title: Effect of calcitonin gene-related peptide antagonist on the cardiovascular events, mortality, and prostaglandin E2 production by nitrate-induced tolerant rats with acute myocardial infarction.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pharmacology, Faculty of Medicine, I. Javakhishvili Tbilisi State University, 2 Chiaureli str., 0159 Tbilisi, Georgia.
authors.forename: Tamar
authors.identifier: 0000-0003-2229-6060
authors.initials: T
authors.lastname: Kezeli
authors.affiliation: Department of Pharmacology, Faculty of Medicine, I. Javakhishvili Tbilisi State University, 2 Chiaureli str., 0159 Tbilisi, Georgia.
authors.forename: Tamari
authors.initials: T
authors.lastname: Rukhadze
authors.affiliation: Department of Medical Pharmacology and Pharmacotherapeutics, Tbilisi State Medical University, 33 Vazha-pshavela ave., 0177 Tbilisi, Georgia.
authors.forename: Nikoloz
authors.initials: N
authors.lastname: Gongadze
authors.affiliation: International Scientific Centre of Introduction of New Biomedical Technology, Assignee of the NV Karsanov Research Centre of Medical Biophysics and Introduction of New Biomedical Technology, Kayrskaya str.19, 0137 Tbilisi, Georgia.
authors.forename: Galina
authors.initials: G
authors.lastname: Sukoyan
authors.affiliation: Grigol Robakidze University, 6 Jano Bagrationi str., 0160 Tbilisi, Georgia.
authors.forename: Nino
authors.initials: N
authors.lastname: Dolidze
authors.affiliation: Department of Pharmacology, Faculty of Medicine, I. Javakhishvili Tbilisi State University, 2 Chiaureli str., 0159 Tbilisi, Georgia.
authors.forename: Mariam
authors.initials: M
authors.lastname: Chipashvili
authors.affiliation: Department of Medical Pharmacology and Pharmacotherapeutics, Tbilisi State Medical University, 33 Vazha-pshavela ave., 0177 Tbilisi, Georgia.
authors.forename: Makrine
authors.initials: M
authors.lastname: Mirziashvili
keywords: Acute myocardial infarction; Baroreflex sensitivity; Calcitonin gene-related peptide antagonist; Hemodynamic; Mortality; Nitroglycerine tolerance; Predictive preventive personalized medicine; Prostaglandin E2; Ventricular arrhythmias