piperidines and mozavaptan

Topics: Animals; Antidiuretic Hormone Receptor Antagonists; Aquaporin 2; Arginine Vasopressin; Benzazepines; Diabetes Insipidus; Diabetes Insipidus, Nephrogenic; Drug Design; Humans; Hyponatremia; Inappropriate ADH Syndrome; Mutation; Piperidines; Quinolones; Receptors, Vasopressin

Vasopressin, or antidiuretic hormone, is a peptide hormone that is released from the posterior pituitary gland in response to changes in blood pressure and plasma osmolality. The main pathophysiological states associated with high plasma vasopressin concentrations are cirrhosis, cardiac failure and syndrome of inappropriate antidiuretic hormone (SIADH) secretion. Pharmacological treatments for disorders of excess vasopressin secretion have been limited. However, oral bio-available selective and non-selective V(1) and V(2) receptor antagonists have recently become available for clinical use. Water retention in cirrhosis is a common problem, leading to ascites, peripheral oedema and hyponatraemia. Raised plasma vasopressin concentrations and decreased delivery of glomerular filtrate are believed to be the most important factors in the development of water retention. V(2) receptor antagonists are aquaretic agents that promote water excretion and improve hyponatraemia. Their potential role in cirrhosis has been examined in a number of recent studies that have shown increased free water clearance and serum sodium concentrations with few adverse effects. V(2) receptor antagonists represent a novel and promising new class of agent that may have major clinical utility in the treatment of patients with liver cirrhosis.

Topics: Animals; Antidiuretic Hormone Receptor Antagonists; Azepines; Benzamides; Benzazepines; Controlled Clinical Trials as Topic; Diuretics; Heart Failure; Homeostasis; Humans; Inappropriate ADH Syndrome; Liver Cirrhosis; Models, Animal; Morpholines; Piperidines; Pyrroles; Quinolones; Rats; Spiro Compounds; Vasopressins

This review summarizes our recent findings in the syntheses of drug metabolites. The metabolites of Grepafloxacin (1) and OPC-14117 (10) were prepared from the common intermediates (5) and (21), respectively. Moreover, treatment of 10 with a model P450 system led to a benzyl alcohol derivative (11) in one step. OPC-31260 (22) was efficiently N-dealkylated using several metalloporphyrins with oxidants to afford three metabolites (23-25). In addition, I succeeded in obtaining the metabolite (23) in high yield from N-oxide (26) not only as an oxygen donor but also as a substrate, there after, in the model P450 system. Optically active metabolites of OPC-29030 (27) were prepared by enzyme-catalyzed enantioselective transesterification of racemic sulfinyl metabolites. On the other hand, a chiral 1,1'-bi-2-naphthol derivative (38a) was found to be an efficient asymmetric acylating agent for a secondary alcohol (36) which is a valuable intermediate for preparing optically active metabolites of 22. Furthermore, metabolites (45) and (47) of OPC-21268 (44) were prepared using SmI2-induced cyclization and oxidative decarboxylation with Pb(OAc)4 as key steps, respectively.

Topics: Animals; Anti-Infective Agents; Benzazepines; Chemistry, Organic; Cytochrome P-450 Enzyme System; Fluoroquinolones; Imidazoles; Indans; Lipase; Organic Chemistry Phenomena; Piperazines; Piperidines; Platelet Aggregation Inhibitors; Quinolones; Stereoisomerism; Sulfur Compounds

Amphibian skin has osmoregulatory functions, with Na(+) crossing from outside to inside. Na(+) transport can be measured as the short-circuit current (SCC). We investigated the short-term and long-term effects of arginine vasotocin (AVT) and mesotocin (MT) (which modulate Na(+) transport) on the activation and development of an amiloride-blockable SCC (adult-type feature) in larval, adult, and corticoid-cultured larval bullfrog skins. We found: (1) AVT-receptor (AVT-R) and MT-receptor (MT-R) mRNAs could be detected in both larval and adult skins, (2) in the short term (within 60 min), the larval SCC (amiloride-stimulated SCC) was increased by AVT, forskolin, and MT, suggesting that AVT and MT did not activate the inactive ENaC (epithelial sodium channel) protein thought to be expressed in larval skin, (3) in the short term (within 90 min), AVT, forskolin, and MT stimulated the adult SCC (amiloride-blockable SCC), (4) AVT and MT increased both the larval and adult SCC via receptors insensitive to OPC-21268 (an antagonist of the V(1)-type receptor), OPC-31260 (an antagonist of the V(2)-type receptor), and ([d(CH(2))(5),Tyr(Me)(2),Thr(4),Orn(8),des-Gly-NH (2) (9) ]VT) (an antagonist of the oxytocin receptor), (5) culturing EDTA-treated larval skin with corticoids supplemented with AVT (1 microM) or MT (1 microM) for 2 weeks (long-term effects of AVT and MT) did not alter the corticoid-induced development of an amiloride-blockable SCC (adult-type feature). AVT and MT thus have the potential to stimulate SCC though channels that are already expressed, but they may not influence the development of the amiloride-blockable SCC (an adult-type feature) in larval skin.

Topics: Adrenal Cortex Hormones; Amiloride; Animals; Antidiuretic Hormone Receptor Antagonists; Benzazepines; Colforsin; Electrophysiological Phenomena; Epithelial Sodium Channel Blockers; Epithelial Sodium Channels; Epithelium; Gene Expression; Larva; Oxytocin; Piperidines; Quinolones; Rana catesbeiana; Receptors, Oxytocin; Receptors, Pituitary Hormone; Receptors, Vasopressin; Skin; Vasotocin

Anuran amphibians do not drink orally but absorb water osmotically through the highly permeable ventral skin. In this cutaneous water absorption, roles of the putative cerebral osmoreceptors and functions of arginine vasotocin (AVT) were examined in the central nervous system of the Japanese treefrog, Hyla japonica. Intracerebroventricular (ICV) or intralymphatic sac (ILS) administration of various hypertonic solutions (NaCl, mannitol and urea) significantly extended the residence time in water in a dose-dependent manner, suggesting facilitation of water absorption in frogs. ICV injection of AVT also increased significantly the residence time in a dose-dependent manner. The water absorption effect of AVT was significantly inhibited by pretreatment of ICV OPC-21268, a vasopressin V(1) receptor antagonist. But pre-ICV injection of OPC-31260, a vasopressin V(2) receptor antagonist, did not block the water absorption effect of AVT. Extension of the residence time induced by hyperosmotic NaCl (1000 mOsm) ICV injection was significantly inhibited by pretreatment of ICV OPC-21268. The present results showed that increases of osmotic pressure in plasma and/or cerebrospinal fluid stimulate water absorption response, suggesting that osmoreceptors are certainly present in the central nervous system and AVT may directly stimulate water absorption in the treefrog. It is also suggested that AVT activates cellular mechanisms via V(1)-like but not V(2)-like receptors in the central nervous system and facilitates water absorption response in the treefrog.

Topics: Animals; Antidiuretic Hormone Receptor Antagonists; Benzazepines; Biological Transport; Central Nervous System; Dose-Response Relationship, Drug; Glucose Solution, Hypertonic; Hypertonic Solutions; Osmotic Pressure; Piperidines; Quinolones; Ranidae; Receptors, Vasopressin; Saline Solution, Hypertonic; Vasotocin; Water; Water-Electrolyte Balance

Physiological function of arginine vasotocin (AVT) and effect of receptor antagonists of vasopressin were electrophysiologically investigated on transepithelial transport of ions in the abdominal skin of Hyla japonica and Rana nigromaculata by means of the Ussing chamber system. Administrations of AVT and forskolin (adenylate cyclase activator) in the serosal side of normal Ringer's solution significantly increased transepithelial potential difference (PD) and short-circuit current (Isc) accounting for Na(+) influx, mucosal to serosal direction, across the skin of H. japonica. In contrast, AVT administrations significantly decreased PD but not Isc on the skin of R. nigromaculata in a concentration-dependent manner ranging from 10(-11) to 10(-8)M. Administration of 10(-5)M forskolin also significantly decreased PD in normal and low Na(+) Ringer's solution and in the presence of amiloride (Na(+) channel blocker) on the mucosal side of normal Ringer's solution. On the other hand, forskolin significantly increased PD and Isc in the Cl(-) free Ringer's solution. These results suggested that AVT and forskolin stimulated mainly Cl(-) influx across the skin of R. nigromaculata. In two frog species, the AVT actions on ion transports were inhibited by pretreatment of OPC-31260 (a vasopressin V(2) receptor antagonist) but not OPC-21268 (a vasopressin V(1) receptor antagonist). These results suggested that AVT activates adenylate cyclase via V(2)-like receptor and stimulates actively net Na(+) and net Cl(-) transports in the abdominal skin of H. japonica and R. nigromaculata, respectively.

Topics: Animals; Antidiuretic Hormone Receptor Antagonists; Anura; Benzazepines; Biological Transport; Chlorides; Colforsin; Dose-Response Relationship, Drug; Electrophysiology; Female; In Vitro Techniques; Male; Piperidines; Quinolones; Receptors, Vasopressin; Skin; Sodium; Species Specificity; Time Factors; Vasotocin

We previously reported that arginine vasopressin (AVP) stimulates the production of nitric oxide (NO) in inner medullary collecting duct (IMCD) via activation of V2 receptors (V2R) and the mobilization of intracellular Ca(2+). The aim of this study was to determine the pathway(s) through which this response is mediated. IMCDs were dissected from male Sprague-Dawley rats and intracellular Ca(2+) concentration ([Ca(2+)](i)) and NO production were measured using a fluorescence imaging system. AVP (100 nmol/l) produced a rapid increase [Ca(2+)](i) of 381 +/- 78 nmol/l that was followed by a significant increase of NO production (166 +/- 61%). The specific nonpeptide V2R antagonist OPC31260 (1 microM), but not the V1R antagonist OPC21268 (1 microM), inhibited the increase in [Ca(2+)](i) (up to 91 +/- 5%) and abolished the NO response to AVP. Both the phospholipase C inhibitor U73112 (3 microM) and the inositol (1,4,5) tri-phosphate 3 receptor blocker 2-APB (75 microM) reduced the peak [Ca(2+)](i) response to AVP (by 65 +/- 9 and 59 +/- 15%, respectively) and abolished the NO response. Although forskolin (100 microM; an activator of adenylyl cyclase) elicited a moderate increase in [Ca(2+)](i), neither preincubation with the adenylyl cyclase inhibitor 2'-5'-dideoxyadenosine (50 microM) nor the protein kinase A (PKA) inhibitor PKA(14-22) (100 microM) significantly inhibited peak [Ca(2+)](i) in response to AVP. IMCD [Ca(2+)](i) responses to AVP were reduced by 72 +/- 8% when incubated in Ca(2+)-free media and could be completely abolished by preincubation with the Ca(2+)-ATPase inhibitor thapsigargin. We conclude that AVP-induced NO production in IMCD is dependent on V2R activation of the phosphoinositide pathway and the mobilization of Ca(2+) from both intracellular and extracellular pools.

Topics: Animals; Antidiuretic Hormone Receptor Antagonists; Arginine Vasopressin; Benzazepines; Calcium; Calcium-Transporting ATPases; Cyclic AMP-Dependent Protein Kinases; Kidney Medulla; Kidney Tubules, Collecting; Male; Nitric Oxide; Phosphatidylinositols; Piperidines; Quinolones; Rats; Rats, Sprague-Dawley; Receptors, Vasopressin; Signal Transduction; Spectrometry, Fluorescence; Type C Phospholipases; Vasopressins

Effects of V(1) (OPC-21268) and V(2) (OPC-31260) vasopressin antagonists on blood pressure (BP) short-term variability were investigated in adult spontaneously hypertensive rats (SHR) under basal conditions and after the stimulation of vasopressin release by hemorrhage. BP was recorded intra-arterially and sampled at 20 Hz to be analyzed on a personal computer. BP time spectra were calculated on 30 stationary overlapping 2048 point-time series. Spectral power was estimated in total (0.00976 - 3 Hz), very low frequency (VLF: 0.00976 - 0.195 Hz), low frequency (LF: 0.195 - 0.605 Hz), and high frequency (HF: 0.8 - 3 Hz) regions. Under basal conditions a V(1) antagonist (5 mg/kg, i.v.) decreased BP without affecting BP variability, while combined (V(1) + V(2)) blockade or V(2) blockade (1 mg/kg, i.v.) alone did not affect cardiovascular parameters. Mild hemorrhage (5 ml/kg per min) increased HF-BP variability, while moderate (10 ml/kg per min) and massive (15 ml/kg per min) hemorrhage did not affect it. In V(1), but not V(2), antagonist pre-treated SHR HF-BP increased significantly after moderate and massive hemorrhage. V(1) or V(2) antagonist pre-treatment also enhanced VLF-BP variability during massive hemorrhage. Moreover V(1) blockade prevented hemorrhage-induced bradycardia, while V(2) blockade potentiated it. It follows that in adult SHR, vasopressin buffers BP oscillations in HF and VLF frequency domains only in hypovolaemic conditions and that the modulation of the autonomic adjustment of the HR to hemorrhage by vasopressin is preserved.

Topics: Animals; Antidiuretic Hormone Receptor Antagonists; Benzazepines; Blood Pressure; Hypertension; Male; Piperidines; Quinolones; Rats; Rats, Inbred SHR; Rats, Wistar; Receptors, Vasopressin

This paper describes the effects of vasopressin nonpeptide selective V1a (OPC-21268) and V2 (OPC-31260) antagonists on fast blood pressure (BP) oscillations in conscious non-haemorrhaged and haemorrhaged rats. Equidistant sampling at 20 Hz allowed direct spectral analysis of BP on 30 overlapping 2048 point-time series. In non-haemorrhaged rats, V1a antagonist (5 mg/kg; i.v) reduced BP and low-frequency (LF-BP) component while subsequent administration of V2 antagonist (1 mg/kg; i.v) reversed these changes and enhanced the very low-frequency (VLF-BP) component. In haemorrhaged rats (5-15 ml/kg/min) V2 antagonist pre-treatment enhanced the VLF-BP component during normotensive bleeding, while the V1a antagonist pre-treatment modified BP variability after hypotensive haemorrhage by enhancing the HF-SBP component. The results suggest that under normotensive conditions vasopressin by the stimulation of both V1a and V2 receptors buffers BP variability in the VLF-BP frequency domain. In addition, under hypotensive conditions vasopressin, by the stimulation of V1a receptors buffers the respiration-induced HF-BP oscillation.

Topics: Analysis of Variance; Animals; Antidiuretic Hormone Receptor Antagonists; Benzazepines; Blood Pressure; Heart Rate; Hemorrhage; Hypovolemia; Male; Piperidines; Quinolones; Rats; Receptors, Vasopressin

Primary cultures of neonatal cardiac myocytes were used to determine both the identity of second messengers that are involved in vasopressin receptor-mediated effects on cardiac hypertrophy and the type of vasopressin receptor that is involved in vasopressin-induced cell growth. Neonatal rat myocytes were plated at a density of 1x10(6) cells per 60 mm dish and were incubated with serum-free medium for 7 days. Treatment of myocytes with vasopressin significantly increased the RNA-to-DNA ratio, by 18-25%, at culture days 4-6 and the protein-to-DNA ratio by 18-20% at culture days 5-7. Rates of protein synthesis were determined to assess their contribution to protein contents during myocyte growth. Vasopressin significantly accelerated rates of protein synthesis by 25% at culture day 6. Intracellular free Ca(2+) ([Ca(2+)](i)) was transiently increased after vasopressin exposure. After the peak increase in [Ca(2+)](i) at less than 30 s, there was a sustained increase for at least 5 min. The specific activity of protein kinase C in the particulate fraction was increased rapidly after exposure to vasopressin, and its activity remained higher for 30 min, returning to its control level within 60 min. The activity of protein kinase C in the cytosol was significantly decreased at all times after exposure to vasopressin. After vasopressin treatment, the content of c-fos mRNA was increased. The stimulatory effects of vasopressin on these parameters were significantly inhibited by vasopressin V(1A) receptor antagonist, OPC-21268, but not by vasopressin V(2) receptor antagonist, OPC-31260. These results suggest that vasopressin directly induces myocyte hypertrophic growth via the V(1A) receptor in neonatal rat heart cells.

Topics: Animals; Animals, Newborn; Antidiuretic Hormone Receptor Antagonists; Benzazepines; Blotting, Northern; Calcium; Cardiomegaly; Cells, Cultured; Culture Media; DNA; Kinetics; Myocardium; Piperidines; Protein Biosynthesis; Protein Kinase C; Proteins; Proto-Oncogene Proteins c-fos; Quinolones; Rats; Rats, Sprague-Dawley; Receptors, Vasopressin; RNA, Messenger; Second Messenger Systems; Vasopressins

We studied the effects of a selective vasopressin V(1A) receptor antagonist [1-(1-(4-(3-acetylaminopropoxy)benzoyl)-4-piperidyl)-3, 4-dihydro-2(1H)-quinolinone (OPC-21268)] and a selective vasopressin V(2) receptor antagonist [5-dimethylamino-1(4-(2-methylbenzoylamino)benzoyl)-2,3,4, 5-tetrahydro-1H-benzazepine (OPC-31260)] on vasopressin-induced contraction of mesenteric and cremasteric arterioles in urethane-anaesthetized rats. Vasopressin was infused intravenously for 60 min or applied topically to arterioles directly. Vasopressin infusion (50, 100 or 500 ng/kg/min) decreased the diameter of both mesenteric and cremasteric arterioles. Vasopressin (500 ng/kg/min)-induced vasoconstriction was antagonized by OPC-21268 (0. 2, 1.0 and 5.0 mg/kg, i.v.), dose-dependently, but not by OPC-31260. Topically applied vasopressin (4.6x10(-10)-4.6x10(-8) M) dose-dependently constricted both microvessels. Pre-administration of OPC-21268 (5.0 mg/kg, i.v.) completely inhibited topically applied vasopressin-induced vasoconstriction in both microvessels, and OPC-31260 partially inhibited it in cremasteric arterioles. These results suggest that vasopressin induces vasoconstriction in rat mesenteric and cremasteric arterioles mainly by stimulating vasopressin V(1A) receptors, while vasoconstriction in cremasteric arterioles is partly associated with stimulation of vasopressin V(2) receptors.

Topics: Animals; Arginine Vasopressin; Arterioles; Benzazepines; Male; Mesenteric Arteries; Muscle, Skeletal; Piperidines; Quinolones; Rats; Rats, Wistar; Receptors, Vasopressin; Vasoconstriction

The aim of the present study was to determine the receptor subtype involved in arginine vasopressin (AVP)-induced modulation of baroreflex function in spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats using novel nonpeptide AVP V1- and V2-receptor antagonists. Baroreceptor heart rate (HR) reflex was investigated in both SHR and WKY rats which were intravenously administered the selective V1- and V2-receptor antagonists OPC-21268 and OPC-31260, respectively. Baroreflex function was assessed by obtaining alternate pressor and depressor responses to phenylephrine and sodium nitroprusside, respectively, to construct baroreflex curves. In both SHR and WKY rats baroreflex activity was tested before and after intravenous administration of vehicle (20% DMSO), OPC-21268 (10 mg/kg), and OPC-31260 (1 and 10 mg/kg). Vehicle did not significantly alter basal mean arterial pressure (MAP) and HR values or baroreflex function in SHR or WKY rats. The V1-receptor antagonist had no significant effect on resting MAP or HR values or on baroreflex parameters in both groups of rats, although this dose was shown to significantly inhibit the pressor response to AVP (5 ng iv; ANOVA, P < 0.05). In SHR but not WKY rats the V2-receptor antagonist significantly attenuated the gain (or slope) of the baroreflex curve (to 73 +/- 3 and 79 +/- 7% of control for 1 and 10 mg/kg, respectively), although AVP-induced pressor responses were also attenuated with the higher dose of the V2-receptor antagonist. These findings suggest that AVP tonically enhances baroreflex function through a V2 receptor in the SHR.

Topics: Animals; Antidiuretic Hormone Receptor Antagonists; Baroreflex; Benzazepines; Blood Pressure; Heart Rate; Injections, Intravenous; Male; Piperidines; Quinolones; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, Vasopressin

Vasopressin--but not the V2 receptor agonist [deamino-cis1,D-Arg8]-vasopressin (dDAVP)--may mediate natriuresis in dogs. The present study investigated this phenomenon by use of nonpeptide antagonists to V1a and V2 receptors 1-¿1-[4-(3-acetylaminopropoxy)benzoyl]-4-piperidyl¿-3,4-dihydro-2 (1H)-quinolinone (OPC-21268) and 5-dimethylamino-1-¿4-(2-methylbenzoylamino)-benzoyl¿-2,3,4,5-tetra hydro-1 H-benzazepine (OPC-31260), respectively) hypothesising that only V1a inhibition would reduce the natriuresis. In conscious dogs vasopressin secretion was suppressed by water loading (2% body weight) and replaced by infusion of vasopressin (50 pg min-1 kg-1) resulting in physiological plasma concentrations (plasma levels of AVP (pAVP) = 2.0 +/- 0.1 pg mL-1). In this setting, OPC-21268 did not change the rate of sodium excretion. OPC-31260 increased water excretion 12-fold without significant changes in sodium excretion. Heart rate, mean arterial blood pressure, glomerular filtration rate, and clearance of endogenous Li+ were unchanged. During vasopressin infusion, both antagonists increased pAVP, OPC-21268 by 20% and OPC-31260 by 100% (2.0 +/- 0.2-4.0 +/- 0.3 pg mL-1). In the absence of vasopressin infusion, OPC-31260 did not increase pAVP. Thus, the increase in pAVP appeared to be due to a decrease in metabolic clearance rate. The results indicate that the present dose of V1a receptor inhibitor OPC-21268 does not reduce sodium excretion and that both vasopressin antagonists inhibit vasopressin metabolism.

Topics: Animals; Antidiuretic Hormone Receptor Antagonists; Benzazepines; Dimethyl Sulfoxide; Dogs; Female; Glomerular Filtration Rate; Hemodynamics; Hormones; Kidney; Natriuresis; Piperidines; Quinolones; Solvents; Vasopressins

Hypertrophy of cardiomyocytes may play an important role in the pathogenesis of cardiac hypertrophy associated with various cardiovascular diseases such as congestive heart failure. The aim of this study was to investigate whether vasopressin (AVP) induces protein synthesis in cultured neonatal rat cardiomyocytes through its specific receptor and whether YM087, a newly synthesized nonpeptide AVP receptor antagonist, inhibits AVP-induced protein synthesis in vitro.. AVP receptors on cardiomyocytes were characterized using the radioligand [3H] AVP. The effects of AVP and YM087 on intracellular free calcium concentration ([Ca2+]i), mitogen-activated protein (MAP) kinase and [3H]-leucine incorporation were investigated in cultured neonatal rat cardiomyocytes.. In cardiomyocytes, Scatchard analysis showed a single population of high-affinity binding sites with the expected AVP V1A receptor subtype profile. YM087 showed high affinity for cardiomyocyte V1A receptors with a Ki value of 0.63 nM. In these same cells, YM087 potently inhibited AVP-induced increases in [CA2+]I and activation of MAP kinase in a concentration-dependent manner. In addition, AVP concentration-dependently stimulated the synthesis of protein without changing the rate of DNA synthesis, and YM087 prevented AVP-induced protein synthesis in a concentration-dependent manner.. These results suggest that AVP directly causes protein synthesis and YM087 is a potent inhibitor of AVP-induced protein synthesis of cardiomyocytes and thus may have beneficial effects in the development and regression of cardiomyocytic hypertrophy.

Topics: Analysis of Variance; Animals; Animals, Newborn; Antidiuretic Hormone Receptor Antagonists; Arginine Vasopressin; Benzazepines; Calcium; Calcium-Calmodulin-Dependent Protein Kinases; Cells, Cultured; Leucine; Myocardium; Piperidines; Protein Biosynthesis; Quinolones; Rats; Rats, Wistar; Receptors, Vasopressin; Stimulation, Chemical; Thymidine

This study was designed to assess the effect of a nonpeptide vasopressin V1-receptor antagonist, OPC-21268, and a vasopressin V2-receptor antagonist, OPC-31260, on hemodynamics in the early phase and the late phase after myocardial infarction in rats. In the early phase, OPC-21268 (30 mg/kg/day) or OPC-31260 (30 mg/kg/day) was orally administered from day 1 to day 5 after the operation; and hemodynamics were measured at day 5, in the late phase from 10 weeks to 11 weeks and measured at the end of 11 weeks. In the early phase, OPC-21268 reduced the left ventricular end-diastolic pressure (LVEDP) concomitantly with the reduction in systemic blood pressure, but did not change LVEDP in the late phase. OPC-31260 reduced LVEDP and central venous pressure in both phases. OPC-21268 improved hemodynamics only in the early phase and OPC-31260 improved it in both phases.

Topics: Administration, Oral; Animals; Antidiuretic Hormone Receptor Antagonists; Benzazepines; Heart Ventricles; Hemodynamics; Male; Myocardial Infarction; Organ Size; Piperidines; Quinolones; Rats; Rats, Wistar; Time Factors; Vasopressins; Ventricular Function, Left

Three subtypes of human (h) arginine vasopressin (AVP) receptors, hV1A, hV1B and hV2, were stably expressed in Chinese hamster ovary (CHO) cells and characterized by [3H]-AVP binding studies. In addition, the coupling of the expressed receptor protein to a variety of signal transduction pathways was investigated. Scatchard analysis of saturation isotherms for the specific binding of [3H]-AVP to membranes, prepared from CHO cells transfected with hV1A, hV1B and hV2 receptors, yielded an apparent equilibrium dissociation constant (Kd) of 0.39, 0.25 and 1.21 nM and a maximum receptor density (Bmax) of 1580 fmol mg(-1) protein, 5230 fmol mg(-1) protein and 7020 fmol mg(-1) protein, respectively. Hill coefficients did not differ significantly from unity, suggesting binding to homogenous, non-interacting receptor populations. Pharmacological characterization of the transfected human AVP receptors was undertaken by measuring the relative ability of nonpeptide AVP receptor antagonists, YM087, OPC-21268, OPC-31260, SR 49059 and SR 121463A, to inhibit binding of [3H]-AVP. At hV1A receptors, the relative order of potency was SR49059>YM087>OPC-31260>SR 121463A> >OPC-21268 and at hV2 receptors, YM087=SR 121463A>OPC-31260>SR 49059> >OPC-21268. In contrast, the relative order of potency, at hV1B receptors, was SR 49059> >SR 121463A=YM087=OPC-31260=OPC-21268. In CHO cells expressing either hV1A or hV1B receptors, AVP caused a concentration-dependent increase in intracellular Ca2+ concentration ([Ca2+]i) with an EC50 value of 1.13 nM and 0.90 nM, respectively. In contrast, stimulation of CHO cells expressing hV2 receptors resulted in an accumulation of cyclic AMP with an EC50 value of 2.22 nM. The potency order of antagonists in inhibiting AVP-induced [Ca2+]i or cyclic AMP response was similar to that observed in radioligand binding assays. In conclusion, we have characterized the pharmacology of human cloned V1A, V1B and V2 receptors and used these to determine the affinity, selectivity and potency of nonpeptide AVP receptor antagonists. Thus they may prove to be a valuable tool in further examination of the physiological and pathophysiological roles of AVP.

Topics: Animals; Benzazepines; Binding, Competitive; Calcium; CHO Cells; Cricetinae; Cyclic AMP; Humans; Indoles; Morpholines; Piperidines; Pyrrolidines; Quinolones; Receptors, Vasopressin; Spiro Compounds; Transfection; Tritium

Species-related specific differences in the pharmacological profile of vasopressin V1a receptors have been reported. Thus, the aim of the present study was to identify a vascular preparation of human origin expressing V1a receptors. Vasopressin was found to contract human gastric artery strips without endothelium with high affinity (pEC50 8.9). The maximal effect induced by vasopressin was inversely related to the diameter of the vessel. Oxytocin was found to contract the human gastric artery strips with low potency (pEC50 7.2). Contraction induced by vasopressin was competitively antagonized by the non peptide vasopressin receptor antagonists SR 49059 (pA2 9.2), OPC 21268 (pA2 6.2) and OPC 31260 (pA2 7.1). The order of potency of agonists (vasopressin > > oxytocin) and of antagonists (SR 49059 > > OPC 31260 > OPC 21268) indicate the contraction induced by vasopressin in the isolated human gastric artery is mediated by the V1a receptor type. The present data are similar to those obtained in different preparations expressing the native human V1a receptor as well as to those obtained in cell transfected with this receptor. The human gastric artery is a monoreceptor system of great utility for studying the effects of new drugs interacting with the human V1a receptor.

Topics: Aged; Aged, 80 and over; Antidiuretic Hormone Receptor Antagonists; Arginine Vasopressin; Arteries; Benzazepines; Humans; In Vitro Techniques; Indoles; Middle Aged; Muscle, Smooth, Vascular; Oxytocin; Piperidines; Pyrrolidines; Quinolones; Receptors, Vasopressin; Stomach; Vasoconstrictor Agents

The vasopressin receptor subtype that causes nitric oxide (NO) release remains controversial. To elucidate this receptor-ligand interaction, we examined the effects of vasopressin receptor antagonists on vasopressin-induced release of NO from isolated perfused rat kidneys by using a sensitive chemiluminescence assay. Vasopressin increased renal perfusion pressure and NO signals in the perfusate in a dose-dependent manner. N omega-Monomethyl-L-arginine abolished this increase in NO release; however, a similar increase in renal perfusion pressure induced by prostaglandin F2 alpha was not associated with the increase in NO release. OPC-21268, a V1 receptor antagonist, significantly reduced the vasopressin-evoked renal vasoconstriction and NO release, whereas OPC-31260, a V2 receptor antagonist, had no effects. Moreover, desmopressin, a selective V2 receptor agonist, did not increase the NO signal. NO release by vasopressin was markedly attenuated in deoxycorticosterone acetate (DOCA)-salt hypertensive rat kidneys compared with control kidneys (10(-10) mol/L vasopressin: +0.8 +/- 0.3 versus +6.9 +/- 1.4 fmol/min per gram kidney, DOCA versus control; P < .001). Histochemical analysis for renal NO synthase revealed a substantial attenuation of the staining of endothelial NO synthase in DOCA-salt rats. These results directly demonstrate that vasopressin stimulates NO release via the endothelial V1 receptor in the rat kidney.

Topics: Animals; Antidiuretic Hormone Receptor Antagonists; Arginine Vasopressin; Benzazepines; Desoxycorticosterone; Dinoprost; Dose-Response Relationship, Drug; Enzyme Inhibitors; In Vitro Techniques; Kidney; Male; Nitric Oxide; omega-N-Methylarginine; Perfusion; Piperidines; Quinolones; Rats; Rats, Wistar; Receptors, Vasopressin; Renal Agents

Strategies for developing selective water diuretic agents have involved development of kappa opioid receptor agonists and vasopressin V2 receptor antagonists; however, these two classes of compounds have not been compared directly. We have investigated the activity of three kappa receptor agonists and one nonpeptide vasopressin receptor antagonist in conscious dogs. SB 215520, SB 215519 and niravoline are selective kappa agonists with variable abilities to cause a water diuresis and ataxia in rats. When administered to conscious hydropenic dogs, the kappa agonists resulted in an increase in free water clearance; however, these effects were associated with an antinatriuresis, an increase in heart rate and, at the higher doses, central nervous system side effects. Conversely, the vasopressin receptor antagonist, OPC 31260, resulted in a significant water diuresis without any accompanying changes in sodium excretion and heart rate, and with no apparent central nervous system effects. These studies suggest that, at least in dogs, a vasopressin receptor antagonist is a more selective water diuretic than a kappa receptor agonist.

Topics: Animals; Antidiuretic Hormone Receptor Antagonists; Benzazepines; Benzeneacetamides; Diuresis; Dogs; Female; Male; Piperidines; Pyrrolidines; Rats; Rats, Sprague-Dawley; Receptors, Opioid, kappa; Water

To characterize the role of arginine vasopressin (AVP) V(1A) or V2 receptors and the possible interaction with the renin-angiotensin system in the pathogenesis of hypertension in spontaneously hypertensive rats (SHR), young male SHR were treated from 6 to 10 wk of age with AVP V(1A) receptor blockade, angiotensin-converting enzyme (ACE) inhibition, combination of V(1A) receptor blockade and ACE inhibition, V2 receptor blockade, and vehicle. Treatments were then withdrawn, and systolic blood pressure (SBP) was measured until 19 wk of age. At both 10 and 19 wk of age, SBP was significantly reduced with V(1A) receptor blockade, ACE inhibition, and combined treatment compared with vehicle treatment, although no treatment normalized SBP to levels of Donryu normotensive rats. Throughout the experimental period, no significant additive effects were observed with combined treatment. At 10 wk of age, plasma AVP concentration and 24-h urinary AVP excretion were increased with AVP V2 receptor blockade. At 19 wk of age, SBP was significantly higher in rats previously treated with V2 receptor blockade (233 +/- 3 mmHg) than with vehicle (221 +/- 2 mmHg) (P < 0.01). Left ventricular mass was significantly reduced in rats previously treated with ACE inhibition or combined treatment. These results suggest that AVP (via V(1A) receptors) and angiotensin II contribute to the pathogenesis of SHR hypertension, whereas the AVP V2 receptor may be involved in preventing the full expression of the hypertension, in male SHR.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antidiuretic Hormone Receptor Antagonists; Arginine Vasopressin; Benzazepines; Blood Pressure; Hypertension; Male; Myocardium; Organ Size; Piperidines; Quinolones; Ramipril; Rats; Rats, Inbred SHR; Rats, Inbred Strains; Systole; Time Factors

To elucidate the precise localization of vasopressin (VP) V1 and V2 receptors in the kidney, we utilized in vitro macroautoradiography (macro-ARG) and microautoradiography (micro-ARG) of these receptors in Wistar rat kidneys. This was done by using OPC-21268 and OPC-31260, two newly developed selective V1 (OPC-21268) and V2 (OPC-31260) receptor antagonists. For macro-ARG, 10-microm kidney sections were incubated with Tris-HCl buffer containing [3H]-VP with or without unlabeled ligand (VP, OPC-21268, or OPC-31260) at 20 degrees C for 40 min. These sections were then loaded into X-ray cassettes with Hyperfilm-[3H] and exposed in the dark for 2 months. The autoradiograms were quantitatively analyzed by using the research analysis system RAS 1,000; the V1 and V2 receptors were quantitated by subtracting the nonspecific binding (incubated with OPC-21268 and OPC-31260, respectively) from the total binding. To assess a more precise localization of the V1 and V2 receptors, we also investigated the micro-ARG of the renal V1 and V2 receptors by dipping the kidney section slides used for macro-ARG into a photographic emulsion and observing the receptors under light microscopy. [3H]-VP binding to the rat kidney was completely displaced by unlabeled excess VP, but not by unlabeled angiotensin II, indicating that [3H]-VP binding was specific for VP receptors. Computerized quantification showed that V2 receptors, visualized by OPC-31260, were the predominant type of VP receptor in the kidney. Conversely, V1 receptors, visualized by OPC-21268, were fewer in number. V1 receptors were partly localized to the glomerulus, cortical vessels, interstitial cells, and the medullary vessels. The V2 receptors localized to the collecting ducts and medullary tubules. Our findings indicated that renal V1 and V2 receptors can be detected by in vitro macro- and micro-ARG by using OPC-21268 and OPC-31260.

Topics: Animals; Antidiuretic Hormone Receptor Antagonists; Autoradiography; Benzazepines; In Vitro Techniques; Kidney; Ligands; Male; Piperidines; Quinolones; Rats; Rats, Wistar; Receptors, Vasopressin; Tissue Distribution; Tritium; Vasopressins

Vasopressin has been implicated in the pathogenesis of heart failure as one of the most potent vasoconstrictors. However, whether the increase in plasma vasopressin levels modifies the pathophysiology of heart failure remains unknown. To investigate the effect of long-term inhibition of vasopressin in the development of heart failure, we administered a selective, orally effective, nonpeptide vasopressin antagonist, the V1 receptor antagonist OPC-21268 (100 mg center dot kg-1 center dot day-1) or a V2 receptor antagonist, OPC-31260 (20 mg center dot kg-1 center dot day-1) to rats with heart failure induced by the creation of an aortocaval fistula (AVF) and to sham-operated rats for 4 weeks, beginning on the first postoperative day. The heart failure in this experiment was characterized by an increase in the weights of the right and left ventricles, the lungs, and the right and left appendage, increase in left ventricular end-diastolic pressure (LVEDP), increase in right ventricular systolic pressure (RVSP), increase in right atrial pressure (RAP), and an increase in the plasma level of atrial natriuretic peptide (ANP) as compared with no change in sham-operated rats. There were no differences in shunt ratio between treated and untreated heart failure groups. Chronic administration of the V2 receptor antagonist OPC-31260 significantly reduced the weight of the right ventricle (1.17 +/- 0.39 vs. 0.90 +/- 0.13 g/kg, p < 0.05), RVSP (53 +/- 18 vs. 39 +/- 4 mm Hg, p < 0.05), LVEDP (11.8 +/- 5.2 vs. 6.5 +/- 2.8 mm Hg, p < 0.05) and the plasma concentrations of ANP (554 +/- 271 vs. 193 +/- 39 pg/ml, p < 0.05) as compared with the values of rats with untreated HF. Chronic treatment with the V1 receptor antagonist OPC-21268 did not alter hemodynamics, organ weights, or hormone concentrations. These results suggest that vasopressin did not contribute mainly to the maintenance of systemic hemodynamics through the V1 receptor in this heart failure model. Vasopressin may play a role, at least in part, in the fluid retention in the development of heart failure through the V2 receptor. OPC-31260 may present a new approach to the treatment of heart failure.

Topics: Animals; Antidiuretic Hormone Receptor Antagonists; Benzazepines; Drug Administration Schedule; Heart Failure; Hemodynamics; Male; Organ Size; Piperidines; Quinolones; Random Allocation; Rats; Rats, Wistar

Recently we clarified the mechanism in which arginine-vasopressin (AVP) applied from the luminal side inhibits the basolateral Cl- conductance, which is stimulated by basolateral AVP. However, to prove that these vasopressin phenomena are expressed via receptor mediated actions, we examined the effect of specific V1 and V2 receptor antagonists, OPC-21268 and OPC-31260, respectively, on the electrical response to vasopressin in the rabbit CCD perfused in vitro. In the presence of the V2-antagonist, basolateral AVP caused only the activation of luminal Na+ conductance, indicating a V1 action. In the presence of the V1 antagonist, basolateral AVP caused the same biphasic responses in electrical parameters as cyclic AMP, representing a pure V2 action. On the other hand, a rise in cell Ca2+ in response to AVP was completely abolished in the presence of the V1-antagonist, but not by the V2-antagonist in the bath. These data confirm our earlier findings that rabbit CCD possesses both V1 and V2 receptors in the basolateral membrane. We conclude that electrical responses to AVP in the rabbit CCD are a complex of V1 and V2 receptor-mediated actions.

Topics: Animals; Antidiuretic Hormone Receptor Antagonists; Arginine Vasopressin; Benzazepines; Calcium; Cyclic AMP; Electrophysiology; In Vitro Techniques; Kidney Cortex; Kidney Tubules, Collecting; Male; Membrane Potentials; Patch-Clamp Techniques; Piperidines; Quinolones; Rabbits; Receptors, Vasopressin; Renal Agents; Sodium

We recently reported that stimulation of the arginine vasopressin (AVP) V1-receptor enhanced the pressor response in spontaneously hypertensive rats (SHR). In the present study, we investigated acute changes in systolic blood pressure (SBP) and heart rate (HR) after intravenous injections of AVP, OPC-21268 (a V1-receptor antagonist), and OPC-31260 (a V2-receptor antagonist), in anesthetized DOCA-salt hypertensive rats (DOCA) and age-matched sham-operated Wistar rats (control) to determine whether the pressor effect is specific to SHR or is present in other hypertensive animal models. SBP increased significantly in DOCA rats 9 min after injection of AVP 5 ng/kg without a concomitant increase in HR. Neither OPC-21268 3mg/kg nor OPC-31260 3mg/kg caused significant changes in SBP or HR. SBP tended to increase when AVP was administered after injection of OPC-31260. HR increased significantly 15 min after the combined treatment with OPC-31260 and AVP in DOCA rats compared with control rats. SBP did not change significantly when AVP was administered after injection of OPC-21268 in DOCA or control rats, but HR decreased significantly from 1 to 4 min after injection of AVP in DOCA rats. Our results suggest that V1-receptor stimulation does not enhance the pressor response in the DOCA rat, which is a model of volume-dependent hypertension, suggesting that the AVP system, especially V1-receptor, is not as important in the development or maintenance of hypertension in DOCA rats as in SHR.

Topics: Animals; Benzazepines; Blood Pressure; Desoxycorticosterone; Disease Models, Animal; Heart Rate; Male; Piperidines; Quinolones; Rats; Rats, Inbred SHR; Rats, Wistar; Receptors, Vasopressin; Time Factors

Efficacy of orally available, selective vasopressin V1 and V2 receptor antagonists on the developing and established stage of DOCA-salt hypertension was investigated. Twenty-nine Wistar rats were heminephrectomized, and administered DOCA (50 mg/kg; intraperitoneally twice a week) and salt (5% NaCl diet) from week 0 to the end of study. Group 1 rats were served as control. Group 2 and 5 rats were given a V1 antagonist, and groups 3 and 6 rats were given a V2 antagonist, while groups 4 and 7 rats received both V1 and V2 antagonists. Each drug was started to groups 2, 3 and 4 at week 0, and to groups 5, 6 and 7 at week 4. Significant amelioration of the increase in blood pressure was observed in groups 3 and 4 at week 10, and a reduction in blood pressure occurred in groups 6 and 7 at week 10. Otherwise, a V1 antagonist alone slightly attenuated blood pressure rise in the group 2 without significance, and failed to lower blood pressure of the group 5 during the study. These results suggest that both V1 and V2 agonisms are involved in an increase in blood pressure at the developing stage of DOCA-salt hypertension, and that V2 agonism, but not V1 plays a major role in the maintenance of high blood pressure at the established stage.

Topics: Administration, Oral; Animals; Antidiuretic Hormone Receptor Antagonists; Benzazepines; Blood Pressure; Body Weight; Desoxycorticosterone; Hypertension; Male; Piperidines; Quinolones; Random Allocation; Rats; Rats, Wistar; Sodium Chloride

To examine the role of vasopressin (AVP) receptors in the regulation of the hemodynamics and release of atrial natriuretic peptide (ANP), and the participation of renal nerve inputs in the osmotic AVP release, hypertonic saline (HS) was infused into conscious, bilaterally nephrectomized rats with non-peptide, selective antagonists for the V1-receptor or V2-receptor of AVP. In the control group, HS alone increased mean arterial pressure, plasma ANP and AVP, plasma volume and plasma osmolality, and decreased the heart rate. In the V1-receptor antagonist group, an increase in the mean arterial pressure and a decrease in heart rate were completely abolished and an increase in plasma ANP was attenuated. In the V2-receptor antagonist group, increases in mean arterial pressure and plasma ANP and a decrease in heart rate were attenuated. However, the ratio of the changes in heart rate to the changes in mean arterial pressure in the V2-receptor antagonist group is significantly higher than that in the control group. In both experimental groups, increases in plasma AVP, plasma volume and plasma osmolality were not different from those in the control group. These results suggest that a HS-induced increase in mean arterial pressure is mediated by the pressor effect of AVP, mainly through V1-receptors, and that the depressor effect of AVP through V2-receptors may not influence tonically HS-induced hypertension. Moreover, HS-induced increase in plasma ANP is mediated mainly by increases in plasma volume and blood pressure, but may not be affected by a direct action of AVP to the heart. Renal afferent nerve inputs may not have effects on the regulation of osmotic AVP release.

Topics: Animals; Atrial Natriuretic Factor; Benzazepines; Blood Pressure; Heart Rate; Hemodynamics; Kidney; Male; Nephrectomy; Neurons, Afferent; Osmolar Concentration; Piperidines; Plasma Volume; Quinolones; Radioimmunoassay; Rats; Rats, Sprague-Dawley; Receptors, Vasopressin; Saline Solution, Hypertonic; Vasopressins

Effects of novel, nonpeptide vasopressin V1 and V2 receptor antagonists on partially nephrectomized and salt-loaded spontaneously hypertensive rats (SHR), which develop severe hypertension and progressive nephrosclerosis, were investigated. SHR were 5/6-nephrectomized and fed a high salt diet. The rats were divided into four groups: group 1 was an untreated control, group 2 received the V1 antagonist OPC-21268, group 3 received the V2 antagonist OPC-31260, and group 4 received both the V1 and V2 antagonists. The V1 antagonist alone or combined with the V2 antagonist significantly decreased the increase in blood pressure (BP) of groups 2 and 4 rats, but the V2 antagonist alone did not reduce the increase in BP of the group 3 rats. The V2 antagonist alone or combined with the V1 antagonist induced a significant diuresis of rats in groups 3 and 4. The increase in urinary protein excretion and the progression of renal hyaline arteriolosclerosis were attenuated by the V1 antagonist with or without the V2 antagonist in rats in groups 2 and 4, but not by the V2 antagonist alone in rats in group 3. This implies that the progressive nephrosclerosis in SHR with partial renoablation and salt-loading was associated with V1 agonism.

Topics: Animals; Antidiuretic Hormone Receptor Antagonists; Benzazepines; Biomarkers; Blood Pressure; Body Weight; Disease Models, Animal; Diuresis; Glomerulosclerosis, Focal Segmental; Hypertension; Kidney; Male; Nephrectomy; Nephrosclerosis; Piperidines; Proteinuria; Quinolones; Rats; Rats, Inbred SHR

To elucidate the effect of the arginine vasopressin (AVP) system in vivo, especially V1 and V2 activity, on blood pressure, we measured the acute changes in blood pressure and heart rate after AVP, OPC-21,268 (a V1 receptor antagonist), and OPC-31,260 (a V2 receptor antagonist) were injected intravenously in anesthetized spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats at the age of 15 weeks. Compared with the control period, single injection of AVP 5 ng/kg significantly increased systolic blood pressure in WKY rats without a concomitant increase in heart rate, but there was no significant increase in blood pressure in SHR. In contrast, single injection of either OPC-21,268 3 mg/kg or OPC-31,260 3 mg/kg did not affect blood pressure or heart rate in either SHR or WKY rats. Injection of AVP after the administration of OPC-31,260 induced a greater increase in blood pressure in SHR than in WKY rats, whereas injection of AVP after the administration of OPC-21,268 did not induce any clear increase in blood pressure in SHR or WKY rats. These results suggest that SHR have enhanced pressor activity mediated by V1 receptors and that this increase may be due to an increase in their number. In conclusion, enhancement of V1 activity may contribute to the development of high blood pressure in SHR.

Topics: Animals; Arginine Vasopressin; Benzazepines; Blood Pressure; Heart Rate; Hypertension; Male; Piperidines; Quinolones; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, Vasopressin; Stimulation, Chemical

Treatment of rat 3Y1 fibroblasts with vasopressin (AVP) results in a transient activation of MAP kinase as potent as with EGF and serum. An antagonist of vasopressin receptor V1, but not an antagonist of V2, inhibited the AVP-induced activation of MAP kinases, indicating that AVP activates MAP kinases through V1 receptor. Prolonged TPA treatment of cells resulted in partial MAP kinase activation, indicating the presence of PKC-independent pathway. The pathway was inhibited by wortmannin, an inhibitor of PI3-kinase. The results suggest that wortmannin-sensitive molecules such as PI3-kinase, are involved in the V1 receptor-mediated activation of the MAP kinase pathway independent of TPA-sensitive PKC.

Topics: Androstadienes; Animals; Antidiuretic Hormone Receptor Antagonists; Arginine Vasopressin; Benzazepines; Calcium-Calmodulin-Dependent Protein Kinases; Cells, Cultured; Deamino Arginine Vasopressin; Dose-Response Relationship, Drug; Enzyme Activation; Enzyme Inhibitors; Fibroblasts; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinases; Piperidines; Quinolones; Rats; Receptors, Vasopressin; Signal Transduction; Tetradecanoylphorbol Acetate; Wortmannin

Contractions induced by [Arg8]vasopressin (vasopressin) and the effect of nonpeptide vasopressin receptor antagonists were studied in the human isolated coronary artery. Vasopressin induced contraction of coronary artery segments with a high pD2 (9.25) but a low Emax (11.8% of the response to 100 mM K+). This response was not affected by removal of the endothelium. Contraction was antagonized by the vasopressin V1 receptor antagonist SR 49059 ((2S) 1-[(2R 3S)-5-chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxybenzene- sulfonyl)-3-hydroxy-2,3-dihydro-1H-indole-2-carbonyl]-pyrrolidine-2- carboxamide) (pA2: 9.76). OPC-31260 ([5-dimethylamino-1-(4-(2-methylbenzoylamino)benzoyl)-2,3,4,5-tetr ahydro-1H- benzazepine]: vasopressin V2 receptor antagonist) and OPC-21268 (1-(1-[4-(3-acetylaminopropoxy) benzoyl]-4-piperidyl)-3,4- dihydro-2(1H)-quinolinone: reported vasopressin V1 receptor antagonist) were less potent antagonists of vasopressin-induced contractions (pA2: 7.31 and 5.6, respectively). The antagonist potency order (SR 49059 > OPC-31260 > OPC-21268) corresponds to the reported affinity order for the human cloned vasopressin V1 receptor. Therefore, the vasopressin V1 receptor antagonist SR 49059, but not OPC-21268, appears to be an appropriate tool to investigate further the role of vasopressin in pathological processes involving coronary vasoconstriction in humans.

Topics: Adolescent; Adult; Antidiuretic Hormone Receptor Antagonists; Arginine Vasopressin; Benzazepines; Child; Coronary Vessels; Endothelium, Vascular; Female; Humans; In Vitro Techniques; Indoles; Male; Middle Aged; Muscle, Smooth, Vascular; Piperidines; Potassium; Pyrrolidines; Quinolones; Vasoconstrictor Agents

To determine whether the vasopressor and antidiuretic actions of arginine vasopressin (AVP) may participate in the development of salt-induced hypertension, we examined the long-term effects of AVP V1 and V2 receptor antagonists on blood pressure (BP) in Dahl-Iwai salt-sensitive (DS) and salt-resistant (DR) rats. From age 7 weeks, DS and DR rats were fed a diet containing 8% NaCl, alone (control group); 8% NaCl and 1% OPC-21268 (V1 antagonist-treated group); or 8% NaCl and 0.05% OPC-31260 (V2 antagonist-treated group). The pressor response to AVP was significantly inhibited in DS rats treated with OPC-21268. Urinary volume and water intake were significantly increased by administration of OPC-31260; this increase was greater in DR rats than in DS rats. Indirect BP measurements obtained using tailcuff plethysmography showed that DS but not DR rats developed hypertension when fed high-salt diets. However, chronic treatment with either OPC-21268 or OPC-31260 did not alter the course of hypertension in DS rats, despite the effective blocking actions of these antagonists. This finding also was confirmed by direct BP measurements. Our results indicate that even if AVP plays a role in salt-induced hypertension peripheral blockade of either subtype of AVP receptors does not prevent the development of hypertension in DS rats.

Topics: Analysis of Variance; Animals; Antidiuretic Hormone Receptor Antagonists; Arginine Vasopressin; Benzazepines; Blood Pressure; Blood Pressure Determination; Diuresis; Hypertension; Male; Piperidines; Quinolones; Rats; Sodium Chloride

Rapid right ventricular pacing could induce congestive heart failure in conscious dogs with significant increase in plasma concentration of arginine vasopressin (AVP) (from 1.2 +/- 0.2 to 3.4 +/- 0.6 pg/ml). In this experimental model of heart failure, oral administration of the selective AVP V1 receptor antagonist OPC-21268 significantly increased cardiac output and improved renal function without significant changes in serum electrolytes and hormones. Oral administration of the selective AVP V2 receptor antagonist OPC-31260 induced marked water diuresis, which resulted in significant increases in serum sodium concentration, plasma renin activity, and plasma concentration of AVP, although it did not produce hemodynamic improvement. Combined administration of OPC-21268 and OPC-31260 showed supra-additive hemodynamic responses as well as additive renal and metabolic responses, i.e., it showed prolonged decrease in mean arterial pressure and profound increase in cardiac output. These results suggest that AVP plays a significant role in elevation of vascular tone through V1 receptors and plays a major role in retaining free water through V2 receptors in this model of heart failure. Furthermore, combined administration of V1 and V2 receptor antagonists could induce not only metabolic and hormonal responses but also more beneficial hemodynamic responses than those observed following treatment with V1 receptor antagonist alone.

Topics: Animals; Antidiuretic Hormone Receptor Antagonists; Arginine Vasopressin; Benzazepines; Body Weight; Capillary Resistance; Cardiac Output; Cardiac Pacing, Artificial; Diuresis; Dogs; Heart Failure; Hemodynamics; Kidney; Male; Natriuresis; Osmolar Concentration; Piperidines; Potassium; Quinolones; Renin; Sodium

Chronic effects of orally available, nonpeptide vasopressin V1 and V2 receptor antagonists on conscious spontaneously hypertensive rats (SHR) were investigated. SHR and Wistar rats were divided into four groups, groups S-1 to S-4 and W-1 to W-4, respectively. Groups S-1 and W-1 were untreated as control. Groups S-2 and W-2 were treated with V1 antagonist, groups S-3 and W-3 received V2 antagonist, and groups S-4 and W-4 were treated with both of V1 and V2 antagonists. V1 and/or V2 antagonists did not affect degree of blood pressure of W-2, W-3, and W-4 rats, and V1 antagonist, alone or combined with V2 antagonist, slightly reduced increases in blood pressure of S-2 and S-4 rats without significance. However, V2 antagonist induced significantly massive and hyposmolar urine in W-3 rats compared with that in S-3 rats. In conclusion, in SHR, circulating vasopressin contributes to increases in blood pressure via either V1 or V2 receptors less than expected from previous studies with antibodies or peptide antagonists.

Topics: Animals; Antidiuretic Hormone Receptor Antagonists; Benzazepines; Blood Pressure; Hypertension; Male; Osmolar Concentration; Piperidines; Quinolones; Rats; Rats, Inbred SHR; Rats, Wistar; Receptors, Vasopressin; Urine; Vasopressins

1. The effects of the non-peptide arginine vasopressin V1 receptor antagonist (OPC-21268) and the non-peptide V2 receptor antagonist (OPC-31260) on vasopressin-induced contraction of human internal mammary arteries and rat mesenteric resistance arteries were investigated. 2. In human internal mammary arteries, the non-peptide V1 receptor antagonist, OPC-21268, failed to antagonize vasopressin-induced contraction at low concentrations and potentiated the contraction at higher concentrations (300 nmol/l, P < 0.05). A peptide selective V1 receptor antagonist ([d(CH2)5, sarcosine7]arginine vasopressin) potently inhibited the vasopressin-induced contraction, indicating the presence of functionally constrictor V1 receptors in human internal mammary arteries. Both peptide (desGly-NH29[d(CH2)5, D-Ile2, Ile4]arginine vasopressin) and non-peptide 'selective' V2 receptor antagonists (OPC-31260, 3 mumol/l) significantly antagonized vasopressin-induced contraction (P < 0.01), indicating partial V1 receptor antagonist activity. 3. The vasopressin-induced contraction in human internal mammary arteries was reversed by high concentrations of the non-peptide V2 receptor antagonist, OPC-31260, but not by the non-peptide V1 receptor antagonist, OPC-21268. 4. The effects of OPC-21268 and OPC-31260 were specific to vascular vasopressin receptors as neither compound influenced endothelin- or noradrenaline-induced contraction in human internal mammary arteries. 5. In rat mesenteric resistance arteries, both OPC-21268 (10 nmol/l) and OPC-31260 (1 mumol/l) antagonized vasopressin-induced contraction (P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Antidiuretic Hormone Receptor Antagonists; Arginine Vasopressin; Benzazepines; Culture Techniques; Dose-Response Relationship, Drug; Female; Humans; Mammary Arteries; Mesenteric Artery, Superior; Piperidines; Quinolones; Rats; Rats, Sprague-Dawley; Species Specificity; Vasoconstriction

Hypotensive hemorrhage decreases heart rate (HR) and renal sympathetic nerve activity (RSNA). Hemorrhage is a potent stimulus for arginine vasopressin (AVP) release; therefore, AVP may contribute to such inhibitory action of HR and RSNA during hemorrhage. We evaluated the roles of vasopressin on the regulation of blood pressure (BP), HR, and RSNA during hemorrhage using nonpeptide and selective V1- and V2-receptor antagonists (OPC-21268 and OPC-31260) in conscious rats. After hemorrhage (20 ml/kg body wt) BP decreased by 62 +/- 10 mmHg along with bradycardia (-110 +/- 15 beats/min) and renal sympathoinhibition (-50 +/- 8). Pretreatment of V1-receptor antagonist (5 mg/kg iv) did not affect the initial fall of BP but attenuated subsequent BP recovery. Bradycardic and renal sympathoinhibitory responses following hemorrhage were abolished (-14 +/- 24 beats/min and -7 +/- 9) by V1-receptor antagonist. Pretreatment of V2-receptor antagonist (1 mg/kg iv) did not affect the response of BP; however, it did slightly strengthen bradycardia and prolong renal sympathoinhibition. Hemorrhage increased the plasma AVP concentration more than 50-fold. These results indicate that when the plasma concentration of AVP is extremely high during hemorrhage, vasopressin via V1 receptor contributes to BP recovery by the peripheral vasoconstriction and exerts an inhibitory action on RSNA, and vasopressin via V2 receptor exerts opposite stimulatory action on RSNA.

Topics: Animals; Antidiuretic Hormone Receptor Antagonists; Arginine Vasopressin; Benzazepines; Blood Pressure; Heart Rate; Hemorrhage; In Vitro Techniques; Kidney; Male; Piperidines; Quinolones; Rats; Rats, Sprague-Dawley; Renal Artery; Sympathetic Nervous System; Time Factors

Our objective was to assess the effect of endogenous AVP on renal hemodynamics and excretory function. We measured mean arterial pressure (MAP), renal blood flow (RBF), glomerular filtration rate (GFR) and urine osmolality before and after the intravenous infusion of a V1 antagonist (OPC-21268), a V2 antagonist (OPC-31260) and their vehicle (saline) in anesthetized male Wistar rats. The infusion of the V2 antagonist increased the urine flow rate and reduced the urine osmolality significantly (p < 0.05). The infusion of saline and the V1 antagonist did not change the urine flow rate or the urine osmolality. The infusion of saline, the V1 antagonist and the V2 antagonist had no effect on MAP, RBF or GFR. These results suggest that endogenous AVP plays a critical role in the regulation of renal water reabsorption mediated through the V2 receptor.

Topics: Animals; Antidiuretic Hormone Receptor Antagonists; Benzazepines; Blood Pressure; Glomerular Filtration Rate; Kidney; Male; Osmolar Concentration; Piperidines; Quinolones; Rats; Rats, Wistar; Renal Circulation; Urine

1. OPC-21268 and OPC-31260 are newly developed orally active non-peptide vasopressin (AVP) V1 and V2 receptor antagonists, respectively. The effects of the two compounds on human vessels have not been studied. 2. The effects of the two compounds on AVP-induced contraction of human internal mammary arteries (IMA) were investigated. Their effects were compared with the peptide V1 and V2 antagonists d(CH2)5Sar7AVP (SAVP) and d(CH2)5D-Ileu2Ileu4AVP (Ileu2Ileu4AVP), respectively. 3. The V1 antagonist OPC-21268 failed to antagonize AVP-induced contraction at low concentrations and potentiated the contraction at higher concentration (3 x 10(-7) mol/L, P < 0.05). It also caused a mild direct contractile effect on IMA. In contrast, the peptide V1 antagonist SAVP potently inhibited the AVP-induced contraction, indicating that functionally constrictor V1 receptors exist in IMA. Both the nonpeptide and peptide V2 antagonists OPC-31260 (3 x 10(-6) mol/L) and Ileu2Ileu4AVP significantly antagonized the AVP-induced contraction (P < 0.01). 4. The AVP-induced contraction was reversed by high concentrations of OPC-31260 (10(-6) mol/L-3 x 10(-5) mol/L) but not by OPC-21268 (up to 3 x 10(-5) mol/L). 5. These studies indicate that, in human IMA, OPC-21268 is a partial V1 receptor agonist with no V1 receptor antagonist activity, while OPC-31260 is a V1 receptor antagonist. The results also indicate that Ileu2Ileu4AVP may be a V1 receptor antagonist in humans.

Topics: Antidiuretic Hormone Receptor Antagonists; Arginine Vasopressin; Arteries; Benzazepines; Breast; Female; Humans; In Vitro Techniques; Muscle Contraction; Muscle, Smooth, Vascular; Norepinephrine; Piperidines; Quinolones; Receptors, Vasopressin; Regional Blood Flow

For the purpose of clarifying the role of vasopressin V1 and V2 receptors in osmolyte accumulation, we determined the effects on the inner medullary osmolyte content of the administration of orally active vasopressin V1 and/or V2 receptor antagonists OPC-21268 (i.e., 1-(1-[4-(3-acetylaminopropoxy)benzoyl]-4-piperidyl)- 3,4-dihydro-2(1H)-quinolinone) and OPC-31260 (i.e., 5-dimethylamino-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tet rah ydro-1H- benzazepine] under a condition of maximal urine concentration achieved by water deprivation for 4 days. Taurine content increased significantly with the use of the V2 antagonist, irrespective of the use of the V1 antagonist. Inner medullary betaine content decreased with the administration of the V1 antagonist, irrespective of the administration of V2 antagonist. The administration of either the V1 or V2 antagonist alone did not affect sorbitol content, aldose reductase activity, or aldose reductase mRNA abundance in renal inner medulla. However, the combined administration of the V1 and V2 antagonists decreased all of these significantly. Myo-inositol content was not affected by the administration of the V1 or V2 antagonists. Glycerophosphorylcholine content was decreased with the use of the V2 antagonist, irrespective of the use of the V1 antagonist, and this effect paralleled urine osmolality. In conclusion, the individual organic osmolytes responded differently to the antagonists of vasopressin V1 and/or V2 receptors. The mechanisms linked to vasopressin V1 and/or V2 receptors appeared to modulate the accumulation of some organic osmolytes in the inner medulla. Aldose reductase mRNA abundance and sorbitol accumulation in the inner medulla appeared to be mediated through either V1 or V2 receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Aldehyde Reductase; Animals; Antidiuretic Hormone Receptor Antagonists; Benzazepines; Diuresis; Kidney Medulla; Male; Osmolar Concentration; Osmosis; Piperidines; Quinolones; Rats; Rats, Wistar; RNA, Messenger; Urine; Water Deprivation

Vasopressin (VP) stimulates adenosine 3',5'-monophosphate (cAMP) formation in an immortalized renal tubule cell line, TKC2, which is derived from transgenic mouse harboring temperature-sensitive SV40 T-antigen gene. VP (10(-8) M)-induced cAMP formation was significantly attenuated by either non-peptide vasopressin receptor V1 or V2 subtype antagonist, OPC-21268 (10(-8) and 10(-6) M) or OPC-31260 (10(-8) and 10(-6) M), respectively, and it was completely abolished by combination of both agents (10(-6) M). VP (10(-8) M) also induced an increase in cytosolic free Ca2+ and prostaglandin (PG) E2 synthesis, both of which were significantly inhibited by OPC-21268 (10(-8) M), but not by OPC-31260 (10(-6) M). Either OPC-21268 (10(-8) M), depletion of extracellular Ca2+ or inhibition of cyclooxygenase attenuated both VP-induced PGE2 synthesis and cAMP formation. In conclusion, both V1 and V2 receptors can stimulate cAMP formation. V1 receptor, however, stimulates cAMP formation via Ca(2+)-dependent PGE2 synthesis, whereas V2 receptor may stimulate it directly.

Topics: Animals; Antidiuretic Hormone Receptor Antagonists; Antigens, Polyomavirus Transforming; Benzazepines; Calcium; Cell Line, Transformed; Cyclic AMP; Dinoprostone; Indomethacin; Kidney Tubules; Mice; Mice, Transgenic; Piperidines; Quinolones; Receptors, Vasopressin; Vasopressins

1. The relationship between vasopressin and the progression of renal failure has been proposed, but not intensively investigated because of a lack of orally available, selective vasopressin antagonists. 2. The effects of novel, orally available vasopressin V1 and V2 receptor antagonists on several indices of the progression of chronic renal failure, i.e. blood pressure, urinary protein excretion, sodium balance and renal histopathology, were investigated by using Wistar rats with adriamycin-induced nephropathy accelerated by deoxycorticosterone acetate-salt hypertension. Groups 2 and 3 were treated with V1 and V2 antagonists, respectively, while the untreated group 1 served as the control. To block the effects of vasopressin efficaciously, V1 and V2 antagonists were simultaneously administered (group 4). 3. At week 6, 2 weeks after the beginning of administration of deoxycorticosterone acetate-salt and vasopressin antagonists after the second injection of adriamycin, V1 and V2 antagonists given either alone or in combination significantly reduced the systolic blood pressure as compared with the control, and urine volume was increased in groups 3 and 4. The proteinuria was also decreased at week 10 in groups 2, 3 and 4. Differences in sodium excretion between all groups were not significant. Histopathological alterations in the kidneys of group 4 were significantly ameliorated. 4. These results suggest that a combination of V1 and V2 antagonists can have therapeutic effects in certain types of chronic renal failure.

Topics: Animals; Antidiuretic Hormone Receptor Antagonists; Benzazepines; Kidney; Kidney Failure, Chronic; Male; Piperidines; Quinolones; Rats; Rats, Wistar; Urine

In conscious dogs, 36-h water deprivation induced a significant increase in renal blood flow (RBF) with elevation of the plasma arginine vasopressin (AVP) concentration to 9.6 +/- 1.8 pg/ml. To simulate such a condition, a mild elevation of plasma AVP was produced by infusing AVP intravenously at a dose of 0.1 ng.kg-1.min-1 for 20 min. The plasma AVP concentration then increased to 6.8 +/- 0.7 pg/ml. This dose of AVP increased the RBF by 21.7 +/- 2.6% and decreased the renal vascular resistance by 18.1 +/- 2.3% without significant changes in mean arterial pressure, cardiac output, or heart rate. The mechanism of this renal vasodilatory action was examined using newly developed, orally effective, selective AVP antagonists OPC-21268 (a V1-receptor antagonist) and OPC-31260 (a V2-receptor antagonist). In 36-h water-deprived dogs, V2-receptor blockade with OPC-31260 significantly decreased the RBF by 20.5 +/- 2.6% without significant changes in cardiac output. The exogenous AVP-induced renal vasodilatory response tended to be augmented when V1 receptors were blocked by pretreatment with OPC-21268, but the change did not achieve statistical significance. On the other hand, V2-receptor blockade by either pretreatment with OPC-31260 or simultaneous infusion of OPC-31260 inhibited this vasodilatory response. Furthermore, intravenous infusion of 1-desamino-8-D-arginine vasopressin (DDAVP) at a dose of 0.3 ng.kg-1 x min-1 for 20 min significantly increased the RBF by 36.5 +/- 1.7%, and this DDAVP-induced renal vasodilation was inhibited by simultaneous infusion of V2-receptor antagonist.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Arginine Vasopressin; Benzazepines; Deamino Arginine Vasopressin; Diuresis; Dogs; Drug Combinations; Hemodynamics; Male; Natriuresis; Osmolar Concentration; Piperidines; Quinolones; Receptors, Vasopressin; Renal Circulation; Vasodilation

Topics: Animals; Benzazepines; Cells, Cultured; Hyponatremia; Inappropriate ADH Syndrome; Kidney Tubules, Collecting; Muscle, Smooth, Vascular; Piperidines; Quinolones; Rats; Rats, Brattleboro; Rats, Sprague-Dawley; Vasopressins

Using a perfusion technique of isolated vessels, constrictor responses to vasopressin (VP) and norepinephrine (NE) were investigated in perfused dog femoral arteries. Both OPC-21268, a selective V1-antagonist, and OPC-31260, a selective V2-antagonist, significantly shifted the VP-induced dose response curves to the right without influencing the NE-induced ones. The blocking effects of OPC-31260 were much greater than those of OPC-21268, suggesting that there may probably be functional V1- and V2-receptors in isolated dog femoral arteries that mediate vasoconstriction.

Topics: Angiotensin Receptor Antagonists; Animals; Benzazepines; Dogs; Dose-Response Relationship, Drug; Femoral Artery; Norepinephrine; Piperidines; Quinolones; Receptors, Vasopressin; Vasoconstriction; Vasopressins

Using a perfusion technique with isolated vessels, we investigated the effect of OPC-21268 (a selective V1 receptor antagonist) and OPC-31260 (a V2 receptor antagonist) on arginine vasopressin (AVP)- or norepinephrine (NE)-induced vasoconstrictions of isolated simian femoral arteries. The dose-response curve for AVP was shifted to the right in parallel by OPC-31260 but not by OPC-21268. Neither antagonist significantly modified the NE-induced vasoconstriction. On the basis of these results, there are functionally constrictory vasopressin V2 receptors but no V1 receptors in isolated simian femoral arteries.

Topics: Animals; Antidiuretic Hormone Receptor Antagonists; Arginine Vasopressin; Benzazepines; Female; Femoral Artery; In Vitro Techniques; Macaca; Male; Norepinephrine; Piperidines; Quinolones; Vasoconstriction

We investigated the effects of V1 IOPC-21268, 1-(1-[4-(3-acetylaminopropoxy)benzoyl]-4-piperidyl)-3,4-dihydro-2( 1H)- quinolinone) and V2 (OPC-31260, 5-dimethylamino-1[4-(2-methylbensoylamino)benzoyl]-2,3,4,5-tetrahy dro-1H- benzazepine) vasopressin receptor antagonists on the negative inotropic response to arginine vasopressin (AVP) in the isolated perfused heart preparations of the dog. AVP (7.5-750 pmol) decreased the atrial and ventricular contractile force when the preparation was perfused with constant pressure or constant flow. AVP induced a small increase in sinus rate. Desmopressin, a selective vasopressin V2 agonist, did not change the sinus rate and atrial or ventricular contractile force. OPC-21268 (0.01-3 mumol) and OPC-31260 (0.01-1 mumol) induced a small negative inotropic effect. Both OPC-21268 and OPC-31260 inhibited the negative inotropic response to AVP in a dose-dependent manner. The doses of 50% inhibition (ID50) for OPC-21268 and OPC-31260 on the inotropic effect were 0.30 +/- 0.16 mumol and 0.084 +/- 0.034 mumol, respectively. Neither OPC-21268 nor OPC-31260 affected the acetylcholine-, adenosine- or norepinephrine-induced inotropic and chronotropic effects. It has been reported that the concentration of OPC-21268 that displaced 50% of specific AVP binding is 0.4 microM for V1 receptors and > 100 microM for V2 receptors and the concentration of OPC-31260 is 0.01 microM for V2 receptors and 1 microM for V1 receptors. We, therefore, suggest that AVP directly causes negative inotropic effects mediated at least in part by V1 receptors in the dog heart.

Topics: Animals; Antidiuretic Hormone Receptor Antagonists; Arginine Vasopressin; Benzazepines; Deamino Arginine Vasopressin; Dogs; Heart; Heart Atria; Perfusion; Piperidines; Quinolones; Receptors, Vasopressin