Renaud Trouve

Nitrendipine: an antidote to cardiac and lethal toxicity of cocaine.

Abstract Nitrendipine, a ca2+ modulator was tested in the rat as an antagonist to the cardiac toxicity of cocaine and as an antidote to the acute lethal effects of this drug. In a first series of experiments, nitrendipine (1.46 x 10-3 mg/kg/min) when simultaneously administered intraarterially with cocaine (2 mg/kg/min) suppresses the arrhythmias induced by cocaine and increases survival time from 73 ± 33 min to 309 ± 118 min and the lethal dose of cocaine from 146 ± 66 mg/kg to 618 ± 236 mg/kg (p < 0.003). Nitrendipine also protects the heart from the acute morphological lesions induced by cocaine administration and antagonizes some of the central effects of cocaine. In a second series, 5 rats administered 60 mg/kg of cocaine intraperitoneally had a survival time of 8′ 06 ± 5′ 20 Death was attributed to convulsions and respiratory arrest. Animals treated with nitrendipine (129 x 23 mg/kg) 4′ 30″ after cocaine administration survived. Nitrendipine appears to have general protective effects against cocaine cardiac toxicity and the acute lethal effects of this alkaloid.

Cocaine, catecholamines and cardiac toxicity

The local anesthetic property of cocaine is related to its ability to block axonal conduction by interfering with sodium channels (1). Its cardiovascular effects have been mostly attributed to the property of inhibiting norepinephrine reuptake (2, 3) . In addition, cocaine releases epinephrine and norepinephrine from the adrenal medulla of the rat (4, 5), and cocaine administration to the squirrel monkey is associated with elevated plasma catecholamines and hypertension (6). These hormonal and functional changes are normalized or prevented by the administration of a dihydropyridine, nimodipine. Acute administration of a lethal dose of cocaine is associated with myocardial damage in the dog (7) and in the rat (8, 9). In the latter, the cardiovascular anomalies and cardiac lesions caused by cocaine are prevented by selected calcium channel antagonists such as nitrendipine (10, 11). This protection was attributed to the ability of Ca2+ channel antagonists to inhibit catecholamine-induced vasoconstriction (12-14) and catecholamine release from tissue stores. In other studies, enalaprilat, a converting enzyme inhibitor associated with diazepam proved to be an effective antidote against cocaine lethal toxicity (15). All of the functional and morphological cardiovascular changes associated with cocaine administration duplicate those induced by epinephrine, norepinephrine or by angiotensin I1 (Ang 11) (16-18). In healthy young men, cocaine self-administration produces elevated blood pressure and tachycardia (19). Cocaine has also been implicated as a cause of sudden arrhythmic death (20), myocardial ischemia (2 1 ), myocardial infarction (22) and myocarditis (23) (Table 1). The present experimental study documents the marked release of catecholamines induced by doses of cocaine which produce acute cardiovascular anomalies and myocardial lesions. The effects of proven antidotes to cocaine on the hormonal and cardiac morphological changes induced by this alkaloid were also studied. Our observations led us to formulate a new hypothesis to account for the neuronal adaptation of catecholaminergic neurons to repetitive cocaine administration. METHODS

Catecholamines, Cocaine Toxicity, and Their Antidotes in the Rat

Abstract Acute lethal cocaine intoxication in the rat induces significant increases of plasma dopamine, norepinephrine, and epinephrine concentrations associated with cardiac functional and morphologic changes. Nitrendipine (a calcium channel antagonist) administered 5 min following cocaine administration lowers catecholamine concentration and restores cardiovascular function to normal, while preventing lethality, and so does enalaprilat (an enzyme-converting inhibitor) administration with diazepam. Cocaine cardiac toxicity in the rat appears to be associated with a significant stimulation of the sympathoadrenal and a sustained elevated plasma concentration of epinephrine. The renin angiotensin system also appears to be activated.

Effects and interactions of natural cannabinoids on the isolated heart.

Abstract A Langendorff perfused rat heart preparation was designed to process dose-response effects of cardioactive drugs on rate, coronary flow, and supraaortic differential pressure (ΔP; an index of cardiac performance). In this preparation, Δ9--tetrahydrocannabinol (THC) 2 × 10-6 M to 10-5 M induces in the isolated perfused rat heart a biphasic increase in rate (maximal at 8 × 10-6 M). Tachycardia is associated with decreases in (ΔP) and no change or decreased coronary flow. Cardiac toxicity is observed with 3 × 10-5 M. Cannabidiol (CBD) at concentrations of 9 × 10-6 M to 10-4 M has limited effect on rate while increasing ΔP and coronary flow. Cannabinol (CBN) 8 × 10-6 M to 3 × 10-4 M depresses rate and ΔP while coronary flow remains constant. Simultaneous equimolar administration of THC with CBD antagonizes or mitigates the cardiac effects of THC on rate, ΔP, and coronary flow.

Interactions of nimodipine and cocaine on endogenous catecholamines in the squirrel monkey

Abstract The effects of nimodipine on the cocaine-induced alterations in blood pressure, heart rate, and plasma catecholamines were studied in the squirrel monkey. Cocaine in intravenously administered doses of 0.5, 1, and 2 mg/kg produced significant increases in blood pressure and significant decreases in heart rate. These cardiovascular changes were associated with transient episodes of arrhythmias and with significant increases in plasma concentrations of dopamine, epinephrine, and norepinephrine. Nimodipine, 1 μg/kg/min for 5 min administered intravenously 5 min after cocaine, corrects the cardiovascular and plasma catecholamine concentration changes induced by this alkaloid. The same dose of nimodipine administered 5 min before cocaine prevents elevations of blood pressure. Plasma catecholamine increments are also prevented except for the highest dose of cocaine. Cardiovascular changes induced by cocaine administration in the squirrel monkey are temporally associated with significant increments in plasma catecholamines. Administration of nimodipine prevents or minimizes these endocrine and physiologic changes.

Nitrendipine as an Antagonist to the Cardiac Toxicity of Cocaine

Cocaine (10−7–10−4) administered to the isolated heart increases rate in the presence of a stable or decreased coronary flow, while pulse pressure is not consistently altered. Arrhythmias and irreversible cardiac impairment occur with concentrations exceeding 10−4 M. While propranolol does not alter these effects, nitrendipine (10−7 M), simultaneously administered with the same range of cocaine concentration, decreases tachycardia and increases pulse pressure and coronary flow. In the intact rat, nitrendipine (1.46 × 10−3 mg/kg/min), when simultaneously administered intra-arterially with cocaine (2 mg/kg/min), suppresses the arrhythmias induced by cocaine and increases survival time from 73 ± 33 min to 309 ± 118 min, and the lethal dose of cocaine increases from 146 ± 66mg/kg to 618 ± 236 mg/kg (p < 0.003). Nitrendipine also protects the heart from the acute morphological lesions induced by cocaine administration and antagonizes some of the central effects of cocaine.

Inhibition by Cocaine of the Baroreflex in the Rat

Abstract Sprague-Dawley rats were fitted under pentobarbital anesthesia with a catheter in the caudal artery and their carotid arteries were exposed. The pressure signal from the caudal artery was treated on line by a microcomputer for continuous display of blood pressure and heart rate measurements. The animals were administered intraperitoneally either 50 mg/kg of cocaine or an equal volume of saline. Five minutes later, stimulation of the baroreflex was performed by bilateral clamping of the two carotids for a period of 2 min. The same maneuver was repeated at 12, 24, and 31 min. Analysis of variance for repeated measures indicated that before carotid artery clamping, there was no significant difference between blood pressure measurements of the saline- and cocaine-treated groups. A two-factor analysis of variance of the repeated measures of the maximal variation in systolic pressure after each clamping showed a significant difference between control and cocaine-administered groups (P < 0.001), with the former displaying a much greater increment in blood pressure after carotid clamping. Cocaine exerts an inhibitory effect on the baroreflex that may be mediated through the increased angiotension II caused by the alkaloid.

Cardiovascular Effects of Marihuana and Cannabinoids

In the isolated heart THC produces a biphasic effect on heart rate with an initial increase followed by a decrease. THC also decreases coronary flow and cardiac contractile force. The depressant effect of THC on cardiac contraction and coronary flow is antagonized by CBD and by Ca2+ antagonists. In humans, THC and marihuana induce increases in heart rate and blood pressure. In the supine position, postural hypotension is observed because of the peripheral vasodilation produced by the drug. THC produces a deregulation of the baroreflex. In dogs, cats, and rats, THC produces hypotension and bradycardia, indicating a predominance of the interaction of the parasympathetic outflow by THC in these animals. Marihuana smoking increases coronary insufficiency in patients with ischemic cardiac disease. Self-administration of cocaine before exercise will result in an increase in the tachycardia and a decreased efficiency. Marihuana smoking and THC have no therapeutic cardiac properties and are contraindicated in patients with coronary problems.

Cardiac Dynamics of the Langendorff Perfused Heart

Abstract The Langendorff perfused heart is studied in a closed system with (i) automatic regulations to maintain constancy of the perfusion column (Krebs-Henseleit + 0.5% albumin or 25–30% washed erythrocyte suspension), (ii) continuous recording of rate, coronary flow, and supravalvular aortic pressure. A microcomputer with software interface is used for storage treatment and on-line analysis of the recorded variables. In 38 preparations perfused with Krebs-Henseleit, minimal diastolic (61.2 ± 2.8 mm Hg) is significantly below and peak systolic (98.7 ± 3.6 mm Hg) significantly above perfusion pressure (80 mm Hg). Pressure difference between minimal diastolic and peak systolic (ΔP) is 37.5 ± 1.8 mm Hg. Increases in perfusion pressure will be associated with increases of coronary flow and ΔP, which is also increased by isoprenaline administration. Oxygen consumption decreased by 76% when perfusion pressure was lowered from 80 to 60 mm Hg in hearts perfused with a 30% erythrocyte suspension. All of these experimental results were interpreted as indicating that ΔP measured in this system resulted from an ejected volume (x acceleration) from the heart. The ejected volume corresponds to a valvular leak caused by the rigid nature of the system which is devoid of aortic compliance. ΔP may be considered an index of left ventricular performance, an indication that the Langendorff preparation studied under the present conditions is a working heart. A 100-μ1 volume constant infusion syringe for time administration of cardioactive drugs may be inserted at the base of the perfusion column to obtain dose-response effects.

Effects of antidotes to cocaine on the deregulation of the baroreflex by the alkaloid.

Abstract Cocaine exerts in the rat an inhibitory effect on the baroreflex induced by bilateral clamping of the carotid arteries. The present series of experiments were designed to test the effectiveness of cocaine antidotes on this deregulation of the baroreflex. Sprague-Dawley rats were fitted under pentobarbital anesthesia with a catheter in the caudal artery, and their carotid arteries were exposed. The pressure signal from the caudal artery was treated on line by a microcomputer for continuous display of blood pressure and heart rate measurements. The animals were administered intraperitoneally either 50 mg cocaine or an equal volume of saline. Five minutes later, they were administered either saline or proven antidotes to cocaine (diltiazem, nicardipine, enzyme converting inhibitor [ECI], enalaprilat associated with diazepam). After 2 min, stimulation of the baroreceptor was performed by bilateral clamping of the two carotids for a period of 2 min. The measures of the maximal variation in systolic pressure before and after clamping indicated a significant difference between saline and cocaine treated animals (P < 0.05), with the former displaying a much greater increment in blood pressure after clamping. The cocaine-treated animals, administered diltiazem, nicardipine, and ECI associated with diazepam, presented after clamping of the carotid arteries a normal baroreflex with increments in blood pressure no significantly different from those occurring in the animals receiving saline, but significantly different from those administered cocaine only (P < 0.05). Baroreflex deregulation by cocaine may also be restored by an angiotensin II receptor antagonist. The possible role of this peptide in mediating in part baroreflex activity is discussed.