Cellular mechanisms of nitric oxide-induced relaxation of corporeal smooth muscle in the guinea-pig

The cellular mechanism of nitric oxide (NO)-induced relaxation in corporeal smooth muscle (CSM) of the guinea-pig was investigated. Changes in the intracellular concentration of calcium ions ([Ca2+](i)), membrane potential and isometric tension were measured. CSM cells exhibited spontaneous depolarizations and transient increases in [Ca2+]i (Ca2+ transients) which were accompanied by contractions. This spontaneous activity was abolished by nifedipine (10 mum). NO released by 3-morpholino-sydnonimine (SIN-1, 10 mum) hyperpolarized the membrane and prevented the generation of spontaneous depolarizations. SIN-1 also abolished Ca2+ transients and associated contractions. These effects of SIN-1 were blocked by 1H-[1,2,4]oxadiazole[4,3-a]quinoxatin-1-one (ODQ, 10 mum), an inhibitor of guanylate cyclase. Noradrenaline (NA, 1 mum) increased [Ca2+](i) to levels similar to those produced by high potassium-containing solution (high K+ solution, [K+](o) = 40 mm), however, NA-induced contractions were three times greater in amplitude than those induced by high K+ solution. In NA precontracted preparations, SIN-1 inhibited 80% of the contraction and decreased [Ca2+](i) by 20%. In contrast, nifedipine reduced [Ca2+](i) by 80%, while the level of contraction was decreased by only 20%. SIN-1-induced reduction in [Ca2+](i) but not the tension effect, was abolished by pretreatment with cyclopiazonic acid (CPA, 10 mum). In high K+ precontracted preparations, SIN-1 inhibited 80% of the contraction and reduced [Ca2+](i) by 20%. Nifedipine, however, largely abolished increases in both [Ca2+](i) and tension under these circumstances. These results suggest that decreasing the sensitivity of contractile proteins to Ca2+ is probably the key mechanism of NO-induced relaxation in CSM of the guinea-pig.