title: Nitric oxide synthase inhibition promotes endothelium-dependent vasodilatation and the antihypertensive effect of L-serine.
abstract: L-serine is a precursor of central neurotransmitters. Its cardiovascular effects are largely unstudied. We compared the in vitro effects of L-serine and acetylcholine in phenylephrine-constricted third-order branches of mesenteric arterioles in the NO synthase inhibitor N(G)-nitro L-arginine methyl ester (L-NAME), pretreated hypertensive rats, and a control group of normotensive male Sprague-Dawley rats. The changes in mean arterial pressure and heart rate evoked by acute intravenous infusion of either L-serine (0.1 to 3.0 mmol/kg) or acetylcholine (0.1 to 10.0 nmol/kg) were determined in anesthetized rats. L-serine evoked concentration-dependent (10 to 200 micromol/L) vasodilatation in endothelium-intact but not in endothelium-denuded vessels. It was abolished by the inclusion of a combination of apamin (SK(Ca) channel inhibitor) and TRAM-34 (IK(Ca) channel inhibitor) or ouabain (Na(+) pump inhibitor) and Ba(2+) (K(ir) channel inhibitor) or when the vessels were constricted by potassium chloride. The maximal response to L-serine was higher in the L-NAME treatment group (control 20% versus L-NAME 40%) in relation to the maximal response to acetylcholine (control 93% versus L-NAME 79%). L-serine evoked a rapid, reversible, dose-dependent fall in mean arterial pressure without increasing heart rate and was more pronounced in L-NAME-treated rats (maximal response: >60 mm Hg) than in the control rats (maximal response: 25 mm Hg). This was inhibited (P<0.01) by apamin+charybdotoxin pretreatment. The in vitro and in vivo data confirm that L-serine promotes vasodilatation in resistance arterioles and evokes a greater fall in mean arterial pressure in NO synthase-inhibited hypertensive rats via activation of apamin and charybdotoxin/TRAM-34-sensitive K(Ca) channels present on the endothelium.
authors.affiliation: Department of Pharmacology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
authors.forename: Ramesh C
authors.initials: RC
authors.lastname: Mishra
authors.forename: Saswati
authors.initials: S
authors.lastname: Tripathy
authors.forename: Kaushik M
authors.initials: KM
authors.lastname: Desai
authors.forename: Dale
authors.initials: D
authors.lastname: Quest
authors.forename: Yanjie
authors.initials: Y
authors.lastname: Lu
authors.forename: Jawed
authors.initials: J
authors.lastname: Akhtar
authors.forename: Venkat
authors.initials: V
authors.lastname: Gopalakrishnan
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001160:Arterioles / Q000187:drug effects / Q000502:physiology; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology*; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D008297:Male; D008643:Mesentery / Q000098:blood supply; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D010656:Phenylephrine / Q000494:pharmacology; D024681:Potassium Channels, Calcium-Activated / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012694:Serine / Q000494:pharmacology*; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*
chemical_list: D000959:Antihypertensive Agents; D024681:Potassium Channels, Calcium-Activated; D014662:Vasoconstrictor Agents; D010656:Phenylephrine; D009569:Nitric Oxide; D012694:Serine; D019001:Nitric Oxide Synthase