Contribution of voltage-dependent K + and Ca 2+ channels to coronary pressure-flow autoregulation

Zachary C. Berwick, Steven P. Moberly, Meredith C. Kohr, Ethan B. Morrical, Michelle M. Kurian, Gregory M. Dick, Johnathan D. Tune

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Abstract

The mechanisms responsible for coronary pressure-flow autoregulation, a critical physiologic phenomenon that maintains coronary blood flow relatively constant in the presence of changes in perfusion pressure, remain poorly understood. This investigation tested the hypothesis that voltage-sensitive K + (K V) and Ca 2+ (CaV1.2) channels play a critical role in coronary pressureflow autoregulation in vivo. Experiments were performed in open-chest, anesthetized Ossabaw swine during step changes in coronary perfusion pressure (CPP) from 40 to 140 mmHg before and during inhibition of KV channels with 4-aminopyridine (4AP, 0.3 mM, ic) or CaV1.2 channels with diltiazem (10 lg/min, ic). 4AP significantly decreased vasodilatory responses to H 2O 2 (0.3-10 lM, ic) and coronary flow at CPPs = 60-140 mmHg. This decrease in coronary flow was associated with diminished ventricular contractile function (dP/dT) and myocardial oxygen consumption. However, the overall sensitivity to changes in CPP from 60 to 100 mmHg (i.e. autoregulatory gain; Gc) was unaltered by 4-AP administration (Gc = 0.46 ± 0.11 control vs. 0.46 ± 0.06 4-AP). In contrast, inhibition of CaV1.2 channels progressively increased coronary blood flow at CPPs>80 mmHg and substantially diminished coronary Gc to -0.20 ± 0.11 (P<0.01), with no effect on contractile function or oxygen consumption. Taken together, these findings demonstrate that (1) K V channels tonically contribute to the control of microvascular resistance over a wide range of CPPs, but do not contribute to coronary responses to changes in pressure; (2) progressive activation of CaV1.2 channels with increases in CPP represents a critical mechanism of coronary pressureflow autoregulation.

Original languageEnglish (US)
Article number0264
JournalBasic Research in Cardiology
Volume107
Issue number3
DOIs
StatePublished - Mar 30 2012

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Keywords

  • Autoregulation
  • Calcium channel
  • Coronary blood flow
  • Potassium channel
  • Swine

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)
  • Physiology

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