ABSTRACT
It is shown that 3-(3-[1,2,4]-triazolo)-oxatriazolium-5-olate (azasidnon-6) can act directly on the vascular wall of isolated segments of caudal ventral artery of SHR rats. Using heme-dependent soluble guanyl cyclase inhibitor 1H-[1,2,4]-oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), it has been found that one of the possible mechanisms of azasidnon-6 vasodilatory action includes heme-dependent activation of a soluble form of guanylate cyclase.
Subject(s)
Arteries/drug effects , Triazoles/pharmacology , Vasodilation/drug effects , Vasodilator Agents/pharmacology , Animals , Guanylate Cyclase/antagonists & inhibitors , Guanylate Cyclase/metabolism , Heme/metabolism , Male , Nitric Oxide/metabolism , Nitroprusside/pharmacology , Oxadiazoles/pharmacology , Phenylephrine/pharmacology , Quinoxalines/pharmacology , Rats , Rats, Inbred SHR , Rats, Wistar , Tail/blood supply , Tissue Culture Techniques , Vasoconstrictor Agents/pharmacologyABSTRACT
Long-term peroral administration of the oxatriazolo-5-olate derivative azasydnon-6 leads to a decrease in the systolic arterial blood pressure in SHR rats. The hypotensive effect of azasydnon-6 is mediated by stimulation of the sGC-cGMP pathway, which triggers vasodilatation of SMC in vessels. The drug effect is inhibited by 1H-[1,2,4]oxadiazolo[4, 3-a]quinoxalin-1-one, a selective sGC inhibitor. During long-term treatment, no tolerance to azasydnon-6 is developed in isolated arterial vessels.
Subject(s)
Antihypertensive Agents/pharmacology , Blood Pressure/drug effects , Triazoles/pharmacology , Vasodilation/drug effects , Animals , Antihypertensive Agents/administration & dosage , Cyclic GMP/antagonists & inhibitors , Guanylate Cyclase/antagonists & inhibitors , Male , Muscle, Smooth, Vascular/drug effects , Muscle, Smooth, Vascular/physiology , Oxadiazoles/pharmacology , Quinoxalines/pharmacology , Rats , Rats, Inbred SHR , Receptors, Cytoplasmic and Nuclear/antagonists & inhibitors , Soluble Guanylyl CyclaseABSTRACT
Intravenous administration of azasidnon-6 (oxatriazolium-5-olate derivative) induces prolonged dose-dependent decrease in arterial blood pressure in awake Wistar and SHR rats. Hypotensive effects of azasidnon-6 in SHR rats is significantly higher during inhibition of endogenous NO synthesis.