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.

No abstract

GTP-binding regulatory proteins (G proteins)

Levcromakalim heterogeneously dilates coronary arterial microvessels via the opening of ATP sensitive potassium channels, and small vessels are more sensitive to levcromakalim.

ndothelin (ET)-1 is an endothelium-derived peptide that has a potent vasoconstrictor effect on a variety of vascular beds including the coronary microcirculation. [1][2][3][4] The plasma concentration of the peptide is increased in cardiovascular diseases such as essential hypertension, 5,6 vasospastic angina, 7 acute myocardial infarction, 8 and congestive heart failure. 9 Pretreatment with a monoclonal antibody against endothelin decreases the size of myocardial infarction in rat hearts. 10 The present authors 11 and other groups 12,13 have reported that the opening of ATP-sensitive potassium channels has a crucial role in the dilation of coronary resistance vessels during ischemia, hypoxemia, reactive hyperemia and autoregulation. We have also reported that pertussis toxin (PTX)-sensitive G protein mediates autoregulation and ischemic dilation in the canine coronary microcirculation. 14 On the other hand, ET-1 has been reported to block ATPsensitive potassium channels in cultured smooth muscle cells of the porcine coronary artery. 15 ET-1 also reversibly inhibits ATP-sensitive potassium channels of rat cardiac myocytes via an effect on PTX-sensitive G protein coupled to ET receptors. 16 Therefore, it is possible that a threshold concentration of ET-1 increases the vulnerability of hearts Japanese Circulation Journal Vol.63, August 1999 to myocardial ischemia by increasing the basal tone of coronary vessels or by attenuating the physiological responses such as autoregulation during the reduction in perfusion pressure. Accordingly, we assessed the effect of low doses of ET-1 on the vascular tone and on the physiological responses of coronary microvessels during a reduction in the coronary perfusion pressure. Methods General PreparationTwenty-four small mongrel dogs of either sex, weighing 5.8-9.9 kg, were premedicated with ketamine (10 mg/kg, im) and then anesthetized with an intravenous injection of -chloralose (60 mg/kg, Wako Chemicals). Additional doses, when necessary, were given to maintain anesthesia. The animals were intubated and mechanically ventilated (Model NSH-34RH, Harvard Apparatus, South Natic, MS, USA) at an end expiratory pressure of 3-5 cm H2O. Metabolic acidosis during the experiments was prevented by intravenous infusion of sodium bicarbonate. Arterial blood gases were maintained within the physiological range by adjusting the rate and volume of a ventilator and/or by using oxygen-enriched air. Body temperature was maintained at 37-38°C by means of a homeo-thermic blanket system. A catheter was introduced into the right external jugular vein for the infusion of drugs and fluid. Aortic pressure was measured at the aortic root with a catheter passed through the right carotid artery and Jpn Circ J 1999; 63: 617 -623 (Received April 15, 1999; accepted May 17, 1999 The plasma level of endothelin-1 (ET-1) increases in several cardiovascular disorders. The present study examined whether threshold doses of ET-1 affect vascular tone and autoregulatory vasodilation during a reduction in perfusion p...