Morphine Mimics the Cardioprotective Effect of Ischemic Preconditioning via a Glibenclamide-Sensitive Mechanism in the Rat Heart

Abstract

Previous results from our laboratory have suggested that opioid receptors are involved in ischemic preconditioning (PC) in rat heart. Furthermore, other investigators have suggested that mu- and delta-opioid receptors mediate analgesia and hypoxic cerebral vasodilatation via opening of ATP-sensitive K+ (KATP) channels. Thus, the purpose of the present study was to test the hypothesis that activation of opioid receptors mimics the cardioprotective effect of ischemic PC and that this effect is produced by activation of KATP channels in the rat heart. Anesthetized open-chest Wistar rats were subjected to six different protocols. All groups were subjected to 30 minutes of occlusion and 2 hours of reperfusion. Ischemic PC was elicited by three 5-minute occlusion periods interspersed with 5 minutes of reperfusion. Similarly, morphine-induced PC was elicited by three 5-minute drug infusions (100 micrograms/kg i.v. ) interspersed with 5-minute drug-free periods before the prolonged 30-minute occlusion. Infarct size (IS) as a percentage of the area at risk (AAR) was determined by triphenyltetrazolium staining. Ischemic PC and morphine infusions resulted in similar reductions in IS/AAR from 56 +/- 5% to 11 +/- 3% and 12 +/- 5%, respectively (P < .05). Administration of glibenclamide (0.3 mg/kg i.v.), a KATP channel antagonist, or naloxone (3 mg/kg i.v.), a nonselective opioid receptor antagonist, both blocked the cardioprotective effects of morphine. These results indicate that opioid receptor stimulation results in a reduction in infarct size similar to that produced by ischemic PC. The effect of morphine is most likely mediated via an opioid receptor-KATP channel-linked mechanism in the rat heart, since glibenclamide abolished its protection.

Annexin A5 Scintigraphy of Forearm as a Novel In Vivo Model of Skeletal Muscle Preconditioning in Humans

“…In animal models, various drugs that are currently used in clinical practice to prevent or treat acute ischemic events interfere with ischemic preconditioning or modulate ischemia-reperfusion injury. For example, adenosine and opiates mimic ischemic preconditioning (pharmacological preconditioning), 10,11 whereas ATP-sensitive potassium channel blockers and adenosine receptor antagonists inhibit ischemic preconditioning. 12 Insulin and statins reduce ischemia-reperfusion injury by a mechanism that is, at least partially, independent from the signal transduction pathway of ischemic preconditioning.…”

Caveolin-3 expression and caveolae are required for isoflurane-induced cardiac protection from hypoxia and ischemia/reperfusion injury

“…Protection of the heart from ischemia/reperfusion injury can be induced by multiple stimuli (e.g., ischemia [1], opioids [2] and volatile anesthetics [3,4]). Though many volatile anesthetics, including isoflurane [3,4], sevoflurane [5,6], and desflurane [6] show cardiac protection in vivo, the precise mechanism for volatile anesthetic-induced cardiac protection has not been elucidated.…”

Ischemia, reperfusion and preconditioning: traditional and new approaches for treatment of myocardial infarction

“…G.J. Gross об-наружено [49], что морфин в дозе 0,3 мг/кг оказы-вает инфарктлимитирующий эффект при экспери-ментальной окклюзии и реперфузии у крыс. В 1997 г. было установлено [50,51], что кардиопротекторный эффект морфина и ишемического прекондицио-нирования связан с активацией периферических δ-опиоидных рецепторов.…”

“…Gross в экспери-ментах с селективными агонистами κ-опиоидных рецепторов [42]. Однако подтвердить данные американских коллег о кардиопротекторной ак-тивности κ 1 -агонистов не удалось [15,30,49]. Инфарктлимитирующий эффект был обнаружен только у агониста δ 2 -опиоидных рецепторов дель-торфина II [4,12,36], который ограничивал соот-ношение РИ/ОР за счет активации периферических δ 2 -опиоидных рецепторов.…”

“…В этой связи следует отметить, что максимальные рекомендованные дозы морфина при лечении острого ИМ составляют от 0,15 (при массе тела в 70 кг) [16] до 0,075 мг/кг [8]. Экспе-риментальные исследования свидетельствуют, что названный опиат оказывает инфарктлимитирующий эффект в дозе 0,3 мг/кг [18,[49][50][51]. К сожалению, сравнительный анализ дозозависимых эффектов морфина при остром ИМ не проводился, как и не проводились клинические испытания агонистов δ-и κ 1 -опиоидных рецепторов.…”