NO(+) but not NO radical relaxes airway smooth muscle via cGMP-independent release of internal Ca(2+).
We compared the effects of two redox forms of nitric oxide, NO(+) [liberated by S-nitroso-N-acetyl-penicillamine (SNAP)] and NO. [liberated by 3-morpholinosydnonimine (SIN-1) in the presence of superoxide dismutase], on cytosolic concentration of Ca(2+) ([Ca(2+)](i); single cells) and tone (intact strips) obtained from human main stem bronchi and canine trachealis. SNAP evoked a rise in [Ca(2+)](i) that was unaffected by removing external Ca(2+) but was markedly reduced by depleting the internal Ca(2+) pool using cyclopiazonic acid (10(-5) M). Dithiothreitol (1 mM) also antagonized the Ca(2+) transient as well as the accompanying relaxation. SNAP attenuated responses to 15 and 30 mM KCl but not those to 60 mM KCl, suggesting the involvement of an electromechanical coupling mechanism rather than a direct effect on the contractile apparatus or on Ca(2+) channels. SNAP relaxations were sensitive to charybdotoxin (10(-7) M) or tetraethylammonium (30 mM) but not to 4-aminopyridine (1 mM). Neither SIN-1 nor 8-bromoguanosine 3',5'-cyclic monophosphate had any significant effect on resting [Ca(2+)](i), although both of these agents were able to completely reverse tone evoked by carbachol (10(-7) M). We conclude that NO(+) causes release of internal Ca(2+) in a cGMP-independent fashion, leading to activation of Ca(2+)-dependent K(+) channels and relaxation, whereas NO. relaxes the airways through a cGMP-dependent, Ca(2+)-independent pathway.
Janssen
L J
LJ
Asthma Research Group, Smooth Muscle Research Group, Department of Medicine, McMaster University, Hamilton, Ontario, Canada L8N 3Z5. janssenl@fhs.csu.mcmaster.ca
Premji
M
M
Lu-Chao
H
H
Cox
G
G
Keshavjee
S
S
D015761:4-Aminopyridine / Q000494:pharmacology; D000818:Animals; D001980:Bronchi / Q000737:chemistry / Q000187:drug effects / Q000201:enzymology*; D002118:Calcium / Q000378:metabolism*; D000252:Calcium-Transporting ATPases / Q000378:metabolism; D018999:Charybdotoxin / Q000494:pharmacology; D006152:Cyclic GMP / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D004229:Dithiothreitol / Q000494:pharmacology; D004285:Dogs; D004789:Enzyme Activation / Q000187:drug effects; D005609:Free Radicals / Q000378:metabolism; D006162:Guanylate Cyclase / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008981:Molsidomine / Q000031:analogs & derivatives / Q000494:pharmacology; D009130:Muscle, Smooth / Q000737:chemistry / Q000187:drug effects / Q000201:enzymology*; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D010084:Oxidation-Reduction; D010396:Penicillamine / Q000031:analogs & derivatives / Q000494:pharmacology; D015221:Potassium Channels / Q000502:physiology; D011189:Potassium Chloride / Q000494:pharmacology; D019789:Tetraethylammonium / Q000494:pharmacology; D014132:Trachea / Q000737:chemistry / Q000187:drug effects / Q000201:enzymology*
D005609:Free Radicals; D020030:Nitric Oxide Donors; D015221:Potassium Channels; C110881:S-nitro-N-acetylpenicillamine; D018999:Charybdotoxin; C016276:8-bromocyclic GMP; D009569:Nitric Oxide; C002385:linsidomine; D019789:Tetraethylammonium; D011189:Potassium Chloride; D015761:4-Aminopyridine; D008981:Molsidomine; D006162:Guanylate Cyclase; D000252:Calcium-Transporting ATPases; D010396:Penicillamine; D006152:Cyclic GMP; D002118:Calcium; D004229:Dithiothreitol