Joseph X, Jordan A W, Balazs T
Res Commun Chem Pathol Pharmacol. 1984 May;44(2):239-49.
Beta-Adrenoceptor agonists, such as isoproterenol, produce ventricular fibrillation and myocardial necrosis in rats. After the initial insult, a resistance develops to the lesion-inducing effects of subsequent doses of the drug. Cyclic AMP has been considered to play a major role in beta-adrenergic amine-induced myocardial necrosis as well as in the genesis of ventricular fibrillation. In the present studies, we investigated the ventricular fibrillation threshold and the responsiveness of myocardium to cAMP formation in isoproterenol-sensitive and resistant rats. Myocardial necrosis was induced in male Sprague-Dawley rats by subcutaneous injection of isoproterenol at 50 micrograms/kg for 2 consecutive days to make them resistant to subsequent challenges. Control rats received saline. Both groups were challenged 10 days later with graded doses of isoproterenol and ECGs were recorded. In another experiment, hearts from rats similarly treated were used for histopathology and cAMP determinations. The incidence of ventricular fibrillation and death was significantly lower in resistant rats compared with isoproterenol-sensitive rats. All rats pretreated with isoproterenol showed healed myocardial necrosis. The basal myocardial cAMP levels and the levels after in vitro isoproterenol stimulation were not significantly different between isoproterenol- and saline-pretreated rats. Moreover, no significant differences in the responsiveness of myocardium to cAMP formation were noted between the more sensitive apical and less sensitive ventricular regions in resistant or sensitive rats. These data indicate that the altered myocardial sensitivity or the mechanism for the increased ventricular fibrillation threshold in isoproterenol resistance appears to involve factors other than cAMP.
β-肾上腺素能受体激动剂，如异丙肾上腺素，可在大鼠中诱发心室颤动和心肌坏死。在初次损伤后，机体对后续剂量该药物的致损伤作用会产生耐受性。环磷酸腺苷（cAMP）被认为在β-肾上腺素能胺诱导的心肌坏死以及心室颤动的发生过程中起主要作用。在本研究中，我们调查了异丙肾上腺素敏感和耐受大鼠的心室颤动阈值以及心肌对cAMP生成的反应性。通过连续2天皮下注射50微克/千克的异丙肾上腺素，诱导雄性Sprague-Dawley大鼠发生心肌坏死，使其对后续刺激产生耐受性。对照大鼠注射生理盐水。10天后，两组大鼠均接受不同剂量的异丙肾上腺素刺激，并记录心电图。在另一项实验中，将经过类似处理的大鼠心脏用于组织病理学检查和cAMP测定。与异丙肾上腺素敏感大鼠相比，耐受大鼠的心室颤动和死亡发生率显著降低。所有预先用异丙肾上腺素处理的大鼠均显示心肌坏死已愈合。异丙肾上腺素预处理大鼠和生理盐水预处理大鼠的基础心肌cAMP水平以及体外异丙肾上腺素刺激后的水平无显著差异。此外，在耐受或敏感大鼠中，较敏感的心尖区域和较不敏感的心室区域之间，心肌对cAMP生成的反应性也无显著差异。这些数据表明，异丙肾上腺素耐受性中心肌敏感性的改变或心室颤动阈值升高的机制似乎涉及cAMP以外的因素。
