Kezeli Tamar, Rukhadze Tamari, Gongadze Nikoloz, Sukoyan Galina, Dolidze Nino, Chipashvili Mariam, Mirziashvili Makrine
Department of Pharmacology, Faculty of Medicine, I. Javakhishvili Tbilisi State University, 2 Chiaureli str., 0159 Tbilisi, Georgia.
Department of Medical Pharmacology and Pharmacotherapeutics, Tbilisi State Medical University, 33 Vazha-pshavela ave., 0177 Tbilisi, Georgia.
EPMA J. 2016 Mar 8;7(1):6. doi: 10.1186/s13167-016-0055-5. eCollection 2016.
Anti-ischemic effects of NO releasing by nitroglycerin (NTG) and the release of calcitonin gene-related peptide (CGRP) are involved in the decrease of vascular remodeling in different cardiovascular diseases. Using a nitrate-free period is still generally required to prevent nitrate tolerance and should be used as the first-line option to maintain adequate symptom control and on an individual basis. Personalized anti-ischemic concerns require the urgent change of paradigm from interventional measures to predictive, preventive, and personalized treatment with organic nitrates and its combination with drugs that may improve prognosis and drugs that can be added for patients who remain symptomatic despite therapy with the other classes of agents. The purpose of this study was to evaluate the influence of human calcitonin gene-related peptide antagonist (CGRP8-37) on cardiohemodynamic events, prostaglandin E2 (PGE2) plasma concentration, the severity of ventricular arrhythmias, and mortality occurring during acute myocardial infarction (AMI) in NTG-tolerant and nontolerant rats.
In the pilot study of efficacy of calcitonin gene-related peptide antagonist (CGRP8-37), 58 male Wistar rats were included. All procedures were performed according to protocols approved by the General Animal Care and Use Committee. Adult male rats underwent surgery to induce AMI by ligating the left anterior descending coronary artery or SHAM. ECG was used to confirm myocardial ischemia. In each experiment, a rat was maintained under anesthesia for the duration of the experiment. At the end of the experiment, the rat was killed by an overdose of pentobarbital. All animals in accordance with the received pharmacological agent were randomized into three groups: I-received only NTG, 50 mg/kg daily, s.c. injections b.i.d. 3 days prior to AMI; II-received NTG by the same dose, route, and frequency of administration + CGRP antagonist (CGRP8-37), 10 μg/kg two times daily by a similar period of administration; and III-served as control (C) group without preliminary tolerance to NTG.
Subcutaneous injections of NTG (50 mg/kg) 30 min prior to AMI in NTG-tolerant animals (group I) and in NTG-tolerant rats + CGRP antagonist (group II) caused minor changes in blood pressure and heart period that was accompanied before NTG s.c. administration with blunted baroreflex sensitivity in response to i.v. administration of sodium nitroprusside in these groups of rats (0.66 ± 0.05 and 0.56 ± 0.04 ms/mmHg, P < 0.05, respectively) in comparison to C (group III) animals (0.9 ± 0.1 ms/mmHg). AMI 1 h duration was associated with a high incidence of ventricular arrhythmia and significant mortality in group I (70 %) and especially in group II (90 %) animals at 72 h after reperfusion as compared with group III rats (56 %), that correlated to a decrease of PGE2 plasma content in group II (2.2 ± 0.4 ng/ml, P < 0.001) and group I (3.6 ± 0.2 ng/ml, P < 0.01) vs. control group of rats (4.8 ± 0.3 ng/ml).
CGRP could be involved in the mechanism of nitrate tolerance via the inhibition of release of the potent vasodilator CGRP leading to exacerbation of acute myocardial ischemia. The influence of CGRP antagonist could enhance this condition.
硝酸甘油（NTG）释放一氧化氮的抗缺血作用以及降钙素基因相关肽（CGRP）的释放参与了不同心血管疾病中血管重塑的减轻。使用无硝酸盐期仍通常被要求以预防硝酸盐耐受性，并且应作为维持充分症状控制的一线选择并根据个体情况使用。个性化的抗缺血问题要求从介入措施迅速转变为使用有机硝酸盐及其与可能改善预后的药物以及对尽管使用其他类药物治疗仍有症状的患者可添加的药物进行预测性、预防性和个性化治疗的模式。本研究的目的是评估人降钙素基因相关肽拮抗剂（CGRP8 - 37）对NTG耐受和不耐受大鼠急性心肌梗死（AMI）期间心脏血流动力学事件、前列腺素E2（PGE2）血浆浓度、室性心律失常严重程度和死亡率的影响。
在降钙素基因相关肽拮抗剂（CGRP8 - 37）的疗效初步研究中，纳入了58只雄性Wistar大鼠。所有程序均按照动物护理和使用委员会批准的方案进行。成年雄性大鼠通过结扎左冠状动脉前降支或假手术进行诱导AMI的手术。心电图用于确认心肌缺血。在每个实验中，一只大鼠在实验期间保持麻醉状态。实验结束时，大鼠通过过量戊巴比妥钠处死。所有根据接受的药物治疗的动物随机分为三组：I组 - 仅接受NTG，每日50mg/kg，皮下注射，bid，在AMI前3天；II组 - 以相同剂量、途径和给药频率接受NTG + CGRP拮抗剂（CGRP8 - 37），每日两次，每次10μg/kg，给药时间相似；III组 - 作为对照组（C），对NTG无预先耐受性。
在NTG耐受动物（I组）和NTG耐受大鼠 + CGRP拮抗剂（II组）中，在AMI前30分钟皮下注射NTG（50mg/kg）导致血压和心动周期有轻微变化，在这些大鼠组中，与对照组（III组）动物（0.9±0.1ms/mmHg）相比，在皮下注射NTG前对静脉注射硝普钠的压力反射敏感性减弱（分别为0.66±0.05和0.56±0.04ms/mmHg，P < 0.05）。与III组大鼠（56%）相比（56%），I组（70%）尤其是II组（90%）动物在再灌注后72小时的1小时AMI与室性心律失常的高发生率和显著死亡率相关，这与II组（2.2±0.4ng/ml，P < 0.001）和I组（3.6±0.2ng/ml，P < 0.01）与对照组大鼠（4.8±0.3ng/ml）相比PGE2血浆含量的降低相关。
CGRP可能通过抑制强效血管扩张剂CGRP的释放参与硝酸盐耐受性机制，导致急性心肌缺血加重。CGRP拮抗剂的影响可能会加剧这种情况。
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