High dose remifentanil increases myocardial oxidative stress and compromises remifentanil infarct-sparing effects in rats

• Published in: European journal of pharmacology Vol. 718; no. 1-3; pp. 484 - 492
• Main Authors: Mei, Bin, Wang, Tingting, Wang, Yuan, Xia, Zhengyuan, Irwin, Michael G., Wong, Gordon T.C.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 15.10.2013
• Subjects: Analgesics, Opioid - adverse effects; Analgesics, Opioid - pharmacology; Animals; Cardiac protection; Deoxyguanosine - analogs & derivatives; Deoxyguanosine - metabolism; Dose-Response Relationship, Drug; fluorescence; Hemodynamics - drug effects; infarction; ischemia; Ischemic Preconditioning, Myocardial - methods; Male; malondialdehyde; Malondialdehyde - metabolism; morphine; Myocardial Infarction - chemically induced; Myocardial Infarction - metabolism; Myocardial Infarction - physiopathology; myocardium; Myocardium - metabolism; narcotics; Nitrosative stress; Opioids; Oxidative stress; Oxidative Stress - drug effects; Piperidines - adverse effects; Piperidines - pharmacology; Rats; Rats, Sprague-Dawley; Remifentanil; superoxide anion; Superoxide Dismutase - metabolism; Superoxides - metabolism; Tyrosine - analogs & derivatives; Tyrosine - metabolism; Oxidative stress; Cardiac protection; Nitrosative stress; Remifentanil; Opioids
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2013.07.030

Chronic administration of high dose opioids such as morphine is known to create intracellular oxidative stress via an opioid receptor dependent mechanism and this can interfere with cellular function. This study aimed at examining whether such changes can occur following short term exposure to high concentration of remifentanil, a potent short acting opioid. We conducted a experimental study using rat myocardium and systematically quantified tissue levels of superoxide anions, malondialdehyde (MDA) and nitrotyrosine following exposure to increasing duration (15min, 1 or 2h) or escalating doses of remifentanil (1μg, 5μg, 10μg or 20μg/kg/min). Concurrently the susceptibility of the heart to ischaemia reperfusion injury was assessed under the similar conditions. For any given duration of remifentanil infusion, there was increasing superoxide anions generated as the dose of remifentanil was increased. MDA concentrations were significantly increased when the animal was exposed to 10μg/kg/min for 2h or 20μg/kg/min for any duration. There was a trend towards an increased nitrotyrosine concentration with increasing dose of remifentanil, becoming significant when the dose was 20μg/kg/min. The infarct limiting ability of remifentanil was compromised when the dihydroethidium fluorescence positive cell percentage exceeded 50%, MDA concentration greater than 2nmol/mg of protein and nitrotyrosine content exceeding 1.5μg/mg of protein. Short term high dose opioid exposure can induce oxidative changes seen previously only with chronic opioid use and this high oxidative stress environment corrupts the heart's sensitivity to be preconditioned by opioids.