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Cardiac and vascular effects of cocaine
J Mol
Cell
Cardiol21
(Supplement
II) (1989)
P.34
CHARACTERIZATION OF COCAINE-INDUCED POTENTIATION OF HEART RATE INCREASES PRODUCED BY ELECTRICAL STIMULATION OF CARDIAC SYMPATHETIC NERVES. R.K. Jain, M.D., M.K. Jain, A. Lewis, R.A. Gillis, Ph.D. Departments of Pharmacology and Medicine (Cardiology) School of Med., Washington, D. C., 20007 Georgetown Univ., (1) the time course of the potentiation The goals of our study were to determine: (2) whether tachyphylaxis develops by cocaine on cardiac syinpathetic nerve stimulation, to this effect and (3) the effect of block of presynaptic alphaz-adrenoceptors on the potentiating effect of cocaine on cardiac nerve stimulation. Cats anesthetized with Control heart rate pentobarbital and subjected to spinal cord transection were used. increases were obtained to submaximal stimulation of postganglionic accelerator nerves, before and after an i.v. dose of 0.25 mg/kg cocaine. In pre-cocaine controls, stimulation increased sinus rate by 3521 beats/min (N=8); thirty see after cocaine, stimulation increased sinus rate by 5821 beats/min. Maximal potentiation was observed at 30 set, and at 1 hr later, the corresponding responses were +42+2 beats/min and 1925% above the control response. Cocaine was repeated twice (0.25 mg/kg i.v.1 at hourly intervals and the degree of potentiation was only 39+7% and 30+2%, respectively, indicating a tachyphylaxis. A second group (N=6) given the alphaz-adrenoceptor and these animals did not exhibi.t antagonist, yohimbine, 25 min prior to cocaine, tachyphylaxis. The potentiation 30 set after the lst, 2nd, and 3rd doses of cocaine was +88+7%, +89+8% and +93+6%, respectively. Thus tachyphylaxis to the potentiating effect of cocaine appears to
P.35
CARDIAC AND VASCULAR EFFECTS OF COCAINE. M.M. Knuepfer, C.A. Branch, V.W. Fischer and D.M. Wehner. Departments of Pharmacology, Pathology and Anatomy and Neurobiology, St. Louis University School of Medicine, St. Louis, MO, USA Cocaine produces a variety of vascular and cardiac effects whose mechanism is, as yet, unclear. We sought to differentiate regional vascular and cardiac effects and the mechanisms involved. We studied rats instrumented for arterial pressure and blood flow measurement using miniaturized pulsed Doppler flow probes. Hindquarters (HQ) and mesenteric (MS) resistance or total peripheral resistance (TPR) and stroke volume (SV) were calculated in each rat. Cocaine (0.1-10 mg/kg, i.v.1 produced a dose-dependent pressor response characterized by MS vasoconstriction, HQ vasodilation, bradycardia, an increase in TPR and little change in SV in conscious, freely-moving rats. Propranolol exacerbated the pressor response by blocking HQ vasodilation and increasing TPR while metoprolol had no effect. Prazosin blocked the pressor response and bradycardia and pentolinium or methyl atropine attenuated the bradycardia only. The increase in TPR was attenuated by calcium channel antagonists. Examination of the myocardium occasionally revealed minor foci of ultrastructural damage and myocardial contraction bands. We suggest that cocaine’s pressor effects are primarily due to an increase in visceral vascular resistance not to excessive cardiac stimulation or to CNS-mediated sympathoexcitation. We propose that the bradycardia is likely to be baroreflex-mediated. Finally, propranolol exacerbates cocaine’s pressor effects by blocking a beta*-adrenergic vasodilatory response in skeletal muscle. Supported by USPHS grant HL 38299.
P.36 EFFECTS OF COCAINE ON HUMAN EPICARDIAL
CORONARY
ARTERIES.
Cynthia
Perreault,
Maurice Briggs, Kathleen G. Morgan, James P. Morgan. Harvard Medical School, Boston, Massachusetts. Increased recreational use.of cocaine (COC) is associated with myocardial ischemia/infarction that may be due to coronary vasospasm. We therefore tested the hypothesis that COC has a direct vasoconstrictor effect on human epicardial coronary arteries (CA). CA’s arteries were obtained from the hearts of 8 patients undergoing cardiac transplantation for end-stage heart failure (CHF). Up to four circular strips were prepared from each heart and placed in an organ bath for isometric tension recording. Muscles were bathed with a physiologic salt solution containing 2.5 mM [Ca++], at 37.5”C. Five muscles from vessels with gross atherosclerotic plaque developed spontaneous phasic activity (SPA). This was suppressed by COC (10-7 to 104 M) in a dose-related manner. COC lO-7 to 1O-3M had no effect on basal tone in ten non-spontaneous strips. In particular, a vasoconstrictor response was never seen, which may be due to the depletion of cardiac catecholamine stores that is known to occur in CHF (strips did not respond to tyramine). However, when strips were contracted with KCL (60-90 n&I), COC produced a dose-related relaxation. These data indicate that 1) COC does not have a direct vasoconstrictor effect on human CA’s, 2) COC may suppress SPA through its local anesthetic actions, 3) COC may produce vasodilation of CA’s withelevatedtone. (Support:DA05171,HL.31117andHLO1611.) Kensuke
Egashira,
s.197
Cell
Cardiol21
(Supplement
II) (1989)
P.34
CHARACTERIZATION OF COCAINE-INDUCED POTENTIATION OF HEART RATE INCREASES PRODUCED BY ELECTRICAL STIMULATION OF CARDIAC SYMPATHETIC NERVES. R.K. Jain, M.D., M.K. Jain, A. Lewis, R.A. Gillis, Ph.D. Departments of Pharmacology and Medicine (Cardiology) School of Med., Washington, D. C., 20007 Georgetown Univ., (1) the time course of the potentiation The goals of our study were to determine: (2) whether tachyphylaxis develops by cocaine on cardiac syinpathetic nerve stimulation, to this effect and (3) the effect of block of presynaptic alphaz-adrenoceptors on the potentiating effect of cocaine on cardiac nerve stimulation. Cats anesthetized with Control heart rate pentobarbital and subjected to spinal cord transection were used. increases were obtained to submaximal stimulation of postganglionic accelerator nerves, before and after an i.v. dose of 0.25 mg/kg cocaine. In pre-cocaine controls, stimulation increased sinus rate by 3521 beats/min (N=8); thirty see after cocaine, stimulation increased sinus rate by 5821 beats/min. Maximal potentiation was observed at 30 set, and at 1 hr later, the corresponding responses were +42+2 beats/min and 1925% above the control response. Cocaine was repeated twice (0.25 mg/kg i.v.1 at hourly intervals and the degree of potentiation was only 39+7% and 30+2%, respectively, indicating a tachyphylaxis. A second group (N=6) given the alphaz-adrenoceptor and these animals did not exhibi.t antagonist, yohimbine, 25 min prior to cocaine, tachyphylaxis. The potentiation 30 set after the lst, 2nd, and 3rd doses of cocaine was +88+7%, +89+8% and +93+6%, respectively. Thus tachyphylaxis to the potentiating effect of cocaine appears to
P.35
CARDIAC AND VASCULAR EFFECTS OF COCAINE. M.M. Knuepfer, C.A. Branch, V.W. Fischer and D.M. Wehner. Departments of Pharmacology, Pathology and Anatomy and Neurobiology, St. Louis University School of Medicine, St. Louis, MO, USA Cocaine produces a variety of vascular and cardiac effects whose mechanism is, as yet, unclear. We sought to differentiate regional vascular and cardiac effects and the mechanisms involved. We studied rats instrumented for arterial pressure and blood flow measurement using miniaturized pulsed Doppler flow probes. Hindquarters (HQ) and mesenteric (MS) resistance or total peripheral resistance (TPR) and stroke volume (SV) were calculated in each rat. Cocaine (0.1-10 mg/kg, i.v.1 produced a dose-dependent pressor response characterized by MS vasoconstriction, HQ vasodilation, bradycardia, an increase in TPR and little change in SV in conscious, freely-moving rats. Propranolol exacerbated the pressor response by blocking HQ vasodilation and increasing TPR while metoprolol had no effect. Prazosin blocked the pressor response and bradycardia and pentolinium or methyl atropine attenuated the bradycardia only. The increase in TPR was attenuated by calcium channel antagonists. Examination of the myocardium occasionally revealed minor foci of ultrastructural damage and myocardial contraction bands. We suggest that cocaine’s pressor effects are primarily due to an increase in visceral vascular resistance not to excessive cardiac stimulation or to CNS-mediated sympathoexcitation. We propose that the bradycardia is likely to be baroreflex-mediated. Finally, propranolol exacerbates cocaine’s pressor effects by blocking a beta*-adrenergic vasodilatory response in skeletal muscle. Supported by USPHS grant HL 38299.
P.36 EFFECTS OF COCAINE ON HUMAN EPICARDIAL
CORONARY
ARTERIES.
Cynthia
Perreault,
Maurice Briggs, Kathleen G. Morgan, James P. Morgan. Harvard Medical School, Boston, Massachusetts. Increased recreational use.of cocaine (COC) is associated with myocardial ischemia/infarction that may be due to coronary vasospasm. We therefore tested the hypothesis that COC has a direct vasoconstrictor effect on human epicardial coronary arteries (CA). CA’s arteries were obtained from the hearts of 8 patients undergoing cardiac transplantation for end-stage heart failure (CHF). Up to four circular strips were prepared from each heart and placed in an organ bath for isometric tension recording. Muscles were bathed with a physiologic salt solution containing 2.5 mM [Ca++], at 37.5”C. Five muscles from vessels with gross atherosclerotic plaque developed spontaneous phasic activity (SPA). This was suppressed by COC (10-7 to 104 M) in a dose-related manner. COC lO-7 to 1O-3M had no effect on basal tone in ten non-spontaneous strips. In particular, a vasoconstrictor response was never seen, which may be due to the depletion of cardiac catecholamine stores that is known to occur in CHF (strips did not respond to tyramine). However, when strips were contracted with KCL (60-90 n&I), COC produced a dose-related relaxation. These data indicate that 1) COC does not have a direct vasoconstrictor effect on human CA’s, 2) COC may suppress SPA through its local anesthetic actions, 3) COC may produce vasodilation of CA’s withelevatedtone. (Support:DA05171,HL.31117andHLO1611.) Kensuke
Egashira,
s.197