Endothelium-dependent vasodilating effect of substance P during flow-reducing coronary stenosis in the dog.

ABSTRACT

The effects of substance P, a putative central and peripheral neurotransmitter, on coronary vasculature and its mechanisms were studied in 31 anesthetized open chest dogs. Without coronary stenosis, intracoronary infusion of substance P (0.001 to 1 pmol/kg per min) for 40 s increased coronary blood flow up to 173 +/- 10.7% in dose-dependent fashion. Application of coronary stenosis created by an inflated intraluminal microballoon that preserved active vasomotion of the stenosed segment produced a pressure gradient of 34 +/- 2 mm Hg, a decrease in rest coronary blood flow of 21 +/- 1.6% and significant depression of the rate of rise in left ventricular pressure (dP/dt). During coronary stenosis, substance P increased coronary blood flow up to 150 +/- 9.4%, lowered mean distal coronary pressure and decreased stenosis resistance in dose-dependent fashion. After endothelial denudation of the proximal part of the coronary artery, the substance P-induced increments in coronary blood flow during coronary stenosis were abolished. In vitro measurements of isometric tension from both intact and denuded portions of coronary arteries confirmed a marked inhibition of substance P-induced relaxation in the denuded segments. These results show the obligatory role of the endothelium in substance P-induced coronary artery dilation. Furthermore, intracoronary infusion of substance P (1 pmol/kg per min) from the site distal to coronary stenosis that precluded the responsiveness of the large coronary artery decreased coronary blood flow by 24 +/- 4%, lowered mean distal coronary pressure by 15 +/- 1.9 mm Hg and intensified stenosis resistance by 77 +/- 7.2%. Thus, substance P exerts a direct potent dilating effect on both large and small coronary arteries. However, because of its strict endothelium-dependency, this peptide may play a detrimental role in the regulation of coronary blood flow when an atherosclerotic stenotic lesion with endothelial damage or dysfunction is present in the proximal part of the coronary artery.