Hydralazine inhibits vascular reactivity by a mechanism independent of vascular prostaglandin biosynthesis: role of thromboxane synthetase in blocking hydralazine actions.
To explore the mechanism of action of hydralazine on vascular reactivity of small vessels we have examined its actions in the isolated perfused mesenteric vascular bed. In buffer perfused preparations hydralazine inhibited responses to nondepolarizing stimuli at concentrations comparable to those achieved in vivo. Inhibition of cyclo-oxygenase activity enhanced hydralazine's action as did inhibition of thromboxane synthetase. Hydralazine stimulated mesenteric vascular bed prostaglandin biosynthesis (6-keto PGF1a and PGE2 determined by radio-immunoassay) and stimulated aorta PG12 synthesis (monitored by platelet bioassay). Extracellular calcium opposed hydralazine's action by a mechanism sensitive to cyclo-oxygenase inhibition. Concentrations of hydralazine substantially greater than those effective in the perfused vascular bed were required to demonstrate inhibition of platelet aggregation and ram seminal vesicles cyclooxygenase activity. These data indicate: Hydralazine acts directly on the smooth muscle to attentuate responses to nondepolarizing stimuli. Hydralazine does not inhibit vascular reactivity by a PG12 dependent mechanism although it stimulates prostaglandin biosynthesis. Reduction of vascular bed prostaglandin and thromboxane A2 biosynthesis enhances hydralazine actions. Hydralazine appears to act at a thromboxane A2 sensitive site however it is not a nonselective prostaglandin antagonist. Hydralazine is effective at concentrations which do not inhibit either platelet aggregation or ram seminal vesicle cyclooxygenase. These data suggest that hydralazine is a potent direct acting vasodilator which stimulates prostaglandin biosynthesis and whose potency may in turn be attenuated by the production of proconstrictory prostaglandins.
Ally
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Horrobin
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D000818:Animals; D001808:Blood Vessels / Q000187:drug effects* / Q000502:physiology; D015232:Dinoprostone; D006830:Hydralazine / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D009638:Norepinephrine / Q000494:pharmacology; D010477:Perfusion; D010974:Platelet Aggregation / Q000187:drug effects; D011453:Prostaglandins / Q000096:biosynthesis*; D011458:Prostaglandins E / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D013152:Splanchnic Circulation / Q000187:drug effects; D013930:Thromboxane-A Synthase / Q000502:physiology*; D014661:Vasoconstriction / Q000187:drug effects
D011453:Prostaglandins; D011458:Prostaglandins E; D006830:Hydralazine; D013930:Thromboxane-A Synthase; D015232:Dinoprostone; D009638:Norepinephrine