title: Mechanisms of coronary microvascular dilation induced by the activation of pertussis toxin-sensitive G proteins are vessel-size dependent. Heterogeneous involvement of nitric oxide pathway and ATP-sensitive K+ channels.
abstract: G proteins are critically important mediators of many signal transduction systems. In the present study, we investigated the effect of direct activation of pertussis toxin (PTX)-sensitive G protein (GPTX) on coronary arterial microvascular tone in 37 open-chest anesthetized dogs in vivo. Coronary arterial microvessels on the surface of the beating left ventricle were visualized by performing fluorescence coronary microangiography using an intravital microscope with a floating objective system. Microvessels were divided into two groups, small microvessels (inner diameter, < or = 130 microns) and large microvessels (inner diameter, > 130 microns). Topically applied mastoparan (G protein activator, 10, 30, and 100 mumol/L) produced homogeneous microvascular dilation in a concentration-dependent manner (10 mumol/L, 7.9 +/- 2.0%; 30 mumol/L, 10.3 +/- 2.4%; and 100 mumol/L, 16.7 +/- 4.5% in small microvessels; 10 mumol/L, 5.3 +/- 1.2%; 30 mumol/L, 9.8 +/- 2.5%; and 100 mumol/L, 15.5 +/- 3.9% in large microvessels). These dilations were reversed to constriction by pretreatment with PTX (300 ng/mL, 2 hours) in both microvessel groups. Blockade of nitric oxide production by NG-nitro-L-arginine (LNNA, 300 mumol/L) offset the mastoparan-induced dilation in large microvessels but not in small microvessels. Cosuperfusion of glibenclamide (10 mumol/L) with LNNA produced constriction of all sizes of microvessels in response to mastoparan, whereas charybdotoxin (10 nmol/L) did not affect the mastoparan effect. Pretreatment with glibenclamide alone reversed mastoparan dilation to constriction in small microvessels, whereas it only offset the dilation without producing constriction in large microvessels. We conclude that the activation of GPTX produces homogeneous coronary arterial microvascular dilation and that the underlining mechanisms of the dilation are vessel size dependent. The L-arginine-nitric oxide pathway mediates the dilation only in large microvessels, whereas ATP-sensitive K+ channel activation plays a central role in the dilation of small microvessels when GPTX is directly activated. ATP-sensitive K+ channels are also involved in the dilation of large microvessels in a synergistic fashion with nitric oxide production.
authors.affiliation: First Department of Internal Medicine, Tohoku University, School of Medicine, Sendai, Japan. komaru@int1.med.tohoku.ac.jp
authors.forename: T
authors.initials: T
authors.lastname: Komaru
authors.forename: T
authors.initials: T
authors.lastname: Tanikawa
authors.forename: A
authors.initials: A
authors.lastname: Sugimura
authors.forename: T
authors.initials: T
authors.lastname: Kumagai
authors.forename: K
authors.initials: K
authors.lastname: Sato
authors.forename: H
authors.initials: H
authors.lastname: Kanatsuka
authors.forename: K
authors.initials: K
authors.lastname: Shirato
mesh_terms: D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D003326:Coronary Circulation / Q000187:drug effects / Q000502:physiology*; D004285:Dogs; D005260:Female; D019204:GTP-Binding Proteins / Q000502:physiology*; D005905:Glyburide / Q000494:pharmacology; D036341:Intercellular Signaling Peptides and Proteins; D008297:Male; D008833:Microcirculation / Q000187:drug effects / Q000502:physiology; D009569:Nitric Oxide / Q000378:metabolism; D019335:Nitroarginine / Q000494:pharmacology; D010455:Peptides; D037342:Pertussis Toxin; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*; D010566:Virulence Factors, Bordetella / Q000494:pharmacology*; D014862:Wasp Venoms / Q000494:pharmacology
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D010455:Peptides; D015221:Potassium Channels; D010566:Virulence Factors, Bordetella; D014862:Wasp Venoms; D019335:Nitroarginine; D009569:Nitric Oxide; C037500:mastoparan; D000255:Adenosine Triphosphate; D037342:Pertussis Toxin; D019204:GTP-Binding Proteins; D005905:Glyburide