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ATP-sensitive K+ channels, adenosine, and nitric oxide-mediated mechanisms account for coronary vasodilation during
Y Ishibashi1, D J Duncker, J Zhang
1Department of Medicine, University of Minnesota Medical School, Minneapolis 55455, USA.
Insights
The study reveals that blocking adenosine receptors and ATP-sensitive K+ channels significantly reduces coronary blood flow during exercise in dogs. Endogenous nitric oxide (NO) plays a crucial role in maintaining this flow when other pathways are inhibited.
Area of Science:
- Cardiovascular Physiology
- Exercise Physiology
- Pharmacology
Background:
- Adenosine receptors and ATP-sensitive K+ (K+(ATP)) channels are known modulators of coronary blood flow.
- Previous research indicated that combined blockade of these pathways partially inhibits exercise-induced coronary vasodilation.
Purpose of the Study:
- To test the hypothesis that the remaining exercise-induced increase in coronary blood flow, after blocking adenosine receptors and K+(ATP) channels, is dependent on endogenous nitric oxide (NO).
Main Methods:
- The study utilized a canine model subjected to a graded treadmill exercise protocol.
- Pharmacological interventions included blockade of K+(ATP) channels with glibenclamide, adenosine receptors with 8-phenyltheophylline (8-PT), and NO synthase with N(G)-nitro-L-arginine (LNNA).
- Coronary blood flow and vascular conductance were measured under various blockade conditions at rest and during exercise.
Main Results:
- Combined blockade of adenosine receptors and K+(ATP) channels reduced resting and exercise coronary blood flow.
- The addition of LNNA further decreased resting flow and significantly blunted the exercise-induced increase in coronary blood flow and conductance.
- In the presence of both receptor and channel blockade, NO contributed approximately 25% of the exercise-induced vasodilation.
Conclusions:
- K+(ATP) channels are critical for maintaining coronary vasodilation at rest and during exercise.
- When K+(ATP) channels are blocked, both adenosine and NO contribute to exercise-induced coronary vasodilation.
- Endogenous NO plays a significant, albeit secondary, role in regulating coronary blood flow during exercise when other major vasodilator pathways are inhibited.
Abstract:
We previously reported that combined blockade of adenosine receptors and ATP-sensitive K+ channels (K+(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+(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+(ATP) channel blockade with glibenclamide (50 microg x kg(-1) x min(-1) i.c.) in the presence of adenosine receptor blockade with 8-phenyltheophylline (8-PT, 5 mg/kg i.v.), and after the addition of the NO synthase inhibitor N(G)-nitro-L-arginine (LNNA, 1.5 mg/kg i.c.). During control conditions, coronary blood flow was 49 +/- 3 mL/min at rest and increased to 92 +/- 8 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+(ATP) channels are intact, neither NO nor adenosine-dependent mechanisms are obligatory for maintaining coronary blood flow. Combined K+(ATP) channel and adenosine blockade decreased resting coronary flow to 27 +/- 3 mL/min (P<.05), but exercise still increased flow to 45 +/- 5 mL/min (P<.05). The subsequent addition of LNNA further decreased resting coronary flow to 20 +/- 2 mL/min and markedly blunted exercise-induced coronary vasodilation (coronary vascular conductance, 0.20 +/- 0.03 mL x min(-1) x mm Hg(-1) at rest versus 0.24 +/- 0.04 mL x min(-1) x mm Hg(-1) during the heaviest level of exercise; P=.22), so that coronary flow both at rest and during exercise was below the control resting level. The findings suggest that K+(ATP) channels are critical for maintaining coronary vasodilation at rest and during exercise but that when K+(ATP) channels are blocked, both adenosine and NO act to increase coronary blood flow during exercise. In the presence of combined K+(ATP) channel blockade and adenosine receptor blockade, NO was able to produce approximately one quarter of the coronary vasodilation that occurred in response to exercise when all vasodilator systems were intact.