Relaxant effect of atorvastatin on isolated rat gastric fundus strips: implications for Ca2+-signalling mechanisms.

Abstract

Statins are determined to have various pleiotropic effects apart from their lipid-lowering properties. Herein, we investigated the direct effects of atorvastatin on gastric smooth muscle tone. Atorvastatin effectively relaxed isolated rat gastric fundus strips precontracted with acetylcholine, potassium chloride, and serotonin. Incubation of the strips with nitric oxide synthase inhibitor, l-NOARG (10-4 M, 20 min), l-type voltage-operated Ca2+ channel (VOCC) blocker, nifedipine (10-6 M, 30 min), KATP channel blocker, glibenclamide (10-5 M, 30 min), or precursor of cholesterol, mevalonate (10-2 M, 45 min) did not change the relaxations to atorvastatin. However, pretreatment of fundus strips with atorvastatin (3×10-5-3×10-4 M, 30 min) inhibited the contractions to calcium chloride (10-4-10-1 M), acetylcholine (10-4 M), and caffeine (20 mM) in the calcium-free medium. Moreover, atorvastatin reduced the contractions induced by sarco-endoplasmic reticulum Ca2+-ATPase (SERCA) inhibitor, cyclopiazonic acid (10-7-3×10-5 M). The current study demonstrated that atorvastatin produces an acute relaxant effect on gastric fundus strips, which appears to be mediated by several Ca2+-signalling mechanisms such as the blockade of l-type VOCC-independent Ca2+ entry, decrease in smooth muscle Ca2+ sensitivity, inhibition of IP3- and ryanodine-sensitive intracellular stores to mediate Ca2+ release, as well as the activation of SERCA. This acute relaxing effect seems unlikely to be related with nitric oxide, KATP channels, and the mevalonate pathway.