Inhibitory role of endothelium‐derived relaxing factor in rat and human pulmonary arteries

The inhibitory role of endothelium‐derived relaxing factor was studied in both rat and human pulmonary arteries in vitro by inhibiting its synthesis with the L‐arginine analogue N G ‐monomethyl‐ l ‐arginine ( l ‐NMMA). In rat pulmonary arteries, l ‐NMMA pretreatment (10–300 μ m ) dose‐dependently inhibited acetylcholine‐induced relaxation (which is endothelium‐dependent). N G ‐monomethyl‐ d ‐arginine ( d ‐NMMA, 100 μ m ) was without effect, l ‐Arginine, but not d ‐arginine, dose‐dependently reversed this inhibition. l ‐NMMA had no effect on relaxation induced by sodium nitroprusside. In human small pulmonary arteries l ‐NMMA (100 μ m ) pretreatment similarly inhibited the acetylcholine‐induced relaxation but had no effect on the sodium nitroprusside‐induced relaxation. In both rat and human pulmonary arteries, l ‐NMMA, but not d ‐NMMA, always caused contraction of preconstricted tissues whereas it had no effect on baseline tone. In the rat this contraction was completely prevented by prior treatment with l ‐arginine. l ‐NMMA (100 μ m ) pretreatment mimicked the effect of endothelium removal on phenylephrine‐induced vasoconstriction, both resulting in an increase in tension development at each concentration of phenylephrine. This enhancement was greatest at low concentrations of phenylephrine but was still present even at the highest concentrations. Pretreatment with l ‐NMMA (100 μ m ) also significantly increased the responses to single doses of phenylephrine. These results suggest that endothelium‐derived relaxing factor from endothelial cells both mediates the relaxation response to acetylcholine and also acts as a physiological brake against vasoconstriction in pulmonary vessels.