Evidence That Contractions of Isolated Arteries by l-NMMA and NOLA Are Not Due to Inhibition of Basal EDRF Release

Abstract

Summary: We have tested the hypothesis that endothelium-dependent contractions to two l-arginine analogues modified in either of the guanidino nitrogens [e.g., NG-monomethyl-l-arginine (l-NMMA) and Nω-nitro-l-arginine (NOLA)] are due to inhibition of basally released EDRF. We found that these contractions in the dog isolated coronary artery were maximal at 10 μM for each compound, as increasing the concentration 10-fold further gave no significant increase in developed force. Over the same concentration range, NOLA was more potent than l-NMMA in blocking relaxations to the endothelium-dependent agonist, acetylcholine. Thus, for l-NMMA, only the highest concentrations (30-100 μM) caused a small but significant depression of the maximum response with no effect on sensitivity (i.e., EC50), whereas for NOLA (10-100 μM), there was a progressive, concentration-dependent decrease in both sensitivity and the maximum response. Oxyhemoglobin (Hb; 1-3 μM) and FeSO4 (3 mM) caused a 4- to 10-fold rightwards displacement of the relaxation curve to sodium nitroprusside and blocked totally the response to nitric oxide (generated from acidified sodium nitrite), respectively. Under these conditions, the contractions to l-NMMA were virtually unaffected. These data suggest that contractions to both l-NMMA and NOLA in the dog coronary artery were not caused by the removal of effects of basally released EDRF.