Role of Nitric Oxide in Cocaine-Induced Acute Hypertension

Abstract Cocaine causes acute hypertension by blocking catecholamine reuptake. There is evidence that it also impairs the peripheral endothelial nitric oxide system, which is normally vasodilatory. We further explored the role of nitric oxide in cocaine-induced vasoconstriction in anesthetized rats, and in vitro by using isolated carotid artery segments. Cocaine administered intravenously in rats increased mean arterial pressure by 30 to 40 mm Hg within 1 min. This effect was dose dependent and the maximum effect was observed at a dose of 1.25 mg/kg. The prototype catecholamine norepinephrine induced a similar increase in blood pressure. When rats were pretreated with NG-monomethyl- -arginine (L-NMMA, a blocker of nitric oxide) and challenged with cocaine, the increase in blood pressure was blocked by 80%, whereas pretreatment with L-NMMA did not block norepinephrine-induced vasoconstriction. Both cocaine and norepinephrine also induced an immediate vasoconstriction in isolated carotid artery preparations. The in vitro vasoconstriction induced by cocaine was blocked by pretreatment with L-NMMA, whereas L-NMMA did not block the norepinephrine-induced vasoconstriction in vitro. Furthermore, carotid artery stripped of endothelium responded to norepinephrine but failed to respond to L-NMMA or cocaine. S-nitroso-N-acetyl- -penicillamine (SNAP)—a precursor of nitric oxide— stimulated nitric oxide production in control coronary artery fragments. When these fragments were incubated with cocaine there was a 20% reduction in the production of nitrite oxide. These results suggest that cocaine exerts its peripheral vasoconstriction at least in part by inhibiting local vasodilator nitric oxide. Article Outline • Materials and methods • Preparation of animals • Drug administration • Measurement of vasoconstriction in isolated blood vessel • Endothelial stripping of isolated carotid artery • Assay for nitric oxide production in arterial vessel fragments • Data collection • Results • Acute hypertension induced in rats by cocaine • Acute effects of NE • Vasoconstrictive effects of cocaine and NE in the isolated carotid artery preparation • Effect of L-NMMA on cocaine-induced acute hypertension • Effect of pretreatment with L-NMMA on cocaine-induced vasoconstriction in isolated carotid artery preparation • Cocaine-induced vasoconstriction in endothelial-stripped carotid artery preparation • The effect of cocaine in the generation of nitric oxide in carotid artery fragments • Discussion • Acknowledgements • References