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1.
Eur J Pharmacol ; 159(2): 103-12, 1989 Jan 10.
Article in English | MEDLINE | ID: mdl-2565241

ABSTRACT

The ability of human ANF-(99-126) (ANF) to affect neuronal function, plasma cGMP levels or various hemodynamic parameters was tested in anesthetized dogs subjected to ganglionic blockade which prevented reflex changes in sympathetic tone. In each group of dogs, heart rate changes due to electrical stimulation of the cardioaccelerator nerve at 0.5, 1, 3 and 10 Hz were measured before and after ANF or vehicle infusion. A possible direct effect of ANF on the beta-adrenoceptor mechanisms was assessed by evaluating changes in heart rate after i.v. administration of isoproterenol (a beta-adrenoceptor agonist). The results showed that i.v. infusion of ANF (200 pmol/kg per min for 60 min), but not vehicle, produced significant inhibition of heart rate responses to low frequency nerve stimulation (0.5-1 Hz) when compared to vehicle 30 min after the end of infusion; high frequency (10 Hz) responses remained unaffected. A significant (P less than 0.05) enhancement in isoproterenol responses was evident in ANF-treated animals at the end of infusion, and 30 min afterward. ANF increased plasma cGMP from pretreatment levels of 28 +/- 4 to 149 +/- 1 pmol/ml at the end of infusion, and falling to 63 +/- 7 pmol/ml 30 min later (t 1/2 = 25.1 +/- 2.2 min). Cardiac output also tended to fall during infusion and remained significantly reduced (-18%) 30 min after infusion's end; blood pressure fell without a decrease in total peripheral resistance. Thus, ANF produced a direct, frequency-dependent depressant action on sympathetic nerve function, reduced both cardiac output and blood pressure, and enhanced chronotropic responses to beta-adrenoceptor stimulation. These persistent changes in hemodynamic parameters and neuronal function may contribute to the mechanism of action of ANF.


Subject(s)
Atrial Natriuretic Factor/pharmacology , Cyclic GMP/blood , Ganglionic Blockers/pharmacology , Hemodynamics/drug effects , Peptide Fragments/pharmacology , Sympathetic Nervous System/drug effects , Anesthesia , Animals , Blood Pressure/drug effects , Cardiac Output/drug effects , Dogs , Heart/innervation , Heart Rate/drug effects , Receptors, Adrenergic, beta/physiology , Vascular Resistance/drug effects
2.
J Med Chem ; 30(4): 627-35, 1987 Apr.
Article in English | MEDLINE | ID: mdl-2435902

ABSTRACT

Substituted 1,2,3,4-tetrahydroaminonaphthols were found to be calcium channel blockers with antihypertensive properties. These compounds also possessed adrenergic beta-receptor blocking activity. From the structure-activity studies, no clear correlation emerged between the in vitro calcium channel blocking activity and the acute anti-hypertensive activity in cannulated spontaneously hypertensive rats. Extensive pharmacological testing of selected compounds indicated that aminonaphthols are antihypertensive agents with many pharmacological properties. The relative contribution of various pharmacological actions toward the observed antihypertensive activity is unclear. Since the clinically useful calcium channel blocker verapamil is structurally related to these compounds, one of the aminonaphthols, trans-3-[(3,3-diphenylpropyl)amino]-1,2,3,4-tetrahydro-6,7 -dimethoxy-2-naphthalenol (12), was compared with verapamil for calcium channel blocking activity, adrenergic blocking activity, and catecholamine-depleting activity. Both compounds were found to be equipotent in these test systems.


Subject(s)
Adrenergic beta-Antagonists/pharmacology , Antihypertensive Agents/pharmacology , Calcium Channel Blockers/pharmacology , Catecholamines/metabolism , Naphthalenes/pharmacology , Naphthols/pharmacology , Tetrahydronaphthalenes/pharmacology , Action Potentials/drug effects , Adrenergic beta-Antagonists/chemical synthesis , Animals , Antihypertensive Agents/chemical synthesis , Blood Pressure/drug effects , Calcium Channel Blockers/chemical synthesis , Cattle , Female , Ion Channels/drug effects , Male , Naphthols/chemical synthesis , Rabbits , Rats , Rats, Inbred SHR , Receptors, Adrenergic, beta/drug effects , Structure-Activity Relationship , Swine , Tetrahydronaphthalenes/chemical synthesis , Verapamil/pharmacology
3.
J Med Chem ; 30(4): 635-40, 1987 Apr.
Article in English | MEDLINE | ID: mdl-2435903

ABSTRACT

2,5-Dihydro-4-methyl-2-phenyl-1,5-benzothiazepine-3-carboxylic acid esters, based on the structures of dihydropyridines and diltiazem, were synthesized from o-aminothiophenol and 2-(phenylmethylene)- 3-oxobutanoic acid esters. Biological evaluation in the potassium-depolarized rabbit aorta suggests that these compounds are calcium channel blockers. The in vitro activity was further confirmed by electrophysiological techniques. Structure-activity studies for the aromatic substitution showed that the 2-nitro derivative was the most potent (IC50 = 0.3 microM) compound in vitro while the ethyl ester was slightly better than the corresponding methyl ester. Replacement of sulfur with nitrogen atom provided 2,5-dihydro-4-methyl-2-(3-nitrophenyl)-1,5-benzodiazepine-3-carboxylic acid ethyl ester, which was only slightly less active than the corresponding benzothiazepine. Derivatization of the nitrogen in 2,5-dihydro-4-methyl- 2-(3-nitrophenyl)-1,5-benzothiazepine-3-carboxylic acid methyl ester with a (dimethylamino)ethyl group (present in diltiazem) provided 2,5-dihydro-5-[(dimethylamino)ethyl]- 4-methyl-2-(3-nitrophenyl)-1,5-benzo-thiazepine-3-carboxylic acid methyl ester, which was found to be equipotent to diltiazem in vitro. Radioligand binding studies using [3H]nitrendipine and [3H]diltiazem showed that the compound with the free nitrogen binds competitively into the dihydropyridine binding site while the molecule in which the nitrogen is alkylated with a (dimethylamino)ethyl group interacts competitively with both diltiazem and dihydropyridine binding sites. Our results therefore show that 2,5-dihydro-4-methyl-2-phenyl-1,5-benzothiazepine-3-carboxylic ester is a good starting point for designing dihydropyridine as well as diltiazem mimics.


Subject(s)
Benzodiazepines/chemical synthesis , Calcium Channel Blockers/chemical synthesis , Dihydropyridines , Thiazepines/chemical synthesis , Action Potentials/drug effects , Animals , Aorta/drug effects , Benzodiazepines/pharmacology , Calcium Channel Blockers/pharmacology , Calcium Channels , Carboxylic Acids/chemical synthesis , Carboxylic Acids/pharmacology , Chemical Phenomena , Chemistry , Diltiazem/pharmacology , Guinea Pigs , Ion Channels/drug effects , Pyridines/pharmacology , Rabbits , Receptors, Nicotinic/drug effects , Structure-Activity Relationship , Thiazepines/pharmacology
4.
Eur J Pharmacol ; 128(1-2): 109-18, 1986 Aug 22.
Article in English | MEDLINE | ID: mdl-3758184

ABSTRACT

The Ca2+ entry blockers diltiazem, nifedipine and verapamil produced dose-dependent increases in atrioventricular conduction time (A-H interval), while decreasing heart rate and mean arterial pressure in anesthetized dogs previously subjected to ganglionic blockade to prevent hypotension-induced reflex changes in sympathetic tone. Nifedipine and verapamil, but not diltiazem, also reduced (P less than 0.05) the tachycardia produced by electrical stimulation of the cardioaccelerator nerve at doses which did not alter the heart rate response to direct beta-adrenoceptor stimulation by isoproterenol (0.1 microgram/kg i.v.). The lowest doses of nifedipine (0.03 mg/kg) and verapamil (0.3 mg/kg) that produced decreases in mean arterial blood pressure were the same as or greater than those which selectivity reduced the tachycardiac effects of low frequency (1 Hz, 25-35 V, 5 ms), but not high frequency (10 Hz, 25-35 V, 5 ms) cardiac nerve stimulation. These data suggest that threshold vasodilator doses of some Ca2+ blockers may selectively reduce low level (or basal) sympathetic neurotransmission and this additional pharmacologic action may contribute to the antihypertensive mechanism. The failure to inhibit the high frequency nerve response may also help to explain the relatively low incidence of orthostatic hypotension associated with the clinical use of Ca2+ blockers as compared to other direct-acting vasodilators.


Subject(s)
Calcium Channel Blockers/pharmacology , Cardiovascular System/drug effects , Sympathetic Nervous System/drug effects , Animals , Autonomic Fibers, Postganglionic/drug effects , Autonomic Nerve Block , Blood Pressure/drug effects , Diltiazem/pharmacology , Dogs , Heart Conduction System/drug effects , Heart Rate/drug effects , Nifedipine/pharmacology , Verapamil/pharmacology
5.
Eur J Pharmacol ; 110(2): 277-81, 1985 Apr 02.
Article in English | MEDLINE | ID: mdl-3157590

ABSTRACT

The cardiovascular effects of atriopeptins (AP) I, II and III were compared in spontaneously beating or electrically stimulated guinea pig atria and in rabbit aortic strips precontracted by various agonists. Atriopeptins did not significantly affect sinus nodal rate or atrial contractility. AP II and III, although more potent than nitroprusside, exhibited similar vasorelaxant profiles against vascular strips maximally stimulated by norepinephrine, high [K+]0 or Ca2+ ionophore A23187. The ability of atriopeptins and nitroprusside to relax ionophore-induced vascular tension implies an intracellular mechanism of action.


Subject(s)
Diuretics/pharmacology , Muscle Proteins/pharmacology , Myocardial Contraction/drug effects , Animals , Aorta, Thoracic/drug effects , Atrial Natriuretic Factor , Calcimycin/pharmacology , In Vitro Techniques , Male , Muscle Contraction/drug effects , Muscle, Smooth, Vascular/drug effects , Nifedipine/pharmacology , Nitroprusside/pharmacology , Rabbits , Sinoatrial Node/drug effects , Verapamil/pharmacology
6.
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
7.
Eur J Pharmacol ; 90(4): 427-31, 1983 Jun 17.
Article in English | MEDLINE | ID: mdl-6884431

ABSTRACT

Naloxone pretreatment (1.0, 3.0 and 10.0 mg/kg i.v.) failed to protect anesthetized pigs from cardiac arrhythmias including ventricular fibrillation (VF) and death following acute occlusion (20 min) or reperfusion of the left anterior descending coronary artery. These findings suggest that opiate-like substances possibly released by the ischemic myocardium do not contribute significantly to the etiology of cardiac arrhythmias, or sudden death associated with the early stages of myocardial infarction in pigs. The effectiveness of naloxone in preventing acute ischemia-induced arrhythmias in rats may be due to mechanisms other than opiate-receptor blockade.


Subject(s)
Arrhythmias, Cardiac/prevention & control , Coronary Disease/complications , Morphine/antagonists & inhibitors , Naloxone/pharmacology , Animals , Arrhythmias, Cardiac/etiology , Blood Pressure/drug effects , Female , Heart Rate/drug effects , Hemodynamics/drug effects , Male , Swine , Ventricular Fibrillation/prevention & control
8.
Arzneimittelforschung ; 33(9): 1258-68, 1983.
Article in English | MEDLINE | ID: mdl-6685506

ABSTRACT

The antiarrhythmic, hemodynamic and cardiac electrophysiological effects of (Wy-42,362, in the following briefly called Wy) N-(2,6-dimethylphenyl)-N'-[3-(1-methylethylamino)propyl]urea were examined in several experimental preparations. Wy is an effective antiarrhythmic agent when administered i.v. or p.o. in various models of canine cardiac arrhythmia. Wy elevated ventricular fibrillatory threshold voltage and reverted ouabain-induced, 24- and 48-h post coronary artery ligation-induced Ventricular arrhythmias,, and aconitine-induced atrial arrhythmias at i.v. doses of 4-15 mg/kg. Wy lacked anticholinergic or CNS-stimulant activity. In closed-chest anesthetized dogs, Wy at 15 or 25 mg/kg i.v. decreased cardiac output (CO). Unlike disopyramide, i.v. Wy did not produce greater reductions in CO in anesthetized dogs subjected to previous infarction (72-96 h) as compared to normal intact dogs. Wy at 10 or 15 mg/kg i.v. produced slight to moderate decreases in contractile force and showed a tendency to reduce heart rate and blood pressure. Wy produced a generalized depression of cardiac impulse conduction in open-chest, pentobarbital anesthetized dogs but conscious dogs exhibited relatively little ECG evidence of such depression following double the therapeutic i.v. dose. In isolated canine cardiac Purkinje fibers bathed in normal K+-containing physiological solutions. Wy (1-2 X 10(-5) mol/l) produced significant reductions in action potential duration while 2 X 10(-5) mol/l also reduced Vmax and shifted membrane responsiveness curves to the right suggesting depressant action on fast Na+ channel conductance. The data indicate that Wy is an effective antiarrhythmic agent presumably with a class I mechanism of action.


Subject(s)
Anti-Arrhythmia Agents , Heart/drug effects , Hemodynamics/drug effects , Phenylurea Compounds/pharmacology , Aconitine/antagonists & inhibitors , Anesthetics, Local , Animals , Coronary Vessels/physiology , Disopyramide/pharmacology , Dogs , Electrophysiology , Female , Guinea Pigs , Heart Conduction System/drug effects , In Vitro Techniques , Male , Myocardial Contraction/drug effects , Ouabain/antagonists & inhibitors , Ventricular Fibrillation/physiopathology
9.
Eur J Pharmacol ; 81(2): 205-16, 1982 Jul 09.
Article in English | MEDLINE | ID: mdl-7117374

ABSTRACT

Arrhythmias which occur following either abrupt occlusion (CO) of the left anterior descending coronary artery (LAD), or rapid reperfusion (CR) of the same, were studied in rats, dogs and pigs. We found that all rats or pigs exhibited ventricular fibrillation (VF) during CO or after CR in contrast to dogs where more than 30% survived both procedures. In rats, the distribution in the onset of non-lethal arrhythmia or VF appeared to be uniform over the CO period, while in pigs and dogs the onset times clustered into two distinct groups. Also unlike dogs and pigs, the rat frequently (75%) underwent spontaneous defibrillation. Quinidine pretreatment (10 mg/kg i.v.) proved effective in protecting all three species from VF while procainamide (20 mg/kg i.v.) was effective only in rats and dogs. Lidocaine pretreatment (10 mg/kg i.v.) was effective in preventing VF in rats, but increased the incidence of CR-induced VF in dogs and significantly (P less than 0.01) reduced the mean time to VF during CO in pigs. However, lidocaine given immediately after CO in pigs did not reduce the time to VF suggesting that lidocaine given post-infarction would not increase the risk of VF, although the drug appears to be of no therapeutic benefit during the early occlusion period. Similarities in the action of lidocaine in pigs and dogs further suggest that the mechanisms of CR-induced VF in dogs and CO-induced VF in pigs may be similar. These data also support a pivitol role of extracellular K+ accumulation of the production of early post-infarction arrhythmias. Thus, the arrhythmogenic as well as antiarrhythmic properties of the various drugs studied here may relate their known effects on potassium permeability in cell membranes.


Subject(s)
Arrhythmias, Cardiac/drug therapy , Lidocaine/therapeutic use , Procainamide/therapeutic use , Quinidine/therapeutic use , Animals , Arrhythmias, Cardiac/etiology , Blood Pressure/drug effects , Coronary Disease/complications , Disease Models, Animal , Dogs , Female , Heart Rate/drug effects , Male , Perfusion , Potassium/metabolism , Rats , Rats, Inbred Strains , Species Specificity , Swine
10.
Arch Int Pharmacodyn Ther ; 253(1): 110-20, 1981 Sep.
Article in English | MEDLINE | ID: mdl-7325751

ABSTRACT

The effects of chronic twice daily s.c. injections of dlpropranolol, metoprolol and d-propranolol on systolic blood pressure and heart rate were assessed in conscious DOC-saline hypertensive rats. Measurements were taken (tail-cuff) 4 hr after the morning injection and 16-18 hr after the afternoon injection during 11 of 19 consecutive treatment days. Only dl-propranolol and metoprolol at 5 mg/kg lowered blood pressure and heart rate significantly relative to the changes occurring in control saline-injected animals. At the lower dose of 0.2 mg/kg, both agents tended to decrease heart rate while having little or no effect on blood pressure. The overall blood pressure and heart rate changes produced by propranolol at 5 mg/kg differed significantly from those of the control group at both the 4 and 16-18 hr post-dosing intervals. Metoprolol at 5 mg/kg produced significant overall changes in blood pressure and heart rate only at the 4 hr post-doing interval. D-propranolol had no effect on either blood pressure or heart rate. The results indicate tha s.c. propranolol and metoprolol lower systolic blood pressure in conscious DOC-saline hypertensive rats only at the higher dose of 5 mg/kg and that cardioselectivity does not afford increased antihypertensive activity in this model.


Subject(s)
Antihypertensive Agents , Metoprolol/pharmacology , Propanolamines/pharmacology , Propranolol/pharmacology , Animals , Blood Pressure/drug effects , Desoxycorticosterone/pharmacology , Heart Rate/drug effects , Hypertension/chemically induced , Male , Rats , Rats, Inbred Strains , Time Factors
11.
Eur J Pharmacol ; 71(2-3): 307-19, 1981 May 08.
Article in English | MEDLINE | ID: mdl-6265236

ABSTRACT

In mammalian cardiac muscle voltage-dependent activation of slow channels, e.g., the slow inward current channel, may be possible only when the channels are phosphorylated. We examined the electrophysiological actions of oximes, mile nucleophilic agents which show 'phosphatase-like' activity in isolated enzyme systems, to assess their actions on slow channels in cardiac Purkinje fibers. Diacetyl monoxime (DAM) and pyridine-2-aldoxime (NorPAM) produced a marked, reversible and concentration-dependent reduction in the action potential (AP) plateau duration and abolished spontaneous phase 4 depolarization, but produced only minimal effects on resting potential, dV/dt max, action potential amplitude, duration of phase 3, or membrane resistance. Slow response action potentials evoked in the presence of elevated potassium plus isoproterenol or in Na-free solution were abolished by DAM. The effects of DAM on the AP plateau were antagonized by epinephrine, but an increase in Ca was relatively ineffective. The results suggest that oximes may act as surrogate phosphatases to remove phosphate groups which regulate the availability of slow current channels for voltage-dependent activation.


Subject(s)
Heart Conduction System/drug effects , Ion Channels/drug effects , Oximes/pharmacology , Phosphoric Monoester Hydrolases/pharmacology , Phosphotransferases/antagonists & inhibitors , Purkinje Fibers/drug effects , Action Potentials/drug effects , Animals , Calcium/antagonists & inhibitors , Cesium/pharmacology , Dogs , Dose-Response Relationship, Drug , Epinephrine/pharmacology , In Vitro Techniques , Purkinje Fibers/physiology
12.
Eur J Pharmacol ; 70(3): 331-43, 1981 Mar 26.
Article in English | MEDLINE | ID: mdl-7227454

ABSTRACT

Verapamil, nifedipine, perhexiline and SKF 525-A (2-diethylaminoethyl-2,2-diphenylvalerate . HCL) were evaluated for cardiac antiarrhythmic activity by assessing their effectiveness in increasing left ventricular fibrillation threshold (FT) and antagonizing ouabain-induced arrhythmias (OA), 24 h post infarction arrhythmias (CLA) and aconitine-induced atrial arrhythmias. Calcium antagonistic doses (ID50) of each agent were approximated by intravenous titration of the amount of drug required to reduce the left ventricular contractile force by 50% in dogs pretreated with hexamethonium (10 mg/kg) to block autonomic reflexes. ID50 doses of calcium antagonists were found not to be universally effective in any single arrhythmia model while causing significant changes in heart rate, blood pressure and frequently producing death or convulsion. It is suggested that local anesthetic or 'class 1' action probably accounts for the antiarrhythmic effectiveness of SKF 525-A (7-20 mg/kg i.v.) in all four arrhythmia models and for perhexiline-induced increased FT and antagonism of CLA (15-20 mg/kg). Antiarrhythmic effectiveness of verapamil against OA may be due to calcium antagonism action.


Subject(s)
Anti-Arrhythmia Agents , Arrhythmias, Cardiac/drug therapy , Nifedipine/pharmacology , Perhexiline/pharmacology , Piperidines/pharmacology , Proadifen/pharmacology , Pyridines/pharmacology , Verapamil/pharmacology , Animals , Blood Pressure/drug effects , Calcium/antagonists & inhibitors , Dogs , Female , Heart Rate/drug effects , Lidocaine/pharmacology , Male , Myocardial Contraction/drug effects
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