Effect of indomethacin on coronary blood flow during graded treadmill exercise in the dog

Abstract

This study tested the hypothesis that metabolites of arachidonic acid may contribute to the coronary vascular response to physiological increases of myocardial O2 consumption that occur during exercise. Studies were performed in eight chronically instrumented dogs with electromagnetic flowmeter probes on the left circumflex coronary artery and aortic and coronary sinus catheters. Data were obtained at rest and during graded treadmill exercise during control conditions and after administration of the cyclooxygenase inhibitor indomethacin. During control conditions heart rate, aortic pressure, and coronary blood flow increased progressively during exercise; this was accompanied by a significant increase in myocardial O2 extraction, as evidenced by a decrease in coronary venous O2 tension (Po2) particularly during the first stage of exercise. Indomethacin (5 mg/kg iv) resulted in marked blunting of the coronary vasodilator response to intracoronary arachidonic acid in anesthetized open-chest dogs. After administration of indomethacin to awake dogs, resting heart rate, aortic pressure, and coronary venous Po2 were unaltered, and the response of these variables to exercise was not changed. The increase in coronary blood flow during exercise was also unchanged after indomethacin, so that the relationship between myocardial O2 consumption and coronary blood flow was unaltered by cyclooxygenase inhibition. Thus we were unable to demonstrate a significant effect of the prostaglandin system in mediating the coronary vascular response to exercise.

Contribution of Vasodilator Prostanoids and Nitric Oxide to Resting Flow, Metabolic Vasodilation, and Flow-Mediated Dilation in Human Coronary Circulation

“…Although experimental studies have not demonstrated a reduction of resting CBF after cyclooxygenase inhibition, 20 in models of coronary artery disease, PG inhibition significantly decreased coronary diameter and CBF. 26,27 In humans with atherosclerosis, indomethacin has been shown to reduce resting CBF and increase CVR [17][18][19] ; these effects are associated with increased MABP, estimated myocardial oxygen demand, and arteriovenous oxygen extraction.…”

“…18 However, experimental studies have suggested that PGs are not essential for coronary metabolic vasodilation. 20 In humans, there has been conflicting evidence regarding the effect of cyclooxygenase inhibition on metabolic vasodilation, 18,19,21,22 and its effect on conduit vessel flow-mediated coronary artery dilation is unknown. Therefore, we aimed to determine the contribution of endothelium-derived NO and PG to resting CBF and to pacing-induced metabolic vasodilation and flow-mediated dilation.…”

Role of K+ ATP channels and adenosine in the regulation of coronary blood flow during exercise with normal and restricted coronary blood flow.

“…This close coupling, which is especially apparent during exercise, has been suggested to depend on messengers released from the myocardium or vascular endothelium. However, specific blockers of established endogenous vasodilators such as adenosine (1), prostacyclin (2), and nitric oxide (3) have not been found to impair coronary blood flow during exercise, indicating that these vasodilators are not mandatory for regulation of coronary vasomotor tone during exercise with normal coronary arterial inflow. In contrast, these vasodilator mechanisms can contribute significantly to regulation of coronary vasomotor tone during exercise in the presence of myocardial hypoperfusion.…”

Endogenous adenosine mediates coronary vasodilation during exercise after K(ATP)+ channel blockade.

“…This close coupling between myocardial metabolic demands and CBF, which is especially apparent during exercise, has been suggested to depend on messengers released from the myocardium or vascular endothelium. However, selective blockers of established endogenous vasodilators such as adenosine (1), prostacyclin (2), and nitric oxide (3) have not been found to impair the normal increases in CBF that occur during exercise, indicating that these vasodilators are not mandatory for coronary vasodilation produced by exercise in the normal heart. In contrast, these vasodilator mechanisms can contribute to regulation of coronary vasomotor tone during exercise in the presence of myocardial ischemia.…”