Nitric oxide‐dependent relaxation is modulated by intermediate conductance Ca2+‐activated potassium channels in rat mesenteric resistance arteries

Abstract

Endothelium-dependent relaxation of isolated rat mesenteric resistance arteries to acetylcholine (ACh) is mediated by the release of nitric oxide (NO) and by endothelium-dependent hyperpolarization. We have investigated the role of Ca2+-activated potassium channels (KCa) in NO-mediated, endothelium-dependent relaxation of mesenteric resistance arteries. Pre-incubation with either 1-[(2-chlorophenyl) diphenylmethyl]-1H-pyrazole (Tram-34; 5 μM), an inhibitor of intermediate conductance KCa (IKCa), or L-NG-nitroarginine methylester (L-NAME; 100 μM), an inhibitor of NO synthase, caused significant inhibition of relaxation to ACh in arterial segments pre-contracted with phenylephrine (1–3 μM). The magnitude of inhibition caused by Tram-34 was not significantly different from that caused by L-NAME and the effects of the two inhibitors were not additive. Pre-incubation with apamin (50 nM), an inhibitor of small conductance KCa, did not significantly alter ACh-evoked relaxation. However, in the presence of L-NAME, apamin significantly inhibited relaxations to ACh and the combination of apamin with Tram-34 reduced the maximum relaxation to ACh by 80%. Addition of L-NAME with apamin and Tram-34 did not cause further significant inhibition. Tram-34 and apamin were without effect on relaxations evoked by the NO donor diethylamine NONOate. These data indicate that endothelial IKCa play a key role modulating NO-dependent relaxation to ACh in rat mesenteric resistance arteries. Supported by Heart & Stroke Foundation of Canada, URGC & USRP.