title: Platelets enhance contractility in perfused rat mesenteric arteries: involvement of endothelin-1.
abstract: We investigated the effects of platelet supernatant on pressor responses to norepinephrine in isolated perfused rat mesenteric arteries. Perfusion of the arteries with platelet supernatant for 2 h markedly enhanced the pressor responses to norepinephrine (10(-6) and 3 x 10(-6) M). This enhancement was significantly inhibited by phosphoramidon (10(-4) M), an endothelin converting enzyme inhibitor. Both BQ788 [N-cis-2,6-dimethylpiperidinocarbonyl-L-gamma-methylleucyl-D -1-methoxycarbonyltryptophanyl-D-norleucine] (10(-6) M), an endothelin ET(B) receptor antagonist, and bosentan (Ro47-0203, 4-tert-butyl-N-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2,2-bipyri midin-4-yl]-benzenesulfonamide) (10(-5) M), a nonselective endothelin receptor antagonist, also prevented the potentiation of responses to norepinephrine evoked by platelet supernatant, but FR 139317 ((R)2-[(R)-2-[(S)-2-[[1-(hexahydro-1H-azepinyl)]carbonyl]amino-4-+ ++methylpentanoyl] amino-3-[3-(1-methyl-1H-indoyl)]propionyl]amino-3-(2-pyridyl) propionic acid) (10-6 M), an endothelin ET(A) receptor antagonist, had little effect. Suppressor doses of endothelin-1 (3 x 10(-10) M) or sarafotoxin S6c (S6c) (3 x 10(-10) M) potentiated significantly the norepinephrine-induced vasoconstriction, in the same preparation. Moreover, supernatant-induced enhancement of pressor responses to norepinephrine was markedly suppressed by TGF-beta1 neutralizing antibody. Transforming growth factor-beta1 (TGF-beta1) (40 pM) also significantly enhanced the pressor responses to norepinephrine (10(-6) M) and this enhancement was significantly inhibited by phosphoramidon. These results suggest that platelet-derived TGF-beta1 stimulates the vascular production of endothelin-1 and thereby enhances vasoconstrictor responses to norepinephrine. Platelet-induced enhancement of vasoconstrictor responses to norepinephrine seems to be mainly mediated by endothelin ET(B) receptor, in rat mesenteric arteries.
authors.affiliation: Department of Pharmacology, Osaka University of Pharmaceutical Sciences, Takatsuki, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Kita
authors.forename: Y
authors.initials: Y
authors.lastname: Matsumura
authors.forename: Y
authors.initials: Y
authors.lastname: Tanida
authors.forename: T
authors.initials: T
authors.lastname: Kusuno
authors.forename: S
authors.initials: S
authors.lastname: Chatani
authors.forename: Y
authors.initials: Y
authors.lastname: Taguchi
authors.forename: M
authors.initials: M
authors.lastname: Takaoka
authors.forename: S
authors.initials: S
authors.lastname: Morimoto
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000502:physiology*; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000494:pharmacology / Q000502:physiology*; D066298:In Vitro Techniques; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000502:physiology*; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology*; D009638:Norepinephrine / Q000494:pharmacology; D010477:Perfusion; D051381:Rats; D017207:Rats, Sprague-Dawley; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014757:Viper Venoms / Q000494:pharmacology
chemical_list: D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D016212:Transforming Growth Factor beta; D014662:Vasoconstrictor Agents; D014757:Viper Venoms; C057354:sarafotoxins s6; D009638:Norepinephrine