Mechanisms of hemodynamic responses to cocaine in conscious rats.
Several agents have been used to treat cocaine-related cardiovascular complications and toxicity occurring in sensitive individuals, yet the causes of hemodynamic responsiveness and differential sensitivity to cocaine are unknown. In this study, we sought to examine the role of different mediators in a model of variable cardiovascular responses to cocaine. As noted previously in conscious rats, cardiac output (CO) and systemic vascular resistance (SVR) responses to cocaine (5 mg/kg, i.v.) varied widely. Twenty of 34 rats exhibited cocaine-induced decreases in CO of > or =8% and large increases in SVR (designated vascular responders). The remaining rats with little change or an increase in CO and smaller increases in SVR were named mixed responders. Pretreatment with propranolol (1 mg/kg) or metoprolol (1 mg/kg) reduced heart rate. In mixed responders, propranolol or metoprolol reversed the cocaine-induced increase in CO and stroke volume and enhanced the increase in SVR, making these rats respond like vascular responders. Nicardipine (25 microg/kg) reduced the pressor response and selectively reversed the CO responses in vascular responders. N omega-nitro-L-arginine methyl ester (L-NAME; 2.7 mg/kg) increased arterial pressure by increasing SVR. Cocaine induced greater pressor and SVR responses apparently because of a shift in baseline values elicited by L-NAME alone. Therefore, differences in hemodynamic responses patterns may be the result of differences in beta-adrenergic activation or subsequent calcium channel activation or both. We predict that calcium channel antagonists may be useful to treat cocaine-induced cardiovascular complications, whereas beta-adrenergic antagonists are not likely to be beneficial.
Knuepfer
M M
MM
Department of Pharmacological and Physiological Science, St. Louis University School of Medicine, Missouri 63104, USA.
Gan
Q
Q
Mueller
P J
PJ
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D015220:Calcium Channels / Q000502:physiology*; D020746:Calcium Channels, L-Type; D003042:Cocaine / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006439:Hemodynamics / Q000187:drug effects*; D008297:Male; D008790:Metoprolol / Q000494:pharmacology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009529:Nicardipine / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology*; D011433:Propranolol / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011943:Receptors, Adrenergic, beta / Q000502:physiology*
D000319:Adrenergic beta-Antagonists; D015220:Calcium Channels; D020746:Calcium Channels, L-Type; D004791:Enzyme Inhibitors; D011943:Receptors, Adrenergic, beta; D009569:Nitric Oxide; D011433:Propranolol; D009529:Nicardipine; D008790:Metoprolol; D003042:Cocaine; D019331:NG-Nitroarginine Methyl Ester