EVIDENCE THAT CONTRACTIONS OF ISOLATED ARTERIES BY L-NMMA AND NOLA ARE NOT DUE TO INHIBITION OF BASAL EDRF RELEASE

We have tested the hypothesis that endothelium-dependent contractions to two L-arginine analogues modified in either of the guanidino nitrogens [e.g., N(G)-monomethyl-L-arginine (L-NMMA) and N-omega-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-mu-M 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-mu-M) caused a small but significant depression of the maximum response with no effect on sensitivity (i.e., EC50), whereas for NOLA (10-100-mu-M), there was a progressive, concentration-dependent decrease in both sensitivity and the maximum response. Oxyhemoglobin (Hb; 1-3-mu-M) 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.