SUPEROXIDE ANIONS CONTRIBUTE TO IMPAIRED REGULATION OF BLOOD-PRESSUREBY 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 o f nitric oxide synthase (NOS) in the maintenance of mean arterial pres sure (MAP) and heart rate (HR) in early and advanced stages of cardiom yopathy. MAP and HR were measured via a carotid arterial cannula in co nscious, unrestrained male Golden Syrian and Syrian cardiomyopathic ha msters. Studies were performed in young hamsters (age, 60-90 days) at the early phase and old hamsters (age, 300-350 days) at the advanced p hase of cardiomyopathy. N-Nitro-L-arginine (LNA; 0.3-30 mu mol/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-indu ced increase in MAP was significantly impaired in YM (young cardiomyop athic) 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-argini ne (200 mg/kg i.a.). Phenylephrine (0.3-300 mu g/kg i.a.), an alpha ad renoceptor agonist, produced a dose-dependent increase in MAP which wa s similar in C and M hamsters at both ages, which indicated that impai red presser responses to LNA were not caused by a nonspecific alterati on 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 mu g/kg i.a.), an NO donor, produced similar effects on MAP a nd HR in all groups of hamsters. Endothelial NOS protein levels in aor ta isolated from each group of hamsters were similar. In the presence of tiron (1000 mg/kg), a superoxide anion scavenger, the effects of LN A on MAP were significantly restored in OM compared with OC hamsters. These results indicate that the role of NO in regulation of MAP is red uced during the development of cardiomyopathy. This effect is not the result of a deficiency of L-arginine, a reduced sensitivity to exogeno us NO or a decrease in vascular endothelial NOS protein in cardiomyopa thic hamsters. However, scavenging of NO by superoxide anions may cont ribute to the diminished role of NO in regulation of blood pressure in the advanced stage of cardiomyopathy.