Role of pertussis toxin-sensitive G protein in metabolic vasodilation of coronary microcirculation

Abstract

We have previously demonstrated that pertussis toxin (PTX)-sensitive G protein (G(PTX)) plays a major role in coronary microvascular vasomotion during hypoperfusion. We aimed to elucidate the role of G(PTX) during increasing metabolic demand. In 18 mongrel dogs, coronary arteriolar diameters were measured by fluorescence microangiography using a floating objective. Myocardial oxygen consumption (MVO(2)) was increased by rapid left atrial pacing. In six dogs, PTX (300 ng/ml) was superfused onto the heart surface for 2 h to locally block G(PTX). In eight dogs, the vehicle (Krebs solution) was superfused in the same way. Before and after each treatment, the diameters were measured during control (130 beats/min) and rapid pacing (260 beats/min) in each group. Metabolic stimulation before and after the vehicle treatment caused 8.6 +/- 1. 8 and 16.1 +/- 3.6% dilation of coronary arterioles <100 microm in diameter (57 +/- 8 microm at control, n = 10), respectively. PTX treatment clearly abolished the dilation of arterioles (12.8 +/- 2. 5% before and 0.9 +/- 1.6% after the treatment, P < 0.001 vs. vehicle; 66 +/- 8 microm at control, n = 11) in response to metabolic stimulation. The increases in MVO(2) and coronary flow velocity were comparable between the vehicle and PTX groups. In four dogs, 8-phenyltheophylline (10 microM, superfusion for 30 min) did not affect the metabolic dilation of arterioles (15.3 +/- 2.0% before and 16.4 +/- 3.8% after treatment; 84.3 +/- 11.0 microm at control, n = 8). Thus we conclude that G(PTX) plays a major role in regulating the coronary microvascular tone during active hyperemia, and adenosine does not contribute to metabolic vasodilation via G(PTX) activation.

Hydrogen Peroxide Derived From Beating Heart Mediates Coronary Microvascular Dilation During Tachycardia

“…The magnitude of the microvascular dilation to the tachypacing was consistent with previous in vivo observations for the size class of microvessels we used (Ϸ200 m). 21 All of these data support the concept that H 2 O 2 released from beating myocardium is a physiological mediator of metabolic coronary microvascular dilation. However, the possibility that H 2 O 2 produced in the vascular endothelium of the beating heart takes part in the DV dilation during tachypacing cannot be ruled out because earlier studies showed that the increased shear stress stimulates H 2 O 2 production from the vascular endothelium.…”

“…21 It is possible that H 2 O 2 activates a signaling pathway which involves G PTX , although how H 2 O 2 links to G PTX is not clear at this point. There is a report that H 2 O 2 acutely upregulates sphingosine-1-phosphate receptors, which activate G PTX .…”

Upregulation of Nitric Oxide Production in Vascular Endothelial Cells by All- trans Retinoic Acid Through the Phosphoinositide 3-Kinase/Akt Pathway

“…Microscopes and fluorescent imaging systems used were previously described. 23,24 Briefly, fluorescent NO images were obtained from microscope (model ECLIPSE E600, Nikon) equipped with ϫ20 (for HMVECs) or ϫ60 (for TRLEC-03) objective. Excitation light was passed though a 495-nm filter, and emitted light was passed through a 510-nm filter.…”

Hypercholesterolemia Impairs Transduction of Vasodilator Signals Derived From Ischemic Myocardium

“…4,5,13,14 Briefly, the dogs were anesthetized and ventilated. A thoracotomy was performed, and the pericardium was cut to expose the heart surface.…”

“…3 Previous in vivo studies have shown that G PTX proteins are critical in the microvascular control during autoregulation and metabolic stimulation. 4,5 Hypercholesterolemia is one of the most important coronary risk factors. Although morphological changes like plaque formation take place only in conduit vessels, various functional changes are known to extend to the coronary microvessels.…”