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 studied their effects on human bronchial smooth muscle. S-Nitroso adducts 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) microM, respectively; they were more potent as inhibitory agonists than the corresponding reduced thiol, NaNO2, or theophylline, but less potent than isoproterenol (P < .001). Despite large differences in their molecular weights and dissociation kinetics, the IC50 of these RS-NO did not differ significantly from one another, from nitric oxide (NO.) or from sodium nitroprusside. Consistent with the role of cyclic GMP (cGMP) in mediating relaxation responses, S-nitroso-N-acetyl cysteine (S-NO-AC) (100 microM) increased tissue cGMP levels 4-fold, and 8-bromo-cGMP caused modest tissue relaxation which was potentiated by the phosphodiesterase inhibitor, dipyridamole (1 microM). However, the guanylyl cyclase inhibitors, methylene blue (100 microM) and LY 83583 (50 microM), failed to modify the relaxation response to S-NO-AC (sodium nitroprusside and NO.), while altering the accumulation of cGMP. Further, hemoglobin (100 microM) failed to inhibit relaxation by S-NO-AC.(ABSTRACT TRUNCATED AT 250 WORDS)
Gaston
B
B
Ina Sue Perimutter Laboratory, Children's Hospital, Boston, Massachusetts.
Drazen
J M
JM
Jansen
A
A
Sugarbaker
D A
DA
Loscalzo
J
J
Richards
W
W
Stamler
J S
JS
D001980:Bronchi / Q000187:drug effects* / Q000502:physiology; D006152:Cyclic GMP / Q000032:analysis; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D005260:Female; D006162:Guanylate Cyclase / Q000502:physiology; D006801:Humans; D008297:Male; D008623:Mercaptoethanol; D008875:Middle Aged; D009126:Muscle Relaxation / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D009603:Nitroso Compounds / Q000494:pharmacology*; D026403:S-Nitrosothiols
D009603:Nitroso Compounds; D026403:S-Nitrosothiols; D008623:Mercaptoethanol; C032635:S-nitrosomercaptoethanol; D006162:Guanylate Cyclase; D006152:Cyclic GMP