Enzymic and nonenzymic release of NO accounts for the vasodilator activity of the metabolites of CAS 936, a novel long-acting sydnonimine derivative.
The molecular mechanism(s) underlying the vasodilator activity of CAS 936 (3-(cis-2,6-dimethylpiperidino)-N-(4-methoxybenzoyl)-sydn oni mine) and its metabolites 3-(cis-2,6-dimethylpiperidino)-sydnonimine (C87 3754) and N-(cis-2,6-dimethylpiperidino)-N-nitroso-2-aminoacetonitrile (C873786) was investigated. These compounds were tested for their relaxant activity in isolated rabbit arterial segments, activation of purified soluble guanylyl cyclase and release of nitric oxide (NO) in vitro and in vivo. C873754 and C873786 inhibited the noradrenaline-induced contraction and increased the cyclic GMP content of endothelium-denuded rabbit aortic and femoral segments, whereas CAS 936 was without effect. Similarly, both metabolites, but not CAS 936, activated purified soluble guanylyl cyclase (EC50 about 30 microM) and released NO in buffered aqueous solutions, as detected by electron spin resonance (esr) spectrometry. Both in vitro and in vivo an accumulation of NO was detected by esr spectrometry in vascular tissues exposed to the metabolites of CAS 936, whereas a significant release of NO from CAS 936 was only detected in the isolated rabbit liver, but not in vascular tissue. It is conceivable, therefore, that the metabolites of CAS 936 appearing in the systemic circulation after hepatic biotransformation induce vasodilatation by release of NO and activation of soluble guanylyl cyclase in vascular smooth muscle. Moreover, the activation of soluble guanylyl cyclase in vitro by the metabolites of CAS 936 was significantly enhanced by co-incubation with certain particulate fractions from bovine aortic endothelial and smooth muscle cells.(ABSTRACT TRUNCATED AT 250 WORDS)
Department of Applied Physiology, University of Freiburg, Federal Republic of Germany.
A
A
Mülsch
M
M
Hecker
P I
PI
Mordvintcev
A F
AF
Vanin
R
R
Busse
D000818:Animals; D001808:Blood Vessels / Q000187:drug effects* / Q000378:metabolism; D002417:Cattle; D006152:Cyclic GMP / Q000378:metabolism; D004578:Electron Spin Resonance Spectroscopy; D004730:Endothelium, Vascular / Q000187:drug effects; D005260:Female; D066298:In Vitro Techniques; D008297:Male; D008981:Molsidomine / Q000031:analogs & derivatives / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009569:Nitric Oxide / Q000378:metabolism*; D009603:Nitroso Compounds / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011817:Rabbits; D013552:Swine; D013558:Sydnones / Q000378:metabolism / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000378:metabolism / Q000494:pharmacology*
D009603:Nitroso Compounds; D010880:Piperidines; D013558:Sydnones; D014665:Vasodilator Agents; C080068:C 873786; C072857:3-(cis-2,6-dimethylpiperidino)sydnonimine; D009569:Nitric Oxide; C002385:linsidomine; C073303:pirsidomine; D008981:Molsidomine; D006152:Cyclic GMP