Critical contribution of KV1 channels to the regulation of coronary blood flow

Abstract

Ion channels in smooth muscle control coronary vascular tone, but the mechanisms require further investigation. The purpose of this study was to evaluate the functional role of KV1 channels on porcine coronary blood flow by using the selective antagonist correolide. KV1 channel gene transcripts were found in porcine coronary arteries, with KCNA5 (encoding KV1.5) being most abundant (P<0.001). Immunohistochemical staining demonstrated KV1.5 protein in the vascular smooth muscle layer of both porcine and human coronary arteries, including microvessels. Whole-cell patch clamp experiments demonstrated significant correolide-sensitive (1–10 µM) current in coronary smooth muscle. In vivo studies included direct intracoronary infusion of vehicle or correolide into a pressure-clamped left anterior descending artery of healthy swine (n=5 in each group) with simultaneous measurement of coronary blood flow. Intracoronary correolide (~0.3–3 µM targeted plasma concentration) had no effect on heart rate or systemic pressure, but reduced coronary blood flow in a dose-dependent manner (P<0.05). Dobutamine (0.3–10 µg/kg/min) elicited coronary metabolic vasodilation and intracoronary correolide (3 µM) significantly reduced coronary blood flow at any given level of myocardial oxygen consumption (P<0.001). Coronary artery occlusions (15 s) elicited reactive hyperemia and correolide (3 µM) reduced the flow volume repayment by approximately 30% (P<0.05). Taken together, these data support a major role for KV1 channels in modulating baseline coronary vascular tone and perhaps vasodilation in response to increased metabolism and transient ischemia.

Smooth Muscle Ion Channels and Regulation of Vascular Tone in Resistance Arteries and Arterioles

“…In pigs, 4-AP also impairs reactive hyperemia (126), but does not affect blood flow autoregulation (127). Also, in contrast to the findings in dogs (1233) and the correolide studies in pigs (492), 4-AP had no effect on the relationship between myocardial oxygen consumption and coronary blood flow suggesting that there may be model-dependent differences in the role played by K V channels (127). In Langendorff-perfused rat hearts, K V 7 channel blockers increase resting vascular resistance and inhibit reactive hyperemia (744).…”

“…Also, the duration of reactive hyperemia is impaired by 4-AP in this model (331). Similarly, the K V 1 channel blocker correolide inhibited dobutamine-induced hyperemia at every level of myocardial oxygen consumption and also impaired reactive hyperemia in anesthetized pigs (492). In pigs, 4-AP also impairs reactive hyperemia (126), but does not affect blood flow autoregulation (127).…”

Regulation of myocardial oxygen delivery in response to graded reductions in hematocrit: role of K+ channels

“…In particular, K V channels have been shown to contribute to the control of coronary blood flow at rest, during increases in MVO 2 , and following a brief coronary artery occlusion [2, 16, 26, 27, 49, 53]. To test the hypothesis that anemic coronary vasodilation is mediated by endogenous factors that converge on K V channels, we performed isovolemic hemodilution experiments in the absence and presence of the non-selective K V channel inhibitor 4-AP [51–53].…”

Regulation of Coronary Blood Flow

“…Second, 4-aminopyridine-sensitive K V channels contribute to the regulation of coronary blood flow at rest and during increases in myocardial oxygen consumption caused by treadmill exercise in swine (94). Third, in swine, correolide-sensitive K V 1 channels regulate baseline coronary vascular tone and vasodilation in response to increased myocardial metabolism [(384) Fig. 35A)].…”

“…Myocardial oxygen consumption (MvO 2 ) was elevated from rest by infusing dobutamine at three increasing doses. K V 1 channels are important for the increase in coronary blood flow elicited by cardiac metabolism, as correolide depressed the relationship between oxygen supply and demand [data, with permission, from Goodwill et al (384)]. Panel B shows myocardial blood flow versus cardiac double product, an index of cardiac metabolic demand, in wild-type mice (WT), global K V 1.5 knockout mice (K V 1.5 −/− ), and mice with smooth muscle-specific restoration of K V 1.5 expression (K V 1.5 −/− RC).…”