Journal of Human Hypertension (2005) 19, 259–266 & 2005 Nature Publishing Group All rights reserved 0950-9240/05 $30.00 www.nature.com/jhh COMMENTARY A free-ranging roundtable discussion on hypertension

JB Standridge, JE Sealey, JH Laragh, MC Houston, H Gavras, RJ Johnson, JD Blumenfeld, M Brown, BM Egan, JI Meltzer, T Shimosawa and T Fujita Family Medicine, University of Tennessee College of Medicine, Chattanooga, TN, USA

Journal of Human Hypertension (2005) 19, 259–266. doi:10.1038/sj.jhh.1001811 Published online 17 February 2005

Tokyo, Japan. The following is not verbatim but instead represents a summary of key points made over a 3-h dinner discussion.

John Laragh, MD, is Professor of Medicine in Cardiothoracic Surgery and Director of the Cardio- vascular Center at New York Presbyterian Hospital, Weill Medical College, Cornell University. He served for 22 years concurrently as chief of the division of cardiology. Both scientist and clinician, Dr Laragh has published nearly 1000 scientific articles that describe his discoveries and insights. In 1986, he founded the American Society of Hypertension, becoming its first president and founded the American Journal of Hypertension serving as its editor in chief.

Dr Laragh: Why don’t we go around the table and let everyone say some things about the work they are During the Nineteenth Annual Scientific Meeting of doing and the particular aspects of hypertension the American Society of Hypertension in New York, they are interested in at this time. We have a very NY, on May 20, 2004, a gathering of international wide ranging group of hypertension experts as- hypertension experts was convened to discuss far- sembled here tonight, and I think that everyone reaching aspects of researching and managing will be excited to learn what areas are of interest to hypertension. Dr John Laragh of Cornell University, each of our participants. Why don’t we start with New York, NY, USA; presided. Additional partici- Jean Sealey? pants were, in order of participation, Jean E Sealey, DSc, New York, NY, USA; Mark C Houston, MD, Jean E Sealey, DSc, is Research Professor Emeritus of Nashville, TN, USA; Haralambos Gavras, MD, Medicine in Physiology & Biophysics, Weill Medical Boston, MA, USA; Richard J Johnson MD, Gaines- College of Cornell University. ville, FL, USA; Jon D Blumenfeld, MD, New York, NY, USA; Morris Brown, MD, Cambridge, England; Dr Sealey: My primary professional interest is to John B Standridge, MD, Chattanooga, TN, USA; explain to medical practitioners how and why the Brent M Egan, MD, Charleston, SC, USA; Jay I plasma renin test is an invaluable tool for the Meltzer, MD, New York, NY, USA; Tatsuo Shimosa- diagnosis and treatment of their hypertensive wa, MD, PhD, Tokyo, Japan; Hans R Brunner, MD, patients—because it discriminates the patient Lausanne, Switzerland; and Toshiro Fujita, MD, whose hypertension is caused by excessive volume expansion (renin suppressed) from one whose hypertension is caused by excess renin (renin not Correspondence: Dr JB Standridge, Family Medicine, University of suppressed). Tennessee College of Medicine, 1100 E. 3rd Street, Chattanooga, TN 37403, USA. In an untreated hypertensive patient, a suppressed E-mail: [email protected] plasma renin test reveals that this patient’s hyperten- Published online 17 February 2005 sion is caused by excessive sodium retention and ASH hypertension roundtable JB Standridge et al 260 volume expansion (PRA less than 0.65 ng/ml/h; the National Vital Statistics Registry and the Direct Renin less than 5 mU/ml). We call this a ‘V’ concurrent rise in ESRD based on the USRDS annual patient. In contrast a plasma renin test that is not data reports from 1980 to 1998. Annual increases in suppressed (PRA greater than 0.65 ng/ml/h; Direct diuretic expenditure and distribution are associated Renin greater than 5 mU/ml) reveals that the hyper- with increases in ESRD incidence rate growth 2 tension is caused by too much renin for the level of years later. Decreases in diuretic distribution are blood pressure. We call this an ‘R’ patient. The renin associated with reductions in ESRD incidence test identifies V and R patients each of whom growth 2 years later. The predominant diuretics responds differently to V or R antihypertensive used were HCTZ and furosemide. drugs. The blood pressure of V patients responds A statistically significant (P ¼ 0.03) direct linear best to V drugs—diuretics, aldosterone receptor association between changes in diuretic distribution antagonists and calcium channel blockers. The and subsequent changes in the growth rate of ESRD blood pressure of R patients responds best to exists. The beneficial effects of diuretics related to antirenin system R drugs—ACE inhibitors, angio- CHF, CVA and, to a lesser extent, CHD may tensin receptor blockers and b-blockers. Moreover, a simultaneously be either permissive of nephrotoxi- primary R drug is only a placebo in a V patient while city or directly nephrotoxic. a primary V drug in an R patient raises plasma renin Published hypertension trials and surveys, such levels even higher and may even worsen the as EWPHE, HEP, STOP, NHANES III survey, Syst- hypertension. EUR, SHEP, INSIGHT and ALLHAT, have indepen- However, more than that, the renin test leads to dently demonstrated this. Possible mechanisms for a logical approach for the treatment of patients renal injury with chronic diuretic therapy include already taking antihypertensive drugs who are glomerulosclerosis with glomerular capillary hyper- seemingly unresponsive. There are only two reasons tension, mesangial matrix expansion, mesangial for resistance to antihypertensive drugs: (i) exces- hypercellularity, dyslipidaemia, hyperglycaemia, sive volume expansion: that patient’s plasma renin hyperuricaemia and increased intrarenal oxidative is suppressed—patient needs more volume deple- stress. tion and doesn’t need R drugs. (ii) Excessive salt Diuretic therapy stimulates growth-promoting, depletion: renin very high (46.5 ng/ml/h)—this profibrotic or proinflammatory mediators such as patient’s lively renin secretion has over-reacted to homocysteine, PAI-1, PDGF, LDL-cholesterol, aldos- diuretics, raising renin even higher and in so doing terone, endothelin and angiotensin II levels, TGF-b, preventing blood pressure from falling. Such pa- TNF-a and COX-2. tients need to cut back on the diuretics and use only Calcium channel blockers (CCBs), ACE inhibitors R drugs instead. (ACEIs) and angiotensin receptor blockers (ARBs) By understanding of how the renin system works, have shown renal protective effects and slowing and by measuring plasma renin levels, deciding on of the development of glomerulosclerosis while the best antihypertensive treatment strategy is as achieving the same magnitude of blood pressure easy as falling off a log! reduction seen with HCTZ therapy. NHANES III survey noted an increased prevalence Dr Laragh: This is certainly an apropos summary of elevated creatinine in patients receiving diuretics of the work Jean and I, and many others, have been for hypertension compared to those receiving any engaged in for the last 50 years. We have published other antihypertensive medication category. over 900 articles on the topic of renin and In addition, exposure to thiazide diuretics has hypertension and believe that this approach is been epidemiologically linked to an increased risk mechanistically correct. The holy grail would be to for the development of renal cell carcinoma, and in control the majority of individuals with elevated patients with congestive heart failure, the mortality blood pressure with one drug, based on whether is higher in those receiving chronic diuretic therapy they are a V or an R patient. than in patients not receiving long-term diuretic Well, let’s move on around the table. Next to Jean therapy. Since diuretic acquisition cost is relatively is seated Dr Mark Houston, who has done some inexpensive, superficial analysis might suggest that fascinating work associating chronic diuretic use diuretic therapy is more ‘cost-effective’ than alter- and the increasing prevalence of chronic renal native therapies. However, the economy of low failure in the US. Mark? acquisition cost is negated by concomitant expenses of treating the iatrogenic chronic complications Mark C Houston, MD, SCH, FACP, is Clinical (new onset diabetes, dyslipidaemia, gout, hypoka- Professor of Medicine, Vanderbilt University Medi- laemia, renal carcinoma, ESRD). cal School, and Director, Hypertension Institute, St Thomas Hospital, Nashville, TN, USA. Dr Laragh: Thank you, Mark. This is very impor- tant work indeed, and we need to get the word out to Dr Houston: A highly significant inverse relation- practitioners who, under the influence of govern- ship exists between the decline in age-adjusted ment-sponsored guidelines, are still in the ‘diuretics cardiovascular disease mortality in the US based on first’ camp.

Journal of Human Hypertension ASH hypertension roundtable JB Standridge et al 261 Now we come to my long-time friend and work is being carried out in this area other than colleague, Dr Harry Gavras. Harry is the current myocardial perfusion imaging. president of the American Society of Hypertension. It helps to predict hypertension if we understand His lovely wife, Irene, who is a physician, scientist, the genomics. A lot of work has been performed and scholar, joins us as well. Harry, what are you with some early enthusiasm, but these things take thinking these days? time. With regard to the diagnosis of monogenic disorders, we have four or five genes that increase Irene Gavras, MD, is a Professor of Medicine at blood pressure—prototypes to see how these geno- Boston University School of Medicine and attending types misbehave in some rare families—but these physician at Boston Medical Center. Haralambos results have not yet shed light on the causes of Gavras, MD, is a Professor of Medicine at Boston essential hypertension, which results from interac- University School of Medicine, Chief of Hyperten- tion of genes with environment. We should continue sion and Atherosclerosis at Boston Medical Center wisely. We are relying on the expression analysis, and Director of a Specialized Center of Research microarray technology and serial analysis of gene in the Molecular Genetics of Hypertension. He is expression (SAGE), to discover how genes get President of the American Society of Hypertension. activated to cause hypertensive damage. We need to develop new technologies. I say to the next Dr Gavras: I have given a lot of thought recently generation, don’t stay with the old methods; find to the future of hypertension research. The last 30 new ones. For example, could gene treatment of the years have seen some tremendous advances in this renin–angiotensin system cure some patients with multifactoral disease. The successes in the drug hypertension? And I’m not talking about treating therapy of hypertension have turned out to be a hypertension but curing it. I throw this out as an bonanza for the prevention and treatment of myo- idea; it doesn’t mean it is going to work that way. cardial infarction and congestive heart failure. The Hypertension and target organ damage is an area future challenges include improving our diagnostic that needs more attention as we focus on treatment evaluation. One new goal is to develop telemetric of this lifelong disease. We need to better define the evaluation of hypertension. My enthusiasm comes links between hypertension and insulin resistance, from research we are doing in our lab with rats. We between hypertension and obesity, links between can measure blood pressure by telemetry within hypertension and hyperuricaemia, reversal of arter- 1 mmHg in our rats. We don’t have this for humans. ial stiffness. These are all very important areas. Since we know that as little as 3 mmHg in blood All of this is nice, but we need population pressure can make a difference in 15–20% of studies—epidemiologic studies that translate new morbidity and mortality, developing technology that information into clinical practice by validating can actually see how blood pressure behaves and our research with outcomes data. ASH and its accurately determine blood pressure levels for chapters have a foundation for addressing this weeks or months is very important. need. Researchers like Brent Egan are addressing Oxidative stress needs a marker for clinical this quite well. diagnostic testing. We do not have a single marker for clinical diagnostic test that we can apply to Dr Laragh: And we will hear from Dr Egan before assess patients for oxidative stress. Pregnancy- too long. Thank you, Harry, for you insights. As my induced hypertension has had little attention in fellow New Yorker, Yogi Berra, would say, ‘It’s tough recent decades. Diagnostic markers for risk for to make predictions, especially about the future’. toxemia are needed. Childhood hypertension needs Next to Harry we have Richard Johnson from more attention. The NIH has spearheaded the Gainesville, Florida. Rick? development of some wonderful new initiatives in the treatment of childhood hypertension. Endothe- Richard J Johnson, MD, FACP, J Robert Cade lial dysfunction is an interesting concept that Professor of Nephrology, Chief of Nephrology, needs better chemical diagnostic markers. Plethys- Hypertension and Transplantation. mographic evaluation gives limited information, it is cumbersome, and people question the specifi- Dr Johnson: Our research has focused on studies of city of this particular test. We need to see if the pathogenesis of essential hypertension. We have interventions to correct endothelial dysfunction are been particularly interested in the role of uric acid. useful in preventing hypertension because it is Interestingly, it has been known since the original not clear whether endothelial dysfunction is the reports on hypertension that gout is associated with cause of hypertension or is a consequence of it. hypertension, and studies by Drs Cannon and Assessing microcirculation, in the heart, in the Laragh in the 1960s showed a strong relationship brain, in the kidney, is an area that needs new between uric acid, hypertension and renal disease. research to develop imaging or other methods to Furthermore, there are now at least six epidemiolo- evaluate these resistance vessels. Current methods gical studies that have found that an elevated uric are cumbersome and inaccurate. We cannot actually acid independently predicts the development of see what is going on in the arterioles and not a lot of hypertension. However, most authorities have

Journal of Human Hypertension ASH hypertension roundtable JB Standridge et al 262 continued to believe that uric acid is likely a marker incidence has fallen—stroke is more of a pressure of cardiovascular risk since it is often elevated in the phenomenon—but ESRD rates have doubled. You subject with established risk factors such as renal are providing us with some very valuable knowl- disease, obesity, insulin resistance or dyslipidaemia. edge, Rick, and we need to confirm the evidence An important point, however, is that until recently with clinical trials, but these are great insights. no one had determined the effect of raising uric acid Next is my friend and colleague, Jon Blumenfeld. on blood pressure in animals. To do this, we raised Jon is coeditor of the American Journal of Hyperten- uric acid in rats by blocking uricase, which is an sion and a splendid researcher. What would you like enzyme that degrades uric acid to allantoin, and to share with the group tonight, Jon? which is present in most mammals but is absent in humans due to a mutation that occurred over 10 Jon Blumenfeld, MD is the Director of Hypertension million years ago. Amazingly, rats made hyperur- and Director of The Susan R Knafel Polycystic icaemic developed hypertension. We then showed Kidney Disease Center at The Rogosin Institute. He that the hypertension was mediated by a uric acid- is an Associate Attending Physician at NewYork- induced endothelial dysfunction as well as a Presbyterian Hospital and an Associate Professor of stimulation of the renin–angiotensin system. This Medicine at Weill Medical College of Cornell Uni- initial phase of hypertension was salt-resistant and versity. He is the current editor of the American would correspond to the ‘R’ type of hypertension Journal of Hypertension. described by Drs Sealey and Laragh. Over time, however, we found that uric acid induced micro- Dr Blumenfeld: We are doing some work with vascular disease in the kidney leading to the autosomal dominant polycystic kidney disease. development of arteriolosclerosis. Once the micro- This is the most common inherited kidney disease, vascular disease developed, the hypertension was affecting more than 400 000 people in the US and 5 then driven by the kidney, the serum uric acid was million people worldwide. It is the 4th most no longer critical, and the hypertension became common cause of kidney failure requiring dialysis volume dependent. and/or kidney transplantation. Most polycystic These studies suggested uric acid may be most kidney disease patients develop kidney failure by important in the initiation of hypertension. To 60 years of age, that varies widely, even among examine this possibility, Dan Feig and I looked at family members. High blood pressure and large new onset hypertension in an adolescent clinic, and kidney size have been linked with the development found that nearly 90% of new onset hypertension is of kidney failure in polycystic kidney disease. associated with uric acid levels 45.5 mg/dl vs 0% The genes involved are referred to as PKD1 and in 63 controls; we are now doing a NIH-funded PKD2. The reason for doing the research that we are placebo-control trial to determine if lowering uric doing is that we hope to learn about the mechanisms acid in these subjects results in lower blood that elevate the blood pressure and cause the kidney pressure. function to worsen in polycystic kidney disease One of the implications of our work relates to patients. Specifically, we will be measuring the diuretics, since they raise serum uric acid in levels of hormones in the blood and urine that addition to facilitating sodium excretion. It has been normally regulate blood pressure and will determine known for many years that diuretics may not if these hormone levels are higher in PKD1 than provide as much cardiac protection as they are PKD2 patients. I can’t talk about results because we predicted for the degree of blood pressure lowering. are not at that stage yet. One possibility is that the hyperuricaemia induced We are doing a complete work-up at Inpatient by diuretics may counter some of its benefits. We Studies at the Rockefeller University Hospital. It currently have submitted a proposal to study this in includes a 24-h urine collection, a history and the African American with Stage I hypertension, by physical examination, a captopril test, magnetic determining if lowering uric acid concomitant with resonance imaging (MRI), an echocardiogram, and diuretics may provide better BP control, with genetic testing. We are still signing people up for the improvement in endothelial function and a reduc- study. tion in the plasma renin activity. Another area that really interests me is primary aldosteronism. This is a lot more common than most Dr Laragh: To the extent that your work can show practitioners realize. We ought to be screening for it evidence of uric acid being responsible for inducing more and dealing with it primarily. Of 50 or so endothelial dysfunction, stimulation of the renin– patients with primary aldosteronism who had angiotensin system, microvascular disease in the adrenalectomy, those most likely to be cured were kidney, and arteriolosclerosis, we can begin to see younger and had lower plasma renin activity. In why our traditional treatment of this metabolic patients with adenomas who were cured or im- disease of hypertension hasn’t protected that most proved, aldosterone secretion was more likely to metabolic organ—the kidney. The last few decades lateralize. A lot more vein sampling is being carried have witnessed hypertension control rates improv- out now. Tests that distinguished adenomas from ing from 10 to 34%. During this same time stroke adrenal hyperplasia included the postural stimulation

Journal of Human Hypertension ASH hypertension roundtable JB Standridge et al 263 test, urinary excretion rates of 18-oxocortisol and 18- AB/CD rule for the treatment of hypertension that hydroxycortisol, and adrenal vein sampling. Hyper- John will recognize as little more than a restatement tension specialists are doing a good job making this of his long-held and long-studied ideas. The rule distinction. Primary aldosteronism represents the predicted that in the older patients taking part in most common form of secondary hypertension, so recent outcome trials there would on average be a we are trying to get more generalist physicians to greater blood pressure response to diuretic or recognize those patients who need scrutiny for this calcium blocker than to an ACE inhibitor (as in condition. ALLHAT) or ARB (as in VALUE). However, age and ethnic group are the very poor man’s surrogate for Dr Laragh: Thank you, Jon. Seated next to Jon is measurement of plasma renin; advent of the cheap, Professor Morris Brown, who has been doing some automated assays for renin mass should now important work in Cambridge, England, that I am rationalise and revolutionise individual manage- eager to hear about. Morris is doing a great job of ment of hypertension. getting the message out in England and I am very glad that he could join us tonight to share his Dr Laragh: Thank you, Morris. Next I would like us insights. to meet Dr John Standridge. Dr Standridge is a family physician who still delivers babies and makes house Morris Brown, MA, MSc, MD, FRCP is Professor calls, but is also a Specialist in Clinical Hyperten- of Clinical Pharmacology at the University of sion, directs geriatric training at a family practice Cambridge, Cambridge, UK, and is a principal residency, and works in the field of addiction investigator at the Clinical Pharmacology Unit, medicine as well. John wrote an article that took Addenbrooke’s Centre for Clinical Investigation, ALLHAT to task and we published it last month in Addenbrooke’s Hospital, where his research inter- the American Journal of Hypertension. John, you ests include hypertension. sound busy. We are glad you could join us tonight.

Dr Brown: My studies developed from an interest John B Standridge, MD, FAAFP is Associate Profes- in using variation in drug response in hypertension sor of Family Medicine, University of Tennessee as a clue to underlying genetic variation in hyper- Health Science Center College of Medicine, Chatta- tension. We therefore planned to rotate patients nooga Unit. among each of the main classes of antihypertensive drugs, in a random, crossover fashion. Some of the Dr Standridge: Just as an artist needs an audience, studies were open-label in design, but some were the rest of you here tonight need me. I represent the completely double-blind and placebo-controlled. physicians out there who actually read, understand, Always we repeated each patient’s best drug at the and apply current research findings to clinical end of rotation, sometimes with 24-h ABPM in practice. Listening to Drs Houston and Johnson addition, in order to distinguish systematic from describe their research concerning the potential random variation in blood pressure response. nephrotoxicity associated with diuretic-influenced Thinking that the relationship between pathogen- hyperuricaemia is interesting and disconcerting. It esis and response may be clearest early in hyperten- adds one more facet to the reservations I have sion, and because (at least in the UK) young patients expressed regarding ALLHAT. The ALLHAT con- are the easiest to recruit prior to any exposure to clusion that thiazide diuretics should be preferred drug treatment, our first rotation study restricted for first-step antihypertensive therapy is unjustified recruitment to patients under the age of 50 years. In because, unlike ANBP2, ALLHAT was not a trial that all, 56 young Caucasians took part. As we should initiated therapy for hypertension. ALLHAT was perhaps have predicted from John Laragh’s work, primarily a study that compared irrational drug the mean blood pressure response to both ACE combinations chosen without regard to an indivi- inhibitors and b-blockers was almost twice as great dual’s renin status. The lisinopril limb was denied a as that to calcium blockade or diuretics. The cross- volume drug in a patient population at risk for heart over design allowed us to show that there was a high failure and when predictably worse outcomes degree of correlation between response to ACE developed, the authors said, ‘See? Diuretics are inhibition and b blockade, and between calcium superior’. Not only was the heart failure subset blockade and diuretic therapy—but not between the analysis not prospectively established, it would not other four possible pairings. In other words, there be ethical to design such a study. was only two main patterns of response—what John, The thing that upset me the most about ALLHAT of course, would call V and R. During preparation of was its mindless endorsement in the ADA journal the manuscript, I was struck by the wonderful piece Clinical Diabetes. ALLHAT was neither designed of serendipity according to which the initials of the nor of sufficient length to detect the poorer out- four major drug classes are the first four letters of the comes that are inevitable with the increased rates alphabet; and moreover, the two pairs of correlations of diabetes detected in the chlorthalidone limb. are between the members of the ‘AB’ and ‘CD’ Additionally, SHEP and other studies confirm the categories. This allowed us to propose a mnemonic diuretic–diabetes link. An article published this

Journal of Human Hypertension ASH hypertension roundtable JB Standridge et al 264 month in Hypertension shows a tripling of relative sion Specialists, the Initiative is working with over risk for first cardiovascular event in hypertensive 400 providers to track the treatment and control of patients who develop diabetes. ALLHAT was not hypertension, lipid disorders, and diabetes in their designed to make the conclusions claimed by its patients. The database, updated quarterly, has authors and blindly adopted by JNC-7. grown to include more than 80 000 hypertensive As family physicians, if we do not take the time patients. The database provides one objective mea- and trouble to understand the mechanisms under- sure for the success of this statewide initiative in lying the diseases that we commonly treat, we are improving cardiovascular risk factor control. still just shaking rattles and practicing voo-doo. Of note, the Initiative received two awards this Then when imperfect guidelines come out, based on year from the US Department of Health and Human flimsy science, we buy into it like everyone else. It Services. The first award recognized the Initiative as would help if there were enough solid evidence to a National Best Practice Model. The second award, inform our treatment decisions on even half of the presented by Secretary Tommy Thompson during human conditions that we encounter, but there isn’t. the celebration for the 40th Anniversary of the Civil Truly evidence-based medicine will have to wait for Rights Amendment, recognized the Initiative for much of what we do. its effort in reducing health disparities. Given the widespread interest, the Hypertension Initiative has Dr Laragh: Thank you, John. It is good to know that crossed the South Carolina borders to work colla- practicing physicians and family doctors are so boratively with other groups with a commitment to involved in the hypertension field. We are trying to the treatment and control of hypertension and encourage more generalist physicians to become concomitant risk factors. certified as specialists in hypertension. Personally, my interests involve the obesity epi- Another group that is working on developing the demic that is driving metabolic syndrome-related specialists programme is the American Society of health problems and tripling coronary heart disease Hypertension Chapter representing the Carolinas risk. Sympathetic hyperfunction in the pathogenesis and Georgia where Brent Egan was recently pre- and complications of the metabolic syndrome sident. Brent has been doing some very important produces higher blood pressure, a more active work at the community and state levels. What can renin–angiotensin system, additional insulin resis- you tell us about that, Brent? tance, faster heart rates, and excess cardiovascular disease and sudden death. While there are several Brent M Egan, MD, Professor of Medicine and factors that may participate in the metabolic syn- Pharmacology, Medical University of South Caroli- drome and sympathetic hyperactivity, our work na, Charleston, South Carolina. focuses mainly on the role of nonesterified fatty acids. High plasma nonesterified fatty acids are Dr Egan: The Hypertension Initiative has as its especially interesting as a risk factor for hyperten- founding goal to help change South Carolina from sion and sudden death. In human studies, nones- a leader in cardiovascular disease to a model of terified fatty acids raise blood pressure, heart rate, cardiovascular health. The intent is to reduce and a1-adrenoceptor vasoreactivity, while reducing cardiovascular disease and end-stage renal disease baroreflex sensitivity, endothelium-dependent vaso- by improving blood pressure control rates among dilatation, and vascular compliance. We are working South Carolinians from 25 to 50% over the next 5 to further identify the mechanisms and conse- years. We are focusing on primary care physicians as quences of sympathetic dysfunction in the meta- the key to success. We have developed a good bolic syndrome to help provide insights to improve working relationship with a large cadre of primary cardiovascular risk and outcomes. care providers through the Experts in Hypertension Seminar Series, which began in April, 1999. Physi- Dr Laragh: Thank you, Brent. I know we all cians that have a special interest in and commitment appreciate your good work and your efforts to get to hypertension are encouraged to become Clinical more doctors certified as Specialists in Clinical Hypertension Specialists through the American Hypertension. Society of Hypertension certifying examination. Dr Jay Meltzer is a long-time friend and colleague, Currently, there are 34 Clinical Hypertension Spe- and professor emeritus at Columbia-Presbyterian cialists in South Carolina with a goal of 110 (5% of University. There is no predicting what Dr Meltzer primary care providers) by 2009 with at least one will share with us but we can be certain it will be Hypertension Specialist in each of the State’s 46 instructive. Jay, what would you like to discuss? counties. These specialists will provide education on hypertension to their medical colleagues, treat Jay I Meltzer, MD, is Clinical Professor of Medicine resistant hypertension, and help us track hyperten- at College of Physicians and Surgeons, Columbia sion, diabetes, and cholesterol control rates through University, New York, NY. the Hypertension Initiative’s data monitoring and feedback programme. In addition to facilitating the Dr Meltzer: I would like to discuss why I use an development of a statewide network of Hyperten- intermittent dosing schedule for diuretic treatment

Journal of Human Hypertension ASH hypertension roundtable JB Standridge et al 265 of patients with essential hypertension. Before oral came back down has never really been explained, diuretics, the drug of choice for the treatment of but in any case the blood pressure lowering effect congestive heart failure was parenteral mercuhy- was maintained during all those changes. The drin. It was given in a single morning dose, and then postdiuretic physiology at 3–4 months and 1 week observed over a period of days for its diuretic and is totally different. natriuretic effect on total body weight and specific I prescribed diuretics every other day (three times manifestations of fluid retention. When oral diure- per week, Monday, Wednesday, Friday was easier to tics were developed, a similar protocol was used. remember), and could achieve goal blood pressures A single large oral dose of a thiazide was given and similar to those claimed for daily use. It was rare the degree of diuresis noted. If more diuretic was that I needed to go to daily diuretics to obtain a needed more would be given, but not till the initial better effect, though I never hesitated doing so if effect had leveled off. This enabled the clinician to necessary. I have continued to use this schedule to measure how well the diuretic was working and give this day, 45 years after I began. I always believed it only what was necessary, minimizing side effects. was the fall in pressure that produced the therapeu- When thiazide diuretics were first used to treat tic effect, not the manner of dosing. Some of my hypertension, the heart failure model was not blood pressure success with low-dose diuretics may adapted and they were given daily. This surprised have been due to efforts made to get patients to me but I realized that the doses used were high avoid a high salt diet and keep their sodium intake because those investigators tested the initial treat- between 80 and 100 mmol/day or less. ments on severe hypertension and were anxious to Sir George Pickering noted the three principle obtain measurable effects rapidly. Under those side effects of diuretics in his 1966 book ‘High Blood conditions, Pickering noted in 1966 that the dose– Pressure’, potassium depletion, diabetes and gout. response curve for all thiazides was relatively flat. He always assumed thiazide-treated patients were However, no one ever gave less than the equivalent potassium depleted and demanded potassium-spar- of 25 mg of hydrochlorothiazide daily. No one ever ing agents when giving diuretics fearing hypokalae- admitted that one couldn’t really say it was flat mia as vasculotoxic. My hope was that intermittent without going lower. Some note was taken of the dosing would reduce the incidence of potassium relation of the diuretic dose to the daily salt intake depletion and the other metabolic effects by allow- but no one really studied that relationship carefully ing the body to recover on the off days. While I never because it was generally accepted that patients measured the net salt balance (that required a preferred taking a diuretic to going on a low salt metabolic balance ward) it is probable that alternate diet. No one compared the heart failure model with dosage eventually went through the same physiolo- the new daily dosage to see which produced the gic changes as daily doses in most patients after 3–4 greatest gain/risk benefit. months. The newest trials use doses of chlorthali- My hypertension therapeutics was always direc- done of 12.5 mg daily, which can’t be too different ted toward the achievement of clearly defined, from 25 every other day, but this remains to be tested calibrated home blood pressure goals, monitored but probably never will be. It would be valuable to by well-taught patients, usually to a level of 135 know whether the many known side effects of systolic or less. Focused on blood pressure goals, I thiazides, in addition to hypokalaemia, diabetes was not committed to any specific drug protocol. and gout, such as hyperlipidaemia, hypomagnesae- This freed me to continue to use the heart failure mia, hyperuricaemia, ventricular ectopy, and sud- model of diuretic therapy as long as goals were den death, postural hypotension in the elderly and well met. erectile dysfunction could be reduced by intermit- I sought the middle of the dose–response curve tent therapy. with all medication. This area of the curve defined the maximum difference between the desired effect Dr Laragh: Thank you, my friend. Next let’s and all the unwanted effects. I also sought a welcome Dr Tatsuo Shimosawa from the University response to the lowest dose possible. So the habit of Tokyo. Tatsuo, tell us about your recent research. of dosing diuretics intermittently served me well, enabling me to test the response to doses below Tatsuo Shimosawa, MD, PhD, FAHA, is an Assistant 25 mg daily. Professor at the University of Tokyo, Faculty of The mechanism of the blood pressure response to Medicine, Department of Clinical Laboratory thiazide diuretic was understood by the early 1960s. Medicine. The natriuetic response was more or less complete by 2–4 days on the daily dose and further treatment Dr Shimosawa: In order treat metabolic syndrome did not change salt balance or extracellular fluid effectively, current therapeutic agents seem not volume. In fact, the initial decrease in cardiac sufficient. Blood pressure, hyperlipidaemia, obesity output, plasma volume, and extracellular fluid and diabetes are treated separately and the patients volume reconstituted over a period of weeks to are required to take many pills and drug compliance months. The peripheral resistance initially fell as is not always high enough. In order to find a new cardiac output lowered renal plasma blow. How it effective therapeutic target, from the point of view

Journal of Human Hypertension ASH hypertension roundtable JB Standridge et al 266 of organ protection, our research has focused on Dr Fujita: A quarter of a century ago, I and Bartter oxidative stress. Renin–angiotensin–aldosterone at NIH reported that, according to blood-pressure– axis is an important factor in producing oxidative response to salt loading, patients with essential stress as well as high glucose, ageing and adipo- hypertension could be divided into two groups; cytokines. We recently established adrenomedullin salt- and nonsalt-sensitive hypertensive ones. knockout mice. Adrenomedullin was first discov- Chronic salt loading increases blood pressure in ered as a vasodilatory peptide from the pheochro- salt-sensitive patients, but potassium supplementa- mocytoma cell. However, it is now recognized as a tion could inhibit salt-induced elevation of blood ubiquitous circulatory peptide and it possesses pressure. Recently, we found salt loading induced pleiotropic effects. Among its physiological effects, insulin resistance in Dahl salt-sensitive (S) rats, we clarified its antioxidative effect by using knock- through overproduction of oxidative stress, but not out mice. Our animal model showed higher oxida- in Dahl salt-resistant rats. Moreover, potassium tive stress together with marked vascular damage supplementation could normalize salt-induced im- and insulin resistance by angiotensin II loading or pairment of insulin sensitivity in Dahl S rats, natural ageing. Also adrenomedullin effectively through the inhibition of oxidative stress prod- suppressed reactive oxygen species production in uction. Thus, high salt diet induces not only vivo and reversed organ damages in animal model. hypertension but also insulin resistance in salt- Recent study of our group showed adrenomedullin sensitive animals and man, resulting in the progres- can antagonize angiotensin II signalling. Adrenome- sion of atherosclerosis. In contrast, diets rich in dullin peptide is still far away from clinical usage, potassium could not only decrease salt-induced BP but so far, inhibition of renin–angiotensin system rise but also improve insulin resistance, resulting with this peptide appears to be clinically relevant to in the inhibition of cardiovascular events. Accord- protect organs in metabolic syndrome patients. ingly, JNC-7 guideline recommends fruits and Also, we are interested in establishing a total vegetables as one of lifestyle modifications for the renin assay system that will be applicable in clinical treatment of hypertension, since the DASH usage to differentiate salt-sensitive patients from study confirmed the antihypertertensive effect of nonsalt sensitive patients, and to apply tailor-made potassium. In the SHEP study, the diuretic treat- medication design to each patient. I would like to ment was effective in reducing stroke incidence in discuss this in detail with Dr Sealey later. elderly patients with isolated systolic hypertension; this beneficial effect of diuretics was observed in Dr Laragh: Also from Tokyo is Dr Toshiro Fujita, normokalaemic patients, but not in hypokalaemic who has been researching salt sensitivity and ones, despite the similar BP reduction. Therefore, I insulin resistance for decades. Dr Fujita, your want to dispute the JNC-7 guideline for the insights are always most welcome. recommendation of diuretics only as the first choice drug, although I approve of the JNC-7 guideline Toshiro Fujita, MD, PhD, Professor and Chairman, for the DASH diet. Department of Internal Medicine, Faculty of Medi- cine, the University of Tokyo, Tokyo, Japan, and Dr Laragh: Thank you, Dr Fujita, and thanks to President, Japanese Society of Hypertension. everyone for a lively and informative evening.

Journal of Human Hypertension