Contribution of voltage-dependent K+ and Ca2+ channels to coronary pressure-flow autoregulation.

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+) (Ca(V)1.2) channels play a critical role in coronary pressure-flow 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 K(V) channels with 4-aminopyridine (4AP, 0.3 mM, ic) or Ca(V)1.2 channels with diltiazem (10 µg/min, ic). 4AP significantly decreased vasodilatory responses to H(2)O(2) (0.3-10 µM, 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 Ca(V)1.2 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 Ca(V)1.2 channels with increases in CPP represents a critical mechanism of coronary pressure-flow autoregulation.

Contribution of IKCa channels to the control of coronary blood flow.

The purpose of this investigation was to elucidate the contribution of intermediate conductance calcium-activated potassium channels (IK(Ca)) to the regulation of coronary blood flow in vivo. We hypothesized that IK(Ca) channels modulate coronary arteriolar resistance at rest and contribute to vasomotor responses to changes in coronary perfusion pressure and/or in response to cardiac ischemia. Experiments were conducted in open-chest anesthetized dogs in the absence and presence of IK(Ca) channel inhibitor, TRAM-34 (1 µg/min, intracoronary), and the nitric oxide (NO) synthase inhibitor, N(G)-nitro-L-arginine-methyl ester (L-NAME) (150 µg/min, intracoronary). We found that administration of the potent SK(Ca) and IK(Ca) channel agonist NS309 dose-dependently increased coronary blood flow and that inhibition of IK(Ca) channels with TRAM-34 attenuated this response by ∼90%. The increase in coronary blood flow to NS309 was also decreased ∼100% by the inhibition of NO production with L-NAME. Multiple linear regression analysis demonstrated that TRAM-34 diminished the autoregulatory capability of the coronary circulation at coronary pressures ranging from 60 to 120 mmHg. However, inhibition of IK(Ca) channels did not affect coronary vasodilation in response to a transient 15 s coronary artery occlusion (i.e. reactive hyperemia). Our data reveal that IK(Ca) channels are functionally expressed in the coronary circulation and that activation of these channels produces marked coronary vasodilation in vivo, primarily via increases in endothelial NO production. In addition, IK(Ca) channels modestly contribute to changes in coronary vascular resistance in response to alterations in coronary perfusion pressure but do not contribute to the reactive hyperemic response following a brief coronary artery occlusion.