Endothelin-1 mediates nitro-L-arginine vasoconstriction of hypertensive rat lungs

Inhibition of endothelium-derived nitric oxide (NO) synthesis by L-arginine analogs such as nitro-L-arginine (L-NNA) elicits marked precapillary vasoconstriction in lungs from rats with chronic hypoxia-induced pulmonary hypertension. To investigate the role of endogenous endothelin (ET)-1 in L-NNA-induced vasoconstriction, we tested, in salt solution-perfused hypertensive lungs isolated from chronically hypoxic (3-4 wk at barometric pressure = 410 mmHg) adult male rats, if the presser responses to L-NNA and exogenous ET-1 were inhibited by either separate or combined ETA and ETB receptor blockade. Whereas only combined pretreatment with 5 mu M BQ-123 (selective ETA receptor blocker) and 5 mu M BQ-788 (selective ETB receptor blocker) inhibited the response to 100 mu M L-NNA, the response to 10 nM ET-1 was reduced by both BQ-123 alone and the combined blockers. Because exogenous ET-1 causes postcapillary vasoconstriction in salt solution-but not blood-perfused normotensive rat lungs, we next compared effects of ETA and ETB receptor blockade on L-NNA and ET-1 vasoconstrictions in blood-perfused hypertensive lungs. In this case, the combined but not the separate effects of BQ-123 and BQ-788 inhibited the responses to both L-NNA and ET-1. The last experiment showed that the use of BQ-788 to inhibit ETB receptor-mediated clearance of circulating ET-1 resulted in greater accumulation of endogenous ET-1 in the perfusate of hypertensive than of normotensive lungs. There was no difference between L-NNA-treated and vehicle control hypertensive lungs in accumulation of ET-1. These results suggest that increased endogenous levels of ET-1 acting through stimulation of both ETA and ETB receptors contribute to the vasoconstriction unmasked by inhibition of NO synthesis in hypertensive rat lungs. The increased ET-1 is apparently not due to the inhibition of NO synthesis, but, instead, its underlying stimulation of smooth muscle cell contraction is counteracted by NO activity.