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

Abstract

The mechanism of coronary vasodilation produced by exercise is not understood completely. Recently, we reported that blockade of vascular smooth muscle KAT channels decreased coronary blood flow at rest, but did not attenuate the increments in coronary flow produced by exercise. Adenosine is not mandatory for maintaining basal coronary flow, or the increase in flow produced by exercise during normal arterial inflow, but does contribute to coronary vasodilation in hypoperfused myocardium. Therefore, we investigated whether adenosine opposed the hypoperfusion produced by KA+P channel blockade, thereby contributing to coronary vasodilation during exercise. 11 dogs were studied at rest and during exercise under control conditions, during intracoronary infusion of the KA channel blocker glibenclamide (50 ,ug/kg per min), and during intracoronary glibenclamide in the presence of adenosine receptor blockade. Glibenclamide decreased resting coronary blood flow from 45±5 to 35±4 ml/min (P < 0.05), but did not prevent exerciseinduced increases of coronary flow. Glibenclamide caused an increase in myocardial oxygen extraction at the highest level of exercise with a decrease in coronary venous oxygen tension from 15.5±0.7 to 13.6±0.8 mmHg (P < 0.05). The addition of the adenosine receptor antagonist 8-phenyltheophylline (5 mg/kg intravenous) to KAT channel blockade did not further decrease resting coronary blood flow but did attenuate the increase in coronary flow produced by exercise. This was accompanied by a further decrease of coronary venous oxygen tension to 10.1±0.7 mmHg (P < 0.05), indicating aggravation of the mismatch between oxygen demand and supply. These findings are compatible with the hypothesis that KATP channels modulate coronary vasomotor tone both under resting conditions and during exercise. However, when KA channels are blocked, adenosine released from the hypoperfused myocardium provides an alternate mechanism to mediate coronary vasodilation in response to increases in oxygen demand produced by exercise. (J. Clin. Invest. 1995. 95:285-295.)

ATP-Dependent K+ Channels Contribute to Local Metabolic Coronary Vasodilation in Experimental Diabetes

“…The experimental protocol described above was repeated in the diabetic animals at least 7 days after the alloxan injection with and without glibenclamide. In addition, three experiments were also conducted at rest and during exercise with glibenclamide in nondiabetic dogs to confirm the previous findings that K ATP channels are not required for exercise-induced coronary vasodilation (3)(4)(5)7,8). Assessing the relationship between coronary blood flow and myocardial metabolism.…”

“…These studies indicate that K ATP channels are important in regulating coronary vascular resistance under baseline conditions (3-10), during hypoxic coronary vasodilation (11,12), and during reactive coronary hyperemia (1,4,13). However, it does not appear that K ATP channels are required to increase coronary blood flow when myocardial metabolism is increased (3)(4)(5)7,8).Recently, Kersten et al (14) found that diabetes enhanced K ATP channel-mediated coronary vasodilation of coronary arterioles, suggesting that K ATP channels are important in local metabolic coronary vasodilation in diabetes. Supporting this notion are the results of Shimoni et al (15) showing that the half-maximal inhibitory concentration (IC 50 ) for ATP-dependent inhibition of K ATP channels was approximately twofold higher for channels from diabetic rat hearts.…”

“…These studies indicate that K ATP channels are important in regulating coronary vascular resistance under baseline conditions (3-10), during hypoxic coronary vasodilation (11,12), and during reactive coronary hyperemia (1,4,13). However, it does not appear that K ATP channels are required to increase coronary blood flow when myocardial metabolism is increased (3)(4)(5)7,8).…”

“…umerous investigations have focused on the role of ATP-dependent K ϩ (K ATP ) channels in coronary blood flow regulation (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14). These studies indicate that K ATP channels are important in regulating coronary vascular resistance under baseline conditions (3)(4)(5)(6)(7)(8)(9)(10), during hypoxic coronary vasodilation (11,12), and during reactive coronary hyperemia (1,4,13).…”

“…Importantly, by plotting coronary response variables as a function of MVO 2 , these plots account for any drug-induced changes in heart rate, blood pressure, or contractility that may significantly affect myocardial oxygen demand. Many studies have used this approach to analyze mechanisms of coronary blood flow control (3)(4)(5)8,20,22,24). Statistical analyses.…”