Cellular mechanisms of action of therapeutic nitric oxide donors.
A survey of the available literature leads to the conclusion that the most probable mechanism by which nitrovasodilators act, is by nitric oxide (NO) formation. This by itself or by formation of a nitrosothiol (e.g. nitroscocysteine) activates guanylyl cyclase which increases the production of cyclic guanosine monophosphate (cGMP). Endothelium-derived relaxing factor (EDRF), which later turned out to be or to form NO, relaxes smooth muscle by stimulating cGMP formation. The effect of cGMP is mediated by a cGMP-dependent protein kinase and causes a reduction in the intracellular concentration of free Ca2+ ions in the smooth muscle cell. The precise mechanism of this effect is not completely clear but sequestration into sarcoplasmatic reticulum seems to play a major role. In order to identify the nature of the endogenous stimulator of guanylyl cyclase, i.e. to decide whether it is a nitrosothiol or the free radical NO, we compared the effects of NO, nitrosocysteine and nitrosoglutathione on vascular relaxation and increases in cGMP levels in isolated bovine circular strips and on guanylyl cyclase activity in vitro. Induction of tolerance and of cross-tolerance between various NO donors was also investigated. Nitrosodium and nitrosoglutathione augmented cGMP and relaxed vascular smooth muscle slightly more powerfully than NO. The three agents induced slight tolerance after repeated administration without affecting cGMP rises or desensitizing guanylyl cyclase. Pretreatment of coronary strips with nitrosoglutathione caused largely similar cross-tolerance as did NO against nitroglycerin, SIN-1 and sodium nitroprusside. The similarities to NO characterize nitrosocysteine as its most likely precursor, e.g. as EDRF.(ABSTRACT TRUNCATED AT 250 WORDS)
Kukovetz
W R
WR
Institut für Pharmakodynamik und Toxikologie, Karl-Franzens-Universitätsplatz 2, Graz, Austria.
Holzmann
S
S
Schmidt
K
K
D000818:Animals; D002417:Cattle; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000502:physiology; D009569:Nitric Oxide / Q000378:metabolism / Q000494:pharmacology*; D005996:Nitroglycerin / Q000494:pharmacology*; D009599:Nitroprusside / Q000494:pharmacology*; D009603:Nitroso Compounds / Q000494:pharmacology*
D009603:Nitroso Compounds; D009599:Nitroprusside; D009569:Nitric Oxide; D005996:Nitroglycerin