Models

The rat model continues to be one of the primary models of choice for the study of the cardiovascular effects of cocaine. Recently, the rat model has been utilized to study the acute and chronic effects of cocaine self-administration behavior on cardiovascular function [81]. When rats were self-administered injections of cocaine 0.5 mg/kg there was a significant increase in blood pressure. Tolerance developed to this effect within 3 daily sessions. During saline-substitution sessions, a significant (p < 0.05) decrease in blood pressure and heart rate was observed. When the injected doses of cocaine were increased (1.0, 2.0, and 4.0 mg/kg per injection)a dramatic increase in blood pressure or heart rate was not produced despite a substantial cumulative cocaine intake(20-27 mg/kg). It has thus been hypothesized that operant-conditioned behavior and/or the direct reinforcing effects of cocaine modulate the cardiovascular effects of cocaine. The results of thejust described study are in agreement with previous reports of acute tolerance to cardiovascular actions of cocaine in humans and rats [82,83],

The rat model is also being used to increase understanding of the pharmacodynamic action of cocaine. The cardiovascular and behavioral effects of cocaine may be intricately connected with respect to their mechanisms of origination [84], Recent behavioral and cardiovascular data indicate that cocaine elicits two distinct and temporally separable effects in conscious rats [84], The first involves a sodium-channel-independent, monoamine effect of a rapid onset. This consists of a brief and intense behavioral arousal associated with rapid and large increases in blood pressure and heart rate, i.e., abrupt hemodynamic stimulation. The second effect appears to be a dopamine-mediated response of a slower onset, whereby cocaine exerts an inhibitory effect on dopamine reuptake in the brain. This is manifested by prolonged and parallel increases in blood pressure, heart rate, and locomotion.

The rat model has also been used to study cocaine's alterations in myocardial cell structure. Several studies have indicated that cocaine is directly toxic to myocardial cells. Cocaine altered cellular structure, producing intracellular vacuolization and pseudopodia in cultured cardiomyocytes [85], These morphological alterations occurred as early aslh after exposure to cocaine, and were followed by a clear indicator of cytotoxicity, that being substantial leakage of lactate dehydrogenase after 24 h of treatment [85], In rats chronically treated with cocaine, alterations of cardiac mitochondria were observed, such as mitochondrial swelling, and disruption of intramitochondrial cristae [86], Furthermore, a recent study conducted in order to evaluate the effect of cocaine on mitochondrial function in cultured rat myocardial cells showed that cocaine may exert cardiotoxic effects by compromising cardiac mitochondrial function since not only was cellular ATP found to be decreased by cocaine, but cocaine was also shown to dissipate the membrane potential (the driving force behind oxidative phosphorylation) in a dose and time dependent manner [87],

The alteration of cardiac gene expression in cocaine-induced cardiomyopathy has recently been investigated using a rat model [88], Specifically, the effects of acute as well as prolonged administration of cocaine were studied with respect to the transcription of atrial natriuretic factor (ANF) mRNAs as a marker of acute mechanical overload [89-91], Acute and prolonged dosing with cocaine was also investigated with respect to the encoding of myosin heavy chain mRNAs as markers of prolonged mechanical overload [90,92-94], Additionally, the study also sought to determine the effect of acute and prolonged administration of cocaine in terms of the transcription of type I and III procollagens as markers of active fibrosis [91,95], The study found that acute injection of cocaine induced ANF gene expression. Cocaine treatment during 28 days resulted in left ventricular hypertrophy (+20% after 24 days) with normal blood pressure, associated with an accumulation of mRNAs encoding ANF and type I and III collagens (+66% and +55%). This chronic treatment also induced a shift in myosin heavy chain gene expression(- 40% and +50%). Results further showed that plasma levels of triiodothyronine and thyroxine were lowered. Thus cocaine activates markers of both hemodynamic overload and fibrosis. Such an activation may result from direct and/or indirect effects of the drug such as myocardial ischemia, mechanical overload, and/or hypothyroidism.

In contrast to the rat model, use of the mouse to study cardiotoxic effects of cocaine is practically nonexistent. A review of the biomedical sciences literature indicates that only one study has even remotely attempted to specifically ascertain cocaine-induced cardiovascular changes in non-fetal, non-embryonic mice. That study sought to determine the effect of cocaine on heart rate in four different inbred mouse strains [96], At the highest dose studied(15 mg/kg), cocaine actually induced a small decrease only in the heart rate of the C3H mice. This is in agreement with other studies that at high doses, cocaine's anesthetic effects on the heart predominate, resulting in a reduction in heart function (see mechanisms review, if needed). This study noted that the strain of mice (among the 4 tested)found to be most resistant to cocaine-induced changes in heart rate was C57BL/6I.

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