Please use this identifier to cite or link to this item:
|Title:||Studies of the mechanisms of action of nicorandil on rat and pig small arteries|
|Authors:||Davie, Christina Savanthi.|
|Presented at:||University of Leicester|
|Abstract:||Concentration-dependent nicorandil relaxations of rat mesenteric arterial rings, measured in the presence of L-NAME to block NO synthesis, were inhibited either by the ATP-sensitive K+ (KATP) channel inhibitor glibenclamide, or by the guanlyl cyclase inhibitor LY 83583. When applied together, glibenclamide and LY 83583 were more effective than either agents alone. Nicordandil was also less potent at inhibiting 60mM K+ concentrations. These results are consistent with nicorandil causing relaxation both by activation of KATP channels and of guanylyl cyclase in this preparation. In whole cell patch clamp experiments, nicorandil activated a K+ current that was inhibited by glibenclamide, but unaffected by the inhibitor of large conductance calcium-activated K+ (BKCa) channels iberiotoxin. Single channels activated by nicorandil, resolved in a whole-cell recording, had a conductance of 31 pS in symmetrical high K+ solutions.;Although BKCa channel activation has been reported to be involved in the vasorelaxant action of nitrovasodilators in some studies, iberiotoxin (IbTX) did not affect nicordandil-induced relaxations of the rat mesenteric artery, nor did it inhibit nicorandil-induced K+ currents. Similarly, IbTX and charybdotoxin (ChTX) failed to inhibit relaxations produced by the pure nitrovasodilators glyceryl trinitrate and SNAP. Interestingly, however, in the absence of L-NAME, ChTX significantly inhibited SNAP dose response curves, implying the activation of BKCa channels under these conditions. Thus, in the rat mesenteric arterial preparation used here, the activation of K+ channels by SNAP appears to be dependent on endogenous NO production. In the absence of endothelial NO, the drug produced full relaxation via K+ channel-independent mechanisms.;The KATP channel opening ability of nicorandil was postulated to be potentiated by cellular stress because such channels are sensitive to the metabolic state of the cell. In rat mesenteric arteries, the potency of nicorandil was enhanced by metabolic inhibition with carbonyl cyanide m-chlorophenylhydrazone (CCP) and 2-deoxyglucosse. This effect was then studied more fully in pig coronary arteries where metabolic inhibition with CCCP or zero glucose solution, external acidosis, and adenosine receptor activation all increased the potency of nicorandil to cause vasorelaxation.|
|Rights:||Copyright © the author. All rights reserved.|
|Appears in Collections:||Theses, Dept. of Cell Physiology and Pharmacology|
Items in LRA are protected by copyright, with all rights reserved, unless otherwise indicated.