Levcromakalim Decreases Cytoplasmic Ca2+ and Vascular Tone in Basilar Artery of SAH Model Dogs

Abstract

We investigated the effects of levcromakalim, a K+ channel opener, on [Ca2+]i and the contractile force of basilar arteries obtained from normal dogs and subarachnoid hemorrhage (SAH) dogs. The responsiveness to serotonin was increased more in the SAH group than in the control group. Levcromakalim decreased the resting [Ca2+]i and force more profoundly than did a Ca2+ channel blocker, nicardipine, and these effects were more prominent in the SAH group than in the control group. Levcromakalim diminished the increases in [Ca2+]i and contractile force induced by serotonin more profoundly than nicardipine did, and these effects were equal in both groups. The effects of levcromakalim were not inhibited by iberiotoxin but were antagonized completely by glibenclamide. These results suggest that levcromakalim-induced opening of adenosine triphosphate (ATP)-sensitive K+ (K(ATP)) channels reduces [Ca2+]i more effectively than does nicardipine and that levcromakalim exerts the vasodilator effects under the condition in which large conductance Ca2+-activated K+ (BK) channels are blocked with iberiotoxin. Consequently, K+ channel openers like levcromakalim may be useful drug candidates to treat delayed cerebral vasospasm after SAH.

Controversies and evolving new mechanisms in subarachnoid hemorrhage

“…Therapeutic manipulation of the K + channels has been attempted to reduce vasospasm after SAH. The K ATP channel activator, levcromakalim, or endogenous activator, calcitonin gene-related peptide, displayed vasorelaxation after SAH in dogs, rabbits and monkeys (Ahmad et al, 1996; Sugai et al, 1999; Zuccarello et al, 1996). However, it failed to significantly attenuate vasospasm to a greater degree than that provided by standard care in a randomized multicenter single-blind clinical trial.…”

Calcium and Potassium Channels in Experimental Subarachnoid Hemorrhage and Transient Global Ischemia

“…The K ATP channel activator levcromakalim increased vasorelaxation in rabbit basilar arteries three days after SAH [4] and in dog basilar arteries seven days after SAH [50]. Furthermore, the endogenous K ATP channel activator calcitonin gene-related peptide (CGRP) displayed therapeutic effects reversing vasospasm after SAH in rabbits and monkeys [51, 52] but failed to significantly attenuate vasospasm to a greater degree than standard of care (nimodipine) in a clinical trial comprising 117 patients [53].…”

Clarification of serotonin‐induced effects in peripheral artery disease observed through the femoral artery response in models of diabetes and vascular occlusion: The role of calcium ions

“…The lack of a decrease in the maximal contractile responses in other groups/subgroups after introducing Ca 2+ ‐free medium actually favors the role of intracellular calcium in this process. These results are consistent with the results of other studies in which serotonin worked to contract blood vessels through the release of calcium from intracellular stores …”

“…These results are consistent with the results of other studies in which serotonin worked to contract blood vessels through the release of calcium from intracellular stores. [19][20][21] In the next set of experiments, nifedipine, a predominantly L-type calcium channel blocker, was used in order to additionally investigate the role of extracellular calcium in serotonin-evoked effects on femoral vascular rings. Initially, similar results to those obtained after the omission of calcium were expected.…”