RELAXATION OF HUMAN BRONCHIAL SMOOTH-MUSCLE BY S-NITROSOTHIOLS IN-VITRO

S-Nitrosothiols (RS-NO) relax tracheal smooth muscle from a variety of animal species, and may have physiological relevance. We therefore st udied their effects on human bronchial smooth muscle. S-Nitroso adduct s of glutathione, cysteine, N-acetylcysteine and bovine serum albumin relaxed tissues contracted with methacholine with mean IC50 +/- S.E.M. of 3.3 (+/-14), 22 (+/-45), 25 (+/-22) and 36 (+/-7.1) mu M, respecti vely; they were more potent as inhibitory agonists than the correspond ing reduced thiol, NaNO2, or theophylline, but less potent than isopro terenol (P < .001). Despite large differences in their molecular weigh ts and dissociation kinetics, the IC50 Of these RS-NO did not differ s ignificantly from one another, from nitric oxide (NO.) or from sodium nitroprusside. Consistent with the role of cyclic GMP (cGMP) in mediat ing relaxation responses, S-nitroso-N-acetyl cysteine (S-NO-AC) (100 m u M) increased tissue cGMP levels 4-fold,and 8-bromo-cGMP caused modes t tissue relaxation which was potentiated by the phosphodiesterase inh ibitor, dipyridamole (1 mu M). However, the guanylyl cyclase inhibitor s, methylene blue (100 mu M) and LY 83583 (50 mu M), failed to modify the relaxation response to S-NO-AC (sodium nitroprusside and NO.), whi le altering the accumulation of cGMP. Further, hemoglobin (100 mu M) f ailed to inhibit relaxation by S-NO-AC. We conclude that 1) RS-NO are stable, potent relaxants of human airway with therapeutic potential, 2 ) the potency of RS-NO and related nitroso compounds in eliciting rela xation is independent of their size and stability; 3) RS-NO are unlike ly to elicit their effects through spontaneous extracellular liberatio n of NO alone and 4) our data are consistent with the observations of others that there may be a mechanism in addition to guanylyl cyclase a ctivation by which these compounds relax bronchial smooth muscle.