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

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), K_ATP 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, K_ATP channels, and the mevalonate pathway.