Muscarinic Cholinergic and β-Adrenergic Contribution to Hindquarters Vasodilation and Cardiac Responses to Cocaine

Abstract

Cocaine produces a pressor response associated with an initial hindquarters vasoconstriction followed by a prolonged vasodilation in conscious rats. Propranolol pretreatment prevented the vasodilation and enhanced the pressor response, whereas atropine methylbromide pretreatment reduced the increase in systemic vascular resistance. We studied the role of selective muscarinic and ␤-adrenoceptor antagonists on responses to cocaine in rats with an increase in systemic vascular resistance to cocaine (vascular responders). Arterial blood pressure and ascending aortic and distal descending aortic blood flow using pulsed Doppler flowmetry were measured. In conscious rats, cocaine (5 mg/kg i.v.) elicited consistent pressor responses but variable systemic and hindquarters vascular resistance responses that were directly correlated, suggesting that skeletal muscle resistance responses comprise an important component of systemic vascular resistance. ICI 118,551 [(Ϯ)-1-[2,3-(dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[(1-methylethyl)-amino]-2-butanol] (0.5 mg/kg i.v.) pretreatment prevented the hindquarters vasodilation, enhancing the increase in systemic vascular resistance and the pressor response while further depressing the cardiac output response, similar to the effects of propranolol. Atenolol (1 mg/kg) pretreatment attenuated the stroke volume and cardiac output responses while enhancing the increase in systemic vascular resistance without affecting the hindquarters responses. In contrast, M 2 antagonist methoctramine (0.3 mg/kg) pretreatment had similar effects as atropine in reducing the decrease in cardiac output by reducing the increase in systemic vascular resistance, whereas the M 1 antagonist pirenzipine (0.02 mg/kg) did not alter responses. Therefore, the cocaine-induced pressor response is ameliorated by ␤ 2 -adrenoceptor mediated skeletal muscle vasodilation, whereas the decrease in cardiac output and the increase in systemic vascular resistance are dependent on M 2 -cholinoceptor activation.

Role of α-adrenoreceptors in cocaine-induced NADPH oxidase expression and cardiac dysfunction

“…Indeed, muscarinic receptors also contribute to the hemodynamic responses to cocaine because atropine prevented the decrease in cardiac output [25]. Knuepfer [26] has also demonstrated muscarinic cholinergic and h adrenergic contribution to cardiac responses to cocaine. Based on our present results and others, we speculate that the increased O 2 IÀ production by NADPH oxidase after a 1 stimulation contributes to initiate a cascade of events leading to cocaine-induced cardiotoxicity.…”

Laurate Biosensors Image Brain Neurotransmitters In Vivo: Can an Antihypertensive Medication Alter Psychostimulant Behavior?

“…Cocaine produces a pressor response associated with an initial hindquarters vasoconstriction followed by a prolonged vasodilation in conscious rats which has been reported to be antagonized by β adrenoreceptor antagonists like propranolol (77).…”

Pulmonary Vasoconstrictive and Bronchoconstrictive Responses to Anaphylaxis Are Weakened via β2-adrenoceptor Activation by Endogenous Epinephrine in Anesthetized Rats

“…In the sensitized control rats (n ϭ 7), the adrenalectomized rats (n ϭ 7), and the nonsensitized control rats (n ϭ 7), saline alone (100 l) was injected before administration of the antigen. The doses of the antagonists were previously shown to be effective in inhibiting relevant ␤-adrenoceptors 19 -21 ; the doses of ICI 118,551 0.5 mg/kg 19 and atenolol 2 mg/ kg 20 were reported to effectively antagonize the action of ␤ 1 -and ␤ 2 -agonists, respectively, in rats. The dose of propranolol, 1 mg/kg, is known to inhibit both ␤ 1 -and ␤ 2 -adrenoceptors in rats.…”