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1.
Clin Exp Pharmacol Physiol ; 44(1): 135-142, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27626620

RESUMO

Cardiac output and rhythm depend on the release and the take-up of calcium from the sarcoplasmic reticulum (SR). Excessive diastolic calcium leak from the SR due to dysfunctional calcium release channels (RyR2) contributes to the formation of delayed after-depolarizations, which underlie the fatal arrhythmias that occur in heart failure and inherited syndromes. Calmodulin (CaM) is a calcium-binding protein that regulates target proteins and acts as a calcium sensor. CaM is comprised of two calcium-binding EF-hand domains and a flexible linker. CaM is an accessory protein that partially inhibits RyR2 channel activity. CaM is critical for normal cardiac function, and altered CaM binding and efficacy may contribute to defects in SR calcium release. The present paper reviews CaM binding to RyR2 and how it regulates RyR2 channel activity. It then goes on to review how mutations in the CaM amino acid sequence give rise to inherited syndromes such as Catecholaminergic Polymorphic Ventricular Tachychardia (CPVT) and long QT syndrome (LQTS). In addition, the role of reduced CaM binding to RyR2 that results from RyR2 phosphorylation or from oxidation of either RyR2 or CaM contributes to the progression of heart failure is reviewed. Finally, this manuscript reviews recent evidence that CaM binding to RyR2 is required for the inhibitory action of a pharmaceutical agent (dantrolene) on RyR2. Dantrolene is a clinically used muscle relaxant that has recently been found to exert antiarrhythmic effects against SR Ca2+ overload arrhythmias.


Assuntos
Antiarrítmicos/uso terapêutico , Calmodulina/fisiologia , Dantroleno/uso terapêutico , Progressão da Doença , Insuficiência Cardíaca/tratamento farmacológico , Canal de Liberação de Cálcio do Receptor de Rianodina/fisiologia , Animais , Arritmias Cardíacas/tratamento farmacológico , Arritmias Cardíacas/metabolismo , Arritmias Cardíacas/patologia , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/patologia , Humanos
2.
Mol Pharmacol ; 88(1): 57-63, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25920678

RESUMO

Dantrolene is the first line therapy of malignant hyperthermia. Animal studies suggest that dantrolene also protects against heart failure and arrhythmias caused by spontaneous Ca(2+) release. Although dantrolene inhibits Ca(2+) release from the sarcoplasmic reticulum of skeletal and cardiac muscle preparations, its mechanism of action has remained controversial, because dantrolene does not inhibit single ryanodine receptor (RyR) Ca(2+) release channels in lipid bilayers. Here we test the hypothesis that calmodulin (CaM), a physiologic RyR binding partner that is lost during incorporation into lipid bilayers, is required for dantrolene inhibition of RyR channels. In single channel recordings (100 nM cytoplasmic [Ca(2+)] + 2 mM ATP), dantrolene caused inhibition of RyR1 (rabbit skeletal muscle) and RyR2 (sheep) with a maximal inhibition of Po (Emax) to 52 ± 4% of control only after adding physiologic [CaM] = 100 nM. Dantrolene inhibited RyR2 with an IC50 of 0.16 ± 0.03 µM. Mutant N98S-CaM facilitated dantrolene inhibition with an IC50 = 5.9 ± 0.3 nM. In mouse cardiomyocytes, dantrolene had no effect on cardiac Ca(2+) release in the absence of CaM, but reduced Ca(2+) wave frequency (IC50 = 0.42 ± 0.18 µM, Emax = 47 ± 4%) and amplitude (IC50 = 0.19 ± 0.04 µM, Emax = 66 ± 4%) in the presence of 100 nM CaM. We conclude that CaM is essential for dantrolene inhibition of RyR1 and RyR2. Its absence explains why dantrolene inhibition of single RyR channels has not been previously observed.


Assuntos
Cálcio/metabolismo , Calmodulina/metabolismo , Dantroleno/administração & dosagem , Fármacos Neuromusculares/administração & dosagem , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Animais , Hipertermia Maligna/tratamento farmacológico , Camundongos , Camundongos Endogâmicos C57BL , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Coelhos , Ovinos
3.
Am J Physiol Heart Circ Physiol ; 300(5): H1661-8, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21335468

RESUMO

A decrease in peak early diastolic filling velocity in postmenopausal women implies a sex hormone-related diastolic dysfunction. The regulatory effect of female sex hormones on cardiac distensibility therefore was evaluated in ovariectomized rats by determining the sarcomere length-passive tension relationship of ventricular skinned fiber preparations. Diabetes also was induced in the rat to assess the protective significance of female sex hormones on diastolic function. While ovariectomy had no effect on myocardial stiffness, collagen content, or titin ratio, a significant increase in myocardial stiffness was observed in diabetic rat only when female sex hormones were intact. The increased stiffness in diabetic-sham rats was accompanied by an elevated collagen content resulting from increases in the levels of procollagen and Smad2. Surprisingly, the increased myocardial stiffness in diabetic-sham rats was accompanied by a shift toward a more compliant N2BA of cardiac titin isoforms. The pCa-active tension relationship was analyzed at fixed sarcomere lengths of 2.0 and 2.3 µm to determine the magnitude of changes in myofilament Ca(2+) sensitivity between the two sarcomere lengths. Interestingly, high expression of N2BA titin was associated with a suppressed magnitude of changes in myofilament Ca(2+) sensitivity only in the diabetic-ovariectomized condition. Estrogen supplementation in diabetic-ovariectomized rats partially increased myocardial stiffness but completely reversed the change in myofilament Ca(2+) sensitivity. These results indicate a restrictive adaptation of myocardium governed by female sex hormones to maintain myofilament activity in compensation to the pathophysiological induction of cardiac dilatation by the diabetic condition.


Assuntos
Sinalização do Cálcio/efeitos dos fármacos , Diabetes Mellitus Experimental/fisiopatologia , Elasticidade/efeitos dos fármacos , Estrogênios/farmacologia , Coração/fisiopatologia , Contração Miocárdica/efeitos dos fármacos , Animais , Sinalização do Cálcio/fisiologia , Colágeno/metabolismo , Conectina , Diabetes Mellitus Experimental/metabolismo , Diástole/fisiologia , Modelos Animais de Doenças , Elasticidade/fisiologia , Feminino , Proteínas Musculares/metabolismo , Contração Miocárdica/fisiologia , Ovariectomia , Pró-Colágeno/metabolismo , Proteínas Quinases/metabolismo , Ratos , Ratos Sprague-Dawley , Proteína Smad2/metabolismo , Estreptozocina
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