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1.
Am J Hypertens ; 3(4): 262-7, 1990 Apr.
Article in English | MEDLINE | ID: mdl-2140688

ABSTRACT

The renal and hemodynamic responses to intravenous anaritide, a human atrial natriuretic factor [102-126] at 0.3 to 20 micrograms/kg in conscious rhesus monkeys with and without acute extracellular hypervolemia were analyzed and compared. Acute isotonic saline loading (intravenous bolus at 10 mL/kg plus continuous infusion at 0.25 mL/kg/min 30 min prior to and maintained throughout experiment) significantly augmented urine output (UV) and urinary Na+ excretion rate (UNaV) by 31% and 91%, respectively. Radial mean arterial pressure (MAP) and heart rate (HR) were not affected by volume expansion. Anaritide at doses higher than 0.3 micrograms/kg reduced MAP in a dose-dependent fashion in euvolemic monkeys. In contrast, reduction in MAP was observed only at the highest dose (20 micrograms/kg) of anaritide in hypervolemic monkeys. The hypotensive responses to anaritide at 20 micrograms/kg in euvolemic and hypervolemic animals were similar (-26 +/- 5 v -24 +/- 5 mm Hg, respective maximum changes in MAP). UV and UNaV were increased by anaritide at 3 to 20 micrograms/kg in both euvolemic and hypervolemic monkeys; however, the increases at each effective dose of anaritide were greater or tended to be greater in hypervolemic rhesus monkeys compared with euvolemic rhesus monkeys. Compared to vehicle responses, HR was not affected by anaritide in either group of animals. In conclusion, acute extracellular hypervolemia potentiates the renal but suppresses the hypotensive responses to anaritide in conscious rhesus monkeys.


Subject(s)
Atrial Natriuretic Factor/pharmacology , Diuretics/pharmacology , Hemodynamics/drug effects , Kidney/drug effects , Peptide Fragments/pharmacology , Plasma Volume/physiology , Animals , Blood Pressure/drug effects , Diuresis/drug effects , Dose-Response Relationship, Drug , Heart Rate/drug effects , Humans , Macaca mulatta , Male , Natriuresis/drug effects
2.
J Cardiovasc Pharmacol ; 11(3): 299-307, 1988 Mar.
Article in English | MEDLINE | ID: mdl-2452922

ABSTRACT

Arylalkylsulfonamides, identified as Wy-46,622 and Wy-47,324, combine pharmacological properties of the Ca2+ entry blocker verapamil and the calmodulin antagonist W-7. These agents directly inhibit arterial actin-myosin interactions via inhibition of myosin light chain (MLC) phosphorylation in actomyosin. Potencies of both Wy-46,622 (IC50 = 26 microM) and Wy-47,324 (IC50 = 18 microM) are greater than W-7 (IC50 = 35 microM); verapamil is inactive at 100 microM. Both Wy-46,622 and Wy-47,324 are less potent than verapamil, but more potent than W-7, at inhibiting K+-depolarized force development in paced rabbit atria. At higher concentrations (30 microM) which inhibit MLC phosphorylation, Wy-46,622 and Wy-47,324 are either equal to or more efficacious than verapamil in inhibiting receptor-mediated contractions in intact porcine coronary (histamine, serotonin, prostaglandin F2 alpha, carbocyclic thromboxane A2) or guinea pig aortic (leukotriene C4) smooth muscle. Both Wy-47,324 (IC50 = 16 microM) and Wy-46,622 (IC50 = 23 microM) are inhibitors of the second phase of epinephrine-induced human platelet aggregation; Wy-47,324 is more potent than verapamil or W-7 (IC50 for each = 29 microM). These results suggest that these agents possess combined Ca2+ entry blocker/MLC phosphorylation inhibitory mechanisms. Furthermore, they are more vascular specific than verapamil, and are effective inhibitors of intracellular Ca2+-mediated events in vascular smooth muscle and platelets.


Subject(s)
Calcium Channel Blockers/pharmacology , Myosins/metabolism , Sulfonamides/pharmacology , Vasodilator Agents/pharmacology , Verapamil/pharmacology , Actomyosin/metabolism , Animals , Cattle , Epinephrine/pharmacology , Heart/drug effects , Humans , In Vitro Techniques , Muscle, Smooth, Vascular/drug effects , Myocardial Contraction/drug effects , Phosphorylation , Platelet Aggregation/drug effects , Rabbits
3.
Am J Hypertens ; 1(1): 47-9, 1988 Jan.
Article in English | MEDLINE | ID: mdl-3259432

ABSTRACT

Calcitonin gene-related peptide (CGRP) is a potent peripheral vasodilator. In the present study, the cardiovascular effects of centrally administered CGRP were examined in conscious, normotensive rats. The rats were chronically instrumented with miniaturized pulsed Doppler flow probes to allow measurement of regional blood flow in the conscious animals. Injection of increasing doses of CGRP (0.3 to 3.0 micrograms/kg) in the lateral cerebroventricles transiently increased arterial pressure (maximal change = 13 +/- 3 mm Hg) and markedly increased heart rate (maximal increase = 88 +/- 10 b/min). The heart rate response was sustained over a period of 20 to 30 minutes. Central CGRP decreased hindquarter vascular resistance but had no effect on renal or mesenteric vascular resistances. In contrast, intravenous injections of CGRP reduced arterial pressure and renal, mesenteric, and hindquarter vascular resistances. The tachycardia response to central CGRP was attenuated by pretreatment with propranolol or hexamethonium, indicating that the heart rate response was mediated, in part, through increases in cardiac sympathetic tone. These data indicate that central CGRP may alter cardiovascular function through alterations in sympathetic outflow.


Subject(s)
Calcitonin/pharmacology , Hemodynamics/drug effects , Neuropeptides/pharmacology , Animals , Blood Pressure/drug effects , Calcitonin/administration & dosage , Calcitonin Gene-Related Peptide , Consciousness , Heart Rate/drug effects , Injections, Intravenous , Neuropeptides/administration & dosage , Rats , Rats, Inbred Strains , Regional Blood Flow/drug effects , Time Factors , Vascular Resistance/drug effects
4.
Regul Pept ; 19(5-6): 307-12, 1987 Dec.
Article in English | MEDLINE | ID: mdl-3501866

ABSTRACT

The cardiovascular effects of calcitonin gene-related peptide (CGRP) were examined in conscious, unrestrained rats. Changes in mean arterial pressure, heart rate and cardiac output were continuously monitored before and after i.v. bolus injection of CGRP (0.1-5 micrograms/kg). Injection of the peptide caused dose-dependent reductions in mean arterial pressure (-24 +/- 4 mmHg), which were accompanied by marked tachycardia. Cardiac output was significantly increased after CGRP but little change was observed in stroke volume. CGRP also reduced total peripheral resistance (-46 +/- 6%). These data indicate that the hypotensive actions of CGRP are mediated through peripheral vasodilation rather than through reductions in cardiac output. Pretreatment with propranolol significantly reduced the tachycardia responses to CGRP from 81 +/- 11 beats/min to 36 +/- 4 beats/min, but did not abolish the increase in heart rate. These data suggest that CGRP produces a tachycardia through reflex increases in cardiac sympathetic tone and through possible direct positive chronotropic effects on the heart.


Subject(s)
Hemodynamics/drug effects , Neuropeptides/pharmacology , Vasodilator Agents/pharmacology , Animals , Blood Pressure/drug effects , Calcitonin Gene-Related Peptide , Cardiac Output/drug effects , Dose-Response Relationship, Drug , Heart Rate/drug effects , Male , Rats , Rats, Inbred Strains , Stroke Volume/drug effects , Vascular Resistance/drug effects
5.
Peptides ; 8(4): 747-9, 1987.
Article in English | MEDLINE | ID: mdl-3498157

ABSTRACT

In the present study the regional hemodynamic effects of CGRP were examined in conscious unrestrained spontaneously hypertensive rats (SHR). The animals were chronically instrumented with miniaturized pulsed Doppler flow probes to allow continuous measurement of renal, mesenteric and hindquarter blood flow. Bolus intravenous injection of CGRP (0.1-5 micrograms/kg) produced a dose-dependent fall in mean arterial pressure (maximal change = -48 +/- 5 mmHg) which was accompanied by a marked tachycardia (maximal change = 143 +/- 16 b/min). Depressor responses to CGRP were sustained for approximately 3-5 min. CGRP markedly reduced regional vascular resistance in all three vascular beds. No regional-selective vasodilator response was observed. These data indicate that CGRP is a potent vasodilator peptide in conscious SHR. The study suggests further that CGRP may contribute to the physiologic regulation of cardiovascular function.


Subject(s)
Neuropeptides/pharmacology , Vasodilation/drug effects , Animals , Blood Pressure/drug effects , Calcitonin Gene-Related Peptide , Heart Rate/drug effects , Male , Rats , Rats, Inbred SHR , Regional Blood Flow/drug effects , Renal Circulation/drug effects
6.
Circ Res ; 61(1): 134-40, 1987 Jul.
Article in English | MEDLINE | ID: mdl-3038365

ABSTRACT

Previous studies have indicated that the hypotensive effects of atrial natriuretic factor were enhanced in renin-dependent hypertensive rats, suggesting that the atrial peptides may antagonize the vasoconstrictor effects of the renin-angiotensin system. The present study was designed to define further the interaction between atrial natriuretic factor and the renin-angiotensin system by examining the hemodynamic effects of Wy-47,663, a synthetic human atrial natriuretic factor, in conscious normotensive rats, in renin-dependent (aortic-ligated) hypertensive rats, and in rats made hypertensive by chronic infusion of angiotensin II. Changes in renal and mesenteric blood flow were continuously monitored in the rats using pulsed Doppler flow probes chronically implanted in the animals one week prior to testing. Infusion of increasing doses of Wy-47,663 caused dose-dependent reductions in mean arterial pressure in all three groups of rats, but the depressor responses were significantly greater in renal hypertensive and angiotensin II-infused rats. Renal blood flow tended to increase during the infusion of the atrial peptide in the angiotensin II-treated rats, and renal vascular resistance fell significantly (-37 +/- 6%). However, Wy-47,663 significantly reduced renal blood flow in the normotensive and renal hypertensive rats, while renal vascular resistance was increased (29 +/- 6%) and unchanged (3 +/- 9%), respectively. Mesenteric blood flow was reduced significantly, and mesenteric vascular resistance was increased markedly in all three groups of rats during infusion of the atrial peptide. In a separate group of renal hypertensive rats, the hemodynamic effects of complete blockade of the renin-angiotensin system were assessed by injection of an angiotensin II converting enzyme inhibitor (Wy-44,655).(ABSTRACT TRUNCATED AT 250 WORDS)


Subject(s)
Atrial Natriuretic Factor/pharmacology , Hemodynamics , Renin-Angiotensin System/drug effects , Vasoconstriction/drug effects , Angiotensin II/pharmacology , Angiotensin-Converting Enzyme Inhibitors , Animals , Dose-Response Relationship, Drug , Hemodynamics/drug effects , Hypertension/chemically induced , Hypertension/physiopathology , Male , Mesenteric Arteries/drug effects , Mesenteric Arteries/physiopathology , Rats , Rats, Inbred Strains , Renal Circulation/drug effects , Rheology , Vascular Resistance/drug effects
7.
J Cardiovasc Pharmacol ; 9(4): 435-44, 1987 Apr.
Article in English | MEDLINE | ID: mdl-2438506

ABSTRACT

Recainam, [N-2,6-dimethylphenyl-N'-3-(1-methylethyl-amino)propylurea] hydrochloride (Wy-42,362), is a new class I antiarrhythmic agent that has been shown to be very effective in suppressing premature ventricular contractions in humans. To clarify the mechanism of antiarrhythmic action, the electrophysiologic effects of recainam were examined in canine cardiac Purkinje fibers using standard microelectrode techniques. Recainam at 3-100 microM (1-30 micrograms/ml) produced concentration-dependent decreases in action potential duration (APD), membrane responsiveness, and maximal upstroke velocity (Vmax). The reduction in Vmax was strongly modulated by the frequency of stimulation--i.e., Vmax block was use dependent. The rate of development of use-dependent block produced by recainam was much slower than typically seen with lidocaine, but comparable with that of the class Ia agents disopyramide and procainamide. However, unlike agents of the Ia subclass, recainam did not prolong APD at any concentration or cycle length tested. In summary, recainam appears to possess a novel cardiac cellular electrophysiologic profile, in that it shares characteristics with all three current class I antiarrhythmic subclasses.


Subject(s)
Anti-Arrhythmia Agents/pharmacology , Heart Conduction System/drug effects , Phenylurea Compounds/pharmacology , Purkinje Fibers/drug effects , Action Potentials/drug effects , Animals , Cardiac Pacing, Artificial , Dogs , In Vitro Techniques , Membrane Potentials/drug effects , Purkinje Fibers/physiology
8.
Clin Exp Pharmacol Physiol ; 14(2): 137-40, 1987 Feb.
Article in English | MEDLINE | ID: mdl-2886239

ABSTRACT

The hemodynamic responses to i.v. infusion of 0.3 and 0.6 microgram/kg per min of human atrial natriuretic factor (hANF [102-126]) in intact, conscious, one-kidney, perinephritic, hypertensive beagles were examined and compared with the responses in ganglionic-blocked dogs. Blood pressure and heart rate were not affected but plasma ANF-like immunoreactivity was increased by as much as 627%. After hexamethonium (20 mg/kg, i.v.) blockade, a dose-dependent hypotensive response of up to 29 mmHg with no change in heart rate was observed. It is concluded that the compensatory mechanisms of the neurally mediated baroreflex system masked the depressor actions of hANF.


Subject(s)
Antihypertensive Agents/therapeutic use , Atrial Natriuretic Factor/therapeutic use , Hemodynamics/drug effects , Hypertension, Renal/drug therapy , Animals , Atrial Natriuretic Factor/blood , Dogs , Hexamethonium , Hexamethonium Compounds/pharmacology , Male
9.
J Cardiovasc Pharmacol ; 8(6): 1168-75, 1986.
Article in English | MEDLINE | ID: mdl-2434743

ABSTRACT

1,4,5,6,7,8-hexahydro-2-methyl-5-oxo-4-(pentafluorophenyl)-1,7- naphthyridine-3-carboxylic acid methyl ester hydrochlorides with either a 3-phenoxy-2-hydroxypropyl (Wy-46,300) or 2-hydroxy-4-phenylbutyl (Wy-46,531) substituent at the 7 position are structurally novel vascular relaxant compounds which lower blood pressure by approximately 35 mm Hg at 25 mg/kg p.o. in spontaneously hypertensive rats (SHR) or perinephritic hypertensive beagles. In contrast to standard Ca2+ blockers, both agents also directly inhibit myosin phosphorylation and actin-myosin interactions in Triton-purified arterial actomyosin. The potency of Wy-46,300 (IC50 = 28 microM) in this system is similar to the calmodulin antagonist W-7, whereas Wy-46,531 (IC50 = 18 microM) is more potent. Inhibition of both parameters is attenuated in the presence of maximal Ca2+-calmodulin, consistent with calmodulin antagonism as the mechanism for myosin phosphorylation inhibition. In intact smooth muscle, these agents inhibit K+-depolarized contractions of rabbit aortic strips in a biphasic manner (0.1-10 microM, 30-40% inhibition; 10 microM-100 microM, 90% inhibition). In contrast to comparable inhibition of force by standard Ca2+ blockers, this latter phase of inhibition is not reversible with the Ca2+ agonist Bay K 8644. Moreover, significantly greater inhibition of receptor-mediated contractions (norepinephrine, angiotensin II, histamine) than that observed with nifedipine is apparent with Wy-46,300. In paced rabbit atria, both Wy-46,300 and Wy-46,531 are 10-100 times less potent as negative inotropic agents (IC25 = 3-5 microM) when compared with standard Ca2+ blockers.(ABSTRACT TRUNCATED AT 250 WORDS)


Subject(s)
Antihypertensive Agents/pharmacology , Calcium Channel Blockers/pharmacology , Muscle, Smooth, Vascular/drug effects , Myosins/metabolism , Naphthyridines/pharmacology , Animals , Aorta, Thoracic/drug effects , Blood Pressure/drug effects , Dogs , Hypertension, Renal/drug therapy , In Vitro Techniques , Male , Muscle Relaxation/drug effects , Phosphorylation , Rabbits
10.
Hypertension ; 8(10): 866-73, 1986 Oct.
Article in English | MEDLINE | ID: mdl-2944826

ABSTRACT

The cardiovascular responses to intravenous bolus administration of several synthetic atrial natriuretic peptides were examined in conscious spontaneously hypertensive rats and compared with the hemodynamic effects of continuous infusions of the peptides. Rats were instrumented with pulsed Doppler flow probes to allow measurement of regional blood flow in the conscious, unrestrained hypertensive rat. Bolus administration of increasing doses (0.036-18 nmol/kg) of atriopeptin II, alpha-rat atrial natriuretic peptide, Wy-47,663, or alpha-human atrial natriuretic peptide caused short-lived, dose-dependent reductions in mean arterial pressure and renal vascular resistance. A marked but transient (10-40 seconds) increase in renal blood flow was observed after administration of the peptides. Mesenteric and hindquarter vasodilation also were observed after bolus injection of high doses of the atrial peptides. Infusion of alpha-rat atrial natriuretic peptide or Wy-47,663 (0.045-1.44 nmol/kg/min) resulted in sustained reductions in mean arterial pressure. The fall in arterial pressure was accompanied by significant reductions in regional blood flow in the renal, mesenteric, and hindquarter vascular beds. Dose-dependent increases in regional vascular resistances were observed in all three vascular beds during the peptide infusions. These data indicate that the hemodynamic responses to synthetic atrial peptides are greatly dependent on the mode of administration of the peptide in conscious spontaneously hypertensive rats. Stable, sustained responses were observed only during infusion steady state conditions.


Subject(s)
Atrial Natriuretic Factor/administration & dosage , Hemodynamics/drug effects , Animals , Atrial Natriuretic Factor/pharmacology , Infusions, Intravenous , Injections, Intravenous , Rats , Rats, Inbred SHR , Vascular Resistance/drug effects
11.
Pharmacol Biochem Behav ; 24(6): 1573-6, 1986 Jun.
Article in English | MEDLINE | ID: mdl-2942948

ABSTRACT

The present study examined the effects of ANF(4-28) [Wy-47,663], a synthetic 25 amino acid human atrial natriuretic factor, on the dipsogenic actions of centrally-administered angiotensin II in conscious rats. Bolus injection (100 ng) or continuous infusion (60 ng/min) of Wy-47,663 or vehicle into the lateral cerebroventricle had no effect on mean arterial pressure or heart rate. No obvious behavioral changes were observed after central administration of Wy-47,663 or vehicle. Central injection of angiotensin II (15 or 30 ng) promptly elicited prolonged drinking responses in vehicle-treated rats. In rats pretreated with Wy-47,663, the onset of the angiotensin II-induced drinking responses was significantly delayed compared to vehicle-treated animals. However, Wy-47,663 had no effect on the total volume consumed over 30 minutes after angiotensin II injection. Intravenous infusion of Wy-47,663 (2 micrograms/kg/min) failed to alter the dipsogenic action of centrally administered angiotensin II. These data indicate that atrial natriuretic factor found within the brain but not the peripheral circulation may participate in the regulation of extracellular fluid volume by modulating the dipsogenic actions of the central renin-angiotensin system.


Subject(s)
Angiotensin II/pharmacology , Atrial Natriuretic Factor/pharmacology , Brain/drug effects , Drinking/drug effects , Animals , Atrial Natriuretic Factor/blood , Blood Pressure/drug effects , Heart Rate/drug effects , Injections, Intraventricular , Male , Rats , Rats, Inbred Strains
12.
J Pharmacol Exp Ther ; 236(1): 187-91, 1986 Jan.
Article in English | MEDLINE | ID: mdl-2867214

ABSTRACT

The effects of fenoldopam, a selective dopamine-1 agonist, on regional blood flow and vascular resistance were examined in conscious unrestrained spontaneously hypertensive rats (SHR). Rats were instrumented chronically with pulsed Doppler flow probes to allow measurement of renal, mesenteric and hindquarters blood flow. Maximal changes in mean arterial pressure, heart rate and regional blood flow were recorded after i.v. administration of fenoldopam (1-1000 micrograms/kg). Fenoldopam produced a dose-dependent reduction in arterial pressure and increased heart rate in the conscious SHR. Significant increases in mesenteric (maximal = 69 +/- 10%) and renal (maximal = 42 +/- 4%) blood flows were observed at all doses of fenoldopam. In the hindquarters, vascular resistance was increased after low doses of fenoldopam (1-30 micrograms/kg), but decreased with higher doses (100-1000 micrograms/kg). After ganglionic blockade, hindquarter vasodilation was observed with fenoldopam at low (10 micrograms/kg) and high (500 micrograms/kg) doses. Pretreatment with metoclopramide (20 mg/kg) or SCH 23390 (30 micrograms/kg), a new selective dopamine-1 antagonist, significantly attenuated the vasodilator responses to fenoldopam in all three vascular beds. Pretreatment with propranolol failed to alter the vascular effects of fenoldopam, but reduced the tachycardia markedly. This study indicates that fenoldopam decreased regional vascular resistance in the renal, mesenteric and hindquarters vascular beds of the conscious SHR with the mesenteric vascular bed demonstrating the greatest reactivity. The vasodilation induced by fenoldopam in these vascular beds appeared to be due to stimulation of vascular dopamine-1 receptors.


Subject(s)
Benzazepines/pharmacology , Hypertension/physiopathology , Vascular Resistance/drug effects , Vasodilator Agents/pharmacology , Animals , Blood Pressure/drug effects , Fenoldopam , Heart Rate/drug effects , Male , Metoclopramide/pharmacology , Rats , Rats, Inbred SHR , Receptors, Dopamine/drug effects
13.
Am J Physiol ; 249(6 Pt 2): R781-6, 1985 Dec.
Article in English | MEDLINE | ID: mdl-2933964

ABSTRACT

Previous studies have demonstrated that infusion of synthetic atriopeptin II (AP II) lowered arterial pressure, reduced regional blood flow, and increased total peripheral and regional vascular resistances in conscious spontaneously hypertensive rats (SHR). This study was designed to examine the mechanism(s) involved in regional vasoconstrictor responses to AP II. In these experiments, hemodynamic actions of AP II were examined in control, 6-hydroxydopamine-treated (chemically sympathectomized), and renal-denervated groups of instrumented conscious SHR. Infusion of AP II (1 microgram X kg-1 X min-1) caused similar reductions in mean arterial pressure in control (-22 +/- 2 mmHg), chemically sympathectomized (-23 +/- 2 mmHg), and renal-denervated (-23 +/- 3 mmHg) SHR. In control SHR, AP II infusion reduced renal (-20 +/- 3%), mesenteric (-26 +/- 2%), and hindquarters (-18 +/- 10%) blood flow and increased regional vascular resistance in all three beds. Chemical sympathectomy prevented the fall in renal blood flow (RBF) and significantly abolished the regional vasoconstrictor responses to AP II infusion. In unilateral renal-denervated groups of SHR, AP II reduced renal vascular resistance (RVR) -11 +/- 3% but failed to alter RBF (-3 +/- 1%) in denervated kidneys. In contrast, RVR increased (20 +/- 7%) and RBF was significantly reduced (-29 +/- 3%) in contralateral-innervated kidneys. This study demonstrated that chemical or surgical destruction of renal sympathetic nerves abolished AP II-induced increases in RVR. These data further indicate that in conscious SHR the regional vasoconstrictor responses to AP II infusion appear to be mediated by increases in sympathetic tone rather than through direct vascular actions of AP II.


Subject(s)
Atrial Natriuretic Factor/pharmacology , Hypertension/physiopathology , Vasoconstriction/drug effects , Animals , Blood Pressure , Heart Rate/drug effects , Hydroxydopamines , Kidney/blood supply , Male , Oxidopamine , Rats , Rats, Inbred SHR , Regional Blood Flow/drug effects , Sympathectomy, Chemical , Vascular Resistance/drug effects
14.
J Pharmacol Exp Ther ; 235(3): 651-6, 1985 Dec.
Article in English | MEDLINE | ID: mdl-3001271

ABSTRACT

The present study was designed to examine the effects of two different converting enzyme inhibitors on regional hemodynamics in conscious spontaneously hypertensive rats. Rats were chronically instrumented with miniaturized pulsed Doppler flow probes for measurement of renal, mesenteric and hindquarters blood flow. Equidepressor doses of captopril (10 mg/kg) or a potent new converting enzyme inhibitor, Wy-44,221 [(-)-(S)-2,3-dihydro-1-[(S)-3-mercapto-2-methyl-1-oxypropyl]-1 H-indoline-2-carboxylic acid] (2 mg/kg) were administered by i.a. bolus injection. The converting enzyme inhibitors caused a reduction in mean arterial pressure, which was accompanied by a tachycardia. Renal blood flow was significantly increased by approximately 30 to 37% within 5 min after administration of the converting enzyme inhibitors, and renal vascular resistance was reduced. The renal hemodynamic effects were sustained for the 45-min duration of the experiment. Pretreatment with an angiotensin II receptor antagonist markedly attenuated the renal vasodilator effects of Wy-44,221, whereas antagonism of kinin or prostaglandin synthesis failed to diminish the renal effects of Wy-44,221. Both converting enzyme inhibitors also caused a significant but transient reduction in mesenteric vascular resistance, but had no significant effect on hindquarter hemodynamics. These data indicated that the converting enzyme inhibitors in conscious spontaneously hypertensive rats caused a prolonged increase in renal blood flow as a result of removing the renal vasoconstrictor effects of angiotensin II. These data further suggest that converting enzyme inhibitors exerted graded actions on regional vascular resistance with renal greater than mesenteric greater than hindquarters dilation.


Subject(s)
Angiotensin-Converting Enzyme Inhibitors , Captopril/pharmacology , Hypertension/physiopathology , Indoles/pharmacology , Vasodilation/drug effects , Angiotensin II/antagonists & inhibitors , Animals , Blood Pressure/drug effects , Rats , Rats, Inbred SHR , Renal Circulation/drug effects , Renin/blood , Splanchnic Circulation/drug effects , Vascular Resistance/drug effects
15.
Circ Res ; 56(4): 606-12, 1985 Apr.
Article in English | MEDLINE | ID: mdl-3156690

ABSTRACT

The cardiovascular actions of the synthetic natriuretic peptide, atriopeptin II, were examined in conscious unrestrained spontaneously hypertensive rats and normotensive Wistar-Kyoto rats. The animals were chronically instrumented with miniaturized pulsed Doppler flow probes to allow measurement of regional blood flow, or with an electromagnetic flow probe on the ascending aorta to facilitate the measurement of cardiac output in the conscious rat. Intravenous infusion of increasing doses of atriopeptin II (0.25-4 micrograms/kg per min) caused a dose-dependent fall in mean arterial pressure in the hypertensive and normotensive rats. Blood flow in the renal, mesenteric, and hindquarters vascular beds was markedly decreased during the infusion of atriopeptin II, and regional vascular resistance was significantly increased in both groups of rats. Heart rate was significantly elevated (47 +/- 14 beats/min) in the spontaneously hypertensive rats during atriopeptin II infusion, but no change in heart rate was observed in the Wistar rats. In the hypertensive rats, atriopeptin II caused a marked dose-dependent decrease in cardiac output (maximal decrease = -39 +/- 4%) and stroke volume (maximal decrease = -48 +/- 4%). Central venous pressure and left atrial pressure were also significantly reduced during atriopeptin II infusion. Total peripheral resistance was increased over the infusion protocol by 26 +/- 3%. These data suggest that atriopeptin II infusion markedly attenuated cardiac output in the conscious spontaneously hypertensive rats. Total and regional vascular resistances were increased, possibly through reflex compensatory mechanisms, to maintain arterial pressure in the face of decreased cardiac output.(ABSTRACT TRUNCATED AT 250 WORDS)


Subject(s)
Hemodynamics/drug effects , Muscle Proteins/pharmacology , Vasodilation/drug effects , Animals , Arteries/physiology , Atrial Natriuretic Factor , Blood Pressure/drug effects , Cardiac Output/drug effects , Rats , Rats, Inbred SHR , Rats, Inbred WKY , Regional Blood Flow/drug effects
16.
J Med Chem ; 27(12): 1743-6, 1984 Dec.
Article in English | MEDLINE | ID: mdl-6502606

ABSTRACT

A series of tetrahydropyrrolo[1,2-a]quinoxalines and tetrahydropyrrolo[1,2-a]pyrido[3,2-a]pyrazines were synthesized and tested for their ability to relax K+-depolarized aortic smooth muscle and antihypertensive activity. It was shown that compounds producing the most relaxation of aortic smooth muscle (5-[2,6-dimethoxyphenyl)methyl]-1,2,3,3a-tetrahydropyrrolo[1,2-a] quinoxalin-4(5H)-one and 5-[(2,6-dimethoxyphenyl)methyl]-5,6,6a,7,8,9-hexahydropyrrolo[1,2- a] pyrazine, 10 and 19, respectively) demonstrated the least hypotensive activity. Those compounds that were the most effective hypotensive agents (6a,7,8,9-tetrahydro-5-(phenylmethyl)pyrido[3,2-a]pyrrolo[1,2-a]++ +pyrazin- 6(5H)-one and 6a,7,8,9-tetrahydro-5-(4-pyridinylmethyl)pyrido[3,2-e]pyrrolo [1,2-a]pyrazin-6(5H)-one, 12 and 13, respectively) displayed little vascular smooth muscle relaxant activity.


Subject(s)
Antihypertensive Agents/chemical synthesis , Muscle, Smooth, Vascular/drug effects , Neuromuscular Depolarizing Agents/chemical synthesis , Pyrazines/chemical synthesis , Pyrroles/chemical synthesis , Quinoxalines/chemical synthesis , Animals , Aorta, Thoracic/drug effects , Chemical Phenomena , Chemistry , Female , Indicators and Reagents , Magnetic Resonance Spectroscopy , Mass Spectrometry , Muscle Relaxation/drug effects , Optical Rotation , Pyrazines/pharmacology , Pyrroles/pharmacology , Quinoxalines/pharmacology , Rabbits , Spectrophotometry, Infrared , Structure-Activity Relationship
17.
J Cardiovasc Pharmacol ; 6 Suppl 5: S748-52, 1984.
Article in English | MEDLINE | ID: mdl-6084118

ABSTRACT

The present study was designed to examine the effects of the calcium entry blocker, nifedipine, on the acute depressor responses to alpha 2-adrenoceptor agonists. Conscious spontaneously hypertensive rats (SHR) were given nifedipine intravenously (25 micrograms/kg) or vehicle (polyethylene glycol). Subsequent intravenous administration of guanabenz (10, 25, or 50 micrograms/kg) or clonidine (5 micrograms/kg) caused biphasic changes in mean arterial pressure (MAP) in vehicle-treated SHR, an initial pressor response, which was followed by a sustained fall in MAP. In nifedipine-treated rats, the pressor actions of guanabenz and clonidine were virtually abolished, while the onset of the depressor responses were significantly accelerated. The maximal depressor responses to guanabenz and clonidine were similar in vehicle- and nifedipine-pretreated SHR. Central administration of nifedipine (5, 10, or 20 micrograms/kg) in the lateral cerebroventricle significantly attenuated the depressor responses to guanabenz in a dose-dependent manner as compared to vehicle-treated rats. Oral pretreatment with nifedipine (2.5 mg/kg) also significantly blunted the hypotensive actions of guanabenz in the conscious SHR. These data indicate that central and oral administration of nifedipine antagonized the centrally mediated hypotensive actions of guanabenz. Intravenous bolus administration of nifedipine failed to attenuate the maximal depressor responses to guanabenz, suggesting that insufficient nifedipine accumulated centrally to affect central alpha 2-adrenoceptor function.


Subject(s)
Adrenergic alpha-Agonists/pharmacology , Blood Pressure/drug effects , Hypertension/physiopathology , Nifedipine/pharmacology , Administration, Oral , Animals , Clonidine/pharmacology , Drug Interactions , Guanabenz/pharmacology , Injections, Intravenous , Injections, Intraventricular , Male , Nifedipine/administration & dosage , Rats , Rats, Inbred SHR
18.
Eur J Pharmacol ; 97(1-2): 95-103, 1984 Jan 13.
Article in English | MEDLINE | ID: mdl-6698112

ABSTRACT

The antiarrhythmic activity of the calcium entry blockers, verapamil, nifedipine and prenylamine, was assessed against arrhythmias occurring during 20 min of acute occlusion, or upon rapid reperfusion of the left anterior descending coronary artery (LAD) in anesthetized pigs. Propranolol, which may indirectly reduce calcium entry by blocking the facilitory action of catecholamines on slow channel conductance, was also evaluated for antiarrhythmic activity in this acute arrhythmia model. Only verapamil (0.2 mg/kg i.v.) reduced both the number of arrhythmias occurring during LAD occlusion and the incidence of ventricular fibrillation (VF) occurring after occlusion and reperfusion. Although both nifedipine (0.04-0.2 mg/kg i.v.) and propranolol (1-2 mg/kg i.v.) produced a slight but significant (P less than 0.05) dose-dependent decrease in the incidence of VF during the occlusion period only, this protection was accompanied by a significant increase in ectopic activity. The increase in ectopic activity produced by propranolol (1.0 mg/kg i.v.) persisted even in combination with verapamil (0.2 mg/kg i.v.) which given alone decreased the ectopic frequency. Prenylamine up to 5 mg/kg was without significant antiarrhythmic or antifibrillatory activity. However, unlike verapamil and nifedipine, this drug produced only slight changes in heart rate or blood pressure which suggested the presence of only minimal calcium entry blocking action on myocardial and vascular tissue at the doses we employed. Because the relative antifibrillatory efficacies of verapamil and nifedipine paralleled the relative efficacies reported for depression of atrioventricular conduction, this may implicate the slow inward current channel in the etiology of VF occurring during acute myocardial ischemia.(ABSTRACT TRUNCATED AT 250 WORDS)


Subject(s)
Arrhythmias, Cardiac/prevention & control , Arterial Occlusive Diseases/prevention & control , Calcium Channel Blockers/therapeutic use , Coronary Disease/prevention & control , Animals , Blood Pressure/drug effects , Female , Heart Rate/drug effects , Male , Myocardium/metabolism , Nifedipine/therapeutic use , Oxygen Consumption/drug effects , Perfusion , Prenylamine/therapeutic use , Propranolol/therapeutic use , Swine , Verapamil/therapeutic use
19.
J Pharmacol Exp Ther ; 224(3): 494-500, 1983 Mar.
Article in English | MEDLINE | ID: mdl-6827474

ABSTRACT

An endogenous opiate mechanism may be involved in mediating the hypotensive effects of clonidine. In the cat anesthetized with alpha-chloralose, the effect of naloxone pretreatment on the lowering of blood pressure, heart rate and sympathetic nerve activity produced by increasing bolus i.c.v. injections of clonidine was studied. Central injections of clonidine (1-32 micrograms at 30-min intervals) decreased blood pressure, heart rate and renal nerve discharge in a dose-related manner. Effects on carotid sinus nerve activity were variable. Pretreatment with naloxone (3.2 mg x kg-1 i.v. or 1 mg i.c.v.) did not prevent the clonidine-induced reduction in blood pressure, heart rate and renal nerve activity. In some instances, the average blood pressure lowering responses to clonidine were greater in cats pretreated with naloxone compared with saline-pretreated animals. Changes in carotid sinus nerve activity were variable after clonidine in cats pretreated with i.v. naloxone. In contrast, sinus nerve activity decreased significantly after clonidine in cats pretreated with i.c.v. naloxone. Additional postclonidine naloxone injections (3.2 mg x kg-1 i.v. in all cats followed by 100 micrograms i.c.v. in the saline- and i.v. naloxone-pretreatment groups) also failed to consistently reverse the clonidine-induced changes in blood pressure, heart rate and sympathetic nerve activity. The results suggest that clonidine reduces blood pressure, heart rate and efferent sympathetic nerve firing in anesthetized normotensive cats by a mechanism independent of an opiate receptor interaction within the central nervous system.


Subject(s)
Blood Pressure/drug effects , Clonidine/antagonists & inhibitors , Heart Rate/drug effects , Naloxone/pharmacology , Sympathetic Nervous System/drug effects , Animals , Cats , Clonidine/pharmacology , Injections, Intravenous , Injections, Intraventricular , Male
20.
J Med Chem ; 26(3): 394-403, 1983 Mar.
Article in English | MEDLINE | ID: mdl-6298429

ABSTRACT

1-(3-Mercapto-2-methyl-1-oxopropyl)indoline-2-carboxylic acids (7b) and related compounds were synthesized in order to examine their ability to inhibit angiotensin converting enzyme (ACE) and to reduce the systolic blood pressure of spontaneously hypertensive rats (SHR). All four possible stereoisomers of the precursor 1-[3-(benzoylthio)-2-methyl-1-oxopropyl]indoline-2-carboxylic acid (6b) were characterized with absolute stereochemical assignment. The removal of the benzoyl group of the precursor to give 7b was conveniently carried out by treatment with 2-methoxyethylamine. Three of the four stereoisomers of the benzoyl derivative 6 showed in vitro ACE inhibitory activity in the following order: 6b(S,S) greater than 6b(S,R) greater than 6b(R,S). The stereoisomer having the R,R configuration was essentially inactive. The substitution at the C5 of the indoline nucleus with the Et or OMe group caused only marginal changes in the inhibitory activity. The mercaptan 7b(S,S) was the most active ACE inhibitor synthesized in this study, showing in vitro potency 3 times that of captopril. The augmentation of the potency may be due to the increased hydrophobicity of 7b(S,S) compared with captopril and suggests the presence of a hydrophobic pocket at the active site of ACE. When tested in spontaneously hypertensive rats, 7b(S,S) exhibited oral antihypertensive activity 27 times that of captopril. The corresponding benzoyl derivative 6b(S,S) was 24 times as potent as captopril. The thio lactone 10 obtained by cyclization of 7b(S,S) as a potential prodrug was less potent than the parent compound, 7b(S,S), in the ACE inhibitory and antihypertensive tests.


Subject(s)
Angiotensin-Converting Enzyme Inhibitors , Antihypertensive Agents , Indoles/pharmacology , Animals , Blood Pressure/drug effects , Indoles/chemical synthesis , Magnetic Resonance Spectroscopy , Rats , Rats, Inbred Strains , Structure-Activity Relationship
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