CAS 936, a novel syndnonimine with direct vasodilating and nitric oxide-donating properties: effects on isolated blood vessels.
Organic nitrates and sydnonimines exert their vasorelaxant activity by a common mechanism of action, i.e., release of nitric oxide (NO) and stimulation of the soluble guanylate cyclase of vascular smooth muscle cells. We wished to investigate the vasodilating activity of the novel sydnonimine CAS 936 in guinea pig isolated pulmonary arteries without endothelium. CAS 936 had no effect on contractions induced by norepinephrine (NE) or by the PGF2 alpha-analogue U46 619, but induced a longlasting relaxation of potassium depolarized arteries and of A23 187-contracted vessels. This effect was concentration-dependent (IC50 approximately 16 microM). Oxyhemoglobin and methylene blue had no inhibitory effect on CAS 936, whereas they inhibited the relaxations induced by SIN-1, a sydnonimine which acts by releasing NO. These results suggest that the vasodilating activity of CAS 936 is not related to NO. On the other hand, in vivo metabolites of CAS 936 inhibited NE- and U46 619-induced contractions. Oxyhemoglobin inhibited this effect. Therefore, we conclude that the CAS 936 molecule possesses a vasodilating activity of its own, whereas the metabolites may function as NO donors. The primary target of the intrinsic vasodilating activity of CAS 936 is very likely the vascular smooth muscle cell membrane. To determine which mechanism of action (NO unrelated or NO related) contributes mainly to the in vivo effects of CAS 936, studies of the metabolic fate of CAS 936 may be crucial.
Bohn
H
H
Department of Medicinal Chemistry, Cassella AG, Frankfurt/Main, Germany.
Beyerle
R
R
Martorana
P A
PA
Schönafinger
K
K
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000818:Animals; D000001:Calcimycin / Q000494:pharmacology; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D008751:Methylene Blue / Q000494:pharmacology; D008981:Molsidomine / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D009638:Norepinephrine / Q000494:pharmacology; D010108:Oxyhemoglobins / Q000494:pharmacology; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology; D011651:Pulmonary Artery / Q000187:drug effects; D013558:Sydnones / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000494:pharmacology*
D010108:Oxyhemoglobins; D011450:Prostaglandin Endoperoxides, Synthetic; D013558:Sydnones; D014665:Vasodilator Agents; D009569:Nitric Oxide; D000001:Calcimycin; C073303:pirsidomine; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D008981:Molsidomine; D008751:Methylene Blue; D009638:Norepinephrine; D007213:Indomethacin