Regional blood flows and cardiac function changes induced by angiotensin II in conscious dogs

Hemodynamic properties of angiotensin (ANG) II 1, 5, 10 and 100 ng/kg i.v. and 10, 100 and 1000 ng/kg i.v.t. were assessed in conscious dogs. ANG II i.v. produced a dose-dependent pressor response (59 +/- 5-124 +/- 16 mmHg) and renal vasoconstriction (1.3 +/- 0.4-96 +/- 32 mmHg/ml/min). Ganglionic blockade (chlorisondamine 2 mg/kg i.v.) diminished mean arterial responses without altering peptide effects on renal circulation. At the highest dose, ANG II i.v. induced cardiac stimulation: increased heart rate (75 +/- 4-115 +/- 6 beats/min), cardiac output (2.0 +/- 0.1-2.4 +/- 0.2 l/min), dP/dt (2308 +/- 181-2773 +/- 173 mmHg/sec) and coronary blood flow (49 +/- 10-96 +/- 23 ml/min). Although with chlorisondamine cardiac response was more pronounced, subsequent beta blockade abolished it. Concomitantly, an isolated increase in plasma epinephrine was recorded (63 +/- 8-1505 +/- 354 pg/ml). A pressor response (59 +/- 8-89 +/- 13 mmHg) and renal vasoconstriction (1.1 +/- 0.1-2.2 +/- 0.5 mmHg/ml/min) were also produced by ANG II i.v.t. at the highest dose. These centrally mediated changes were prevented by chlorisondamine. Our study demonstrates 1) i.v. ANG II-mediated pressor responses are dependent on direct and indirect components, the relative contribution of each being dependent on the regional circulation; ANG II i.v. also produced a biphasic cardiac response--an initial centrally mediated depression and a secondary stimulation dependent on epinephrine via cardiac beta receptors and 2) i.v.t. ANG II-mediated pressor effects are essentially indirect. Finally, no evidence was found to support the role of vasopressin in ANG II effects.     

Endogenous opioid peptide inhibition of the central actions of angiotensin

Effects of endogenous opioid peptides (leucine5-enkephalin; methionine5-enkephalin; and beta-endorphin) and morphine on isoleucine5-angiotensin II (All)-stimulated increase in plasma vasopressin concentration, blood pressure and drinking behavior were characterized in conscious rats. Plasma vasopressin concentration, drinking frequency and latency were measured 90 sec after intracerebroventricular (i.v.t.) All in animals pretreated with enkephalins, beta-endorphin or morphine, i.v.t. Vasopressin was measured by radioimmunoassay. A consistent dose-related, naloxone-sensitive inhibition of the All-stimulated increase in plasma vasopressin concentration and drinking behavior (frequency) occurred after enkephalins, beta-endorphin or morphine. beta-Endorphin and morphine were longer acting and more potent than enkephalins. In other experiments, All (i.v.t.) pressor activity, drinking volume and latency were measured at hourly intervals after opiates, i.v.t. The All-stimulated increase in mean blood pressure and drinking volume were inhibited by endogenous opioid peptides and morphine, i.v.t. Naloxone prevented opiate inhibition of the All pressor response. Endogenously synthesized opiates may modulate All activity as naloxone potentiated the pressor response and decreased water consumption after All, i.v.t. Continuous i.v. infusion of leucine-enkephalin did not affect All drinking or pressor activity, indicating a central nervous system site of inhibition. Opiate inhibition of the central actions of All appeared independent of sedation; head shakes or wet dog shakes occurred at effective doses of enkephalins. Naloxone did not affect basal blood pressure or plasma vasopressin concentration. Endogenous opioid peptides may modulate the central actions of angiotensin II affecting blood pressure and hydration.     

Nonpeptide angiotensin II receptor antagonists. VIII. Characterization of functional antagonism displayed by DuP 753, an orally active antihypertensive agent

In the spinal pithed rat, DuP 753, 2-n-butyl-4-chloro-5-hydroxy-methyl-1-[(2'-(1H-tetrazol-5-yl)biphe nyl-4-yl) methyl] imidazole potassium salt, inhibited competitively the pressor response to angiotensin II (AII), whereas saralasin showed a noncompetitive pattern of interaction. It did not alter the pressor responses to vasopressin and norepinephrine as well as the heart rate response to isoproterenol. In the anesthetized rat, DuP 753 did not affect the vasodepressor response to bradykinin. Given p.o. or i.v., DuP 753 did not lower blood pressure in conscious normotensive rats, but it inhibited the pressor response to AII but not to vasopressin. It lowered blood pressure in furosemide-treated normotensive rats. Unlike saralasin, DuP 753 did not cause a transient increase in blood pressure even at 100 mg/kg i.v. DuP 753 at 3.5 micrograms i.c.v. inhibited the pressor response to i.c.v. AII, whereas DuP 753 at 10 mg/kg p.o. did not, suggesting that a single p.o. administration of DuP 753 does not affect brain AII receptors which are accessible by i.c.v. injection. Our study indicates that DuP 753 is a p.o. active, nonpeptide, selective, competitive AII receptor antagonist.     

Fluoxetine-induced pressor response in freely moving rats: a role for vasopressin and sympathetic tone

The present study was performed in order to assess, in freely moving rats, the cardiovascular effects of central administration of fluoxetine, a serotonin reuptake inhibitor. Two kinds of experiments were performed: 1) acute central administration of fluoxetine. and 2) chronic intraperitoneal administration of fluoxetine plus selegiline, a monoamine oxidase B inhibitor. Intracerebroventricular (i.c.v.) administration of fluoxetine (5-50 microg) induced an increase in blood pressure. This fluoxetine-induced pressor response reached its maximal 1 hour after injection without any significant change in heart rate. At the dose of 10 microg i.c.v., fluoxetine significantly increased mean blood pressure by 16 +/- 4 mmHg. This pressor response was reduced by an intravenous (i.v.) pretreatment with the alpha1-adrenoceptor antagonist, prazosin (500 microg kg(-1)) (+ 7 +/- 4 mmHg, P <0.05) or with the V1A-vasopressin receptor antagonist (20 microg kg(-1)) (+5 +/- 3 mmHg, P < 0.05). The pressor response was completely abolished by a concomitant pretreatment with prazosin plus the V1A-vasopressin receptor antagonist. Pretreatment with the beta-adrenoceptor antagonist, propranolol (1 mg kg(-1) i.v.), or the 5-HT2 receptor antagonist, ketanserine (5 mg kg(-1) i.v.), did not modify the fluoxetine-induced pressor response. In freely moving rats receiving fluoxetine (10 microg i.c.v.), vasopressin plasma levels were significantly higher (39 +/- 5 pg mL(-1) than in rats receiving 10 microL i.c.v. saline (14 +/- 4 pg mL(-1)). A 30 day intraperitoneal (i.p.) administration of fluoxetine in association with selegiline induced an increase in noradrenaline plasma levels and locomotor activity without any significant change in blood pressure and heart rate. These data suggest that, the pressor response elicited by central acute administration of fluoxetine is mediated by both an increase in sympathetic tone and vasopressin release. This observation could suggest the putative interest of alpha1-adrenoceptor and or V1A-vasopressin receptor antagonists in the treatment of "Serotonin Syndrome".     

Mechanism of the pressor action of LY171555, a specific dopamine D2 receptor agonist, in the conscious rat

Administration of LY171555, a specific dopamine D2 receptor agonist, (10-1000 micrograms/kg i.v.) produced dose-related increases in mean arterial pressure in conscious Sprague-Dawley rats. Pretreatment with metoclopramide (5 mg/kg i.v.) abolished the pressor action of LY171555, whereas pretreatment with domperidone (2.5 mg/kg i.v.) and propranolol (10 mg/kg i.p.) did not affect the pressor action of LY171555. The vasopressor antagonist of arginine vasopressin (AVP), d(CH2)5Tyr(Me)AVP (10 micrograms/kg i.v.) and phenoxybenzamine (1 mg/kg i.v.) partly blocked and hexamethonium (25 mg/kg i.v.) enhanced the pressor action of LY171555. After combined treatment with both d(CH2)5Tyr(Me)AVP and phenoxybenzamine, LY171555 induced a depressor response which was completely blocked by pretreatment with domperidone. LY171555 administration induced a rapid, short-acting depressor response followed by a pressor response in conscious adrenomedullectomized Sprague-Dawley rats which was smaller in magnitude than that seen in intact Sprague-Dawley rats. LY171555 administration increased plasma norepinephrine, epinephrine and AVP in conscious Sprague-Dawley rats. These results suggest that the pressor action of LY171555 in conscious rats is dependent on activation of sympathetic outflow and AVP release through the central D2 dopaminergic system and that the central pressor effects of LY171555 could mask a depressor effect of LY171555 at the peripheral D2 dopamine receptor.     

Role of arginine vasopressin and angiotensin II in cardiovascular responses to combined acute hypoxemia and hypercapnic acidosis in conscious dogs.

The physiological relationship of increased circulating angiotensin II and vasopressin to circulatory changes during combined hypoxemia and hypercapnic acidosis is unclear. To evaluate the role(s) of angiotensin II and vasopressin, seven unanesthetized female mongrel dogs with controlled sodium intake (80 meq/24 h X 4 d) were studied during 40 min of combined acute hypoxemia and hypercapnic acidosis (PaO2, 36 +/- 1 mmHg; PaCO2, 55 +/- 2 mmHg; pH = 7.16 +/- 0.04) under the following conditions: (a) intact state with infusion of vehicles alone; (b) beta-adrenergic blockade with infusion of d,l-propranolol (1.0 mg/kg bolus, 0.5 mg/kg per h); of the vasopressin pressor antagonist d-(CH2)5Tyr(methyl)arginine-vasopressin (10 micrograms/kg); and (d) simultaneous vasopressin pressor and angiotensin II inhibition with the additional infusion of 1-sarcosine, 8-alanine angiotensin II (2.0 micrograms/kg per min). The rise in mean arterial pressure during the combined blood-gas derangement with vehicles appeared to be related to increased cardiac output, since total peripheral resistance fell. Beta-adrenergic blockade abolished the fall in total peripheral resistance and diminished the rise in cardiac output during combined hypoxemia and hypercapnic acidosis, but the systemic pressor response was unchanged. In addition, the rise in mean arterial pressure during the combined blood-gas derangement was unaltered with vasopressin pressor antagonism alone. In contrast, the simultaneous administration of the vasopressin pressor and angiotensin II inhibitors during combined hypoxemia and hypercapnic acidosis resulted in the abrogation of the overall systemic pressor response despite increased cardiac output, owing to a more pronounced fall in total peripheral resistance. Circulating catecholamines were increased during the combined blood-gas derangement with vasopressin pressor and angiotensin II blockade, suggesting that the abolition of the systemic pressor response in the last 30 min of combined hypoxemia and hypercapnic acidosis was not related to diminished activity of the sympathetic nervous system. These studies show that vasopressin and angiotensin II are major contributors to the systemic pressor response during combined acute hypoxemia and hypercapnic acidosis.     

Responses of atrial natriuretic peptide, vasopressin, aldosterone and renal function to intracerebroventricular infusion of angiotensin II in dogs.

To assess the mechanisms how angiotensin II (Ang II) given intracerebroventricularly (i.c.v.) induces natriuresis, the effects of Ang II (10 ng/kg/min, for 30 min) on the renin-angiotensin-aldosterone system, the release of vasopressin (AVP) and atrial natriuretic peptide (ANP) and on cardiovascular and renal functions were investigated in anesthetized dogs. In control dogs, vehicle alone (artificial cerebrospinal fluid) was infused at a rate of 10 microliters/min. Ang II given i.c.v. produced a gradual increase in urine flow, urinary sodium and potassium excretion and osmolar clearance, but had no effect on plasma ANP, aldosterone, arterial blood pressure, and renal blood flow. However, i.c.v. Ang II increased plasma AVP and decreased heart rate, plasma renin activity, inulin clearance and filtration fraction. In the cotrol group, vehicle treatment had no effect on these parameters except for decreases in inulin clearance and filtration fraction. These results suggest that circulating ANP and blood pressure may not play an important role in i.c.v. Ang II-induced natriuresis, but increased AVP release and decreased renal sympathetic nervous activity may contribute to the natriuresis.     

Sympathoadrenal stimulation, not endothelin, plays a role in acute pressor response to cyclosporine in anesthetized rats.

The possible role of sympathoadrenal stimulation and endothelin release in cyclosporine (CS)-induced hypertension was ascertained in intact and pithed rats. CS (20 and 40 mg/kg), administered by i.v. infusion over 10 min, produced a dose-dependent increase in blood pressure: 19 +/- 5 and 31 +/- 2 mm Hg in intact rats and 13 +/- 4 and 18 +/- 2 mm Hg in pithed rats. In intact rats, pretreatment with reserpine (5 mg/kg, i.p.) or hexamethonium (10 mg/kg, i.v.) greatly blunted the pressor responses to CS (40 mg/kg) (7 +/- 3 and 11 +/- 2 mm Hg, respectively). In pithed rats, the blood pressure responses to CS (40 mg/kg) were significantly impaired, but were not further modified by phenoxybenzamine (3 mg/kg, i.v.), whereas adrenalectomy completely abolished the CS-induced pressor responses (0 +/- 1 mm Hg). CS (40 mg/kg) did not potentiate pressor responses to sympathetic nerve stimulation (0.1 and 0.3 Hz) or vasoconstrictors, including angiotensin II (0.03 microgram/kg, i.v.), phenylephrine (1 microgram/kg, i.v.) and arginine vasopressin (0.075 microgram/kg) in pithed rats. In addition, CS (40 mg/kg, i.v.) did not cause elevation of plasma immunoreactive endothelin-1 and -3. Furthermore, phosphoramidon (0.25 mg/kg/min x 30) abolished pressor response to big endothelin-1 (5 micrograms/kg, i.v.) but failed to affect CS-induced hypertension. It is concluded that the acute blood pressure response to CS manifests great dependence on sympathetic nervous system but appears independent of endothelin release.     

Central and peripheral injections of the 5-HT2 agonist, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane, modify cardiovascular function through different mechanisms.

The mechanisms underlying the cardiovascular effects of central and peripheral administration of the 5-HT2 (serotonin) receptor agonist (+-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI) were studied in conscious rats. Intravenous (10-1000 nmol/kg) and i.c.v. (3-300 nmol) administration of DOI produced dose-related elevations of arterial pressure without altering heart rate except after injection of the highest doses. Pretreatment with xylamidine tosylate, a 5-HT2 receptor antagonist that does not cross the blood-brain barrier, blocked the pressor response to i.v., but not i.c.v., administration of equivalent doses of DOI. Pretreatment with the vasopressin receptor antagonist d(CH2)5Tyr(Me)AVP significantly reduced the pressor response to i.c.v., but not i.v., administration of DOI. Prior ganglionic blockade with chlorisondamine amplified the pressor response to both i.v. and i.c.v. administration of DOI. Pretreatment with a combination of chlorisondamine, xylamidine and d(CH2)5Tyr(Me)AVP abolished the pressor response to i.c.v. administration of DOI. Thus, the pressor response to i.v. administration of DOI was mediated at sites outside the blood-brain barrier, most likely at vascular 5-HT2 receptors, and was not secondary to vasopressin release. Inappropriate heart rate changes attended the pressor responses to i.v. administration of DOI, suggesting an action at extravascular sites. The pressor response to i.c.v. administration of DOI resulted from a combination of vasopressin release, modulation of autonomic nervous outflow and some leakage into the periphery.     

Vasopressin mediates the pressor effect of hypertonic saline solution in endotoxic shock

The administration of lipopolysaccharide (LPS) to experimental animals results in a septic shock-like syndrome characterized by hypotension, and the hemodynamic management includes the restoration of adequate tissue perfusion by administration of resuscitation fluids to achieve an effective circulating volume. In the present study, we sought to investigate the effects of hypertonic saline solution administration on vasopressin secretion and mean arterial pressure in endotoxic shock. The pressor response to isotonic saline solution (0.9% sodium chloride) or hypertonic saline (7.5% sodium chloride, 4 mL/kg i.v.) was evaluated 4 h after LPS (1.5 mg/kg) administration. At this moment, plasma vasopressin did not differ from control; however, the blood pressure was lower in the LPS-treated group. The hypertonic saline administration was followed by an immediate recovery of blood pressure and also by an increase in plasma vasopressin levels compared with isotonic saline solution. The vasopressin V1 receptor antagonist (10 microg/kg, i.v., 5 min before infusion) blocked the pressor response to hypertonic saline solution. These data suggest that the recovery of blood pressure after hypertonic saline solution administration during endotoxic shock is mediated by vasopressin secretion.     

Nonpeptide angiotensin II receptor antagonists. XI. Pharmacology of EXP3174: an active metabolite of DuP 753, an orally active antihypertensive agent

This report describes the pharmacology of (2-n-butyl-4-chloro-1- [(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazole-5-carboxylic acid (EXP3174). EXP3174 is a major metabolite generated after the oral dosing of 2-n-butyl-4-chloro-5-hydroxymethyl-1-[(2'-(1H- tetrazol-5-yl)biphenyl-4-yl)methyl]imidazole, potassium salt in rats. It displaced [3H]angiotensin II (AII) from its specific binding sites in rat adrenal cortical membranes with an IC50 of 3.7 x 10(-8) M. In the isolated rabbit aorta, EXP3174 caused nonparallel shifts to the right of the AII concentration-contractile response curves and reduced the maximal response by 30 to 40% with an apparent pA2 value of 10.09 and a KB value of 10(-10) M. At 10(-6) M, EXP3174 did not alter the contractile responses to norepinephrine and KCl. In the spinal pithed rat, EXP3174 at 0.03 to 0.3 mg/kg i.v. also inhibited the pressor responses to AII and angiotensin III noncompetitively and did not change the pressor responses to vasopressin and norepinephrine. When given i.v. and cumulatively to normotensive rats at 0.003 to 0.3 mg/kg, EXP3174 did not alter blood pressure but inhibited the pressor response to AII. In conscious renal artery-ligated rats, EXP3174 decreased blood pressure with an i.v. ED30 of 0.038 mg/kg and a p.o. ED30 of 0.66 mg/kg. These results demonstrate that EXP3174 is a selective and noncompetitive AII receptor antagonist and lacks agonistic effect. As EXP3174 is a potent antihypertensive agent, it may be responsible for part of the antihypertensive effect of DuP 753 in rats.     

Cardiovascular responses to cocaine are initially mediated by the central nervous system in rats.

Cocaine produces a pressor response reportedly resulting from both potentiation of peripheral catecholamine activity and a centrally mediated sympathoexcitation. In the present study we sought to differentiate the central nervous system and peripheral contributions to the hemodynamic effects of cocaine. In conscious rats, cocaine (5 mg/kg i.v.) produced a pressor response with two distinct components consisting of a brief, substantial increase in mean arterial pressure (MAP) associated with hindquarters and mesenteric vasoconstriction followed by a sustained, modest response associated with mesenteric vasoconstriction and bradycardia. Pentolinium (7.5 mg/kg i.v.) or adrenal demedullation attenuated the peak increase in MAP by attenuating increases in mesenteric and hindquarters vascular resistance, but did not affect the sustained increase in MAP. Methyl atropine (0.5 or 1 mg/kg i.v.) pretreatment reduced the cocaine-induced increase in systemic vascular resistance and enhanced the hindquarters vasodilation during the sustained MAP response. In contrast, adrenal demedullation abolished the hindquarters vasodilation. The bradycardic response was prevented by pentolinium and reduced by methyl atropine. Sympathetic nerve activity was reduced dramatically after cocaine or procaine administration for several minutes in conscious and in chloralose-anesthetized rats. In several anesthetized rats, the sympathoinhibition was preceded by a brief (3-8 sec) increase in renal sympathetic nerve activity. Procaine or cocaine produced little change in cortical cerebral blood flow as estimated by using a laser Doppler flowmeter. These data suggest that cocaine produces an initial, brief centrally mediated sympathoexcitation, but the sustained, modest pressor response is dependent upon peripheral actions that are diminished by baroreflex activation.     

The role of central and autonomic neural mechanisms in the cardiovascular effects of cocaine in conscious squirrel monkeys

The effects of cocaine on cardiovascular function were studied in six conscious squirrel monkeys. Cocaine (0.01-3 mg/kg i.v.) increased mean arterial blood pressure and heart rate (HR) in a dose-dependent manner. The effect of cocaine on HR reached a maximum at 0.3 mg/kg. Doses of cocaine up to 3 mg/kg did not evoke cardiac rhythm disturbances. Pentobarbital or halothane anesthesia attenuated the pressor and tachycardiac effects of 3 mg/kg of cocaine. Antagonism of the pressor response to cocaine by halothane was significantly greater than that by pentobarbital. Halothane, but not pentobarbital, also significantly reduced the pressor response to norepinephrine (1 micrograms/kg i.v.). Blockade of autonomic ganglia by hexamethonium failed to antagonize the pressor and tachycardiac effects of 3 mg/kg of cocaine. The pressor response to 3 mg/kg of cocaine was antagonized by alpha adrenoceptor blockade with phentolamine, whereas the tachycardiac response to cocaine was antagonized by beta adrenoceptor blockade with propranolol. These results suggest that the blood pressure and HR increasing effects of cocaine in conscious squirrel monkeys are not due to stimulation of the central nervous system-sympathoadrenal neural axis, but are due to its peripheral actions on catecholaminergic systems. The 1- and 3-mg/kg doses of cocaine caused an initial reduction in HR of 5 to 30 beats/min in three monkeys and 90 to 110 beats/min in one animal before the onset of their tachycardiac effect. None of the above pharmacological interventions were effective in preventing this initial, moderate reduction in HR in three monkeys.(ABSTRACT TRUNCATED AT 250 WORDS)     

Stimulation of vasopressin release by gamma-aminobutyric acid antagonists in spinal cord transected rats

Picrotoxin, a gamma-aminobutyric acid (GABA) antagonist, administered to spinal rats elicited dose-related increases in mean blood pressure and circulating plasma vasopressin concentration which were found to be highly correlated (r = 0.952; P less than .001) 6 min after infusion of picrotoxin. Pretreatment with the vasopressin antagonist d(CH2)5Tyr(Me)arginine vasopressin (10 microgram/kg i.v.) blocked the picrotoxin-induced pressor response. Administration of bicuculline (1.0 mg/kg i.v.), a second GABA antagonist, caused an increase in mean blood pressure and plasma vasopressin, whereas strychnine, another central nervous system stimulant thought not to act via a GABAergic mechanism, failed to evoke a significant change in either mean blood pressure or plasma vasopressin. Midcollicular decerebration decreased base-line plasma vasopressin concentrations and also prevented the picrotoxin-induced increase in pressure and vasopressin. The data from this study suggest that blockade of tonic GABAergic inhibition by GABA antagonists causes the release of vasopressin into the systemic circulation which results in a pressor response in spinal rats. The level at which this GABAergic inhibition occurs is not known; however, the GABA antagonists appear to require an intact supraspinal neuraxis to cause the release of vasopressin from the neurohypophysis.     

Pharmacology of DuP 532, a selective and noncompetitive AT1 receptor antagonist

DuP 532 (2-propyl-4-pentafluoroethyl-1-[(2'-(1H-tetrazol-5-yl)bip hen yl- 4-yl)methyl]imidazole-5-carboxylic acid) inhibited the specific binding of [125I]angiotensin II (AII) for the subtype receptor AT1 in rat adrenal cortical membranes with an IC50 of 3.1 X 10(-9) M, but not the [125I]AII binding for the subtype AT2 sites in rat adrenal medulla tissues. It inhibited the contractile response to AII selectively and noncompetitively in the isolated rabbit aorta with a KB value of 1.1 X 10(-10) M. The selective AII antagonism was confirmed in the guinea pig ileum and the pithed rat. In conscious rats, DuP 532 inhibited the AII-induced pressor effect, aldosterone secretion, and water drinking induced by AII. In conscious renal hypertensive rats, DuP 532 decreased blood pressure with i.v. and p.o. ED30 of 0.02 and 0.21 mg/kg, respectively. The antihypertensive effect of DuP 532 at 0.3 to 3 mg/kg p.o. lasted for at least 24 hr. In conscious spontaneously hypertensive rats, DuP 532 given i.v. or p.o. at 0.3 to 3 mg/kg reduced blood pressure dose-dependently. DuP 532, at doses up to 100 mg/kg i.v., did not cause a pressor response in conscious normotensive rats, suggesting lack of agonism. DuP 532 exerted selective AII antagonism in conscious dogs. In conscious furosemide-treated dogs, DuP 532 given either at 0.3 and 1 mg/kg i.v. or at 1 to 10 mg/kg p.o. decreased blood pressure. As the AT1 receptors are responsible for AII-induced vasoconstriction, aldosterone secretion, and water drinking, our study indicates that DuP 532 is a potent, orally active, selective, and noncompetitive AT1 receptor antagonist and antihypertensive agent.     

Pharmacological characterization of the nonpeptide angiotensin II receptor antagonist, SK&F 108566.

The angiotensin II (AII) antagonist activity of (E)-alpha-[[2-butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5- yl]methylene]-2-thiophenepropanoic acid (SK&F 108566), was examined in a number of in vitro and in vivo assays. In rat and human adrenal cortical membranes, SK&F 108566 displaced specifically bound [125I]AII with IC50 of 9.2 and 3.9 nM, respectively. SK&F 108566 also inhibited [125I]AII binding to human liver membranes (IC50 = 1.7 nM) and to rat mesenteric artery membranes (IC50 = 1.5 nM). In rabbit aortic smooth muscle cells, SK&F 108566 caused a concentration-dependent inhibition of AII-induced increases in intracellular Ca++ levels. In rabbit aortic rings, SK&F 108566 produced parallel rightward shifts in the AII concentration-response curve without affecting the maximal contractile response. Schild analysis of the data yielded a KB value of 0.26 nM and a slope not different from 1, indicative of competition antagonism. SK&F 108566 had no effect on the contractile responses to KCl, norepinephrine or endothelin in rabbit aorta. In conscious normotensive rats, i.v. administration of SK&F 108566 (0.01-0.3 mg/kg) produced dose-dependent parallel shifts in the AII pressor dose-response curve. Administration of SK&F 108566 (3-10 mg/kg) intraduodenally or intragastrically to conscious normotensive rats resulted in a dose-dependent inhibition of the pressor response to AII (250 ng/kg, i.v.). At 10 mg/kg, i.d., significant inhibition of the pressor response to AII was observed for 3 hr. In this same rat model, SK&F 108566 had no effect on base-line pressure or on the pressor response to norepinephrine or vasopressin. The data demonstrate that SK&F 108566 is a potent, highly selective, competitive nonpeptide AII antagonist.(ABSTRACT TRUNCATED AT 250 WORDS)     

Central effects of quinpirole on blood pressure of spontaneously hypertensive rats.

The i.v. administration of the dopamine D-2 receptor agonist quinpirole induced a rapid increase in blood pressure in spontaneously hypertensive rats (SHR). Heart rate showed little change. The pressor response to quinpirole was similar in SHR and normotensive Wistar-Kyoto rats (WKY) at doses of 0.03 to 0.3 mg/kg but, at 1 mg/kg, quinpirole induced a greater increase in blood pressure in SHR than in WKY. In contrast, although both strains showed a decreased locomotor activity after administration of 0.01 to 0.05 mg/kg of quinpirole, only in WKY was activity enhanced by 0.25 to 1.25 mg/kg of quinpirole. The i.v. administration of the dopamine agonists apomorphine, N-propylnorapomorphine and (R)-(+)-3-(3-hydroxyphenyl)-N-propylpiperidine, but not the putative presynaptic D-2 agonist (S)-(-)-3-(3-hydroxyphenyl)-N- propylpiperidine, induced pressor responses in SHR comparable to those after quinpirole administration. The pressor effect of quinpirole was enhanced by pretreatment with the peripheral D-2 antagonist domperidone, but blocked by the centrally acting dopamine antagonists haloperidol or sulpiride. In SHR, which were pretreated centrally with pertussis toxin, quinpirole induced a significantly smaller increase in blood pressure than in control SHR. Pretreatment centrally with 6-hydroxydopamine had no effect on the pressor action of quinpirole in SHR. Thirty minutes after i.v. administration of quinpirole, an additional injection of quinpirole did not significantly change blood pressure. Increasing the interval between two subsequent injections of quinpirole showed that this desensitization slowly reversed, but only after 24 hr had the pressor response to quinpirole fully recovered.(ABSTRACT TRUNCATED AT 250 WORDS)     

Functional studies of nonpeptide angiotensin II receptor subtype-specific ligands: DuP 753 (AII-1) and PD123177 (AII-2)

DuP 753 and PD123177 are two nonpeptide angiotensin II (AII)-specific ligands, which show high affinities for two respective and distinct subtypes of AII binding sites, i.e., AII-1 and AII-2 sites, respectively, in the rat adrenal gland, brain and uterus. The objective of this study is to identify the functions of these subtype binding sites in the adrenal, sympathetic ganglia, brain and vascular smooth muscle. In conscious rats, DuP 753 at 1, 3 and 10 mg/kg i.v. but not PD123177 at 30 and 100 mg/kg i.v. inhibited the AII-induced aldosterone increase. In the isolated perfused rat adrenal gland, DuP 753 at 10(-6) and 10(-4) M but not PD123177 at 10(-3) M blocked the AII-induced epinephrine secretion. In control and chemically sympathectomized pithed rats, the pressor and tachycardiac responses to AII were blocked by DuP 753 at 10 mg/kg i.v. but not by PD123177 at 100 mg/kg i.v. In conscious rats, DuP 753 at 10 mg/kg s.c. but not PD123177 at 100 mg/kg s.c. inhibited the AII-induced water drinking. In the rabbit aorta, DuP 753 at 10(-6) M but not PD123177 at 10(-4) M inhibited the contractile effect of AII. In conscious renal artery-ligated hypertensive rats, DuP 753 but not PD123177 at 0.1 to 10 mg/kg i.v. lowered blood pressure. In summary, a function of the PD123177-sensitive AII binding site (AII-2) has not yet been identified. However, the DuP 753-sensitive site (AII-1) appears to mediate the AII-induced responses such as adrenal aldosterone and catecholamine secretion, release of catecholamine from sympathetic ganglia, drinking and vasoconstriction.     

Adrenergic mechanisms underlying cardiac and vascular responses to cocaine in conscious rats.

The contribution of adrenergic receptors to the cardiovascular responses to cocaine (5 mg/kg i.v.) were examined in conscious, free-moving rats instrumented for continuous measurement of arterial pressure, heart rate and blood flows in the mesentery and hindquarters or ascending aorta. Cocaine elicits an immediate (peak) and sustained pressor response with a concomitant reduction in heart rate. Prazosin (0.1 mg/kg i.v.) pretreatment significantly reduced both the peak and sustained pressor responses by attenuating the increases in systemic, mesenteric and hindquarters vascular resistances. Idazoxan pretreatment (1 mg/kg i.v.) attenuated the peak increase in hindquarters vascular resistance. Whereas propranolol pretreatment (1 mg/kg i.v.) attenuated the peak pressor response, the sustained pressor response was enhanced due to increased hindquarters and systemic vascular resistances. Metoprolol pretreatment (1 mg/kg i.v.) enhanced the sustained pressor response to cocaine, in part due to increased heart rate and mesenteric vascular resistances. Upon examination of the cardiac effects of cocaine, a sustained bradycardic response was observed, whereas stroke volume and cardiac output were relatively unaffected. The bradycardic response to cocaine was attenuated by yohimbine (0.1 mg/kg i.v.), prevented by prazosin and converted to a tachycardia after idazoxan (1 mg/kg) pretreatment. After propranolol pretreatment, cocaine substantially decreased cardiac output and stroke volume. Our results demonstrate that cocaine produces a biphasic pressor response in conscious rats and that the mechanisms underlying the dual responses vary in intensity and mode of action in different vascular beds, but are primarily dependent upon alpha-1 adrenergic receptor-mediated vasoconstriction.     

Nonpeptide angiotensin II receptor antagonists. IX. Antihypertensive activity in rats of DuP 753, an orally active antihypertensive agent

In conscious renal artery-ligated rats, a high renin hypertensive rat model, DuP 753, a p.o. active nonpeptide angiotensin II (AII) receptor antagonist, decreased blood pressure at 0.1 to 3 mg/kg given i.v. or at 0.3 to 10 mg/kg given p.o. with an i.v. ED30 of given i.v. or at 0.3 to 10 mg/kg given p.o. with an i.v. ED30 of 0.78 mg/kg and a p.o. ED30 of 0.59 mg/kg. The antihypertensive efficacy of DuP 753 was similar to that of captopril. Unlike the peptide AII antagonist saralasin, DuP 753 did not cause a transient increase in blood pressure, suggesting absence of agonistic activity. At 3 mg/kg p.o., DuP 753 lowered blood pressure for at least 24 hr and did not change heart rate, suggesting a long duration of antihypertensive effect. At 3 mg/kg i.v., DuP 753 inhibited the pressor response to AII but not to norepinephrine or vasopressin. Pretreatment of renal artery-ligated rats with captopril, saralasin or propranolol, but not with prazosin, hydralazine or indomethacin, abolished or reduced the antihypertensive effect of DuP 753. In the deoxycorticosterone acetate hypertensive rat, a low renin model, DuP 753 did not lower blood pressure. These results suggest that DuP 753 is a p.o. active, antihypertensive agent in renal artery-ligated rats with a similar antihypertensive efficacy as captopril. The antihypertensive effect of DuP 753 is most likely related to the blockade of the vasoconstrictor effect of AII. Unlike saralasin, DuP 753 does not have agonistic activity.