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Effect of calcitonin gene-related peptide antagonist on the cardiovascular events, mortality, and prostaglandin E(2) production by nitrate-induced tolerant rats with acute myocardial infarction
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 tole...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4782301/ https://www.ncbi.nlm.nih.gov/pubmed/26958096 http://dx.doi.org/10.1186/s13167-016-0055-5 |
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author | Kezeli, Tamar Rukhadze, Tamari Gongadze, Nikoloz Sukoyan, Galina Dolidze, Nino Chipashvili, Mariam Mirziashvili, Makrine |
author_facet | Kezeli, Tamar Rukhadze, Tamari Gongadze, Nikoloz Sukoyan, Galina Dolidze, Nino Chipashvili, Mariam Mirziashvili, Makrine |
author_sort | Kezeli, Tamar |
collection | PubMed |
description | 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 (CGRP(8-37)) on cardiohemodynamic events, prostaglandin E(2) (PGE(2)) 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 (CGRP(8-37)), 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 (CGRP(8-37)), 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 PGE(2) 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. |
format | Online Article Text |
id | pubmed-4782301 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-47823012016-03-09 Effect of calcitonin gene-related peptide antagonist on the cardiovascular events, mortality, and prostaglandin E(2) production by nitrate-induced tolerant rats with acute myocardial infarction Kezeli, Tamar Rukhadze, Tamari Gongadze, Nikoloz Sukoyan, Galina Dolidze, Nino Chipashvili, Mariam Mirziashvili, Makrine EPMA J Research 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 (CGRP(8-37)) on cardiohemodynamic events, prostaglandin E(2) (PGE(2)) 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 (CGRP(8-37)), 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 (CGRP(8-37)), 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 PGE(2) 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. BioMed Central 2016-03-08 /pmc/articles/PMC4782301/ /pubmed/26958096 http://dx.doi.org/10.1186/s13167-016-0055-5 Text en © Kezeli et al. 2016 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Kezeli, Tamar Rukhadze, Tamari Gongadze, Nikoloz Sukoyan, Galina Dolidze, Nino Chipashvili, Mariam Mirziashvili, Makrine Effect of calcitonin gene-related peptide antagonist on the cardiovascular events, mortality, and prostaglandin E(2) production by nitrate-induced tolerant rats with acute myocardial infarction |
title | Effect of calcitonin gene-related peptide antagonist on the cardiovascular events, mortality, and prostaglandin E(2) production by nitrate-induced tolerant rats with acute myocardial infarction |
title_full | Effect of calcitonin gene-related peptide antagonist on the cardiovascular events, mortality, and prostaglandin E(2) production by nitrate-induced tolerant rats with acute myocardial infarction |
title_fullStr | Effect of calcitonin gene-related peptide antagonist on the cardiovascular events, mortality, and prostaglandin E(2) production by nitrate-induced tolerant rats with acute myocardial infarction |
title_full_unstemmed | Effect of calcitonin gene-related peptide antagonist on the cardiovascular events, mortality, and prostaglandin E(2) production by nitrate-induced tolerant rats with acute myocardial infarction |
title_short | Effect of calcitonin gene-related peptide antagonist on the cardiovascular events, mortality, and prostaglandin E(2) production by nitrate-induced tolerant rats with acute myocardial infarction |
title_sort | effect of calcitonin gene-related peptide antagonist on the cardiovascular events, mortality, and prostaglandin e(2) production by nitrate-induced tolerant rats with acute myocardial infarction |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4782301/ https://www.ncbi.nlm.nih.gov/pubmed/26958096 http://dx.doi.org/10.1186/s13167-016-0055-5 |
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