Inducible Nitric Oxide Synthase Mediates Delayed Cardioprotection Induced by Morphine In Vivo 

Abstract

: Pretreatment with morphine induces delayed cardioprotection in mice. The authors demonstrated an obligatory role for iNOS in mediating morphine-induced delayed cardioprotection.

Late preconditioning induced by NO donors, adenosine A1 receptor agonists, and δ1-opioid receptor agonists is mediated by iNOS

“…PC mimetics such as NO donors (15,18), TAN-670, and CCPA have obvious clinical potential. Combined with previous studies (6,16,(25)(26)(27), the present data support the development of strategies aimed at selectively upregulating iNOS in cardiac myocytes to induce a chronic PC state.…”

“…Specifically, no data exist regarding the contributions of iNOS to the delayed infarct-sparing effects elicited by NO donors. With regard to ␦ 1 -opioid receptor-induced late PC, a recent study (16) has concluded that iNOS mediates the delayed infarctsparing actions of morphine. However, morphine is not a specific ␦ 1 -opioid receptor agonist, and, in that investigation, the duration of coronary reperfusion was limited to 2 h. It is unknown whether a 2-h reperfusion period is sufficient for accurate assessment of infarct size in mice.…”

“…Research performed in the past 10 years has identified nitric oxide (NO) as both a trigger and a mediator of the late phase of ischemic PC (6). In particular, Guo et al (12) have demonstrated that genetic disruption of the iNOS gene completely abrogates the infarct-sparing effect of ischemia-induced late PC, establishing inducible NO synthase (iNOS) as an obligatory mediator.The cardioprotection afforded by ischemia-induced late PC can be mimicked by the administration of a variety of pharmacological agents, including NO-releasing agents (16,19,23,24), adenosine A 1 receptor agonists (2,3,22,27), and ␦ 1 -opioid receptor agonists (10), in dogs, rabbits, and mice. However, the mechanism of pharmacologically induced late PC, and the role of iNOS in particular, remains unclear.…”

“…Although iNOS is a necessary mediator of ischemia-induced late PC (4), its role in NO donor-induced late PC is presently unknown. A recent study (16) concluded that iNOS mediates morphine-induced late PC in mice, but the short duration of reperfusion (2 h) may not have afforded accurate assessment of final infarct size. In addition, controversy exists as to whether adenosine A 1 agonist-induced late PC is mediated by iNOS.…”

Interactions between morphine and nitric oxide in various organs

“…These authors speculated that an increased level of endogenous opioids in bile duct-ligated rats chronically increased [Ca 2+ ]i [90]; thus, ACh could no longer increase the [Ca 2+ ]i level to stimulate cNOS to release NO. Jiang et al [91] found that infarct size in a heart subjected to coronary occlusion/reperfusion was reduced by morphine in wild-type mice, and this cardioprotective effect was abolished by S-methylthiourea sulfate and was absent in iNOS-gene-knockout mice; an increase in myocardial iNOS expression was observed after morphine administration. These authors suggested an obligatory role for iNOS in mediating morphineinduced delayed cardioprotection.…”