Ríha Michal, Vopršalová Marie, Pilařová Veronika, Semecký Vladimír, Holečková Magdalena, Vávrová Jaroslava, Palicka Vladimir, Filipský Tomáš, Hrdina Radomír, Nováková Lucie, Mladěnka Přemysl
Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Králové, Charles University in Prague, Heyrovského 1 203, Hradec Králové, 500 05, Czech Republic.
Naunyn Schmiedebergs Arch Pharmacol. 2014 Sep;387(9):823-35. doi: 10.1007/s00210-014-0995-z. Epub 2014 Jun 5.
Catecholamines are endogenous amines that participate in the maintenance of cardiovascular system homeostasis. However, excessive release or exogenous administration of catecholamines is cardiotoxic. The synthetic catecholamine, isoprenaline (isoproterenol, ISO), with non-selective β-agonistic activity has been used as a viable model of acute myocardial toxicity for many years. Since the pathophysiology of ISO-cardiotoxicity is complex, the aim of this study was to elucidate the effect of oral quercetin pretreatment on myocardial ISO toxicity. Wistar-Han rats were randomly divided into four groups: solvent or quercetin administered orally by gavage in a dose of 10 mg kg(-1) daily for 7 days were followed by s.c. water for injection or ISO in a dose of 100 mg kg(-1). Haemodynamic, ECG and biochemical parameters were measured; effects on blood vessels and myocardial histology were assessed, and accompanying pharmacokinetic analysis was performed. Quercetin was unable to protect the cardiovascular system against acute ISO cardiotoxicity (stroke volume decrease, cardiac troponin T release, QRS-T junction elevation and histological impairment). The sole positive effect of quercetin on catecholamine-induced cardiotoxicity was the normalization of increased left ventricular end-diastolic pressure caused by ISO. Quercetin did not reverse the increased responsiveness of rat aorta to vasoconstriction in ISO-treated animals, but it decreased the same parameter in the control animals. Accompanying pharmacokinetic analysis showed absorption of quercetin and its metabolite 3-hydroxyphenylacetic acid formed by bacterial microflora. In conclusion, a daily oral dose of 10 mg kg(-1) of quercetin for 7 days did not ameliorate acute ISO-cardiovascular toxicity in rats despite minor positive cardiovascular effects.
儿茶酚胺是参与维持心血管系统稳态的内源性胺类物质。然而，儿茶酚胺的过度释放或外源性给药具有心脏毒性。合成儿茶酚胺异丙肾上腺素（isoproterenol，ISO）具有非选择性β激动活性，多年来一直被用作急性心肌毒性的可行模型。由于ISO心脏毒性的病理生理学较为复杂，本研究旨在阐明口服槲皮素预处理对心肌ISO毒性的影响。将Wistar-Han大鼠随机分为四组：溶剂组或每天经口灌胃给予10 mg kg⁻¹槲皮素，连续7天，随后皮下注射生理盐水或100 mg kg⁻¹ ISO。测量血流动力学、心电图和生化参数；评估对血管和心肌组织学的影响，并进行伴随的药代动力学分析。槲皮素无法保护心血管系统免受急性ISO心脏毒性（每搏输出量减少、心肌肌钙蛋白T释放、QRS-T间期抬高和组织学损伤）。槲皮素对儿茶酚胺诱导的心脏毒性的唯一积极作用是使ISO引起的左心室舒张末期压力升高恢复正常。槲皮素并未逆转ISO处理动物中大鼠主动脉对血管收缩反应性的增加，但它降低了对照动物中的相同参数。伴随的药代动力学分析表明槲皮素及其由细菌微生物群形成的代谢产物3-羟基苯乙酸被吸收。总之，尽管有轻微的积极心血管作用，但连续7天每天口服10 mg kg⁻¹的槲皮素并不能改善大鼠急性ISO心血管毒性。
