The long term goal of this work is to understand the mechanisms of regulation of the coronary circulation in order to improve prevention and treatment of coronary artery disease. The general hypothesis is that neuropeptides act in concert with other endogenous compounds to regulate coronary blood flow, especially during normal and abnormal vasoconstriction. This hypothesis is consistent with two preliminary observations. First, neuropeptide tyrosine (NPY) has been found in human coronary arteries. Second, NPY decreased CBF severely enough to produce myocardial ischemia in preliminary canine studies. These results indicate the need to define the roles in CBF regulation of neuropeptides, acting either alone, or in concert with other endogenous compounds. The specific goals of this proposal are to determine: A) the mechanisms of NPY-induced vasoconstriction; B) the endogenous vasodilator mechanisms that compete with NPY-induced vasoconstriction; C) the physiological roles of NPY; and D) pathological roles of NPY.
Our specific aims are to identify: 1) the mechanisms of NPY-induced vasoconstriction, ie., whether it is mediated by release of another compound such as norepinephrine, thromboxane or serotonin; 2) whether NPY constricts primarily large or small coronary arteries, and whether NPY-vasoconstriction is blocked by nitroglycerin, which dilates primarily large coronary arteries; 3) the nature of the endogenous vasodilator system which opposes NPY-vasoconstriction, e.g., adenosine, prostaglandins or other neuropeptides. If one of these endogenous products offsets NPY-vasoconstriction, then an antagonist to the compound should potentiate NPY-vasoconstriction; and an agonist should counteract the NPY effect. 4) To assess the physiological role of NPY we will determine whether electrical or reflex neural stimulation causes residual coronary vasoconstriction that persists after alpha and beta adrenergic blockade. If there is residual vasoconstriction, we will determine whether this residual coronary vasoconstriction is blocked by agents that should interfere with NPY released from nerve endings, eg., ganglionic block but not reserpine, """"""""chemical denervation"""""""", and specific NPY receptor blocking agents; 5) whether NPY can act in the brain to cause coronary vasoconstriction; 6) whether the potentiation of NPY-induced myocardial ischemic injury by norepinephrine is mediated by vascular alpha or cardiac beta-adrenergic receptors; 7) whether NPY-induced coronary vasoconstriction is potentiated by ergonovine, an agent used to test whether chest pain in human subjects is caused by coronary spasm; 8) whether denuding vascular endothelium potentiates NPY-vacoconstriction; 9) whether NPY is released from ischemic myocardium; and 10) whether enkephalins or endorphins play a role in CBF regulation. The proposed methods use chloralose-anesthetized, open-chest dogs measuring CBF by a flowmeter while infusing NPY and other compounds via a non-obstructive coronary artery catheter or by a catheter inserted into the lateral cerebral ventricle, while recording epicardial electrograms and intramyocardial pH by a fiber optic pH probe. NPY will also be given intracoronary or intravenously to awake dogs that were chronically instrumented during sterile surgery to measure CBF, hemodynamics, epicardial electrograms and regional cardiac dimensions to assess the consequences of any CBF reduction. NPY will be measured in blood and myocardium by radioimmunoassay before and during stellate ganglion stimulation or coronary artery occlusion. Preliminary studies during graded reductions in CBF have documented linear correlations between intramyocardial pH and the myocardial concentrations of high energy phosphates and lactate (r=0.76 to -0.88). These studies indicate the usefulness of pH as an index of ischemic injury. This project should produce significant results because it will clarify the physiological and pathological roles in coronary regulation of a new class of compounds, neuropeptides. Also, this project will attempt to identify the physiological compensatory mechanisms which act as a negative feedback system to oppose coronary vasoconstriction by any agent, using NPY as a """"""""probe"""""""" to study this important physiological """"""""host defense"""""""" system.
