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 (3x10(-5)-3x10(-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)-3x10(-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

Caveolae depletion contributes to impaired relaxation induced by hydrogen sulfide in isolated human saphenous vein

3rd European Conference on the Biology of Hydrogen Sulfide (H2S) -- MAY 03-06, 2015 -- Athens, GREECEWOS: 00035331390005

Aggravating effect of atorvastatin on indomethacin-induced gastric injury: Focus on PGE(2), TNF-alpha, neutrophils and iNOS

Statins are suggested to possess healing properties due to their antioxidant and antiinflammatory effects in animal ulcer models. In contrary, a clinical report indicated the formation of gastric ulcer by the use of atorvastatin. In this study, we aimed to investigate the effects of atorvastatin (0.5, 5 and 50 mg/kg, p.o.) after single (acute) and multiple (subchronic, 5 days) applications on indomethacin-induced gastric ulcer in rats. In both acute and subchronic models high dose atorvastatin (50 mg/kg), unlike to lower doses (0,5 and 5 mg/kg), significantly aggravated ulcer lesions induced by indomethacin (30 mg/kg) although, a direct ulcerogenic influence was lacking. Proulcerogenic effect of atorvastatin are likely to be associated with decreased mucosal defense mechanisms (GSH and PGE(2)), and increased neutrophil infiltration and proinflammatory factors (TNF-a and iNOS) possibly via independently from mevalonate pathway. Thus, atorvastatin therapy should be monitorized in patients for an increased risk of gastric ulcer particularly when used concomitantly with NSAIDs. (c) 2015 Published by Elsevier Inc

Resveratrol ameliorates the cyclosporine-induced vascular and renal impairments: possible impact of the modulation of renin-angiotensin system.

Cyclosporine, an immunosuppressive drug, exhibits a toxic effect on renal and vascular systems. The present study investigated whether resveratrol treatment alleviates renal and vascular injury induced by cyclosporine. Cyclosporine (25 mg/kg per day, s.c.) was given for 7 days to rats either alone or in combination with resveratrol (10 mg/kg per day, i.p.). Relaxation and contraction responses of aorta were examined. Serum levels of blood urea nitrogen, creatinine, angiotensin II, and angiotensin 1-7 were measured. Histopathological examinations as well as immunostaining for 4-hydroxynonenal and nitrotyrosine were performed in the kidney. RNA expressions of renin-angiotensin system components were also measured in renal and aortic tissues. Cyclosporine decreased the endothelium-dependent relaxation and increased vascular contraction in the aorta. It caused renal tubular degeneration and increased immunostaining for 4-hydroxynonenal, an oxidative stress marker. Cyclosporine also caused upregulations of the vasoconstrictive renin-angiotensin system components in renal (angiotensin-converting enzyme) and aortic (angiotensin II type 1 receptor) tissues. Resveratrol co-treatment prevented the cyclosporine-related deteriorations. Moreover, it induced the expressions of vasodilatory effective angiotensin-converting enzyme 2 and angiotensin II type 2 receptor in aorta and kidney, respectively. We conclude that resveratrol may be effective in preventing cyclosporine-induced renal tubular degeneration and vascular dysfunction at least in part by modulating the renin-angiotensin system

Barnidipine ameliorates the vascular and renal injury in L-NAME-induced hypertensive rats.

The present study was aimed to investigate the influence of Barnidipine treatment on early stage hypertension by determining the function and morphology of the mesenteric and renal arteries as well as the kidney in N-omega-Nitro-L-Arginine Methyl Ester (L-NAME)-induced hypertensive rats. Barnidipine (3 mg/kg/day p.o) was applied to rats after 2 weeks of L-NAME (GO mg/kg/day) administration, and continued for the next 3 weeks concomitantly with L-NAME. The systolic blood pressure (SBP) of rats was determined to decrease significantly in Barnidipine treated hypertensive group when compared to that of rats received L-NAME alone. Myograph studies demonstrated that the contractile reactivity to noradrenaline were significantly reduced in both of the resistance arteries while endothelium dependent relaxations to acethylcholine were significantly diminished particularly in the mesenteric arteries of NAME induced hypertensive rats. The impaired contractile and endothelial responses were completely restored by concomitant treatment of Barnidipine with L-NAME. Histopathological examinations verified structural alterations in the arteries as well as the kidney. Moreover, a decrease in endothelial nitric oxide synthase (eNOS) expression was presented both in the arteries and kidney of hypertensive rats which were increased following Barnidipine treatment. Elevated plasma levels of malondialdehyde (MDA) and myeloperoxidase (MPO) were also reduced in Barnidipine treated hypertensive rats. In conclusion, besides to its efficacy in reducing the elevated SBP, amelioration of vascular function, modulation of arterial and renal eNOS expressions as well as reduction of the plasma levels of oxidative and inflammatory biomarkers are possible supportive mechanisms mediating the favorable implications of Barnidipine in L-NAME-induced hypertension model. (C) 2015 Elsevier B.V. All rights reserved