Pinelli Arnaldo, Trivulzio Silvio, Tomasoni Livio, Bertolini Boris, Brenna Sergio, Bonacina Edgardo, Vignati Silvano
Department of Pharmacology, Via Vanvitelli 32, 20129 Milano, Italy.
Fundam Clin Pharmacol. 2004 Dec;18(6):657-67. doi: 10.1111/j.1472-8206.2004.00296.x.
Myocardial infarction is usually induced in small animals by means of invasive procedures: the aim of this study was to cause heart necrosis lesions by non-invasive means. We injected rabbits with isoproterenol (3 mg/kg, i.p.) and vasopressin (0.3 mg/kg/5 min, i.v.) alone and in combination, and studied their effects on myocardial histology, electrocardiographic profiles, the appearance of the plasma cardiac necrosis marker c-troponin I (c-TPN I), hemodynamic parameters (blood pressure, heart rate), the coagulative process partial throboplastine time (PTT), and plasma nitric oxide (NO) levels. In the rabbits treated with vasopressin alone, the ischemic damage was associated with a decrease in NO values, and the appearance of electrocardiographic T-wave inversion and low plasma c-TPN I levels, whereas the animals treated with isoproterenol alone had necrotic bands in the myocardium, plasma c-TPN I, and electrocardiographic modifications (ST-segment changes and T-wave inversion). Combined treatment increased myocardial alterations such as contraction band necrosis, induced the appearance of specific hypoxic lesions such as areas of coagulative necrosis and leukocyte infiltration, and led to higher plasma c-TPN I levels and altered ECG profiles. Both drugs favored a decrease in plasma NO values and further alterations in hemodynamic parameters, such as higher blood pressure and greater procoagulant activity. The myocardial necrosis and modified cardiovascular parameters were attributed to calcium activated processes and the decrease in NO levels. As this model of myocardial damage involves the use of drugs that facilitate the opening of L-calcium channels, we also investigated their effects on cardiovascular parameters and heart histology after pretreatment with the calcium antagonist verapamil; this drug protected against the appearance of histological myocardial lesions, electrocardiographic alterations and high plasma c-TPN I levels, and prevented the hemodynamic and procoagulation changes, but did not affect the decrease in plasma NO values. The protective effects were attributed to the drug's calcium antagonist activity. In conclusion, the injection of isoproterenol and vasopressin induces a myocardial infarction non-invasively and seems to be suitable for studying early myocardial ischemic lesions and the effects of drugs interfering with myocardial damage and its related phenomena.
本研究的目的是通过非侵入性手段造成心脏坏死性病变。我们单独及联合给兔子注射异丙肾上腺素（3毫克/千克，腹腔注射）和血管加压素（0.3毫克/千克/5分钟，静脉注射），并研究它们对心肌组织学、心电图特征、血浆心脏坏死标志物肌钙蛋白I（c-TPN I）的出现、血流动力学参数（血压、心率）、凝血过程部分凝血活酶时间（PTT）以及血浆一氧化氮（NO）水平的影响。在单独用血管加压素治疗的兔子中，缺血性损伤与NO值降低、心电图T波倒置以及血浆c-TPN I水平降低有关，而单独用异丙肾上腺素治疗的动物心肌出现坏死带、血浆c-TPN I升高以及心电图改变（ST段改变和T波倒置）。联合治疗增加了心肌改变，如收缩带坏死，诱发了特定的缺氧性病变，如凝固性坏死区域和白细胞浸润，并导致血浆c-TPN I水平升高和心电图特征改变。两种药物都导致血浆NO值降低以及血流动力学参数的进一步改变，如血压升高和促凝血活性增强。心肌坏死和心血管参数改变归因于钙激活过程和NO水平降低。由于这种心肌损伤模型涉及使用促进L-钙通道开放的药物，我们还研究了在预先用钙拮抗剂维拉帕米处理后它们对心血管参数和心脏组织学的影响；这种药物可防止组织学心肌病变、心电图改变和血浆c-TPN I水平升高的出现，并预防血流动力学和促凝血变化，但不影响血浆NO值的降低。这些保护作用归因于该药物的钙拮抗剂活性。总之，注射异丙肾上腺素和血管加压素可非侵入性地诱发心肌梗死，似乎适合用于研究早期心肌缺血性病变以及干扰心肌损伤及其相关现象的药物的作用。
