Activation of Barium-Sensitive Inward Rectifier Potassium Channels Mediates Remote Dilation of Coronary Arterioles

Abstract

Background-Conducted vasodilation seems to be critical for the functional distribution of blood flow in the skeletal muscle microcirculation. However, this vasoregulatory phenomenon has not been documented in the coronary microcirculation, and its underlying mechanism remains elusive. Because potassium ions are potent metabolic vasodilators in the heart, by activating vascular inward rectifier K ϩ (K ir ) channels, we tested the hypothesis that coronary arterioles exhibit remote vasodilation through activation of this type of channel. Methods and Results-Porcine coronary arterioles were isolated, cannulated, and pressurized for in vitro study. Vessels dilated concentration-dependently to extraluminal KCl (5 to 20 mmol/L), bradykinin, adenosine, pinacidil, and sodium nitroprusside. A K ir channel blocker, BaCl 2 (30 mol/L), inhibited vasodilatory responses to KCl and bradykinin but not to adenosine, pinacidil, or nitroprusside. In a flow chamber, localized administration of bradykinin, adenosine, and KCl to the downstream end of the arterioles caused Ϸ80% dilation at the site of drug application (local site) and also produced 30% to 60% dilation at the upstream end of arterioles (remote site). Nitroprusside produced a similar dilation at the local site but failed to initiate remote vasodilation. In the presence of Ba 2ϩ , adenosine still dilated the local site, but the local dilations to bradykinin and KCl and the remote dilations to adenosine, bradykinin, and KCl were inhibited. Conclusions-We demonstrated that some modes of local vasodilation can be conducted to remote sites in coronary arterioles and that local and remote dilations can occur through different vasodilatory mechanisms. Activation of K ir channels seems critical for some agonist-induced local vasodilations and also for the initiation and/or transmission of signals causing remote vasodilation. Key Words: vasodilation Ⅲ physiology Ⅲ ion channels Ⅲ potassium Ⅲ microcirculation I n the skeletal muscle microcirculation, it has been shown that vasomotor responses elicited at one location (direct local response) can result in changes in vessel diameter at remote sites (conducted response). 1 Conducted vasomotor responses have been considered a result of changes in membrane potential through cell-cell electrical conduction along the vessel wall. 2 Although this conducted response has been described in a number of tissues and has been suggested to play an important role in the integrative coordination of blood flow distribution during increased metabolic demand, 3 it remains unclear whether this vasomotor response also exists in the heart. In addition, the underlying mechanisms involved in the propagation of vasodilation have not been elucidated.A possible mechanism for remote dilations in microvessels could involve K ϩ channels because they play a central role in the maintenance and regulation of the membrane potential in smooth muscle cells. 4 In excitable cells, the release of K ϩ during metabolic activation can contribute to flow recruitment through m...

Contributions of A2Aand A2Badenosine receptors in coronary flow responses in relation to the KATPchannel using A2Band A2A/2Bdouble-knockout mice

“…K ϩ channels have been suggested to be involved in the regulation of blood flow and blood pressure and in AR signaling pathways (29,49,78). For example, inward rectifier K ϩ channels may play a role, since their presence has been reported on coronary artery SMCs (54,60,65) in addition to their role as the dominant K ϩ conductance in resting membrane potential (38). Moreover, adenosine has been reported to activate K ATP channels in rabbit mesenteric arteries and isolated coronary artery SMCs (58,65).…”

Coordination of Vasomotor Responses by the Endothelium

“…Candidate ion channels involved in this process currently favor an important role for inwardly rectifying K + (KIR) channels. 63,70,71 However, this does not appear to be universal, as Ba 2+ alone (to inhibit KIR channels) has no effect on spreading dilatation to either ACh or levcromakalim in rat mesenteric arteries, 62 but the Na + /K + -ATPase, which we know can also be activated by modest increases in extracellular [K + ], 5 may play an as yet to be determined role. This raises the possibility that the release of K + from vascular cells during hyperpolarization may act as an amplification mechanism, with a distinct parallel to its action as an EDHF.…”

“…18,51,72 Together with Na + /K + -ATPase, this may serve to amplify the spreading dilatation response. 62,63,70 Various Ca 2+ influx (eg, voltage-gated Ca 2+ -channels in SMCs, purple) and release channels, transporters and Ca 2+ pumps (all represented generically as grey) are found in both ECs and SMCs. 11 which is consistent with expression of M3 muscarinic ACh receptors within this microdomain.…”

Remote arteriolar dilations caused by methacholine: a role for CGRP sensory nerves?

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