K_V7 channels contribute to paracrine, but not metabolic or ischemic, regulation of coronary vascular reactivity in swine

Abstract

Goodwill AG, Fu L, Noblet JN, Casalini ED, Sassoon D, Berwick ZC, Kassab GS, Tune JD, Dick GM. K V7 channels contribute to paracrine, but not metabolic or ischemic, regulation of coronary vascular reactivity in swine. Am J Physiol Heart Circ Physiol 310: H693-H704, 2016. First published January 29, 2016 doi:10.1152 doi:10. /ajpheart.00688.2015 and voltage-dependent K ϩ (KV) channels play key roles in regulating coronary blood flow in response to metabolic, ischemic, and paracrine stimuli. The K V channels responsible have not been identified, but K V7 channels are possible candidates. Existing data regarding KV7 channel function in the coronary circulation (limited to ex vivo assessments) are mixed. Thus we examined the hypothesis that K V7 channels are present in cells of the coronary vascular wall and regulate vasodilation in swine. We performed a variety of molecular, biochemical, and functional (in vivo and ex vivo) studies. Coronary arteries expressed KCNQ genes (quantitative PCR) and K V7.4 protein (Western blot). Immunostaining demonstrated K V7.4 expression in conduit and resistance vessels, perhaps most prominently in the endothelial and adventitial layers. Flupirtine, a K V7 opener, relaxed coronary artery rings, and this was attenuated by linopirdine, a K V7 blocker. Endothelial denudation inhibited the flupirtine-induced and linopirdine-sensitive relaxation of coronary artery rings. Moreover, linopirdine diminished bradykinin-induced endothelial-dependent relaxation of coronary artery rings. There was no effect of intracoronary flupirtine or linopirdine on coronary blood flow at the resting heart rate in vivo. Linopirdine had no effect on coronary vasodilation in vivo elicited by ischemia, H 2O2, or tachycardia. However, bradykinin increased coronary blood flow in vivo, and this was attenuated by linopirdine. These data indicate that K V7 channels are expressed in some coronary cell type(s) and influence endothelial function. Other physiological functions of coronary vascular K V7 channels remain unclear, but they do appear to contribute to endothelium-dependent responses to paracrine stimuli. (3,14). Recent evidence suggests that myocardial production of hydrogen peroxide (H 2 O 2 ) may be a signal responsible for the near lockstep increases of coronary blood flow that accompany intensified metabolic demand (21,40,47). H 2 O 2 is generated in a variety of cellular processes and may be the primary transmitter of physiological redox signals (9, 45). For example, in coronary microvessels, H 2 O 2 is an endogenous hyperpolarizing factor released by mechanical and paracrine stimulation of the endothelium (31, 46). The specific redox-sensitive targets mediating H 2 O 2 -induced vasodilation of coronary vascular smooth have not been firmly established. Our previous findings suggest that voltage-dependent K ϩ (K V ) channels may play an important role, but the identities of individual K V channels involved remain elusive (4,5,12,38,39). K V 7 channels are expressed in a variety of vascular smooth muscle ...

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

“…This overall effect of correolide is similar to our earlier findings in dogs with 4-AP, which diminished baseline flow and the overall volume of repayment [9]. In contrast, we recently documented that inhibition of K V 7 channels with linopirdine had no effect on coronary reactive hyperemic responses in swine [15]. Although correolide diminished the duration of reactive hyperemia, it is important to point out that peak hyperemia was unaffected by the correolide, which could be interpreted as no role for K V 1 channels.…”

“…Expression of other K V channel isoforms (e.g., K V 3 and K V 7 families) has also been documented in coronary arteries of mice, rats, and swine [3, 15, 19, 20, 23, 24]. Correolide blocked a majority of the K + current in smooth muscle cells; therefore, it is reasonable to conclude that channels composed of K V 1 channel subunits produce a significant portion of the delayed rectifier K + current.…”

“…Given emerging data regarding the role of H 2 O 2 in endothelial and metabolic coronary vasodilation [16, 22, 36], recent studies have focused on redox-sensitive K V channels with varying conclusions. While data do not support a prominent role for K V 7 channels in coronary metabolic dilation of rodents or swine [15, 23], genetic deletion of K V 1.5 channels was found to significantly inhibit the tight coupling of coronary blood flow to myocardial metabolism in mice [31]. These findings support an evolving paradigm in which K V 1 channels play requisite roles in controlling coronary blood flow responses to physiological and pathophysiological stimuli.…”

Contribution of K V 1.5 Channel to Hydrogen Peroxide–Induced Human Arteriolar Dilation and Its Modulation by Coronary Artery Disease

“…Redox-sensitive K V 7 channels represent another potential candidate, but a recent study indicate that they do not contribute to H 2 O 2 dilation in porcine coronary arteries. 41 Further investigations are needed to elucidate the role of other K + channels in human arterioles.…”

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].…”