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The interaction between vasopressin and modulators of the cardiovascular system

Streefkerk, J.O.

Publication date 2004

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Citation for published version (APA): Streefkerk, J. O. (2004). The interaction between vasopressin and modulators of the cardiovascular system.

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Download date:27 Sep 2021 CHAPTERR 1

INTRODUCTION N

PublishedPublished in part in the Pharmaceutisch Weekblad 2002; 137(21): 766-9: andand Modern Medicine 2002; (6):343-6 8 8 Introduction Introduction

11 Historical background

Argininee Vasopressin (vasopressin, AVP), or the antidiuretic hormone (ADH), is secretedd by the posterior lobe of the pituitary gland. Oliver and Schaefer in 18955 were the first to describe its vasoconstrictor activity. 1 They demonstratedd that hypophyseal extracts display vasoconstrictive properties. In 1913,, the antidiuretic effect of injections of extracts of the pituitary gland was firstt observed in patients with diabetes insipidus. 2;3 The synthesis and isolationn of vasopressin in the 1950s confirmed that one and the same hormonee of the pituitary gland is responsible for the vasoconstrictive and the antidiureticc effects. 4;5 Subsequently, several analogues of vasopressin were synthesized,, such as desmopressin, 6;7 a vasopressin agonist with selective antidiureticc properties, which is used in the treatment of diabetes insipidus. An importantt subsequent step was the development of the peptide vasopressin- antagonistss 8;9 in the nineteen sixties and onwards. This development of analoguess and antagonists enabled scientists to evaluate the role of vasopressinn in human physiology and pathophysiology. This progress was furtherr stimulated by the discovery of nonpeptide vasopressin antagonists, whichh display sufficient bioavailability for oral use. 10

2.11 Biosynthesis of vasopressin

Thee oxytocin-vasopressin superfamily is found both in vertebrates and invertebrates,, and characterised by a peptide structure of 9 amino acids. The preservedd nonapeptide pattern throughout the evolution indicates that both thee precursor structures and the processing enzymatic machinery were largely conservedd to ensure the generation of a specific conformation. Virtually all vertebratee species possess an oxytocin- and a vasopressin-like peptide, respectively,, thus allowing the tracing of two evolutionary lineages. The ancestrall gene encoding the precursor protein antedates the divergence betweenn the two groups, about 700 million years ago. n Vasopressin is a peptidee with a disulfide bond between the two cysteine-amino acids in the positionss 1 and 6. All mammal vasopressins have the same amino acid sequencee with an arginine in position 8, except the porcine vasopressin, which hass a lysine in position 8 (Figure 1). Introduction Introduction 9 9

Phenylalaninee Glutamin

Tyrosinee Asparagine

NH22 —Cysteine S-S Cysteine —Proline — Arginine — Glycinamide

Figuree 1: The primary amino acid structure of the vasopressin.

Vasopressinn is synthesized predominantly in the neurosecretory cells of the supraoptic-- and secondarily the paraventricular-nucleus, both located in the hypothalamus.. The gene is located on chromosome 20pl3 and consists of 3 exons.. These exons form the preprohormone of 168-amino-acids. The first 23 aminoo acids form the signal peptide, which is responsible for the connection to thee ribosomes. During the protein synthesis this signalling peptide is removed, afterr which the prohormone is transported via the endoplasmic reticulum (ER) andd the Golgi apparatus into secretory granules. In these granules the prohormonee disintegrates, under the influence of the enzymes monooxygenase,, exopeptidase, endopeptidase and lyase, to yield three proteins.. These proteins are vasopressin (9 amino acids), vasopressin- neurophysinn (92 amino acids) and vasopressin-glycopeptide (39 amino acids), respectively.. Vasopressin-neurophysin is responsible for correct intracellular transportt and processing. The function of the vasopressin-glycopeptide is unknown.. After internalisation of vasopressin into the granules, it is transportedd from the paraventricular- and the supraoptic-nuclei, via axons locatedd in the internal zone of the median eminence, towards the nerve endingss at capillaries in the posterior pituitary. 12

Att present more than 35 mutations have been related to hereditary forms of centrall diabetes insipidus. 13 Most of the mutations are found in the signalling peptidee or in the vasopressin-neurophysin part, and only two are found in the primaryy structure of vasopressin itself. This finding emphasizes the importance off the correct configuration of the (pre) prohormone necessary for correct intracellularr processing. Most known forms of familial central diabetes insipiduss have an autosomal dominant inheritance pattern, which becomes 10 0 Introduction Introduction clinicallyy manifest in the period several months after birth until early adolescence.. The reason why this autosomal dominant disease displays a delayedd clinical onset so far remains unknown. Several authors suggest that thee large accumulation of misfolded precursors is ultimately toxic towards the secretoryy cells that produce them. 13;14 This hypothesis is supported by in vitro experimentss that demonstrated the occurrence of cellular toxicity due to the accumulationn of misfolded precursors in the ER, resulting in morphological derangements.. 14 Another possibility is the formation of heterodimers by the normall allele and the mutant (pre) prohormone resulting in an impaired expressionn of the initial normal function of the non-mutant gene. 15

Itt has already been suggested two decades ago that vasopressin can be generatedd in peripheral tissues. 16;17 Recently two independent publications demonstratedd a local generation of vasopressin outside the central nervous system.. 18;19 Guillon et al. demonstrated by means of PCR and perfusion experimentss that the rat and human adrenal medulla may express and release vasopressinn under basal conditions and also as a result of stimulation by acetylcholine.. Activation of the cortical Vi receptor (see paragraph 2.1) results inn both steroid secretion and cortical growth. In the medulla, both Vi and V3 receptorr subtypes are expressed. V3 receptors have been shown to stimulate catecholaminee secretion. The role of the Vi receptor in the medulla remains unclear.. Hupf et al. described the occurrence of low basal levels of vasopressin andd the corresponding mRNA in the rat heart. After applying ventricular wall stresss the vasopressin levels as well as vasopressin mRNA levels appeared to bee increased. Systemic effects of this local vasopressin production remain uncertain.. However, the combination of wall stress and coronary infusion of a Vi-antagonistt resulted in a decreased coronary perfusion pressure. This finding implicatess that besides the centrally regulated release of vasopressin with its systemicc effects, vasopressin may serve as a local tissue hormone.

2.22 Regulation of vasopressin secretion

Thee central secretion of vasopressin is regulated by several stimuli. The most importantt one is a change in plasma osmolality (P0sm). Changes in P0Sm are perceivedd by specialized so called 'osmoreceptor-neurons' localized in the Introduction Introduction 11 1 hypothalamus.. Plasma vasopressin levels (PAVP) start to increase after an increasee of P0Sm above a threshold level of about 280-290 mOsm/kg. The rise off the PAVP, in the lower range of (0-10 pg/ml), causes after this threshold levell an increase by 1 pg/ml, whereas the P0Sm increases by only 1 %. An 20 increasee of PAVP by 1 pg/ml significantly increases osmolality of the urine.

Maximall osmotic stress will increase the PAVP to a level of 15-20 pg/ml.

PAVPP is also affected by changes in blood volume and blood pressure, detected byy mechano-receptors of the vagal nerve endings in the aorta, the cardiac atriaa and pulmonary veins. Furthermore, endings of the glossopharyngeal nervee from the carotid sinus stimulate the release of vasopressin. 21 Small decreasess by about 8% of the extracellular fluid volume do not result in an increasee of PAVP- Beyond that point PAVP increases steeply up to levels of 50- 1000 pg/ml. These levels result in a maximal antidiuresis and an increased peripherall resistance to prevent cardiovascular collapse. Besides these two importantt regulatory systems, several other factors are known to increase PAVP suchh as hypoglycaemia, 22 hypoxia, 23 acidosis, 24 pharyngeal stimuli, 25 pain, 266 and emetic stimuli. 27 Vasopressin release can also be directly stimulated by hormoness and mediators, such as acetylcholine, histamine, nicotine, dopamine,, prostaglandins and angiotensin II, and inhibited by others such as opioidss and the atrial natriuretic peptide. 28

33 Vasopressin-receptors and their subtypes

3.11 The Vj-receptor (or Vla-receptor)

Michelll et al. subdivided vasopressin-receptors into two major subtypes, that 29 iss the Vi- and the V2-receptor, respectively. The Vi-receptors (Fig. 2) are primarilyy members of the Gq/n family, but the Gj family can also be involved underr certain conditions. 30;31 In analogy with ai- and the Hi-receptors, the VV receptorr activates, via a Gq/n-protein, phospholipase C-(3 which cleaves phosphatidylinositol-4,5-bisphosphate,, thus yielding inositol-1,4,5- triphosphatee (IP3) and diacylglycerol (DAG). IP3 induces the release of calcium ionss from intracellular stores. 32 Furthermore the activation of the Vi-receptor leadss to an enhanced influx of extracellular Ca2+ ions, via L-type Ca2+- 12 2 Introduction Introduction channels.. The mechanism underlying channel activation so far remains unknown.. The Vi-receptor also activates phospholipase D, resulting in the hydrolysiss of other phospholipids to produce phosphatidic acid, which is furtherr metabolised to yield DAG. DAG in its turn activates protein kinases C andd this results in the phosphorylation of key proteins further downstream.

Finally,, the Vi-receptor mediates the activation of phospholipase A2, and it activatess the cyclooxygenase pathway via the mobilisation of arachidonic acid fromm phospholipids. 33 All these effects result in either immediate or late responses.. Direct responses cause an activation of the contractile elements of thee vascular smooth muscle cells, 34 stimulation of the glycogenosis in the

Figuree 2: Signal transduction mechanism mediated by the Vi-receptor. Abbreviations:

PLA2,, phospholipase A2; PLC-6, phospholipase C-6; PLD, phospholipase D; PIP2, L-3- phosphatidyl-D-myo-inositol-4,5-bisphosphate;; IP3, inositol-(l,4,5)-trisphosphate; DAG,, 1,2-diacylglycerol; PA, phosphatidic acid; AA, arachidonic acid; PS's, prostaglandins;; LTE's, leucotriens; TXA, Thromboxanes; PKC, Protein Kinase C; Ras GRF,, Ras guanine-nucleotide releasing factor; PYK2, proline-rich tyrosine kinase 2; MAPK,, mitogen-activated protein kinase; ERK, extracellular signal-regulated kinase; MKK,, MAPK kinase; MKKK, MAPK kinase kinase. Introduction Introduction 13 3 hepatocytes,, 35;36 and increased platelet aggregation. 37 The late responses involvee the Vi-receptor-mediated effects on cellular hyperplasia and hypertrophy.. These effects seem to involve an increased expression of the proto-oncogeness c-fos and c-jun, which are both active in transcription regulationn of many other genes necessary for cellular growth. 38 Also the activationn of MAP kinases seems to be partly regulated by vasopressin. 39;40 erkl/2 Thee Vi-receptor as Gq-coupled receptor can activate the MAPK pathway viaa the upstream stimulation of MAPK Kinase Kinase Rafl (MKKKRaf *). MKKKRafl inn this setting can be stimulated through protein kinase C and via an increase inn intracellular Ca2+ concentration 41.

Untill the nineteen seventies research was focused on the antidiuretic effects of vasopressin,, because physiological and pathophysiological levels of vasopressinn were thought not to play a role in the regulation of vascular tone. However,, it is now assumed that vasopressin at normal or increased plasma levelss does indeed play a role in the regulation of blood pressure. Several importantt findings support this view. Vasopressin has been demonstrated to bee a potent vasoconstrictor in vitro. This vasopressin-induced vasoconstriction iss most prominent in the splanchnic, muscular and cutaneous vascular beds. 42 Inn vivo, the vasoconstrictor effects of vasopressin are compromised by a decreasee in activity of the sympathetic nervous system. 43 Under physiological conditions,, even large elevations of plasma vasopressin levels do not influence bloodd pressure, as a result of a counteracting activity of the baroreflex system.. 44 Conversely, it has been demonstrated that ganglionic blockade enhancedd vasopressin-induced pressor activity. 45;46 The comparison of vasopressinn dose-response relationships in conscious normal and sinoaortic denervatedd dogs, revealed an enhancement after denervation of the pressor sensitivityy to vasopressin that was far stronger than that observed for either angiotensinn II or norepinephrine. 43;47 Lumbers et al. demonstrated that there weree no peripheral vasopressin-mediated interactions with baroreceptor discharge,, when measured by electrical activity in dissected single fibres from thee carotid sinus nerve of anaesthetized dogs. 48 This finding suggests that the vasopressin-inducedd augmentation of the baroreflex system is centrally locatedd and not dependent on alterations in the sensitivity of carotid sinus baroreceptors.. Several authors evaluated the effect of an increased vasopressin-plasmaa concentration enhancing the inhibitory action of the baroreceptors.. 49"52 The inhibitory action stimulated by vasopressin was 14 4 Introduction Introduction preventedd by local destruction of the area postrema and this effect appeared too be mediated by the Vi-receptor. This observation confirms the central localisationn of vasopressin-induced sensitisation of the baroreflex. Interestingly,, in contrast with this feedback mechanism of vasopressin- mediatedd vasoconstriction, several recent studies show that vasopressin may exertt direct potentiating effects on the perivascular nerve fibers of the sympatheticc nervous system. 53~55 This peripheral facilitation of the sympatheticc nervous system has been demonstrated only in single vessel preparationss and it results in an increase of vascular tone. This effect is probablyy Vi-receptor mediated. Conflicting results are presented regarding theirr pre- or post-synaptic site of action (Figure 3).

Sympatheticc nerve terminal

Nervee varicosity (Pre-Synaptic) )

Vasopressin n Synapticc cleft

Vascularr Smooth ++ + musclee cell I I (Post-Synaptic) ) Vasoconstriction n

Figuree 3: Potentiating actions of vasopressin on the sympathetic nerve varicosity and thee vascular smooth muscle cell. Abbreviations: NA, noradrenaline; m and a2, ai- and a2-- adrenoceptors.

Althoughh vasopressin-induced peripheral vasoconstrictor effects are consideredd to be the main hemodynamic function of the Vi-receptor, this Introduction Introduction 15 5

receptorr may also mediate direct cardiac effects. It has been suggested that thee strong reduction in cardiac output induced by circulating vasopressin is not causedd by a sensitised baroreflex system, but rather provoked by direct cardiacc actions of this peptide. 56 Graf et al. demonstrated, that the VV receptorr is involved in the regulation of cardiac function and perfusion. 57 The mostt prominent Vi-mediated effects on cardiac physiology appear to be coronaryy vasoconstriction and impaired relaxation. 58 Furthermore, it is plausiblee that Vi-receptor activation exerts positive inotropic effects, due to increasedd intracellular calcium levels in cardiac myocytes. 59;60 Besides these directt effects, protein synthesis is also increased by Vi-receptor stimulation, andd this phenomenon may be important for the development of cardiomyocyte hypertrophyy and cardiac remodelling. 61~63 The relevance of these Vi-mediated effectss is emphasized by the assumption that vasopressin possibly serves as a locall tissue hormone in the heart. 19

Figuree 4: Transmembrane topology of the human vasopressin Vi-receptor showing functionallyy important residues. Amino acids highlighted in black circles are critically involvedd in agonist binding. Potential glycosylation (on Asn 14, 27 and 196) and palmitoylationn (on Cys 365 and 366) sites are also indicated. Adapted from Barberis et al.,, with permission. 64

Inn addition to the cardiovascular effects on end organs, the Vi-receptor also mediatess many interactions of vasopressin with other neurohormones. The 16 6 Introduction Introduction centrall pressor action of angiotensin II is partly mediated by an increased releasee of vasopressin. 65"67 Furthermore, Vi-receptor activation of endothelial cellss increases the release of endothelin 1. 68~70 In the deoxycorticosterone acetatee (DOCA)-salt hypertension model in rats, some of the vascular effects off vasopressin provoking hypertension are mediated by endothelin 1. 71 The Vi-receptorr activation is also involved, although indirectly, in the inhibition of Atriall Natriuretic Factor (ANF) secretion in the isolated heart by stimulating NO-releasee from the endothelium. 72 This interaction with endothelium-derived NOO causes a reduction of Vi-mediated vasoconstriction in the rat kidney. 73 Furthermore,, exogenous vasopressin induces the release of NO, resulting in vasodilationn both in dog brain stem arteries and in the human forearm. 74;7S In certainn vascular beds the increase in peripheral resistance may also be diminishedd by vasodilator prostaglandins from the endothelial cells. 76;77 Moreover,, the prostaglandin-regulated proliferative effects may be induced by Vi-receptorr activation. 78;79

3.22 Vi-receptor agonists and -antagonists

Inn the past decades close to a thousand analogues of vasopressin and oxytocinn have been synthesised. 80;81 These agonists and antagonists have playedd an important role in the pharmacological identification of the three classicall vasopressin receptors. In thee past decade several new Vi-receptor antagonistss have been developed. OPC-21268 was the first nonpeptidergic W antagonistt described. 10 Although this antagonist was potent in the rat, it failedd to induce an inhibition of Vi-receptor mediated effects in humans. 82;83 Anotherr nonpeptide antagonist is SR-49059 (relcovaptan), which displays a markedd affinity, selectivity and efficacy towards both animal and human Vi- receptors,, without any partial agonistic activity. 84 SR-49059 has been studied inn women with primary dysmenorrhea, since in such patients the plasma concentrationss of vasopressin are known to be elevated. 85"87 Furthermore the effectt of vasopressin on uterine activity is known to increase premenstrually, andd a premenstrual rise in the density of Vi-receptors has been demonstrated. SR490599 proved to be beneficial in the symptomatic treatment of primary dysmenorrhea.. In addition SR-49059 was studied in hypertensive patients. Thee outcomes of these investigations will be discussed in paragraph 4.2. 88 In Introduction Introduction 17 7 alll human studies so far performed no serious adverse effects of the W antagonistt were observed.

Figuree 5: Chemical structures of Vi-antagonists: The quinolinone derivative OPC- 212688 and the /V-Sulfonyl-indoline derivative SR-49059.

3.33 The V2-receptor

V2-receptorr activation causes second messenger activation, which is comparablee to other stimulants of Gs-protein coupled receptors. When occupiedd by an agonist, the V2-receptor (Fig. 6) catalyses the conversion of

GDPP into GTP on the Gs-protein, with subsequent dissociation of Gs into its as andd py subunits. The as subunit stimulates the well-known second messenger systemm of adenylyl cyclase, which catalyzes the generation of cyclic AMP, thus triggeringg the activation of cyclic AMP-dependent protein kinase (PKA). PKA controlss several cellular functions by phosphorylating various substrates. In thee principal cells of the entire renal collecting duct, this results in a decreased ratee of endocytosis of water channels (aquaporins-2) from the apical membrane.. Also the exocytosis-rate of aquaporin-2 containing vesicles to the apicall membrane is increased. 89 Furthermore, PKA phosphorylates cyclic-AMP responsee binding protein, which in its turn increases the transcription rate of thee gene encoding aquaporin-2. The increased number of aquaporins on the apicall membrane due to V2-receptor activation results in an increased reabsorptionn of water by the renal collecting duct. 18 8 Introduction Introduction

Figuree 6: Signal transduction mechanism mediated by the V2-receptor involved in thee regulation Aquaporin-2 translocation to the apical membrane in the collecting duct.. Abbreviations: PKA, Protein Kinase A; cAMP, cyclic AMP; AQP2, Aquaporin 2

Vasopressinn regulates urine osmolality and volume (Fig. 7) by adapting the permeabilityy to water of the cortical- and medullary-collecting duct to water

viaa the V2-receptor. Furthermore, activation of the V2-receptor induces an increasedd number of active Na-K-2CI cotransporters (NKCC2), epithelial sodiumm channels (ENaC) and renal outer medullary potassium channels (ROMK)) in the luminal membrane. 90~93 This results in increased sodium reabsorptionn and potassium secretion in the thick ascending limb and the corticall and medullary-collecting ducts. Recent studies suggest that vasopressinn also decreases extra renal fluid losses via the upregulation of 94 ENaC'ss in the lung. V2-receptor antagonists are able to prevent this effect.

Inn the terminal inner medullary collecting duct V2-receptor activation increases permeabilityy to urea. This process probably involves a PKA - inducedd phosphorylation of the vasopressin-regulated urea-transporter Al (UT-A1).. 95 IntroductionIntroduction 19

Nr. . Location n Receptor r Effectt via the activation of the followingg mechanism. 1 1 Talll ascending limb v2 2 ENaC C 2 2 Corticall collecting v2 2 AQP2,, NKCC2, ENaC and ROMK duct t 3 3 Terminall collecting v2 2 AQP22 and UT-A1 duct t 4 4 Medullaryy interstitial Vi i Stimulationn of the prostaglandin cells s production n 5 5 Vasaa recta Vi i Vasoconstriction n Pneumocytess 2 in 6 6 v2 2 ENaC C thee lung

Tablee 1: Vasopressin-mediated effects in water and electrolyte homeostasis. Abbreviations:: AQP2, aquaporin-2; EnaC, epithelial sodium channels; NKCC2, Na-K- 2CII co-transporters; ROMK, renal outer medullary potassium channels; and UT-A1, vasopressin-regulatedd urea-transporter Al

Figuree 7: Effects of vasopressin on the Nephron. Numbers refer to those given in tablee 1. 20 0 Introduction Introduction

Alll V2-mediated effects can be partly counteracted by a Vi-receptor mediated productionn of prostaglandin E2 (Pgs) in the medullary interstitial cells and are thoughtt to play a role at plasma vasopressin levels of 15 pg/ml and higher. 96 Prostaglandinn E2 is known to inhibit cyclic AMP in the collecting duct. This explainss the well-known antidiuretic side effect of indomethacin and other prostaglandinn synthesis-inhibitors (NSAID's). In addition, physiological elevationss of plasma vasopressin levels (up to 8 pg/ml) reduce blood flow to thee inner medulla, whereas a constant blood flow in the outer medulla is maintained.. This is a VVreceptor dependent effect at the level of the microvesselss of the medullary vasa recta. Accordingly, urine osmolality during waterr restriction is optimised, without any changing of baseline arterial pressuree or renal cortical blood flow. This mechanism appears to be of utmost importancee because of the high oxygen consumption by the renal cortex. 97

Thee V2-receptor is less widely distributed than the Vi-receptor. The Wreceptor iss especially known for its renal effects, but in the past decade evidence was presentedd that extra-renal Wreceptor activation may result in vasodilation of severall vascular beds. 75;98-100

3.44 V2-receptor agonists and -antagonists

AA well-known vasopressin analogue is l-deamino-8-D-arginine vasopressin (DDAVP,, or Desmopressin). This agonist is about 3000 times more functionally 6 selectivee for the V2 than for the Vi-receptor. V2-receptor activation by desmopressinn causes a strong antidiuretic effect. Desmopressin forms the cornerstonee in the treatment of all forms of central diabetes insipidus.

Itt was already demonstrated around nineteen hundred that stress enhanced bloodd clotting via the increase of plasma adrenaline concentrations. Later it becamee evident that this effect was caused by an increase in coagulation factorr VIII (VTII:C). Besides adrenaline also vasopressin and insulin were able too induce an increase in VIII:C. This increase in VIII:C was comparable in healthyy humans and in patients with mild Hemophilia A. 101 The development off the synthetic vasopressin analogue desmopressin, which is virtually devoid off hemodynamic side effects, allowed the application of a blood-transfusion- Introduction Introduction 21 1 freee therapy for the prevention and treatment of bleeding in these patients.

Thee source of VIII:C release is not known, but V2-receptor mediated, since patientss with nephrogenic diabetes insipidus are unresponsive to desmopressin.. 102 In addition to the increase of VIII:C, desmopressin increasess plasma levels of tissue-type plasminogen activator (t-PA) and von Willebrandd factor (vWF) and it enhances platelet adhesion to the vessel wall. io3;io44 Endothelial cells release both t-PA and vWF. Only t-PA release can be acutelyy initiated by desmopressin, whereas the release of the vWF seems to bee synthesis dependent. 105;106 The fibrinolysis induced by the release of t-PA iss generally mild, desmopressin is therefore suitable to reduce the clotting timee for clinical purposes.

Thee following V2-antagonists are currently under investigation SR-121463, OPC-31260,, OPC-41061 (tolvaptan), VPA-985 (lixivaptan), WAY-140288, VP- 343,, VP-339 and FR-161282. The first 4 compounds are presently undergoing phasee II clinical tials. These 4 compounds have been shown to produce a dose dependentt aquaresis (increase in urine volume, with a low urine osmolality) andd a correction of hyponatremia if present. The major potential clinical indicationss for the V2-antagonist are conditions that are associated with hyponatremiaa and fluid retention, such as congestive heart failure, liver cirrhosiss with ascites and the syndrome of inappropriate antidiuretic hormone (SIADH). .

YM-0877 (conivaptan) is a mixed Vi/V2-antagonist, with a comparable affinity forr the Vi and V2 receptor. This compound is under evaluation in phase III clinicall trials, in particular for the treatment of hyponatremia associated with congestivee heart failure. Currently three other Vi/V2-antagonists are in the pre-clinicall stage of investigation: YM-471, JTV-605 and CL-385004. 22 2 Introduction Introduction

OPC-41061; ; tolvaptan n

SR-121463 3

YM-087;; conivaptan

*HC1 1

Figuree 8: Chemical structures of V2-antagonists and a Vi/2-antagonist: The benzazepinee derivatives OPC-31260, OPC-41061 and VPA-985 and the /V-Arylsulfonyl- oxindolee derivative SR-121463, all selective V2-antagonists. The benzazepine derivativee YM-087 a combined V1/2-antagonist Introduction Introduction 23 3

3.55 V3-receptor (or Vlb-receptor)

Studiess of ligand binding profile, coupling to phospholipase C and adenylyl cyclase,, revealed a unique pharmacological profile for this pituitary gland receptor.. Depending on the level of receptor expression, the V3-receptor coupless to members of the Gq/n family, alone or in combination with G\, and it mayy also recruit Gs. Consequently, the human V3-receptor displays a pharmacologicall profile clearly distinct from that of the human Vi- and V2- receptor.. 107 Accordingly, the earlier nomenclature designating this receptor as Vib,, suggesting that this receptor evokes a comparable second messenger activationn as the Vi(a)-receptor, has become obsolete.

Stimulationn of the V3-receptor enhances the release of adreno-corticotrophic hormonee (ACTH) from the anterior pituitary gland. Furthermore, recent studiess have demonstrated that the V3-receptor is expressed in multiple brain regionss and in a number of peripheral tissues, such as the kidney, adrenal medulla,, pancreas, thymus, heart, lung, spleen, uterus, and breast. 108 In the

humann adrenal medulla the V3-receptor is thought to be involved in the 109 regulationn of adrenal function. In the rat pancreas, the V3-receptor may enhancee both insulin n0 and glucagon release. in Vasopressin induces insulin andd glucagon release in a glucose-dependent manner, the higher the glucose concentration,, the stronger the enhancement of vasopressin-induced insulin release,, and vice versa. u2 The possible physiological importance of the

peripherall V3-receptor in other organs remains to be established. Recently, the 113 firstt selective, nonpeptide V3-antagonist, SSR149415, was described. The developmentall status of this compound is still preclinical.

3.66 Recently discovered vasopressin receptor-subtypes

Severall new vasopressin-receptors, with varying scientific evidence with regardd to their biological activity and functional relevance, are currently under investigation.. An example is the vasopressin-activated calcium-mobilizing (VACM-1)) receptor. The VACM-1 receptor does not share any structural or

sequencee homology with the cloned VV or V2-receptors, has one putative transmembranee domain and belongs to the recently discovered gene family 24 4 Introduction Introduction termedd cullins. 114 VACM-1 receptors are localised in endothelial-, renal medullaryy collecting tubule- and brain cells. 115;116 The biological role of the VACM-11 receptor so far remains unknown. The VACM-1 receptor has, in analogyy with other cullin family members, been implicated in the regulation of thee cell cycle. Furthermore, VACM-1-receptor activation is likely to influence intracellularr signalling pathways. 117

Besidess the VACM-1 receptor a dual angiotensin II (Ang II)-vasopressin receptorr was discovered, by screening of a rat kidney complementary DNA library.. This receptor has probably 7 transmembrane regions and seems to be Gj-coupled.. It appears to be substantially different from other G-protein coupledd receptors. The corresponding mRNA has been cloned in many human peripherall tissues. Functional analysis revealed specific binding to both Ang II andd vasopressin, and to Ang II- and vasopressin-induced coupling to the adenylatee cyclase second messenger system. Site-directed mutagenesis of the predictedd Ang II binding domain obliterated Ang II binding, but preserved vasopressinn binding, suggesting the presence of distinct Ang II and vasopressinn binding domains. 118

Recently,, the screening of a rat kidney complementary DNA library revealed a

"V66 encoded vasopressin Vi-type receptor", with a high density in vascular smoothh muscle cells. U9 Pharmacological studies have suggested the possible existencee of another receptor, displaying vasodilator activity after stimulation withh vasopressin-derived peptides and exhibiting little or no functional interactionss with the classic three vasopressin-receptors. 120 These peptides aree structural analogues of V2 receptor ligands. Indeed, Johns et al. demonstratedd a desmopressin-induced vasodilation, which proved insensitive too Vi- or V2-antagonists, without evoking an increase of cAMP or cGMP levels. 121 1 Introduction Introduction 25 5

44 Clinical relevance of vasopressin and the related drugs

Thee present investigation is predominantly concerned with the vascular effects off vasopressin and therefore three cardiovascular syndromes in which vasopressinn or its antagonists could play a role will be discussed.

4.11 Shock

Haemorrhagic,, 122 cardiogenic, 123 and septic shock 124 are associated with an increasee in plasma vasopressin levels. In the early phase these levels are the highestt reported for the release of endogenous vasopressin. The plasma levels rangee between 100 and 1000 pg/ml, compared to the level of 20 pg/ml, which iss needed to maximally increase urine osmolality during water deprivation. Duringg the progression of shock, the vasopressin levels are decreasing for so farr unexplained reasons. 125 It has been speculated that inappropriately low plasmaa levels of vasopressin are, at least partly, related to a depletion of vasopressinn stores in the pituitary gland. 126

Besidess the well-known effectiveness of vasopressin in the treatment of bleedingg from oesophageal varices, there exists limited evidence with the systemicc use of vasopressin in patients with a severe haemorrhage. 127 Two randomisedd clinical trials, in which the therapeutic potential of vasopressin in septicc shock was investigated, have been conducted. 128'129 The first study randomlyy assigned 10 patients to vasopressin 0.04 U/min or placebo. This treatmentt resulted in an increased peripheral resistance and blood pressure; moreover,, all patients receiving vasopressin were withdrawn from all other catecholaminee pressor agents 24 hours later. The second study, randomly assignedd 24 patients to a 4-hour double-blinded infusion of noradrenaline or vasopressin.. In contrast to noradrenaline, vasopressin decreased the need for conventionall therapy and increased urine output and creatinine clearance. Theree were no signs of myocardial or gastric ischaemia due to the treatment withh vasopressin.

Inn patients subjected to cardiopulmonary resuscitation (CPR) endogenous vasopressinn plasma levels are higher in those who survived. 13 The use of 26 6 Introduction Introduction vasopressinn in a CPR setting has theoretically, an advantage over adrenaline, sincee 0-adrenergic receptor-mediated effects do not occur. Accordingly vasopressinn does not increase myocardial oxygen consumption and it prevents skeletall muscle vasodilation. Furthermore, in contrast to cathacholamine- inducedd vasoconstriction, the vasoconstriction elicited by vasopressin is maintainedd during severe acidosis. This suggests that vasopressin becomes relativelyy more effective with a longer duration of cardiac arrest. 131 During a shortt period of experimentally-induced ventricular fibrillation in animals, exogenouss vasopressin during CPR increased coronary perfusion pressure 132, cerebrall oxygen delivery, and the blood flow was redistributed in favour of the vitall organs. 133;134

Twoo trials have been performed in patients with cardiac arrest comparing vasopressinn to adrenaline. One study demonstrated, in patients with out-of- hospitall ventricular fibrillation, a significantly better survival for the vasopressin-treatedd group. 135 Another study evaluated the same drugs in 104 patientss with in-hospital cardiac arrest (20 % ventricular fibrillation), however, thiss study failed to detect an advantage for vasopressin over adrenaline. 136 An ongoingg large trial (1500 patients) is conducted under the guidance of the Europeann Resuscitation Council in order to study the possible benefits of vasopressinn in patients with cardiac arrest.

Accordingg to the Guidelines of the American Heart Association, vasopressin mayy be a more effective than adrenaline in promoting the return of spontaneouss circulation in cardiac arrest due to ventricular fibrillation. 137 The evidencee from prospective clinical trials in humans is limited but consistently positivee (Class lib). Vasopressin (40 U IV, not repeated) may be substituted forr adrenaline as an alternative Class lib agent (acceptable; fair supporting evidence).. The better adverse effects profile of vasopressin may be the major indicationn for its use. So far, this advice has not yet been incorporated into the guideliness of the European Resuscitation Council. 138 Introduction Introduction 27 7

4.22 Hypertension

Thee role of vasopressin in the pathogenesis of hypertension is controversial. In animall models of experimental hypertension the role of vasopressin has been extensivelyy investigated. In Spontaneous Hypertensive Rats (SHR), 139 two- kidneyy one clip hypertension in rats, 14 Dahl's salt sensitive rats receiving a highh salt diet, 141 and DOCA-salt induced hypertension in rats, 142'143 bolus injectionss of peptidergic- and non- peptidergic Vi-receptor antagonists resultedd in a significant decrease in blood pressure. These results suggest that vasopressinn is involved in the maintenance of hypertension, at least in these animall models.

Chronicc administration of the Vi-receptor antagonist OPC 21268 in an experimentall rat model of DOCA-salt induced hypertension significantly preventedd the development of hypertension. 142 Treatment with a Vi-receptor antagonistt reduced the full development of hypertension in SHR. 144;145 These resultss are in contrast with those of others who, in the same model, did not observee a beneficial effect for chronic treatment with a Vi-antagonist. 146 In thee two-kidney one clip model of hypertension chronic treatment with Vi- and

V2-antagonistss did not demonstrate a role for vasopressin in the maintenance off blood pressure. 147 In another model evaluating the chronic administration off vasopressin antagonists the role of vasopressin seems to be less important. Chronicc NO-synthesis inhibition induced hypertension was not influenced by thee chronic administration of a Vi-receptor antagonist. 148

Researchh in humans concerning the role of vasopressin in hypertension has beenn performed as well. These studies demonstrated increased plasma vasopressinn levels. 149*153 The major question already asked by Padfield 149 in 19766 is: are the increased levels of vasopressin a cause or an effect of hypertension?? Vi-receptor blockade in healthy volunteers does not influence bloodd pressure, suggesting that vasopressin is not involved in normal blood pressuree regulation. 154;155 Moreover infusion of vasopressin in normal subjects,, beyond the levels found in malignant hypertensive patients, did not influencee blood pressure. 149 In patients with the syndrome of inappropriate antidiureticc hormone (SIADH) the clinical picture is characterised by fluid retentionn and low serum sodium levels. However, in patients with SIADH the 28 8 Introduction Introduction elevationn of vasopressin plasma levels do not result in the development of hypertension.. 155~157

Thee outcomes of these studies in combination with the results from animal experimentss do not support a major role of vasopressin in the development andd maintenance of hypertension, although some criticism on this view has beenn expressed. Ribeiro et al. demonstrated that random sequential blockade off the sympathetic nervous system, the renin-angiotensin system, or the vasopressinn system increased the blood pressure dependence of the two unblockedd systems in patients with severe hypertension. Although the contributionn of the vasopressin system was rather limited, the vasopressin componentt in blood pressure maintenance was evident. 158 It is generally acceptedd that ACE-inhibition in patients decreases vasopressin release, 153;159 butt under certain conditions the sensitivity to vasopressin may be increased underr ACE inhibition. 16 Furthermore, acute blood pressure lowering with sodiumm nitroprusside or clonidine in hypertensive patients increased vasopressinn plasma levels. 161 Antihypertensive drug treatment at present is mainlyy based upon suppression of the activities of the sympathetic nervous systemm and of the renin-angiotensin aldosteron system (RAAS). It can be imaginedd that the vasopressin "system" may gain importance in the pathophysiologyy of hypertension, and also as a target for drug treatment.

4.33 Vasopressin in negroid hypertensives

Vasopressinn levels appear to increase with age in normotensive subjects, partlyy as a result of decreased urinary concentrating capacity, and vasopressin iss assumed to play a more prominent role in the regulation of blood pressure inn the elderly. 162"166 Ethnic factors also differentiate hypertensive patients in thiss respect. 151 African-American hypertensives are known to display increasedd vasopressin plasma levels compared to age-matched hypertensive Caucasianss or African-American normoten-sives. 167 The involvement of vasopressinn in blood pressure control was emphasized by Bakris et al., who foundd that only in African-American hypertensives a Vi-antagonist decreased bloodd pressure. This effect was not seen in age-matched Caucasians. 168 African-Americann hypertensives are known to display a low renin, salt Introduction Introduction 29 9 sensitivee form of essential hypertension, which is usually associated with higherr levels of vasopressin. 142;15 169;170 Thibonnier et al. evaluated the effect off a single oral dose of the Wantagonist SR-49059 in 24 patients with hypertensionn and observed no reduction in blood pressure. However, after a hypertonicc salt infusion (a procedure known to increase the release of endogenouss vasopressin levels) in the presence of SR49059, the heart rate increasee was limited, while the blood pressure peak proved decreased. 88 Althoughh the role of vasopressin in hypertension is certainly not straightforward,, in certain categories of patients treatment with vasopressin- antagonistss seems worthwhile to be investigated. In hypertension vasopressin-antagonistss are thought to be preferably effective against both thee Vi- and V2- receptor, in order to lower both the peripheral vascular resistancee and the circulating volume. 81

4.44 Congestive heart failure

Severall authors have described elevated vasopressin plasma levels in patients withh congestive heart failure. 171"178 Francis et al. reported that patients with asymptomaticc left-ventricular dysfunction had elevated plasma vasopressin levelss when compared to control patients, whereas patients with symptomatic mild-to-moderatee heart failure had even higher vasopressin plasma levels. 171 Rouleauu et al. emphasized the prognostic value of vasopressin levels in the Survivall and Ventricular Enlargement (SAVE) population of post-myocardial infarctionn patients with left-ventricular dysfunction. 179 In this study, 1 month afterr myocardial infarction vasopressin levels were associated with adverse long-termm cardiovascular outcomes, including heart failure, recurrent myocardiall infarction, and death. In patients with congestive heart failure somee studies could not demonstrate a direct relation between cardiac output andd serum sodium levels on the one-hand and vasopressin levels on the other. i74;i76;i777 jn parents with congestive heart failure, two groups may be distinguished:: one group displays relatively low to slightly increased vasopressinn levels, showing a 'normal' relationship between vasopressin and osmoregulatoryy control. Conversely, in the second group, with moderate to highlyy increased vasopressin levels, no relationship between vasopressin and plasmaa osmolality is established. In particular parameters reflecting renal functionn like blood urea nitrogen and serum creatinine levels, proved to be 30 0 Introduction Introduction deterioratedd in the second group. Furthermore, plasma sodium levels were stronglyy decreased in the second group, which is an ominous sign in the prognosiss for patients with congestive heart failure.

Thee possible role of vasopressin was evaluated in several animal models of congestivee heart failure. 18 191 in all studies an increase in vasopressin plasma levels,, or an increased vascular sensitivity, was established. Acute administrationn of a Vi-antagonist induced various hemodynamic effects, rangingg from no observed effect at all, 183 to an increase in cardiac output, a decreasee in systemic vascular resistance and improved renal function without 18 184 189 191 194 significantt changes in serum electrolytes and hormones. - ; - in one studyy the effect of administration of an ACE inhibitor was comparable to that off a Vi-antagonist with regard to the reduction of peripheral resistance. Furthermore,, total peripheral resistance was normalised after the combined 186 administrationn of an ACE inhibitor and a Vi-antagonist. A selective V2- receptorr antagonist (OPC-31260) induced marked water diuresis, reduced urinee osmolality, increased plasma sodium and vasopressin concentrations, andd increased plasma renin activity.188 The combined administration of a Vi andd a V2-antagonist (OPC-21268 and OPC-31260) has yielded synergistic hemodynamicc as well as additive renal and metabolic responses. These results weree confirmed by the use of conivaptan, a nonpeptidergic combined Vi/V2- antagonist.. 189;195

Inn the nineteen eighties several studies were conducted to evaluate the responsee to a peptide Vi-receptor antagonist in patients with advanced congestivee heart failure. 196"198 A decrease of peripheral resistance was observedd in 5 to 30 % of the patients. In a randomised, double blind, placebo controlledd trial the effect of short-term treatment with conivaptan at a single intravenouss dose (10, 20, or 40 mg) was evaluated in 142 patients with congestivee heart failure (NYHA III and IV). 199 Conivaptan at 20 and 40 mg significantlyy reduced pulmonary capillary wedge pressure and right atrial pressure.. Furthermore, a dose-dependent increase in urine output was observed. .

Thee possibilities of chronic treatment with Vi-,V2-, or combined Vi/V2- antagonistss have been evaluated in animal models of congestive heart failure. 200-2033 chronic Vi-receptor blockade improved left ventricular function as well Introduction Introduction 31 1 ass neurohormonal profiles in rapid pacing-induced congestive heart failure in 20 pigs.. Chronic treatment with a V2-antagonist provoked a marked water 201 202 diuresiss in a rat model of coronary artery ligation. ; Dual Vi/V2-receptor blockadee (conivaptan) induced a decrease in urine osmolality and an increase inn urinary volume and plasma vasopressin levels. Furthermore, the right ventricularr mass appeared to be reduced. Treatment with the ACE inhibitor captoprill did not influence any renal parameter, but as expected it reduced left andd right ventricular mass. Combination treatment of both conivaptan and captoprill resulted, besides the above-mentioned effects, in a reduction of bloodd pressure, natriuretic peptide plasma levels, and pulmonary congestion. Therefore,, in the management of vasoconstriction and fluid retention in the syndromee of congestive heart failure, treatment with Vi and/or V2 antagonists inn addition to ACE-inhibitors could be favourable. 204 Treatment of chronic congestivee heart failure in pigs with a VVreceptor antagonism (SR-49059) or Angg II type 1 (ATJ-receptor antagonism (irbesartan), resulted in a reduction off left ventricular end diastolic dimensions, peak wall stress values and noradrenalinee levels. Combination treatment by VV and ATi-receptor blockade furthermoree resulted in improved left ventricular and myocyte shortening. 200 32 2 Introduction Introduction

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Aimm of the present investigation

Thee neurohormone vasopressin plays an important role in the maintenance of thee circulating volume and as a regulator of the vascular tone. The vasopressinn receptor subtypes and their regulating function are reasonably welll characterised. The availability of new non-peptidergic vasopressin- antagonistss enables us to perform a more detailed analysis of the various effectss of vasopressin. Accordingly, the major aim of the present study was to elucidatee possible interactions of vasopressin with three other neurotransmitterss and modulators associated with the cardiovascular system.

1)) The sympathetic nervous is one of the major control mechanisms of the cardiovascularr system. Circulatory impairment, in syndromes like congestivee heart failure or shock, results in a reflex activation of the sympatheticc nervous system. Vasopressin has been demonstrated to potentiatee the inhibitory action of the baroreceptor-reflex on the sympatheticc nervous system. In addition, several recent studies show thatt vasopressin may have direct potentiating effects on the perivascularr nerve fibres of the sympathetic nervous system. This peripherall facilitation of the sympathetic nervous system has been demonstratedd only in single vessel preparations, and it is possibly Vi- receptorr mediated. With respect to their pre- or post-synaptic site of actionn conflicting results have been presented. We have adressed these issuess by evaluating the facilitating effect of vasopressin on the sympatheticc system in three experimental models. Accordingly, we used thee single vessel preparation of the rat mesenteric artery for isometric tensionn recordings, the intact circulation of the pithed rat to study the effectss on the blood pressure, and the forearm-circulation of healthy humann volunteers for the local effects on blood flow, respectively. Using thee new, relatively selective, vasopressin-antagonists, the receptor characteristicss were determined. Furthermore we assessed the location off the vasopressin receptors with respect to the pre-, or postsynaptic sites. .

2)) It is well established that the endothelium plays a pivotal role in the regulationn of the vascular tone. In addition vasopressin interacts with Introduction Introduction 45 5

severall local endothelium-dependent factors. To clarify their relative contributionn we assessed the interaction of vasopressin with the NO-, thee cyclooxygenase-, the lipoxygenase-pathways, endothelium-derived hyperpolarizingg factor (EDHF) and the endothelin system, respectively. Inn these experiments we focussed on the role of these factors in the vasopressin-inducedd vasoconstriction using the isolated renal artery of thee rabbit for isometric tension recordings.

3)) In recent years, intensive research has been conducted to analyse the intracellularr regulatory pathways and mechanisms that are associated withh cardiovascular diseases. The MAPKerkl/2 pathway appears to be highlyy relevant, since it has been associated with the development of congestivee heart failure, cardiac hypertrophy and vasoconstriction. The establishedd role of vasopressin in the regulation of the MAPKerkl/2 pathwayy has so far only been investigated in cultured cells. A variety of otherr G-coupled receptors have demonstrated a MAPKerkl/2 pathway dependencee in the mediation of vasoconstriction in vascular tissue. Therefore,, we focussed on the relation between vasopressin, vasoconstriction,, and the MAPKerkl/2 pathway. For this purpose, we performedd experiments with isolated rat aortae in an organ bath set-up forr isometric tension recording in combination with Western blot analysis. . 466 Introduction