Superoxide anions contribute to impaired regulation of blood pressure by nitric oxide during the development of cardiomyopathy.

Basal release of endothelium-derived nitric oxide (NO) has been shown to modulate vascular tone and arterial pressure, and may be altered in disease states. The present study was designed to evaluate the role of nitric oxide synthase (NOS) in the maintenance of mean arterial pressure (MAP) and heart rate (HR) in early and advanced stages of cardiomyopathy. MAP and HR were measured via a carotid arterial cannula in conscious, unrestrained male Golden Syrian and Syrian cardiomyopathic hamsters. Studies were performed in young hamsters (age, 60-90 days) at the early phase and old hamsters (age, 300-350 days) at the advanced phase of cardiomyopathy. N-Nitro-L-arginine (LNA; 0.3-30 micromol/kg i.a.), an inhibitor of NOS activity, produced a dose-dependent increase in MAP in YC (young control) and OC (old control) hamsters. The LNA-induced increase in MAP was significantly impaired in YM (young cardiomyopathic) and was abolished in OM (old cardiomyopathic) hamsters compared with control hamsters. Bradycardia in response to LNA was similar in all groups. The effects of LNA on MAP and HR were reversed by L-arginine (200 mg/kg i.a.). Phenylephrine (0.3-300 microg/kg i.a.), an alpha adrenoceptor agonist, produced a dose-dependent increase in MAP which was similar in C and M hamsters at both ages, which indicated that impaired pressor responses to LNA were not caused by a nonspecific alteration in vascular responsiveness of M hamsters. Additionally, L-arginine (100 or 300 mg/kg i.a.), the precursor to NO and sodium nitroprusside (0.3-300 microg/kg i.a.), an NO donor, produced similar effects on MAP and HR in all groups of hamsters. Endothelial NOS protein levels in aorta isolated from each group of hamsters were similar. In the presence of tiron (1000 mg/kg), a superoxide anion scavenger, the effects of LNA on MAP were significantly restored in OM compared with OC hamsters. These results indicate that the role of NO in regulation of MAP is reduced during the development of cardiomyopathy. This effect is not the result of a deficiency of L-arginine, a reduced sensitivity to exogenous NO or a decrease in vascular endothelial NOS protein in cardiomyopathic hamsters. However, scavenging of NO by superoxide anions may contribute to the diminished role of NO in regulation of blood pressure in the advanced stage of cardiomyopathy.