title: Mechanism of hydralazine-induced relaxation in resistance arteries during pregnancy: Hydralazine induces vasodilation via a prostacyclin pathway.
abstract: The cellular mechanisms of hydralazine-induced relaxation were investigated in isolated mesenteric resistance arteries from pregnant rats. Administration of hydralazine relaxed phenylephrine-constricted mesenteric arteries with an EC50 of 3.6 ± 0.3 μM and an efficacy of 75 ± 6.2%. These vasodilatory effects were abolished by: (1) preconstriction with a potassium depolarizing solution, (2) endothelial denudation (for concentrations of hydralazine<10 μM), (3) addition of non-selective cyclooxygenase-1 and cyclooxygenase-2 inhibitors, and (4) pretreatment with a prostacyclin receptor antagonist (R01138452). Nitric oxide synthase (NOS) inhibition did not significantly alter the sensitivity or magnitude of the vasodilatory response; surprisingly, exposure to hydralazine also did not elevate endothelial cell Ca(2+), suggesting a novel mechanism of activation. In summary, hydralazine is a potent resistance artery vasodilator that affects both endothelial and vascular smooth muscle (VSM) cells in a concentration-dependent manner. At clinically relevant concentrations (<10 μM), its effects in the splanchnic resistance vasculature are: (1) primarily endothelial in origin, require (2) hyperpolarization and (3) activation of COX, and (4) are mediated by the PGI2 (IP) receptor.
authors.affiliation: Department of Obstetrics and Gynecology and Reproductive Sciences, University of Vermont College of Medicine, USA.
authors.forename: Nicole
authors.initials: N
authors.lastname: Maille
authors.affiliation: Department of Obstetrics and Gynecology and Reproductive Sciences, University of Vermont College of Medicine, USA.
authors.forename: Natalia
authors.initials: N
authors.lastname: Gokina
authors.affiliation: Department of Obstetrics and Gynecology and Reproductive Sciences, University of Vermont College of Medicine, USA; Department of Biology, Ecology and Earth Science, University of Calabria, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Mandalà
authors.affiliation: Department of Obstetrics and Gynecology and Reproductive Sciences, University of Vermont College of Medicine, USA.
authors.forename: Ilsley
authors.initials: I
authors.lastname: Colton
authors.affiliation: Department of Obstetrics and Gynecology and Reproductive Sciences, University of Vermont College of Medicine, USA. Electronic address: George.Osol@uvm.edu.
authors.forename: George
authors.initials: G
authors.lastname: Osol
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000494:pharmacology; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000378:metabolism; D011464:Epoprostenol / Q000378:metabolism*; D005260:Female; D006830:Hydralazine / Q000008:administration & dosage / Q000494:pharmacology*; D008638:Mesenteric Arteries / Q000187:drug effects / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D010656:Phenylephrine / Q000494:pharmacology; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D000959:Antihypertensive Agents; D016861:Cyclooxygenase Inhibitors; D014665:Vasodilator Agents; D010656:Phenylephrine; D006830:Hydralazine; D011464:Epoprostenol
keywords: Endothelium; Hypertension; Pregnancy; Prostacyclin; Vascular smooth muscle