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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A number of endogenous mediators, including opioids, adenosine and bradykinin, which act on cardiac cell membrane receptors have been demonstrated to trigger the phenomenon termed ischemic preconditioning (IPC). IPC is an endogenous protective mechanism, whereby a brief period of ischemia or hypoxia protects a cell or organ, in this review the heart, against injury from a subsequent more prolonged stressful insult. Recent data suggest that opioid receptors are important triggers and/or mediators of this protective response. Selective pharmacological antagonists of the delta-or kappa-opioid receptor have been shown to block IPC, and agonists of these same receptors have been shown to mimic IPC in intact animals, isolated hearts or isolated cardiomyocytes. This review will summarize the current state of knowledge, which exists defining the role and cellular signaling pathways by which endogenously or exogenously administered opioids produce their cardioprotective response. The potential clinical application and evidence to suggest that opioids produce a similar protective effect in man will also be discussed.
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PMID:Role of opioids in acute and delayed preconditioning. 1281 60

The role of delta-opioid receptors in mediating ischemic preconditioning (IPC) in rats, rabbits, and pigs has been well-established; however, no studies have been performed in dogs. Therefore, the purpose of the present study was to determine if activation of delta-opioid receptors can mimic the cardioprotective effects of IPC in the canine heart and to determine if a nonselective opioid receptor antagonist could block IPC. All dogs were subjected to 60 minutes of left anterior descending (LAD) coronary artery occlusion and 3 hours of reperfusion. Ischemic preconditioning was produced by one 5-minute period of ischemia 10 minutes before LAD coronary artery occlusion. Infarct size (IS) expressed as a percent of the area at risk (AAR; IS/AAR) was determined by triphenyltetrazolium staining. Two selective delta-opioid receptor (DOR) agonists, TAN-67 and BW373U86, were administered by intracoronary infusion for 30 minutes before LAD occlusion and the opioid receptor antagonist naloxone was administered 30 minutes before IPC. Both TAN-67 and BW373U86 produced significant reductions in IS/AAR similar to that of IPC (control: 28+/-2.1; TAN: 12.3+/-2.2; IPC: 9.3+/-3.0: BW: 11.7+/-2.6). Naloxone attenuated the effect of IPC (control: 28+/-2.1; naloxone: 18.2+/-4.5). These results suggest that opioid receptors are important in IPC in dogs, and stimulation of delta-opioid receptors with selective agonists can mimic the cardioprotective effects of IPC and may have therapeutic potential.
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PMID:Delta-opioid receptor activation mimics ischemic preconditioning in the canine heart. 1282 30

The selective kappa-opioid receptor agonist spiradoline mesylate (U62,066E), an arylacetamide, was synthesized with the intention of creating an analgesic that, while still retaining its analgesic properties, would be devoid of the, mainly mu receptor mediated, side effects such as physical dependence and respiratory depression associated with morphine. Spiradoline is highly selective for the kappa receptor with K(i) of 8.6 nM in guinea pig. Examination of the enantiomers of spiradoline, showed the (-)enantiomer to be responsible for the kappa agonist properties. Spiradoline easily penetrates the blood brain barrier, and does not seem to have any significant active metabolites. In preclinical studies, spiradoline has a short duration of action with a peak at around 30 min after administration. The analgesic properties of spiradoline are well documented in mice and rats. Antitussive properties have also been reported in rats. Furthermore, spiradoline was reported to display effects suggestive of neuroprotective properties in animal models of ischemia. In humans, spiradoline is a potent diuretic. It also produces significant sedation presumably due to its antihistamine properties. Preclinical studies have shown that spiradoline reduces blood pressure and heart rate, and has possible antiarrhythmic properties. Clinical studies did not confirm these findings. kappa Receptors inhibit dopaminergic neurotransmission. Spiradoline, given systematically to rats, produces a significant and long lasting decrease in dopamine release, and in locomotor activity. It has also antipsychotic-like effect in animal behavioral tests. At low doses spiradoline was reported to decrease tics in patients with Tourette's syndrome. Although spiradoline had promising effects in animal tests of analgesia, and a reasonably good safety profile in preliminary studies, it did not replace morphine as an analgesic. The available clinical data suggest that spiradoline produces disturbing adverse effects such as diuresis, sedation, and dysphoria at doses lower than those needed for analgesic effects. Thus, future development of spiradoline-like analgesic compounds should preferably focus on reduction of unwanted effects on the central nervous system. Spiradoline, which currently is commercially available for preclinical research, might prove useful in some psychiatric conditions and possibly as a neuroprotective agent.
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PMID:A review of the properties of spiradoline: a potent and selective kappa-opioid receptor agonist. 1284 58

The protective effects of ischemic preconditioning on the myocardium can be abolished by pretreatment with opioid receptor antagonists. We investigated, if--vice versa--the protective effect of preconditioning may be induced by systemic pretreatment with the delta-opioid receptor agonist D-Ala2-DLeu5-enkephalin (DADLE). DADLE is known to be very similar to the trigger substance that induces natural hibernation. Isolated working rat hearts of male Wistar rats (n = 32) were subjected to 45 minutes of global hypothermic ischemia at 30 degrees C followed by 25 minutes of normothermic reperfusion. Hearts from rats injected with 1 mg/kg DADLE intravenously 1 hour before isolated perfusion were either preconditioned by one cycle of 5 minutes of normothermic ischemia followed by 5 minutes of normothermic reperfusion or hearts were not preconditioned during preischemic perfusion. Untreated preconditioned and non-preconditioned hearts served as controls. Ischemic preconditioning alone and DADLE alone improved the recovery of aortic flow and reduced the creatine kinase leakage significantly during postischemic reperfusion. Over and above that, pretreatment with DADLE prior to ischemic preconditioning significantly further enhanced functional recovery and reduced the creatine kinase leakage, when compared to DADLE alone and preconditioning alone. Therefore we conclude, that DADLE attenuates ischemic injury in isolated rat hearts and enhances the protective effects of ischemic preconditioning. The data suggest that ischemic preconditioning and DADLE act via a similar pathway.
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PMID:[Ischemic preconditioning of the heart can be simulated by pharmacologic hibernation enkephalins]. 1451

Controversy exists regarding the relative roles of delta- and kappa-opioid receptor activation as a potential cardioprotective mechanism. Furthermore, the function of opioid receptor activation in cardioprotection has not been examined in the murine heart. To this end, we employed various concentrations of selective delta - and kappa-opioid receptor agonists in an isolated murine heart model undergoing 20 min global ischemia followed by 45 min reperfusion. Left-ventricular developed pressure (LVDP) returned to 50.7 +/- 2.1% of baseline values in untreated hearts. Infusion of the non-selective opioid agonist, morphine (10 micro M), lead to a marked improvement in post-ischemic contractile recovery where LVDP returned to 65.5 +/- 2.4% of baseline function. The delta-opioid selective agonist BW373U86 hydrochloride elicited maximal protection at a concentration of 1 micro M which afforded 63.9 +/- 3.4% recovery of LVDP. This effect was blocked by the delta-opioid selective antagonist, BNTX. Furthermore, administration of the kappa-opioid selective agonist U50,488 (1 micro M) produced a marked improvement in contractile recovery leading to a 72.5 +/- 5.3% recovery of LVDP. This degree of protection was also abolished by the kappa-opioid receptor antagonist, nor-BNI. No differences were noted in LDH efflux from post-ischemic hearts. These data suggest that exogenous activation of delta- and kappa-opioid receptors afford protection against myocardial stunning in the isolated murine heart, an effect attenuated by selective receptor antagonists.
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PMID:Exogenous activation of delta- and kappa-opioid receptors affords cardioprotection in isolated murine heart. 1468 3

Acute cardioprotection is mediated primarily through delta opioid receptor stimulation independent of micro or kappa opioid receptor stimulation. Delayed cardioprotection is mediated by delta opioid receptor agonists but ambiguity remains about direct receptor involvement. Therefore, we investigated the potential of SNC-121, a non-peptide delta opioid agonist, to produce delayed cardioprotection and characterized the role of opioid receptors in this delayed response. All rats underwent 30 minutes of ischemia followed by 2 hours of reperfusion. SNC-121 induced a significant delayed cardioprotective effect. To determine the nature of this SNC-121-induced delayed cardioprotection, rats were treated with specific opioids receptor antagonists and underwent pertussis toxin (PT) treatment prior to opioid agonist stimulation. Control rats were injected with saline and allowed to recover for 24 hours. Pretreatment and early treatment with opioid receptor antagonists failed to inhibit the delayed protective effects of SNC-121, as did pretreatment with PT. Treatment with a free radical scavenger, 2-mercaptopropionyl glycine, at the time of opioid stimulation attenuated the delayed cardioprotective effects of SNC-121. These data suggest that delayed cardioprotection is stimulated via non-peptide delta opioid agonists by a mechanism unrelated to opioid receptor activation. The mechanism appears to be a non-opioid receptor mediated production of reactive oxygen species that triggers the signaling cascade leading to delayed cardioprotection.
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PMID:Delayed cardioprotection is mediated via a non-peptide delta opioid agonist, SNC-121, independent of opioid receptor stimulation. 1468 4

Opioids have been shown to confer late preconditioning against ischemia/reperfusion injury in several species. However, it is unknown whether gender or aging affects opioid-induced cardioprotection. Isolated perfused hearts from Fischer 344 rats were subjected to 20 min of global ischemia followed by 20 min of reperfusion. BW373U86, a delta-opioid receptor agonist, was administered s.c. at varying doses (0.1, 0.33, 1.0 mg/kg) 24 h before (BW0.1, BW0.33 and BW1.0, respectively). In 12-week-old male (YM) rats, the recovery of LV developed pressure (LVDP) after ischemia/reperfusion improved significantly in BW0.33 and BW1.0, compared with the control (C). In 78-week-old male (OM) rats, the recovery of LV function after ischemia/reperfusion improved and the total release of CK and LDH during reperfusion was attenuated in BW1.0. In 12-week-old female (YF) rats, the recovery of LV function improved only in BW0.33 but not in BW0.1 and BW1.0. The cardioprotective effect afforded by BW373U86 was completely abolished by NS-398, a COX-2 selective inhibitor, in YM, YF, and OM, although NS-398 in itself did not affect myocardial ischemia/reperfusion injury. The levels of 6-keto-PGF(1alpha) (a stable metabolite of PGI(2)) in coronary effluent during reperfusion were higher in the BW373U86-pretreated group that showed cardioprotection than in C and this increase in PGI(2) production was also inhibited by NS-398 in YM, YF, and OM. In conclusion, BW373U86-induced late preconditioning can be observed in aged and female hearts. A COX-2-dependent increase in PGI(2) production is essential for BW373U86-induced late PC in both sexes and in both young and old rats.
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PMID:Gender and aging do not impair opioid-induced late preconditioning in rats. 1468 5

We examined whether interleukin-2 (IL-2) protects the myocardium against injury induced by ischemia and reperfusion via the kappa-opioid receptor (OR). The cardioprotective effect of IL-2 was evaluated by measuring infarct size and lactate dehydrogenase (LDH) release in response to ischemia and reperfusion in the isolated rat heart. IL-2 at an optimal dose of 50 U/ml mimicked the effect of ischemic preconditioning by reducing infarct size and LDH release. The infarct and LDH-reducing effects of IL-2 were blocked by nor-binaltorphimine (5 microM), a kappa-OR antagonist, but not naltrindole (5 microM), a delta-OR antagonist known to block the action of its stimulation. Moreover, blockade of the mitochondrial ATP-sensitive potassium (mito-K(ATP)) channel with a selective antagonist, 5-hydroxydecanoate (100 microM), or a nonselective antagonist of K(ATP) channels, glybenclamide (100 microM), or blockade of protein kinase C (PKC) with its inhibitors chelerythrine (5 microM) or GF 109203X (10 microM) [3-[1-[3-(dimethylaminopropyl]-1H-indol-3-yl]-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione monohydrochloride] abolished the protective effect of IL-2. Administration of free radical scavengers N-acetylcysteine (4 mM) or N-(2-mercaptopropionyl)-glycine (1 mM) also abolished the protective effects of IL-2 and U50,488H [(trans)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]benzeneacetamide], a selective kappa-OR agonist. This study provides the first evidence that IL-2 confers cardioprotection against injury induced by ischemia/reperfusion. The effect of IL-2 is mediated via kappa-OR as evidenced by kappa-OR antagonism and similar signaling mechanisms, mito-K(ATP), PKC, and reactive oxygen species involved in the cardioprotective effects of both IL-2 and kappa-OR stimulation.
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PMID:Cardioprotection of interleukin-2 is mediated via kappa-opioid receptors. 1474 12

Glycogen synthase kinase (GSK) inhibition produced by ischemic preconditioning has been previously shown to be regulated through phosphatidylinositol-3 kinase (PI3K). Therefore, we determined whether opioid-induced cardioprotection (OIC) occurs during reperfusion by altering GSK phosphorylation through PI3K and target of rapamycin (TOR). Furthermore, we determined if selective GSK inhibitors, SB216763(SB21) or SB415286(SB41), emulate OIC. Rats were treated with the nonselective opioid agonist, morphine (MOR, 0.3 mg/kg), the delta-selective opioid agonist BW373U86 (BW, 1 mg/kg), or the GSK inhibitors, SB21 (0.6 mg/kg) or SB41(1.0 mg/kg), either 10 minutes before ischemia or 5 minutes before reperfusion. Five minutes before opioid or SB21 treatment, some rats received either the PI3K inhibitor wortmannin (15 microg/kg) or LY294002 (0.3 mg/kg) or the TOR inhibitor rapamycin (3 microg/kg). After 30 minutes of ischemia followed by 2 hours of reperfusion, infarct size was assessed. MOR, BW, SB41, and SB21 reduced infarct size compared with vehicle when administered before ischemia (42.9+/-2.6, 40.3+/-2.3, 46.6+/-1.6, 42.2+/-1.8 versus 60.0+/-1.1%, respectively; P<0.001) and showed similar protection when administered 5 minutes before reperfusion (43.6+/-2.3, 40.2+/-2.6, 44.8+/-2.8, 39.4+/-0.8%, respectively; P<0.001). Wortmannin, LY294002, and rapamycin were found to inhibit OIC; however, they did not abrogate SB21-induced infarct size reduction. At 5 minutes of reperfusion, both MOR and BW increased P-GSKbeta at Ser9 in the ischemic zone compared with vehicle (181+/-20, 178+/-15 versus 75+/-17 DU, respectively; P<0.05), and this effect was abrogated by prior administration of wortmannin or rapamycin in MOR-treated rats. Furthermore, no differences were seen in phosphorylation of GSKalpha (Ser21 or Tyr279) or phosphorylation of GSKbeta (Tyr216). These data indicate that OIC occurs via the phosphorylation of GSKbeta at Ser9 during reperfusion.
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PMID:Opioid-induced cardioprotection occurs via glycogen synthase kinase beta inhibition during reperfusion in intact rat hearts. 1497 26

The involvement of opioid receptor activation during ischemia-reperfusion is somewhat controversial. While it is generally accepted that activation of the delta-opioid receptor (DOR) is cardioprotective, and may indeed be an important mediator of ischemic preconditioning, the role of the kappa-opioid receptor (KOR) is less well understood. To this end, we examined three different KOR agonists and their effects upon infarct size and arrhythmia development. Male Sprague-Dawley rats were subjected to 30 minutes of occlusion followed by 90 minutes of reperfusion. Opioid receptor agonists were administered 10 minutes before the onset of ischemia, while the opioid antagonists were given 20 minutes before occlusion. Untreated rats exhibited an infarct size (IS/AAR%) of 52.4 +/- 2.7%. Pretreatment with the DOR agonist, BW373U86, limited infarct development to 37.2 +/- 1.8%, which was reversed by the selective DOR antagonist, BNTX. All three KOR agonists studied, U50,488, ICI 204,448, and BRL 52537 significantly reduced infarct size to levels comparable to that of BW373U86. The infarct-sparing effects of U50,488 and ICI 204,448 were abolished by the selective KOR antagonist, nor-BNI. Nor-BNI failed to inhibit the cardioprotective effects of BRL 52537. Furthermore, U50,488 and BRL 52537, but not ICI 204,448, significantly reduced the incidence of arrhythmias. These effects were not blocked by nor-BNI. These data demonstrate that KOR activation provides a similar degree of infarct size reduction as DOR activation. KOR agonists also reduced arrhythmogenesis; however, these responses appear to be independent of KOR activation.
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PMID:Effect of exogenous kappa-opioid receptor activation in rat model of myocardial infarction. 1507 25


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