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Blockade of the ATP-sensitive potassium channel modulates reactive hyperemia in the canine coronary circulation
T Aversano1, P Ouyang, H Silverman
1Johns Hopkins Medical Institutions, Baltimore, Md.
Insights
Reactive hyperemia, a crucial blood flow response, is largely mediated by ATP-sensitive potassium channels. Blocking these channels significantly reduces this vasodilation, indicating their key role in coronary blood flow regulation.
Area of Science:
- Cardiovascular Physiology
- Cellular Electrophysiology
Background:
- The precise mechanisms underlying reactive hyperemia, the increase in blood flow following a period of reduced or absent flow, are not fully understood.
- Existing hypotheses suggest a role for cellular signaling pathways in regulating vascular tone during reactive hyperemia.
Purpose of the Study:
- To investigate the role of ATP-sensitive potassium channels in the phenomenon of reactive hyperemia in the coronary circulation.
- To test the hypothesis that opening of ATP-sensitive potassium channels contributes to vasodilation during reactive hyperemia.
Main Methods:
- Utilized an open-chest canine model under anesthesia.
- Induced transient coronary occlusions to elicit reactive hyperemia.
- Administered intracoronary glibenclamide, an ATP-sensitive potassium channel blocker, at low and high doses.
- Measured coronary blood flow and calculated flow debt repayment.
- Assessed coronary vascular sensitivity to adenosine and acetylcholine.
Main Results:
- Coronary occlusion led to significant flow debt repayment (200 +/- 41%).
- Glibenclamide administration dose-dependently reduced flow debt repayment (low dose: 76 +/- 14%; high dose: 50 +/- 8%).
- This reduction was associated with decreased maximal coronary conductance and duration of hyperemia.
- Glibenclamide impaired adenosine-induced vasodilation but not acetylcholine-induced vasodilation.
Conclusions:
- ATP-sensitive potassium channels play a significant role in mediating reactive hyperemia, likely via effects on smooth muscle membrane potential and calcium channels.
- While these channels are critical, other mechanisms likely contribute to reactive hyperemia as it was not completely abolished.
Abstract:
The mechanism of reactive hyperemia remains unknown. We hypothesized that reactive hyperemia was related to the opening of ATP-sensitive potassium channels during coronary occlusion. The resulting hyperpolarization of the smooth muscle cell plasma membrane might reduce calcium influx through voltage-dependent calcium channels and result in relaxation of smooth muscle tone and vasodilation. In eight open-chest, anesthetized dogs, 30-second coronary occlusions resulted in an average flow debt repayment of 200 +/- 41%. After low-dose (0.8 mumol/min) and high-dose (3.7 mumol/min) infusion of intracoronary glibenclamide, flow debt repayment fell to 76 +/- 14% and 50 +/- 8%, respectively (p less than 0.05 compared with control for both). The decline in flow debt repayment was due to a significant reduction both in maximum coronary conductance during reactive hyperemia and in its duration. In addition, there was a significant decline in the sensitivity of the coronary circulation to adenosine-induced vasodilation after glibenclamide. While more variable, there was no overall change in the sensitivity of the coronary vasculature to acetylcholine-induced vasodilation after glibenclamide. We conclude that reactive hyperemia is determined in a large part by the ATP-sensitive potassium channel, probably through its effect on membrane potential and voltage-sensitive calcium channels. Because reactive hyperemia was never fully abolished at the highest doses of glibenclamide tested, it is possible that additional mechanisms are involved in the genesis of this complex phenomenon.