RESUMO
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.
Assuntos
Atorvastatina/farmacologia , Sinalização do Cálcio/efeitos dos fármacos , Relaxamento Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Músculo Liso/fisiologia , Animais , Fundo Gástrico/efeitos dos fármacos , Fundo Gástrico/fisiologia , Masculino , Músculo Liso/citologia , Ratos , Ratos Wistar , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismoRESUMO
Essential for survival and reproduction, the circadian timing system (CTS) regulates adaptation to cyclical changes such as the light/dark cycle, temperature change, and food availability. The regulation of energy homeostasis possesses rhythmic properties that correspond to constantly fluctuating needs for energy production and consumption. Adipose tissue is mainly responsible for energy storage and, thus, operates as one of the principal components of energy homeostasis regulation. In accordance with its roles in energy homeostasis, alterations in adipose tissue's physiological processes are associated with numerous pathologies, such as obesity and type 2 diabetes. These alterations also include changes in circadian rhythm. In the current review, we aim to summarize the current knowledge regarding the circadian rhythmicity of adipogenesis, lipolysis, adipokine secretion, browning, and non-shivering thermogenesis in adipose tissue and to evaluate possible links between those alterations and metabolic diseases. Based on this evaluation, potential therapeutic approaches, as well as clock genes as potential therapeutic targets, are also discussed in the context of chronotherapy.
RESUMO
Statins are known to display benefits in various diseases independently from their cholesterol lowering properties. In this study, we investigated the acute effects of atorvastatin on vascular reactivity to various spasmogens in isolated rat aorta. The responses to noradrenaline (NA, 10(-8) -10(-4) m), endothelin-1 (ET-1, 10(-10) -10(-7) m), and potassium chloride (KCl, 10-100 mm) were evaluated in aortic rings pretreated with atorvastatin (10(-7) -10(-4) m, 30 min). To verify the mechanism of action, the effects of atorvastatin were studied in the presence of cholesterol precursor, mevalonate (10(-2) m, 45 min), mevalonate-derived isoprenoids, namely geranylgeranyl pyrophosphate (GGPP, 5 × 10(-6) m, 30 min) and farnesyl pyrophosphate (FPP, 5 × 10(-6) m, 30 min), and in the absence of endothelium. In parallel, aortic rings were pretreated with the specific inhibitor of Rho kinase, Y-27632 (10(-7) -10(-6) m). Atorvastatin significantly and concentration-dependently reduced the contractions to spasmogens in rat aorta. This acute inhibitory effect was also evident in endothelium-denuded rings. Pretreatment with mevalonate and GGPP, but not with FPP, reversed the inhibitory effect of atorvastatin (10(-4) m) on NA and ET-1 induced contractions. Similar to atorvastatin, pretreatment with Y-27632 inhibited the contractions to NA and KCl in a concentration-dependent manner. Western blot analysis revealed that both atorvastatin (10(-4) m) and Y-27632 (10(-6) m) pretreatment inhibited the phosphorylation of myosin phosphatase target subunit-1 (MYPT-1) triggered by NA, indicating an inhibitory influence on myosin phosphatase. In conclusion, atorvastatin displayed an acute inhibitory effect on vascular contractility evoked by various spasmogens and the inhibitory effect was possibly mediated by the inhibition of mevalonate and GGPP synthesis as well as the prevention of MYPT-1 phosphorylation induced by Rho/Rho kinase.