Nonlinear effects of potassium channel blockers on endothelium-dependent hyperpolarization

Abstract

In a number of published studies on endothelium-dependent hyperpolarization and relaxation, the results of the effects of K blockers have been difficult to interpret. When the effects of two blockers have been studied, often either blocker by itself had little effect, whereas the two blockers combined tended to abolish the responses. Explanations suggested in the literature include an unusual pharmacology of the K channels, and possible blocker binding interactions. In contrast, when we applied the same blockers to segments of small blood vessels under voltage clamp, the blockers reduced the endothelium-dependent K current in a linearly additive manner. Resolution of these contrasting results is important as endothelium-derived hyperpolarization (EDH) makes its greatest contribution to vasorelaxation in arterioles and small resistance arteries, where it can exert a significant role in tissue perfusion and blood pressure regulation. Furthermore, EDH is impaired in various diseases. Here, we consider why the voltage-clamp results differ from earlier free-running membrane potential and contractility studies. We fitted voltage-clamp-derived current-voltage relationships with mathematical functions and considered theoretically the effects of partial and total block of endothelium-derived K -currents on the membrane potential of small blood vessels. When the K -conductance was partially reduced, equivalent to applying a single blocker, the effect on EDH was small. Total block of the endothelium-dependent K conductance abolished the hyperpolarization, in agreement with various published studies. We conclude that nonlinear summation of the hyperpolarizing response evoked by endothelial stimulation can explain the variable effectiveness of individual K channel blockers on endothelium-dependent hyperpolarization and resulting relaxation.

Vasodilation of rat skeletal muscle arteries by the novel BK channel opener GoSlo is mediated by the simultaneous activation of BK and Kv7 channels

“…A possible explanation for our observations has been suggested recently (Coleman, Tare, & Parkington, ). If the GoSlo compounds produce a considerable hyperpolarisation, the membrane potential will be much closer to the potassium equilibrium potential resulting in a small driving force for potassium ions.…”

4‐Aminopyridine: a pan voltage‐gated potassium channel inhibitor that enhances Kv7.4 currents and inhibits noradrenaline‐mediated contraction of rat mesenteric small arteries

“…These data show that 4‐AP‐mediated relaxations occur, at least in part, through the activation of K v 7 channels and either a direct or indirect enhancement of BK Ca channel activity. Another possible explanation is the nonlinear relationship between K + ‐conductance and membrane potential inherent in the biophysics of membrane electrophysiology (Coleman et al ., ), which would make a ‘second’ K + ‐conductance inhibitor appear more effective than the ‘first’ K + ‐conductance inhibitor.…”

Bonus Effects of Antidiabetic Drugs: Possible Beneficial Effects on Endothelial Dysfunction, Vascular Inflammation and Atherosclerosis

“…In addition to reducing NO bioavailability, diabetes also decreases endothelium-derived hyperpolarization [27,28] [EDH, previously associated with the availability and actions of endothelium-derived hyperpolarizing factors; EDH(F)] [29][30][31][32].…”