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 pressor 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 microM BQ-123 (selective ETA receptor blocker) and 5 microM BQ-788 (selective ETB receptor blocker) inhibited the response to 100 microM 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.
Muramatsu
M
M
Department of Medicine, University of Colorado Health Sciences Center, Denver 80262, USA.
Rodman
D M
DM
Oka
M
M
McMurtry
I F
IF
D000818:Animals; D001769:Blood; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000378:metabolism / Q000502:physiology*; D006976:Hypertension, Pulmonary / Q000150:complications / Q000503:physiopathology*; D017380:Hypertrophy, Right Ventricular / Q000209:etiology; D066298:In Vitro Techniques; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D019335:Nitroarginine / Q000494:pharmacology*; D010477:Perfusion; D011652:Pulmonary Circulation / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012965:Sodium Chloride; D014661:Vasoconstriction / Q000502:physiology*
D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D019335:Nitroarginine; D012965:Sodium Chloride