کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
5824102 | 1118412 | 2010 | 9 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Anti-ischemic properties of a new spiro-cyclic benzopyran activator of the cardiac mito-KATP channel
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کلمات کلیدی
MPTPIPC5-HD5-hydroxydecanoic acidKATPI/R - I / Rmitochondrial permeability transition pore - انتقال نفوذی میتوکندری منفی استCSA - ایالات مؤتلفهٔ آمریکاischemia/reperfusion - ایسکمی / رپرفیوژنMyocardial ischemia/reperfusion - ایسکمی / رپرفیوژن میوکاردCyclosporine A - سیکلوسپورینALAD - لادوischemic pre-conditioning - پیش آمادگی ایسکمیکleft anterior descending coronary artery - چپ قدامی نزولی عروق کرونرMitochondrial KATP channel - کانال KATP میتوکندریATP-sensitive potassium channel - کانال پتاسیم حساس به ATP
موضوعات مرتبط
علوم پزشکی و سلامت
داروسازی، سم شناسی و علوم دارویی
داروشناسی
پیش نمایش صفحه اول مقاله
چکیده انگلیسی
Many activators of KATP channels exhibit cardioprotective effects, mainly mediated by channels expressed on mitochondria (mito-KATP). Previous results showed anti-ischemic effects of the spiro-cyclic derivative A, on isolated rat hearts. In this work this molecule was more extensively studied and diazoxide was used as reference mito-KATP opener. The studies were performed on an in vivo rat model of myocardial infarct and on heart-derived H9c2 cells exposed to an anoxic environment. The mechanism of action was further investigated on isolated rat heart mitochondria. In the model of myocardial infarct compound A and diazoxide produced significant cardioprotective effects, antagonised by the selective mito-KATP blocker 5-hydroxydecanoic acid (5-HD). Compound A, like diazoxide, produced modest and non-significant hypotensive responses, while the hyperglycaemic effects of diazoxide were not observed for the new compound. Protective effects of compound A and diazoxide were also recorded in H9c2 cells and again were inhibited by 5-HD. Compound A and diazoxide caused swelling of cardiac mitochondria, in agreement with the profile of mito-KATP openers. Both compounds evoked concentration-dependent Ca2+-release from Ca2+-preloaded mitochondria, prevented mitochondrial Ca2+-uptake and caused mitochondrial membrane depolarisation. These effects were antagonised by ATP, the endogenous KATP inhibitor. In conclusion, compound A exhibits a promising profile of an anti-ischemic agent, with a mechanism likely to be linked to the activation of mito-KATP channels, and, because of its chemical characteristics such as structural rigidity and chirality due to the spiro-cyclic moiety, represents an interesting template for development of analogues further improved in activity and selectivity.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Biochemical Pharmacology - Volume 79, Issue 1, 1 January 2010, Pages 39-47
Journal: Biochemical Pharmacology - Volume 79, Issue 1, 1 January 2010, Pages 39-47
نویسندگان
Vincenzo Calderone, Lara Testai, Alma Martelli, Simona Rapposelli, Maria Digiacomo, Aldo Balsamo, Maria C. Breschi,