Endothelin stimulates an endogenous nitric oxide synthase inhibitor, asymmetric dimethylarginine, in experimental heart failure

Congestive heart failure (CHF) is characterized by increased peripheral vascular resistance. Endothelin-1 (ET-1), a potent endothelium-derived vasoconstrictor, is present at increased concentrations in the plasma and contributes to the regulation of vascular tone in CHF. An endothelium-derived relaxing factor, nitric oxide (NO), also regulates vascular tone, but endothelium-dependent NO-mediated vasodilation is blunted in CHF. An endogenous NO synthase inhibitor, asymmetric dimethylarginine (ADMA), which inhibits NO production and endothelium-dependent relaxation, is present at increased levels in the plasma and plays a role in impaired endothelial function in CHF. However, at present, the relationship between ET-1 and impaired vascular relaxation in CHF is not well known. We hypothesized that ET-1 inhibits NO-mediated vasodilation via increased ADMA production in CHF, and that an endothelin receptor antagonist can prevent this increase in plasma ADMA levels. In the present study, we first examined whether circulating ADMA levels were increased in a dog model of CHF induced by 3 weeks of rapid ventricular pacing (n=5; 270 beats/min) compared with normal dogs (n=5). After 3 weeks of pacing, cardiac output had decreased significantly (1.56+/-0.16 compared with 2.93+/-0.25 litres/min; P<0.01) and systemic vascular resistance had increased (4653+/-374 compared with 3227+/-396 dyn.s.cm(-5); P<0.01) in dogs with CHF compared with normal dogs. Plasma levels of both ET-1 (4.95+/-0.83 compared with 2.12+/-0.39 pg/ml; P<0.05) and ADMA (3.27+/-0.49 compared with 1.91+/-0.25 nmol/ml; P<0.05) were significantly increased in CHF dogs. A significant positive correlation was observed between plasma ET-1 and ADMA levels (r=0.72, P<0.05). Secondly, we chronically administered an ET(A) receptor antagonist, TA-0201 (0.3 mg/kg; n=5), to paced CHF dogs. Drug administration started on day 8 of pacing and continued throughout the experiment. TA-0201 significantly increased cardiac output (2.58+/-0.24 litres/min; P<0.01) and suppressed the increases in plasma ADMA levels and systemic vascular resistance (2.36+/-0.30 nmol/ml and 2423+/-188 dyn.s.cm(-5) respectively; P<0.05 for each) compared with CHF dogs without TA-0201 treatment. In conclusion, ET-1 contributes to the regulation of vascular tone due, in part, to increased levels of an endogenous NO synthase inhibitor in CHF, and an ET(A) receptor antagonist can prevent the inhibition of NO production and the increased peripheral vascular resistance observed in CHF.