ATP-Sensitive K ⁺ Channels, Adenosine, and Nitric Oxide–Mediated Mechanisms Account for Coronary Vasodilation During Exercise

Abstract

Abstract-We previously reported that combined blockade of adenosine receptors and ATP-sensitive Kϩ channels (K ϩ ATP channels) blunted but did not abolish the response of coronary blood flow to exercise. This study tested the hypothesis that the residual increase in coronary flow in response to exercise after adenosine receptor and K ϩ ATP channel blockade is dependent on endogenous NO. Dogs were studied at rest and during a four-stage treadmill exercise protocol under control conditions, during K ϩ ATP channel blockade with glibenclamide (50 g ⅐ kg Ϫ1 ⅐ min Ϫ1 IC) in the presence of adenosine receptor blockade with 8-phenyltheophylline (8-PT, 5 mg/kg IV), and after the addition of the NO synthase inhibitor N G -nitro-L-arginine (LNNA, 1.5 mg/kg IC). During control conditions, coronary blood flow was 49Ϯ3 mL/min at rest and increased to 92Ϯ8 mL/min at peak exercise. LNNA alone or in combination with 8-PT did not alter resting coronary flow and did not impair the normal increase in flow during exercise, indicating that when K ϩ ATP channels are intact, neither NO nor adenosine-dependent mechanisms are obligatory for maintaining coronary blood flow. Combined K ϩ ATP channel and adenosine blockade decreased resting coronary flow to 27Ϯ3 mL/min (PϽ.05), but exercise still increased flow to 45Ϯ5 mL/min (PϽ.05). The subsequent addition of LNNA further decreased resting coronary flow to 20Ϯ2 mL/min and markedly blunted exercise-induced coronary vasodilation (coronary vascular conductance, 0.20Ϯ0.03 mL ⅐ min Ϫ1 ⅐ mm Hg Ϫ1 at rest versus 0.24Ϯ0.04 mL ⅐ min Ϫ1 ⅐ mm Hg Ϫ1 during the heaviest level of exercise; Pϭ.22), so that coronary flow both at rest and during exercise was below the control resting level. The findings suggest that K Key Words: blood flow Ⅲ endothelium Ⅲ K ϩ channel Ⅲ ischemia Ⅲ reactive hyperemia R ecent evidence indicates that hyperpolarization of the vascular smooth muscle cell membrane caused by opening of K ϩ ATP channels is an important mechanism for metabolic coronary vasodilation. 1 We previously reported that blockade of vascular smooth muscle K ϩ ATP channels in chronically instrumented dogs decreased resting coronary blood flow but did not attenuate the increase in flow that occurred in response to treadmill exercise.2 However, after K ϩ ATP channel blockade had been established, the subsequent addition of adenosine receptor blockade reduced the exercise-induced increase in coronary flow by more than half, 3 indicating increased importance of adenosine in causing metabolic vasodilation after K ϩ ATP channels are blocked. Nevertheless, even after the combination of K ϩ ATP channel blockade and adenosine receptor blockade, exercise still produced a substantial increase in coronary flow.Bernstein et al 4 have reported that exercise causes increased NO production across the coronary circulation. We have previously observed that NO contributes to coronary vasodilation distal to a coronary artery stenosis, which results in hypoperfusion during exercise. 5 It is possible that NO could similarly contr...

Nitric Oxide Synthase Inhibition Reduces Glucose Uptake During Exercise in Individuals With Type 2 Diabetes More Than in Control Subjects

“…Indeed, animal studies have indicated substantial redundancies in vasodilator mechanisms. In the coronary vasculature, for example, the important role of NO in coronary vasodilation during exercise was unmasked only after blockade of K ϩ ATP channels and adenosine receptors (57). Under exercise conditions, when NO production is inhibited, it is feasible that these other agents provide an increased contribution to exercise hyperemia and thus maintain normal exercise blood flow.…”

Nitric Oxide Modulates Myocardial Oxygen Consumption in the Failing Heart

“…12,13 This increase in CBF appeared to result from an increase of MV O 2 with secondary coronary vasodilation, 14 inasmuch as coronary sinus PO 2 decreased significantly after L-NNA, indicating increased myocardial oxygen extraction. NO can compete with oxygen at cytochrome oxidase, 1 and nonselective NOS inhibition has been reported to increase both total body and skeletal muscle oxygen consumption in normal dogs.…”

Responses of the bovine mammary glands to absorptive supply of single amino acids

“…Nitric oxide stimulates relaxation through a cGMP cascade. In this scenario, blockage of any one vasodilatory pathway can be compensated by the others until O 2 supply matches consumption (Ishibashi et al 1998). A variation on this theme is that adenosine acts to relax the smooth muscle cell exclusively through stimulation of the ATP-sensitive K + channel and, furthermore, is responsible for NO release from the endothelium (Hein and Kuo 1999;Murrant and Sarelius 2000).…”