Arginine Vasopressin Antagonist Research Articles

Vasopressin interactions with oxytocin in the control of female sexual behavior

Previous studies have found that central administration of arginine vasopressin and arginine vasopressin receptor V1a antagonists respectively inhibited and stimulated receptivity but did not examine effects on other aspects of female sexual behavior. Central oxytocin facilitates both proceptive and receptive components of sexual behavior and diminishes male-directed agonistic behavior. The present study examined i.c.v.-administered arginine vasopressin and V1a antagonist effects on proceptive, receptive and agonistic behaviors, and interactions with oxytocin. In experiment 1, rats were primed s.c. with 2 μg estradiol benzoate ×2 days and with 500 μg of progesterone on day 3. Arginine vasopressin (0.2, 0.4 μg) or normal saline vehicle was administered 5 h after progesterone treatment and sexual and agonistic behavior measured 30, 60 and 90 min later. Compared with saline, both doses of arginine vasopressin significantly decreased lordosis responses to mounting and hop-dart proceptive behavior and trended toward significantly increasing agonistic behaviors. In experiment 2, oxytocin (2 μg) infusion just after arginine vasopressin (0.4 μg) significantly increased lordoses and decreased agonistic behaviors but did not affect hopping and darting. In experiment 3, conducted in ovariectomized rats primed with estradiol benzoate (1 μg/day s.c.×2 days), i.c.v. infusion of 0.5 and 1.0 μg of the selective V1a antagonist, d(CH 2) 5Tyr-(Me)arginine vasopressin on day 3 significantly increased lordoses and trended toward increasing hopping and darting 4 and 6 h after i.c.v. treatment. In experiment 4, 1 μg of the selective oxytocin antagonist, d(CH 2) 5[Tyr(Me) 2, Thr 4, Tyr-NH 2 9]OVT given 1 h before d(CH 2) 5Tyr-(Me)arginine vasopressin (1 μg) significantly decreased lordoses. Previous studies indicate that arginine vasopressin contributes to light phase inhibition of female sexual behavior. Our findings suggest that arginine vasopressin may exert this effect through interactions that decrease oxytocin stimulation of sexual behavior and raise the question whether sex steroid conditions that stimulate sexual behavior may suppress central arginine vasopressin and V1a receptor activity.

Analogues of oxytocin antagonists bearing a ureido group in the amino acid side chain at position 4 or 5

Substitution of the side chain carboxamido group at position 4 in the potent oxytocin antagonist (OTA) [ThiaPmp(1), D-Trp(2), Cys(6), Arg(8)]-OT, PA, in which ThiaPmp = beta,beta-(3-thiapentamethylene)-beta-mercaptopropionic acid, led to [Orn(Car)(4)]-PA, ([Cit(4)]-PA), which had uterotonic antagonistic activity equal to that of PA. The same modification at position 5, leading to [Cit(5)]-PA, resulted in antagonistic potency more than 10 times lower than that of PA. This paper also describes the same substitutions introduced in the highly potent OTA [Pen(6)]-PA (antioxytocic in vitro pA(2) = 8.72). Analogues of the general formula [U(4)-X(5)-Pen(6)]-PA, in which U = Lys, Orn, Dab, Dap or X = Orn, Dab or Dap, were synthesized by SPPS. Each of these analogues was carbamoylated by treatment with KCNO in DMF-H(2)O, yielding the corresponding U(Car)(4) or X(Car)(5) derivatives. In the uterotonic assay, the substitution with the ureido group at Gln(4) results in retention of high antagonistic potency, albeit somewhat lower than that of PA, e.g. [Orn(Car)(4), Pen(6)]-PA and [Dab(Car)(4), Pen(6)]-PA having pA(2) = 8.52 and pA(2) = 8.42 respectively. In the pressor assay, [Lys(Car)(4), Pen(6)]-PA and [Dab(Car)(4), Pen(6)]-PA were somewhat weaker antagonists of arginine vasopressin than [Pen(6)]-PA; [Dap(Car)(4), Pen(6)]-PA showed only a faint trace of pressor agonistic activity. The substitution with the ureido group at position 5 leads to a significant loss of OTA potency in the in vitro uterotonic assay. The [Orn(Car)(5), Pen(6)]-PA was the most potent of the series (pA(2) = 8.05). An interesting finding is that [Dap(Car)(5), Pen(6)]-PA is equipotent with its precursor [Dap(5), Pen(6)]-PA (potency in the uterotonic test in vitro, pA(2) = 7.71 and pA(2) = 7.68, respectively). Furthermore, neither [Dap(5), Pen(6)]-PA nor [Dap(5), Pen(6), Gly(9)]-PA exhibited activity in the antidiuretic or pressor assays. Although these last two analogues show some decrease in antioxytocin potency, they behave as pure oxytocin antagonists, which makes them attractive candidates for further studies on the development of potent and specific OTAs.

Overview of Vasopressin Receptor Antagonists in Heart Failure Resulting in Hospitalization

Patients with worsening heart failure (HF) requiring hospitalization commonly have a history of progressive fluid retention, decreased renal function, and hyponatremia. For these patients, diuretics have traditionally been the mainstay of treatment, but they are associated with electrolyte abnormalities and impaired renal function. Previous studies have shown that levels of the endogenous arginine vasopressin (AVP) hormone are elevated in patients with HF and may be the contributing factor to fluid retention and hyponatremia, and probably progression of HF. Vasopressin antagonists represent a unique class of therapeutic agents because of their potential role in both the short- and long-term treatment of patients hospitalized with worsening HF. As "aquaretics," AVP antagonists offer the possibility of added efficacy in relieving congestion and improving symptoms with minimal adverse effects in combination with standard medical therapy. Some AVP receptor antagonists have shown promising results in animal studies and small-scale clinical trials. The purpose of this review was to update the current status of studies with the available AVP antagonists.

Sustained aquaretic effect of the V2‐AVP receptor antagonist, RWJ‐351647, in cirrhotic rats with ascites and water retention

1 A disturbance in body water homeostasis is a common feature in advanced cirrhosis. This disturbance is always associated with the existence of ascites and is characterized by an inability to adjust the amount of water excreted in the urine to the amount of water ingested. Vasopressin (AVP) is of major importance in the pathogenesis of water retention and hyponatremia in cirrhosis. 2 The current study assessed the renal, hormonal and hemodynamic effects induced by 10-day chronic oral administration of RWJ-351647 (0.5 mg kg(-1) daily), a new nonpeptide V(2)-AVP antagonist, in rats with CCl(4)-induced cirrhosis, ascites and severe water retention. Urine volume (UV), urine osmolality and sodium and potassium excretion were measured daily. At the end of the study, systemic hemodynamic parameters were also assessed. 3 Long-term administration of RWJ-351647 has an aquaretic effect in rats with cirrhosis, ascites, water retention and hypo-osmolality. It increases UV (ANOVA: F=7.32, P<0.0001) and reduces urine osmolality (ANOVA: F=12.69, P<0.0001) throughout the entire period of treatment, thereby leading to a greater renal ability to excrete a water load at the end of the 10-day treatment period (the percentage of water load excreted improved from 30+/-8 to 92+/-21%, P<0.025). 4 The nonpeptide AVP V(2)-receptor antagonist RWJ-351647 also increased sodium excretion without affecting creatinine clearance and blood pressure. 5 These data suggest that RWJ-351647 could be therapeutically useful in the treatment of water retention in human cirrhosis.

A Scalable Process for the Synthesis of 2-Methyl-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepine Monohydrate and 4-[(Biphenyl-2-ylcarbonyl)amino]benzoic Acid: Two New Key Intermediates for the Synthesis of the AVP Antagonist Conivaptan Hydrochloride

A process for the multikilogram synthesis of the dual vasopressin-receptor antagonist, conivaptan hydrochloride, has been developed. This method relies on the introduction of operationally simple chemistry during the final stages of the process when two key intermediates, isolated by crystallization, are reacted to assemble the final molecule. A three-stage sequence has been developed for the synthesis of the first key amine hydrate intermediate, and modifications of the original process are described here. Major strategic improvements have been made in defining the final route to the “side chain” precursor molecule, which is the second key intermediate. These advances revolve around the acylation of an unprotected amino benzoic acid and subsequent high-yield telescoped processes for the synthesis of 4-[(biphenyl-2-ylcarbonyl)amino]benzoic acid. This novel method leads to a 4-fold increase in the overall yield of the target materials, circumvents the restricted synthetic intermediates, and constitutes a safe, reliable, adaptable, environmentally friendly, and cost-effective approach with improved manipulability.

Angiotensin II AT1 receptor antagonists inhibit the angiotensin‐CRF‐AVP axis and are potentially useful for the treatment of stress‐related and mood disorders

AbstractThe corticotropin‐releasing factor (CRF), arginine‐vasopressin (AVP), atrial natriuretic peptide (ANP), and Angiotensin II (Ang II) interact, regulating the central sympathetic system, the hypothalamic‐pituitary‐adrenal (HPA) axis, and the central behavioral mechanisms involved in the response to stress and the development of mood disorders. Non‐peptidic, orally active AVP V1, V3, or CRF1 receptor antagonists reduce anxiety in animals. ANP is anxiolytic when administered to rodents and humans with anxiety disorders. These compounds are being developed for the therapy of anxiety and depression, but their clinical efficacy has not yet been established.Brain Ang II, a physiological ANP antagonist, promotes CRF and AVP release and stimulates the peripheral and central sympathetic systems. The degree of Ang II AT1 receptor stimulation determines the response to stress. An orally active, non‐peptidic Ang II AT1 receptor antagonist blocks CRF and AVP release during stress, prevents the sympathoadrenal and hormonal stress reaction, the cortical CRF1 and benzodiazepine receptor alterations, facilitates the effects of ANP, prevents stress‐induced gastric ulcerations, and is anxiolytic in rodents. CRF, AVP, ANP, and the sympathetic system are intimately linked parts of a fundamental regulatory mechanism controlled by the brain Ang II system through AT1 receptor stimulation, and should be studied together. Selective, safe antagonists of Ang II AT1 receptors, with central effects after oral administration, have been actively used for the treatment of hypertension and should be considered also as potential anti‐stress, anti‐anxiety, and antidepressant compounds with properties similar or superior to the CRF and AVP antagonists or the ANP agonists under development. Drug Dev. Res. 65:237–269, 2005. © Published 2005 Wiley‐Liss, Inc.

ACTH releasing activity of KP-102 (GHRP-2) in rats is mediated mainly by release of CRF

KP-102 (GHRP-2: pralmorelin) is a synthetic growth hormone releasing peptide (GHRP) that powerfully stimulates the release of GH by acting (i.v.) at both hypothalamic and pituitary sites. Intravenous (i.v.) administration of KP-102 also elicits slight but significant release of adrenocorticotropic hormone (ACTH) in both animals and humans, as is seen with other GHRPs. GHRPs are thought to stimulate the hypothalamic-pituitary-adrenal axis by releasing endogenous ACTH secretagogues such as arginine vasopressin (AVP) and/or corticotropin releasing factor (CRF), though neither AVP nor CRF has been shown clearly to be involved significantly in GHRP-evoked ACTH release. In the present study, we investigated the effects of KP-102 on ACTH release in conscious rats under improved experimental conditions that minimized the influence of stress. Administration of KP-102 i.v. increased plasma ACTH significantly, but did not stimulate ACTH release from rat primary pituitary cells. Administration of KP-102 together with either AVP or CRF elicited significantly greater increases in plasma ACTH levels than any of the agonists alone. Notably, the combination of KP-102 and AVP produced a much greater increase in ACTH than KP-102 plus CRF, indicating that KP-102 augments the effect of exogenous CRF only weakly. Conversely, a CRF antagonist markedly inhibited KP-102-induced ACTH release in conscious rats, whereas an AVP antagonist or anti-AVP antiserum did not. Taken together, these findings suggest that KP-102 acts via the hypothalamus to stimulate ACTH release in rats, and that these effects are mediated mainly by the release of CRF.

AVP V 1b selective antagonist SSR149415 blocks aggressive behaviors in hamsters

Arginine vasopressin (AVP) has been implicated in a variety of physiological and behavioral responses to stress. Synthesis of receptor-selective AVP agonist and antagonist compounds allows differential analysis of the specific roles of particular receptor subtypes with respect to these responses. Here, effects of the recently synthesized AVP V 1b selective antagonist, SSR149415, were examined for offensive aggression in male Syrian hamsters, using a resident-intruder paradigm. Oral administration of vehicle or 1, 10, or 30 mg/kg of SSR149415 to resident hamsters was followed by evaluation of a range of aggression-related measures of residents confronted by intruders. The 10 and 30 mg/kg doses significantly reduced the duration of offensive sideways and chase behaviors, and the 30 mg/kg dose also reduced chase frequency. The 10 and 30 mg/kg dose also significantly reduced frequency and duration of olfactory investigation and duration of flank marking. These findings suggest a link between activity of the V 1b receptor and the modulation of offensive aggression. These findings agree with previous research on V 1b receptor effects in suggesting that antagonism of this receptor may be useful in modulating a range of emotional responses to highly stressful or threatening conditions.

A New Synthetic Route to YM087, an Arginine Vasopressin Antagonist.

ChemInformVolume 35, Issue 36 Heterocyclic Compounds A New Synthetic Route to YM087, an Arginine Vasopressin Antagonist. Takashi Tsunoda, Takashi Tsunoda Chem. Technol. Lab., Bulk Manuf. Technol. Div., Yamanouchi Pharm. Co., Ltd., Ibaraki 318, JapanSearch for more papers by this authorAkihiro Tanaka, Akihiro Tanaka Chem. Technol. Lab., Bulk Manuf. Technol. Div., Yamanouchi Pharm. Co., Ltd., Ibaraki 318, JapanSearch for more papers by this authorToshiyasu Mase, Toshiyasu Mase Chem. Technol. Lab., Bulk Manuf. Technol. Div., Yamanouchi Pharm. Co., Ltd., Ibaraki 318, JapanSearch for more papers by this authorShuichi Sakamoto, Shuichi Sakamoto Chem. Technol. Lab., Bulk Manuf. Technol. Div., Yamanouchi Pharm. Co., Ltd., Ibaraki 318, JapanSearch for more papers by this author Takashi Tsunoda, Takashi Tsunoda Chem. Technol. Lab., Bulk Manuf. Technol. Div., Yamanouchi Pharm. Co., Ltd., Ibaraki 318, JapanSearch for more papers by this authorAkihiro Tanaka, Akihiro Tanaka Chem. Technol. Lab., Bulk Manuf. Technol. Div., Yamanouchi Pharm. Co., Ltd., Ibaraki 318, JapanSearch for more papers by this authorToshiyasu Mase, Toshiyasu Mase Chem. Technol. Lab., Bulk Manuf. Technol. Div., Yamanouchi Pharm. Co., Ltd., Ibaraki 318, JapanSearch for more papers by this authorShuichi Sakamoto, Shuichi Sakamoto Chem. Technol. Lab., Bulk Manuf. Technol. Div., Yamanouchi Pharm. Co., Ltd., Ibaraki 318, JapanSearch for more papers by this author First published: 11 August 2004 https://doi.org/10.1002/chin.200436161Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume35, Issue36September 7, 2004 RelatedInformation

Effect of GABA(A) receptor antagonist bicuculline methiodide on hypotension in endotoxin-intoxicated rats.

Gamma-aminobutyric acid (GABA) receptor plays an important regulatory role in human and animal blood pressure; however, whether a GABAergic mechanism is involved in endotoxin intoxication-associated hypotension has never been reported. In vivo effect of the GABA(A) receptor antagonist bicuculline methiodide (BMI) on mean arterial pressure (MAP), heart rate (HR), and serum nitrite levels were investigated in endotoxin (lipopolysaccharide; LPS)-treated rats. BMI increased MAP and decreased HR in LPS-stimulated rats. DOAV ([deamino-Pen, O-Me-Tyr, Arg3]-vasopressin), an arginine vasopressin (AVP) antagonist, reversed the hemodynamic improvement resulted from BMI in LPS-intoxicated rats. Based on a two-factor (BMI treatment by LPS dose) factorial design, BMI reduced the serum nitrite production induced by LPS. DOAV plus BMI, however, did not affect the serum nitrite level in LPS-intoxicated rats. Thus, GABA receptor antagonist BMI might attenuate hypotension in endotoxin intoxication in rats.

Effect of GABAA receptor antagonist bicuculline methiodide on hypotension in endotoxin-intoxicated rats

γ-Aminobutyric acid (GABA) receptor plays an important regulatory role in human and animal blood pressure; however, whether a GABAergic mechanism is involved in endotoxin intoxication-associated hypotension has never been reported. In vivo effect of the GABA A receptor antagonist bicuculline methiodide (BMI) on mean arterial pressure (MAP), heart rate (HR), and serum nitrite levels were investigated in endotoxin (lipopolysaccharide; LPS)-treated rats. BMI increased MAP and decreased HR in LPS-stimulated rats. DOAV ([deamino-Pen, O-Me-Tyr, Arg 3 ]-vasopressin), an arginine vasopressin (AVP) antagonist, reversed the hemodynamic improvement resulted from BMI in LPS-intoxicated rats. Based on a two-factor (BMI treatment by LPS dose) factorial design, BMI reduced the serum nitrite production induced by LPS. DOAV plus BMI, however, did not affect the serum nitrite level in LPS-intoxicated rats. Thus, GABA receptor antagonist BMI might attenuate hypotension in endotoxin intoxication in rats.

Preparation of Non‐Peptide, Highly Potent and Selective Antagonists of Arginine Vasopressin V1A Receptor by Introduction of Alkoxy Groups.

AbstractFor Abstract see ChemInform Abstract in Full Text.

A New Synthetic Route to YM087, an Arginine Vasopressin Antagonist

A new synthesis of N-{4-[(2-methyl-4,5-dihydroimidazo[4,5-d][1]benzazepin-6(1H)-yl)carbonyl]phenyl}biphenyl-2-carboxamide monohydrochloride (1, YM087) via new imidazobenzazepine intermediates is described. This method remarkably improves the overall yield of 1 compared to the original synthesis providing a more safe, reliable and cost-efficient approach to 1.

Clinical trials update from the American Heart Association meeting: Omega-3 fatty acids and arrhythmia risk in patients with an implantable defibrillator, ACTIV in CHF, VALIANT, the Hanover autologous bone marrow transplantation study, SPORTIF V, ORBIT and PAD and DEFINITE.

The American Heart Association meeting reported the results of several clinical trials of particular interest to those who care for patients with heart failure. Omega-3 fatty acids were associated with a trend to increased recurrence of ventricular arrhythmias but not mortality in patients with an implantable debrillator. The ACTIV in CHF study provides more evidence of a therapeutic role for arginine vasopressin antagonists in the treatment of heart failure. The VALIANT study provides further evidence to suggest that a combination of angiotensin receptor antagonist and ACE inhibitor does not reduce mortality but may reduce morbidity in post-MI patients with heart failure or major LV systolic dysfunction. A study of autologous bone marrow cell transplantation into myocardial scar give gave encouraging results. SPORTIF V showed ximelagation to be as effective as warfarin but with improved safety. ORBIT and PAD showed public access defibrillators saved lives but questioned their cost effectiveness. DEFINITE supported a role for ICDs in patients with non-ischemic cardiomyopathy, although cost-effectiveness remains in doubt.

Blood pressure effects of intravenous apomorphine in conscious deoxycorticosterone-acetate salt-hypertensive rats.

The present study reports the effects of apomorphine (APO) on blood pressure and the principal site of action of this agonist in 4-week deoxycorticosterone-acetate (DOCA)-hypertensive conscious rats. In these preprations, intravenous (i.v.) administration of APO (0.50-1 mg/kg) induced short-lasting and dose-dependent decreases in mean arterial pressure. The hypotensive response to APO (0.3 mg/kg) was reversed into a significant pressor effect by i.v. hexamethonium (30 mg/kg), whereas it was enhanced by i.v. pretreatment with the vasopressor antagonist of arginine vasopressin (AVP) d(CH2)5Tyr(Me)AVP (10 microg/kg) and/or prazosin (1 mg/kg). This depressor effect was suppressed by the central and peripheral dopamine D2 receptor antagonist metoclopramide (5 mg/kg i.v.), unaffected by the selective dopamine D1 receptor antagonist SCH 23390 (0.2 mg/kg i.v.), partly reduced by intrathecal domperidone (40 microg per rat at T9-T10 level), a dopamine D2 receptor antagonist which does not cross the blood-brain barrier, and reversed into a significant pressor effect by i.v. domperidone (0.5 mg/kg). The latter pressor effect was fully abolished by combined i.v. pretreatment with the vasopressor antagonist of AVP and prazosin. These results show that, in conscious DOCA salt-hypertensive rats, APO induced a brief, initial depressor effect, which is opposed to a central pressor component. The depressor component is related to an inhibition of norepinephrine transmission through activation of dopamine D2 receptors, some of which are located in the spinal cord and some of which are located in the peripheral circulation. The central pressor component, which became manifest after peripheral dopamine D2 receptor blockade, appears to be related to an increase in vasopressin release and sympathetic tone through activation of brain dopamine D2 receptors.

Synthesis and structure-activity relationships of 5,6,7,8-tetrahydro-4H-thieno[3,2-b]azepine derivatives: novel arginine vasopressin antagonists.

A variety of novel heterocyclic compounds having thienoazepine, pyrroloazepine, furoazepine, and thienodiazepine skeletons were synthesized, most of which exhibited potent antagonism of [(3)H]-AVP specific binding in assays using rat liver (V1), rat kidney (V2), human platelet plasma membranes, and recombinant human CHO cells (V2), as well as antagonizing AVP-induced hypertension in rats (V1, intravenous) and showing a diuretic effect in rats (V2, oral). By detailed studies of the structure-activity relationships of these compounds, the thienoazepine derivative 1 was found to be a very potent combined V1 and V2 antagonist. After further pharmacological and toxicological evaluation as well as physical properties, the hydrochloride 2 (JTV-605) of compound 1 was selected for clinical studies as a potent AVP antagonist with a long duration of action.

Subchronic phencyclidine administration alters central vasopressin receptor binding and social interaction in the rat

Arginine vasopressin (AVP) is a peptide involved in social behaviors in rodents. To investigate the mechanism underlying the deficits in social behavior induced by blockade of N-methyl- d-aspartate (NMDA) receptors, this study examined the effect of noncompetitive NMDA antagonists on AVP receptor binding and social interaction in the rat. Subchronic phencyclidine (PCP) administration (2 mg/kg/day, 14 days, i.p.) significantly reduced the density of V1a receptor binding sites, labeled by an [ 125I]-Linear AVP antagonist, in several brain regions. Subchronic treatment with PCP or MK-801 (0.13 mg/kg/day, 14 days, i.p.) impaired social interactions in rats, as has been previously reported. These results suggest that NMDA antagonists have modulatory effects on the central vasopressinergic system and social interaction.

Structure-activity study of novel tricyclic benzazepine arginine vasopressin antagonists.

Novel tricyclic benzazepine derivatives were synthesized as arginine vasopressin (AVP) antagonists. Several tricyclic compounds showed potent antagonistic activity in rat AVP receptors V(1a) and V(2). Derivatives containing pyrrolo-tricyclic amines, 13i-k, 30, and 31 also showed selectivity for the V(2) receptor.

Neuropeptide specificity of prostaglandin E 2-induced activation of splenic and renal sympathetic nerves in the rat

Sympathetic activation occurs rapidly following intracerebroventricular (icv) injection of prostaglandin E 2 ( PGE 2) . This study examined whether neuropeptides mediate PGE 2-induced sympathetic nerve activation in urethane/chloralose-anesthetized Sprague–Dawley rats. Animals were pretreated (20.0 μg, icv) with the following receptor antagonists; CRF ([ d-Phe 12,Nle 21,38,C α-MeLeu 37]CRF 12–41), AVP-V 1 (Des-Gly-[Phaa 1, d-Tyr(Et) 2,Lys 6,Arg 8]-vasopressin), or OT (OT+V 1, [ d( CH 2) 5, Tyr( Me) 2, Orn 8 ]-vasotocin) followed 20 min later by PGE 2 (2.0 μg, icv). Pretreatment with the CRF antagonist attenuated the increase in renal nerve activity induced by PGE 2 when measured 10 and 30 min post-injection. PGE 2-induced renal nerve activity was also inhibited at both time points by the AVP antagonist and, to a similar extent, the OT antagonist. The AVP antagonist did not effect splenic nerve responses to PGE 2 whereas the CRF antagonist produced an incomplete and transient reduction in PGE 2-induced activation of the splenic nerve. However, the OT antagonist completely blocked the activation of the splenic nerve after central injection of PGE 2. ICV injections of AVP and OT produced immediate changes in splenic and renal nerve activity whereas CRF failed to alter the activity of either nerve in anesthetized or conscious animals. Thus, PGE 2 acts through neuropeptide-specific pathways to initiate sympathetic outflow and OT is a specific component of the sympathetic pathway innervating the spleen.

Congestive heart failure: potential role of arginine vasopressin antagonists in the therapy of heart failure.

Neurohormonal imbalances clearly contribute to the pathophysiology of chronic congestive heart failure. Agents that interfere with the generation or effects of angiotensin II and aldosterone, or which block the effects of excess sympathetic drive, all favorably affect mortality. Arginine vasopressin, through its V(1A) and V(2) receptor-mediated effects, could theoretically also contribute to progression of left ventricular dysfunction and heart failure by aggravating systolic and diastolic wall stress, and by directly stimulating myocardial hypertrophy. Arginine vasopressin levels are increased in congestive heart failure patients; acutely, both V(1A) and V(2) antagonists produce beneficial hemodynamic responses in both clinical and experimental congestive heart failure. Experimental studies also indicate beneficial effects of V(1A) and V(2) antagonists (alone or in combination) on hemodynamics and possibly ventricular remodeling after myocardial injury. Currently, there are no long-term studies of any type of arginine vasopressin antagonist in human heart failure, but both the theoretical rationale and preclinical data would appear to justify such efforts.