title: Mechanism of thrombin-induced vasodilation in human coronary arterioles.
abstract: Thrombin (Thromb), activated as part of the clotting cascade, dilates conduit arteries through an endothelial pertussis toxin (PTX)-sensitive G-protein receptor and releases nitric oxide (NO). Thromb also acts on downstream microvessels. Therefore, we examined whether Thromb dilates human coronary arterioles (HCA). HCA from right atrial appendages were constricted by 30-50% with endothelin-1. Dilation to Thromb (10(-4)-1 U/ml) was assessed before and after inhibitors with videomicroscopy. There was no tachyphylaxis to Thromb dilation (maximum dilation = 87.0%, ED(50) = 1.49 x 10(-2)). Dilation to Thromb was abolished with either hirudin or denudation but was not affected by PTX. Neither N(omega)-nitro-l-arginine methyl ester (n = 7), indomethacin (n = 9), (1)H-[1,2,4] oxadiazolo-[4,3-a]quinoxalin-1-one (n = 6), tetraethylammonium chloride (n = 5), nor iberiotoxin (n = 4) reduced dilation to Thromb. However, KCl (maximum dilation = 89 +/- 5 vs. 20 +/- 10%; P < 0.05; n = 7), tetrabutylammonium chloride (maximum dilation = 79 +/- 7 vs. 21 +/- 4%; P < 0.05; n = 5), and charybdotoxin (maximum dilation = 89 +/- 4 vs. 10 +/- 2%; P < 0.05; n = 4) attenuated dilation to Thromb. In contrast to animal models, Thromb-induced dilation in human arterioles is independent of G(i)-protein activation and NO release. However, Thromb dilation is endothelium dependent, is maintained on consecutive applications, and involves activation of K(+) channels. We speculate that an endothelium-derived hyperpolarizing factor contributes to Thromb-induced dilation in HCA.
authors.affiliation: Medical College of Wisconsin, Cardiovascular Center, Milwaukee, Wisconsin 53226, USA.
authors.forename: John J
authors.initials: JJ
authors.lastname: Bosnjak
authors.forename: Ken
authors.initials: K
authors.lastname: Terata
authors.forename: Hiroto
authors.initials: H
authors.lastname: Miura
authors.forename: Atsushi
authors.initials: A
authors.lastname: Sato
authors.forename: Alfred C
authors.initials: AC
authors.lastname: Nicolosi
authors.forename: Monica
authors.initials: M
authors.lastname: McDonald
authors.forename: Sara A
authors.initials: SA
authors.lastname: Manthei
authors.forename: Takashi
authors.initials: T
authors.lastname: Saito
authors.forename: Ossama A
authors.initials: OA
authors.lastname: Hatoum
authors.forename: David D
authors.initials: DD
authors.lastname: Gutterman
mesh_terms: D000328:Adult; D000368:Aged; D001160:Arterioles / Q000187:drug effects* / Q000502:physiology; D002318:Cardiovascular Diseases; D018999:Charybdotoxin / Q000494:pharmacology; D002704:Chlorates; D003331:Coronary Vessels / Q000187:drug effects* / Q000502:physiology; D019332:Endothelin-1 / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000502:physiology; D005260:Female; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000502:physiology; D006629:Hirudins / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D018715:Microscopy, Video; D008875:Middle Aged; D009569:Nitric Oxide; D037342:Pertussis Toxin / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology; D012307:Risk Factors; D013917:Thrombin / Q000494:pharmacology*; D014664:Vasodilation / Q000187:drug effects*
chemical_list: D002704:Chlorates; D019332:Endothelin-1; D006629:Hirudins; D000644:Quaternary Ammonium Compounds; D018999:Charybdotoxin; D009569:Nitric Oxide; D011189:Potassium Chloride; C009405:tetrabutylammonium; D037342:Pertussis Toxin; D013917:Thrombin; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; C022842:chloric acid