EFFECTS OF THE NONPEPTIDE, NONSELECTIVE ENDOTHELIN ANTAGONIST, BOSENTAN, ON REGIONAL HEMODYNAMIC-RESPONSES TO N-G-MONOMETHYL-L-ARGININE IN CONSCIOUS RATS

1 Male, Long Evans rats (350-450 g) were chronically instrumented to a llow monitoring of mean arterial blood pressure, heart rate and change s in renal, mesenteric and hindquarters haemodynamics. In the first ex periment, animals (n = 8) were given a bolus i.v. injection of the nit ric oxide synthase inhibitor, N-G-monomethyl-L-arginine hydrochloride (L-NMMA; 30 mg kg(-1)) on four consecutive days. Fifteen min prior to L-NMMA administration on the fourth day, the endothelin, ET(A)-, ET(B) -receptor antagonist, bosentan, was injected (30 mg kg(-1), i.v.). Rel ative to the response on the third day, bosentan caused 33+/-14%, 24+/ -3%, 14+/-13%, and 18+/-5% inhibition of the presser, and renal, mesen teric and hindquarters vasoconstrictor effects of L-NMMA, respectively . 2 In the second experiment, bosentan was given 15 min before L-NMMA in a group of rats (n=6) which had not received L-NMMA previously. Rel ative to the responses to L-NMMA on the first day in the previous expe riment, bosentan caused a 30%, 24%, 18% and 27% inhibition of the pres ser, and renal, mesenteric and hindquarters vasoconstrictor effects of L-NMMA, respectively. 3 The results indicate a significant contributi on from endothelin to the haemodynamic effects of L-NMMA in conscious rats. However, since our previous studies have shown the renin-angiote nsin and sympathoadrenal systems are not involved, it is likely that t he major component of the cardiovascular response to L-NMMA in conscio us rats is due to loss of vasodilator action of endothelial nitric oxi de.