Endothelium‐independent constriction of isolated, pressurized arterioles by N ω ‐nitro‐ L ‐arginine methyl ester ( L ‐NAME)

Background and purpose: Nitric oxide synthase (NOS) inhibitors cause vasoconstriction in pressurized arterioles with myogenic tone. This suggests either tonic production of NO modulates myogenic tone or a direct, NOS‐independent effect of the NOS inhibitors. The nature of the contractile effect of the nitric oxide synthase inhibitor N ω ‐nitro‐L‐arginine methyl ester (L‐NAME, 100 μM) on pressurised arterioles was investigated. Experimental approach: Segments of rat cremaster muscle first‐order arteriole were cannulated on glass micropipettes and maintained at an intraluminal pressure of 50, 70 or 120 mmHg. Key results: L‐NAME and the related compound L‐NA (100 μM) constricted pressurized vessels with myogenic tone. Removal of the endothelium did not cause constriction or alter myogenic tone, however the constrictor effect of L‐NAME persisted. The constrictor effect of L‐NAME was abolished by L‐arginine (1 mM). Other NO and cGMP pathway inhibitors, including the nNOS inhibitor 7‐nitroindazole (100 μM), the NO scavenger carboxy‐PTIO (100 μM), the guanylate cyclase inhibitor ODQ (10 μM) and the cGMP inhibitor Rp‐8CPT‐cGMPS (10 μM) did not cause constriction of the arterioles. L‐NAME caused a small (3‐4 mV) but not statistically significant depolarization of the arteriolar smooth muscle at both pressures. The constrictor effect was not prevented by the K + ‐channel antagonist tetraethyl ammonium (TEA, 1 mM) or the K ATP channel antagonist glibenclamide (1 μM). Conclusions and implications: These observations demonstrate that L‐NAME causes an endothelium‐ and NOS‐independent contraction of vascular smooth muscle in isolated skeletal muscle arterioles. It is suggested that the underlying mechanism relates to an arginine binding interaction. British Journal of Pharmacology (2007) 151 , 602–609; doi: 10.1038/sj.bjp.0707262