medi• muscle by pyridine nucleotides and hypoxia." cine, London: £331,659 for 48 months. "Mecha• nisms underlying muscle strength and size in• Prof P H Sugden, Cardiac Medicine Section, creases in elderly people. A combined physiologi• National Heart & Lung Institute Div, Imperial cal and molecular biological approach." College School of Medicine, London: £157,239 for 36 months. "Activation of "stress-responsive" mitogen-activated protein kinases by G protein- coupled receptor agonists in the heart." Junior Post Doc Fellowships Dr IA Greenwood, Department of Pharmacol• Dr Claire E Sears, Laboratory of Physiology, ogy & Clinical Pharmac, Jenner Wing, St University of Oxford, Oxford: £31,198 for 12 George's Hospital Medical School, London. months "Cardiovascular Initiative - Is the £16,259 for 41 months. "Investigation into the upregulation of NOS activity and the If current in factors regulating calcium-activated chloride cur• ventricular myocytes part of the myocardial adap• rents in vascular smooth muscle cells." tive process to increase workloads?"

19 THE BRITISH SOCIETY FOR CARDIOVASCULAR RESEARCH

BSCR Autumn Meeting 1999 MYOCARDIAL RESPONSES TO SUB-LETHAL ISCHAEMIA: PRECONDITIONING, STUNNING AND HIBERNATION Dates: Monday 20 and Tuesday 21 September 1999 Venue: University College London Organiser: DrGF Baxter Speakers will include: D J Hearse (London), M V Cohen (Mobile, Alabama), G F Baxter (London), R J Heads (London), D M Yellon (London), G Heyndrickx (Aalst, Belgium), R Lerch (Geneva, Switzerland), D J Miller (Glasgow), R Hall (London), M S Marber (London), R Schulz (Essen, Germany), A Shah (London), J Pepper (London), L H Opie (Cape Town, South Africa) Major Symposia: Basic and clinical clinical aspects of: myocardial preconditioning; myocardial stunning; hibernating myocardium Communications: Part of this meeting will be devoted to the presentation of free communications. Abstracts, on any topic, are welcomed and several abstracts related to the main theme of the meeting may be selected for oral presentation. Accepted abstracts will be printed in the Quarterly Bulletin of the British Society for Cardiovascular Research. Abstract deadline: 30 July 1999. Bursaries: The Society will consider awarding travel grants of up to £ 150 to bonafide PhD students. Application forms are availablefrom D r Gary F Baxter or Ms Andrea Burdus at the address below Travel: University College London is centrally located in Bloomsbury, London WC 1, close to several main line and underground stations and on several bus routes. Car parking space is limited. Accommodation: A limited number of reasonably priced College rooms will be available. There are several hotels within walking distance of the College offering facilities and rates to suit all pockets. Registration: Free to members, £40 to non-members. Buffet lunches, tea and coffee is included. A dinner will be held at the Royal Society of Medicine, Wimpole Street, at a cost of £25 per head. Additional registration and abstract forms, application forms for BSCR membership and student bursary application forms are available from the meeting organiser/BSCR secretary: Dr G F Baxter, The Hatter Institute, Division of Cardiology, UCL Hospital & Medical School, Grafton Way, London WCIE 6DB. Telephone 0171 380 9888; Facsimile 0171 388 5095; E-mail g,[email protected]