Ethanol alters hemodynamic responses to cocaine in rats

Pharmacology Biochemistry and Behavior, 1999

KNUEPFER, M. M. AND P. J. MUELLER. Review of evidence for a novel model of cocaine-induced cardiovascular toxicity. PHARMACOL BIOCHEM BEHAV 63 (3) 489-500, 1999.-Cocaine is known to produce life-threatening cardiovascular complications in some but not all individuals. This review considers the premise that an appropriate animal model for cocaine-induced cardiotoxicity should be characterized by varying sensitivity in the population to the deleterious effects of cocaine. We have studied such a model in which physiological, biochemical, and pathological sensitivity to cocaine varies in rats. Our studies have identified a subset of rats that respond to cocaine with a decrease in cardiac output and a substantial increase in systemic vascular resistance (named vascular responders). In contrast, another group, designated mixed responders, is characterized by a smaller increase in systemic vascular resistance and a small increase in cardiac output. We reported that vascular responders are more likely to develop hypertension and cardiomyopathies with repeated cocaine administration. Under chloralose anesthesia, vascular responders have more profound pressor responses to cocaine and an initial brief spike in renal sympathetic nerve activity not usually noted in mixed responders. Vascular responders have higher resting and cocaine-induced dopamine turnover in the striatum. In addition, vascular responders have higher alpha-adrenergic vasoconstrictor tone, whereas mixed responders have higher adrenergic cardiac tone. The difference in cardiac output and systemic vascular resistance responses to cocaine in these two subsets of the population can be prevented by L-type calcium channel, muscarinic, or alpha-adrenergic blockade. Similar hemodynamic response variability is noted with other psychoactive agents and with acute stress, suggesting that the response patterns are not unique to cocaine. We propose that individual hemodynamic response variability is dependent on differences in CNS responsiveness and correlated with the incidence of cardiovascular disease.

Journal of Pharmaceutical Sciences, 1999

0 The pharmacokinetics and pharmacodynamics of cocaine and its three metabolites, benzoylecgonine, norcocaine, and cocaethylene, were investigated in awake, freely moving rats. This work was performed to examine the effect of alcohol coadministration on the metabolic profile of cocaine and to determine the contribution of cocaine metabolites to the pharmacological responses observed after cocaine administration. The plasma and brain extracellular fluid concentration−time profiles were characterized after intravenous (iv) administration of cocaine and the three metabolites in a crossover experimental design. The neurochemical response, measured as the change in dopamine concentration in the nucleus accumbens, and the cardiovascular responses, measured as the change in the mean arterial blood pressure, heart rate, and QRS interval, were monitored simultaneously. Cocaethylene had the highest brain-to-plasma distribution ratio, followed by cocaine, norcocaine, and benzoylecgonine. The estimated total body clearances for cocaine, benzoylecgonine, norcocaine, and cocaethylene were 140 ± 19, 14.7 ± 1.2, 130 ± 19, and 111 ± 16 mL/min/kg, respectively. Alcohol coadministration increased the formation of norcocaine, decreased the formation of benzoylecgonine, and resulted in the formation of the pharmacologically active metabolite cocaethylene. When cocaine was administered with alcohol, 12.9 ± 3.1% to 15.3 ± 2.9% of the cocaine dose was converted to cocaethylene. Benzoylecgonine did not have any central nervous system or cardiovascular activities after iv administration. Compared with cocaine, norcocaine and cocaethylene had more potent and prolonged effects on the neurochemical, heart rate, and QRS interval responses, and were equipotent in increasing the mean arterial blood pressure. These results indicate that changes in the cocaine metabolic profile and the formation of the pharmacologically active metabolite cocaethylene are, at least partially, responsible for the more intense and longer lasting effects reported after using this drug in combination with alcohol.

Journal of Pharmaceutical Sciences, 1999

0 The effect of alcohol coadministration on cocaine pharmacokinetics and pharmacodynamics was investigated in awake, freely moving rats. Cocaine plasma and brain extracellular fluid (ECF) concentration−time profiles were characterized after intraperitoneal (ip) administration of 30 mg/kg cocaine to rats that were pretreated with either normal saline or alcohol at 5 g/kg in a balanced crossover experimental design. The neurochemical response to cocaine administration, measured as the change in dopamine concentration in the nucleus accumbens (N ACC) and the change in the mean arterial blood pressure were monitored simultaneously. Intragastric alcohol administration significantly increased cocaine systemic bioavailability after ip administration from 0.550 ± 0.044 to 0.754 ± 0.071. Also, the absorption rate constant increased from 0.199 ± 0.045 to 0.276 ± 0.059 min -1 due to alcohol coadministration; however, this increase was not significant. Alcohol inhibition of cocaine metabolism caused an increase in cocaine elimination half-life from 26.3 ± 3.6 to 40.0 ± 8.1 min. Also, cocaine tissue distribution was enhanced by alcohol, resulting in a significant increase in cocaine volume of distribution. Analysis of the brain cocaine concentration−neurochemical effect relationship by the sigmoid-E max pharmacodynamic model showed that E max increased from 850 ± 200 to 1550 ± 640% of baseline due to alcohol coadministration, whereas EC 50 decreased from 3400 ± 580 to 2000 ± 650 ng/mL, indicating higher cocaine potency in the presence of alcohol. The estimates of the indirect inhibitory pharmacodynamic model used to examine the plasma cocaine concentration− change in blood pressure relationship were not significantly different after the two treatments. These results indicate that alcohol significantly alters cocaine absorption, distribution, and elimination, resulting in higher and prolonged cocaine plasma concentration. Alcohol coadministration also potentiates the neurochemical response to cocaine administration.

Life Sciences, 1996

The effects of repeated cocaine administration on contractile responses were studied in adult rabbits. Repeated cocaine exposure caused a significant increase in the maximal response of the aorta to the agonists norepinephrine and serotonin as well as the receptor-independent stimulus KC1 when compared to the saline controls. Cocaine exposure caused a signiIicant increase in the wet weights of both the heart and aorta. When the contraction was normalized to the wet weight of the aorta there was no difIerence between rabbits administered cocaine and saline. Acute cocaine administration caused a time-dependent increase in immunoreactivity of the proto-oncogene c-Fos in the aorta. These results show that repeated cocaine administration leads to the development of cardiovascular hypertrophy.

Journal of medical toxicology : official journal of the American College of Medical Toxicology, 2009

Concurrent abuse of alcohol and cocaine results in the formation of cocaethylene, a powerful cocaine metabolite. Cocaethylene potentiates the direct cardiotoxic and indirect neurotoxic effects of cocaine or alcohol alone. A 44-year-old female with history of cocaine and alcohol abuse presented with massive stroke in the emergency department. CT scan revealed extensive left internal carotid artery dissection extending into the left middle and anterior cerebral arteries resulting in a massive left hemispheric infarct, requiring urgent decompressive craniectomy. The patient had a stormy hospital course with multiple episodes of torsades de pointes in the first 4 days requiring aggressive management. She survived all events and was discharged to a nursing home with residual right hemiplegia and aphasia. The combination of ethanol and cocaine has been associated with a significant increase in the incidence of neurological and cardiac emergencies including cerebral infarction, intracrania...

Drug and Alcohol Dependence, 1995

The squirrel monkey is a reliable model for the cardiovascular effects of cocaine in that it mimics the human response to cocaine; low to moderate doses of cocaine produce a sustained pressor effect and tachycardia. Pretreatment experiments have indicated the importance of o-1 and o-1 adrenoceptor mechanisms in mediating the pressor and tachycardiac effects of cocaine, respectively. Little support for a role of dopaminergic mechanisms in the hemodynamic effects of cocaine has been found. Toxicity to cocaine is often observed hours after its administration, pointing to a potential role of the cocaine metabolites. Studies on the direct effects of a variety of cocaine metabolites indicate that their cardiovascular effects do not necessarily mimic those produced by cocaine, and therefore these differing effects of the metabolites should be considered when evaluating the cardiovascular toxicity of cocaine. Further, as these metabolites are present in the body for long periods of time, these results suggest a role of the metabolites in producing toxicity long after cocaine administration. Finally, studies using both dopaminergic and calcium channel antagonists indicate that the pharmacological mechanisms involved in the cardiovascular effects of cocaine are not the same as those involved in its behavioral effects.

Alcoholism: Clinical and Experimental Research, 1996

The heart is a major locus for the toxic actions of cocaine and ethanol, each of which has been shown to interfere with excitation-contraction coupling in cardiac muscle cells. Because these drugs are frequently used in combination, the present study was designed to investigate how they interact to modify the Ca2+ transient and associated contraction in fura2-loaded cardiomyocytes. A high-speed imaging technique using a charge-coupled device as detector and short-term image store was used to measure cytosolic Ca2+ and contraction simultaneously from fluorescence images obtained during the contractile cycle. Ethanol (1 00 mM) and cocaine (So pM) caused reversible reductions in Ca2+ transient amplitude of 24.3 f 3.0% and 25.1 & 3.6%, respectively. Neither agent modified basal Ca2+. Ethanol treatment decreased peak shortening by 44.3 f 3.5%, whereas the contractile depression by cocaine was 31.4 5.3%. The relatively greater effect of ethanol on contraction resulted from a Ca2+-independent component of ethanol action on contractility.

Life Sciences, 2006

Chronic ethanol intake and hypertension are related. In the present work, we investigated the effect of chronic ethanol (20% v/v) intake for 2, 6 and 10 weeks on basal arterial blood pressure, baroreflex and heart rate levels, as well as on the cardiovascular responses to the infusion of vasoactive agents in unanesthetized rats. Mild hypertension was observed after 2 weeks, 6 weeks or 10 weeks of treatment. On the other hand, no changes were observed in heart rate after long-term ethanol intake. Similar baroreflex changes were observed in 2-or 6-week ethanol-treated rats, and affected all parameters of baroreflex sigmoid curves, when compared to the control group. These changes were characterized by an enhanced baroreflex sympathetic component and a reduction in the baroreflex parasympathetic component. No differences in baroreflex parameters were observed in 10-week ethanol-treated animals. The pressor effects of i.v. phenylephrine were enhanced in 2-week ethanol-treated rats; not affected in 6-week treated animals and reduced in 10-week ethanol-treated rats, when compared to respective control and isocaloric groups. The hypotensive response to i.v. sodium nitroprusside (SNP) was enhanced at all different times of treatment, when compared to respective control and isocaloric groups.

Life Sciences, 1989

Physiological, pharmacological and toxicological responses to two regimens of cocaine administration were compared between spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats. An initial experiment examined renal excretory and hemodynamic function in response to an acute volume load in anesthetized SHR and WKY following subaeute cocaine treatment (20 mg/kg, s.c., twice a day for 9 days). Anticipated renal responses to volume loading were obtained but the responses of cocaine-treated SHR and WKY did not differ from vehicle-treated rats. A second group of experiments compared responses to continuous i.v. infusions of cocaine (1.25 mg/kg.min). In freely moving animals, no differences were noted between SHR and WKY in the increases in mean blood pressure (MBP) and heart rate 0tR) produced during cocaine infusion. The elapsed time-to-onset of convulsions (To) elicited by cocaine was similar in both strains. However, when rats were subjected to restraint during the infusion period, pressor and tachycardic responses were observed to be significantly less in WKY than in SHR or in freely moving rats of either strain. Restraint also differentially affected rectal temperature (RT) responses to cocaine. Hypothermie responses to cocaine were observed in all WKY. Both hypothermic and hyperthermic responses were observed in SHR. A significant correlation was demonstrated between the Tc and the maximal change in RT produced during cocaine infusion. Division of SHR into two arbitrary groups was made, based on the direction of cocaine-induced change in RT. A significant (p<0.01) shortening of the Tc was obvious in SHR (8 of 15) in whom cocaine produced a hyperthermia. These animals were designated SHR H. The mean value for Tc in those SHR which demonstrated a lowering in RT (SHRL; 7 of 15) in response to cocaine was similar to that for WKY. Moreover, the SHR H evidenced significantly greater increases in HR, but not MBP, to cocaine infusion thandid SHR L. The results indicate that restraint stress causes expression of a significant heterogeneity in the RT response of SHR to cocaine. The magnitude and direction of the RT responses are negatively correlated with sensitivity to the convulsive effects of cocaine in SHR. Stress may modify toxic responses to cocaine by interactions with body temperature homeostasis. Cocaine is a tropane alkaloid whose toxic effects have been noted following both medicinal and recreational use. Convulsions, hyperthermia and respiratory depression are of concern in acute overdosage. The circulatory toxicity of cocaine can be pronounced. Tachycardia, pressor responses, acceleration of coronary artery disease, dysrhythmias and myocardial infarction have been frequently reported (1-4), indicating that effects of cocaine on the cardiovascular system are of major concern. The etiology of cocaine-induced cardiovascular toxicity remains uncertain. Until recently, it was suspected that adverse circulatory and cardiac responses occurred secondary to cocaine-mediated stimulation of sympathetic nervous system neurotransmission (5, 6). Thus, cocaine has been shown to potentiate and prolong the cardiac responses to epinephrine infusion in dogs (7, 8). Intravenous administration of cocaine to human subjects has been

Journal of the American College of Cardiology, 1988

The Journal of pharmacology and experimental therapeutics, 1997

The effects of 100 mg of intranasal cocaine in acute alcohol intoxication (0.8 g/kg) were evaluated in eight experienced and nondependent healthy volunteers in a double-blind double-dummy, controlled, randomized, crossover clinical study. The combination of alcohol and cocaine produced greater increases in HR, rate-pressure product and pleasurable-related subjective effects (euphoria, well-being) compared with the effects of cocaine. The drug combination reduced the alcohol-induced sedation, but feelings of drunkenness were not significantly counteracted. Cardiovascular changes induced by the combination condition caused an increase in myocardial oxygen consumption that may be related to an increased risk of cardiovascular toxicity. The augmented subjective euphoria may explain why the drug combination is more likely to be abused than is cocaine or alcohol alone. Plasma cortisol concentrations were significantly higher after concomitant alcohol and cocaine use than with cocaine alon...

Journal of the American College of Cardiology, 1990

This study investigated the effect of intravenous cocaine (0.5 to 2 mg/kg body weight) on the coronary circulation and systemic hemodynamies in closed chest sedated dogs. The role of alpha. and beta-adeenoceptor stimulation in mediating these effects was aim investigated. Cocaine produced dose-dependent increases in mean arterial pressure and rate-pressure product. Although the lower doses of cocaine had no significant effect on the coronary ciccuiation, the 2 mg/kg dose produced a 55 ± 1 .1% increase in coronary vascular resistance (p < 0 .05 versus baseline) and a 19 m 3% reduction in diametor of the left anterior descending coronary artery (p < 0 .05 versus baseline). Despite these potentially deleterious effects on the coronary circulation (occurring at a time of markedly increased myocardial oxygen demand), the electrocardiogram did not demonstrate ischemic changes and there was no myocardial lactate production. Cocaine-induced coronary vasoconstriction was sholtshed by pretreatment with the alpha-adrenoceptor antag-The incidence of cocaine abuse has reached epidemic proportions in numerous communities throughout the United States. It is estimated that 30 million Americans have used cocaine at some time and 5 million use it regularly (1). Over the past 5 years, numerous cases of myocardial ischemia and infarction have been reported to be associated with the

Alcoholism: Clinical and Experimental Research, 2007

Observational clinical studies have demonstrated that there is a U-shaped relationship between ethanol consumption and all-cause mortality or risk of ischemic stroke. Although the exact cause of the U-shaped relationship is unclear, the pharmacokinetics of ethanol during the time course of chronic intake of ethanol may be involved, in relation to its cardiotoxic effects. The present study has assessed the cause of the U-shaped relationship between the ethanol consumption and left ventricular (LV) systolic dysfunction in a pharmacokinetic way.

American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 2001

Hemodynamic responses to cocaine vary greatly between animals, and the variability is related to the incidence of cocaine-induced cardiomyopathies and hypertension. The variability in cardiac output and systemic vascular resistance responses to cocaine in individuals is correlated with the responses to acute startle (air jet). This experiment was designed to determine whether responses to cocaine and to air jet are related to those evoked by a conditioned stimulus (tone preceding foot shock) and to an unconditioned stimulus (cold water). We verified the relationship in hemodynamic response patterns between cocaine and cold stress using selective receptor antagonists. Rats were instrumented with a pulsed Doppler flow probe on the ascending aorta for determination of cardiac output and with an arterial cannula for recording arterial pressure and heart rate. After recovery, some rats were tested multiple times with four different stimuli: air jet (6 trials), 15-s tone preceding 1-s foo...

Journal of Applied Toxicology, 2005

Chronic cocaine abuse is known to cause endothelial dysfunction and atherosclerosis. The present study investigated the effect of binge cocaine treatment, a model for chronic cocaine abuse, on the blood flow responses to the adrenergic agonists norepinephrine, phenylephrine and isoproterenol, the endothelium-dependent vasodilator acetylcholine, and the endothelium independent vasodilator sodium nitroprusside (SNP) in the hindlimb vascular bed of male Sprague Dawley rats. Rats received either single binge or double binge treatment. Each binge treatment consisted of three doses of cocaine (30 mg kg − − − − −1 i.p.) for 3 days. For double binge treatment, there was a 4 day recovery period between the binges. At the end of the treatment the rats were anesthetized and agonists were administered into the right hindlimb circulation through a catheter in the left iliac artery and blood flow responses were measured with a flow probe around the right iliac artery. Rats receiving double cocaine binges showed a significant decrease in the magnitude and duration of the blood flow response to norepinephrine and a decrease in the duration of the blood flow response to phenylephrine, isoproterenol and acetylcholine when compared with saline controls. The blood flow response to SNP was not changed. Total plasma nitrate-nitrite levels were significantly reduced and big endothelin levels were significantly increased in rats receiving double cocaine binges. This study demonstrates that binge cocaine treatment can alter endothelial function, while not changing smooth muscle function, and impairs the adrenergic pathway.