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

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Abstract
Objective: We assessed whether α1-adrenoreceptor (α1-AR) stimulation contributes to activation of myocardial NADPH oxidase in a rat model of cocaine-induced cardiac dysfunction. Methods and results: After 7 days of cocaine injection (2 × 7.5 mg/kg/day, i.p., Coc), NADPH activity assessed by chemiluminescence increases as well as phosphorylation of p47phox, one of the cytosolic components of NADPH oxidase. The α1-AR antagonist prazosin (Prz), administered 1 h before each cocaine injection (2 × 1 mg/kg/day, i.p., Coc+Prz), prevents these effects. Moreover, Prz pretreatment reduces left ventricular/body weight (LV/BW) ratio and partially prevents the cocaine-induced alterations in fractional shortening and cardiac index assessed by echocardiography. In order to confirm the involvement of α1-AR stimulation in NADPH oxidase up-regulation in vivo, we used phenylephrine (Phe) administration with the same protocol of injections as that used with cocaine (2 × 5 μg/kg/day, i.p.). After Phe administration, as expected, NADPH oxidase activity increases as well as phosphorylation of p47phox. These effects occur in the absence of sustained hemodynamic changes. Conclusion: This study demonstrates the involvement of the α1-AR in NADPH oxidase activation and in cocaine-induced LV dysfunction. We suggest that α1-AR stimulation, at least in part via NADPH oxidase induction, plays a critical role in the events leading to the cardiomyopathy observed after cocaine abuse.

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