Role of alpha1-adrenoreceptors in cocaine-induced NADPH oxidase expression and cardiac dysfunction.
OBJECTIVE
We assessed whether alpha1-adrenoreceptor (alpha1-AR) stimulation contributes to activation of myocardial NADPH oxidase in a rat model of cocaine-induced cardiac dysfunction.


RESULTS
After 7 days of cocaine injection (2 x 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 alpha1-AR antagonist prazosin (Prz), administered 1 h before each cocaine injection (2 x 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 alpha1-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 x 5 microg/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.


CONCLUSIONS
This study demonstrates the involvement of the alpha1-AR in NADPH oxidase activation and in cocaine-induced LV dysfunction. We suggest that alpha1-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.
Isabelle
Marc
M
INSERM U644, Faculté de médecine-Pharmacie de Rouen, UFR de Medecine et de Pharmacie, 22 boulevard Gambetta, 76183 Rouen, France.
Monteil
Christelle
C
Moritz
Fabienne
F
Dautreaux
Brigitte
B
Henry
Jean-Paul
JP
Richard
Vincent
V
Mulder
Paul
P
Thuillez
Christian
C
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000818:Animals; D006332:Cardiomegaly / Q000139:chemically induced / Q000378:metabolism; D009202:Cardiomyopathies / Q000139:chemically induced* / Q000378:metabolism; D003042:Cocaine / Q000494:pharmacology*; D008297:Male; D009206:Myocardium / Q000201:enzymology; D019255:NADPH Oxidases / Q000378:metabolism*; D010656:Phenylephrine / Q000494:pharmacology; D011224:Prazosin / Q000494:pharmacology*; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D014662:Vasoconstrictor Agents / Q000494:pharmacology*; D018487:Ventricular Dysfunction, Left / Q000139:chemically induced / Q000378:metabolism
D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D014662:Vasoconstrictor Agents; D010656:Phenylephrine; D019255:NADPH Oxidases; D003042:Cocaine; D011224:Prazosin