Ragone María Inés, Bayley Matías, Colareda Germán A, Bonazzola Patricia, Consolini Alicia E
Cátedra de Farmacología, Grupo de Farmacología Experimental y Energética Cardíaca, Departamento de Ciencias Biológicas, Facultad de Ciencias Exactas, Universidad Nacional de La Plata, La Plata, Argentina.
Instituto de Investigaciones Cardiológicas, Facultad de Medicina, Universidad de Buenos Aires-CONICET, Buenos Aires, Argentina.
J Cardiovasc Pharmacol Ther. 2020 Jan;25(1):72-85. doi: 10.1177/1074248419872957. Epub 2019 Sep 8.
Hypothyroidism is considered a cardiac risk factor, but there is controversial evidence about its effects on coronary disease. The aim of this work was to evaluate the influence of hypothyroidism in rat hearts exposed to 2 degrees of stunning due to ischemia and reperfusion (I/R) as well as the underlying mechanisms. Hypothyroid (HypoT) rats were obtained by drinking 0.02% methimazole during 15 days. Isolated hearts were perfused and introduced in a flow calorimeter to measure contractile performance (P), total heat rate (Ht), and muscle economy (P/Ht). Hearts were exposed to 2 models of I/R, moderate and severe (respectively 20 or 30 minutes I/45 minutes R). Moreover, free cytosolic and mitochondrial calcium changes were measured by confocal fluorometry on cardiomyocytes. Comparison to euthyroid (EuT) hearts was done. Hypothyroidism was cardioprotective, but HypoT hearts were more sensitive than EuT hearts to the preischemic blockade of mitochondrial transporters mNCX and mK channels. Moreover, the postischemic recovery of P and P/Ht in HypoT hearts was strongly reduced by inhibition of the cellular pathways of PI3K/Akt and protein kinase C (PKC), and it was increased by nitric oxide synthase (NOS) inhibition. However, physiological concentrations of adrenaline reduced the cardioprotection of HypoT, but oral treatment with 20 mg/kg/day carvedilol prevented it. Results show that hypothyroidism reduces the mitochondrial Ca overload during I/R by mK channel activation and Ca extrusion through mNCX, while the PI3K/Akt and PKC pathways are involved in that cardioprotection. Contrarily, NOS activation and adrenaline blunt such cardioprotection, but carvedilol prevented the adrenergic dysfunction. These results would explain why hypothyroidism is a clinical risk factor in angor patients under adrenergic exacerbation but reduced the incidence of acute episodes of coronary syndrome in hospitalized patients. Results suggest that a treatment with carvedilol could be a potential therapeutic agent to prevent cardiac postischemic dysfunction in hypothyroid patients.
甲状腺功能减退被认为是一种心脏危险因素，但其对冠状动脉疾病的影响存在争议性证据。本研究的目的是评估甲状腺功能减退对因缺血再灌注（I/R）导致的2级心肌顿抑大鼠心脏的影响及其潜在机制。通过在15天内饮用0.02%的甲巯咪唑获得甲状腺功能减退（HypoT）大鼠。分离心脏并灌注，将其置于流量热量计中以测量收缩性能（P）、总热率（Ht）和肌肉经济性（P/Ht）。心脏暴露于2种I/R模型，中度和重度（分别为20分钟I/45分钟R和30分钟I/45分钟R）。此外，通过共聚焦荧光法测量心肌细胞中游离细胞质和线粒体钙的变化。与甲状腺功能正常（EuT）心脏进行比较。甲状腺功能减退具有心脏保护作用，但HypoT心脏比EuT心脏对线粒体转运体mNCX和mK通道的缺血前阻断更敏感。此外，HypoT心脏中P和P/Ht的缺血后恢复因PI3K/Akt和蛋白激酶C（PKC）细胞途径的抑制而显著降低，而因一氧化氮合酶（NOS）抑制而增加。然而，生理浓度的肾上腺素降低了HypoT的心脏保护作用，但每天口服20mg/kg卡维地洛可预防这种情况。结果表明，甲状腺功能减退通过mK通道激活和通过mNCX的钙外排在I/R期间减少线粒体钙超载，而PI3K/Akt和PKC途径参与了这种心脏保护作用。相反，NOS激活和肾上腺素减弱了这种心脏保护作用，但卡维地洛预防了肾上腺素能功能障碍。这些结果可以解释为什么甲状腺功能减退在肾上腺素能加重的心绞痛患者中是一种临床危险因素，但在住院患者中降低了冠状动脉综合征急性发作的发生率。结果表明，卡维地洛治疗可能是预防甲状腺功能减退患者心脏缺血后功能障碍的一种潜在治疗药物。
