Use of “Natural” Hibernation Induction Triggers for Myocardial Protection

Bolling, Steven F.; Tramontini, Nicole L.; Kilgore, Kenneth S.; Su, Tsung Ping; Oeltgen, Peter R.; Harlow, Henry J.

doi:10.1016/s0003-4975(97)00631-0

Cited by 86 publications

(68 citation statements)

References 17 publications

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“…Many parallels exist between SLP and hibernation: hibernation is triggered by ␦-opioid agonism, which can also induce hibernation in nonhibernating primates (Oeltgen et al, 1982(Oeltgen et al, , 1988; ␦-opioid triggered hibernation increases stress resistance (Bolling et al, 1997); hibernating and anoxiatolerant species harness PKA signaling (Storey, 1996;Holden and Storey, 1998); and repression of Akt suppresses energy-costly anabolic/growth processes to maintain cell viability over extended periods (Cai et al, 2004;Abnous et al, 2008). The SLP phenotype is induced by ␦-opioid agonism, involves PI3K-dependent signals and repression of Akt expression (Fig.…”

Section: Discussionmentioning

confidence: 99%

Sustained Ligand-Activated Preconditioning via δ-Opioid Receptors

Peart¹,

Hoe²,

Gross³

et al. 2010

J Pharmacol Exp Ther

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We have previously described novel cardioprotection in response to sustained morphine exposure, efficacious in young to aged myocardium and mechanistically distinct from conventional opioid or preconditioning (PC) responses. We further investigate opioid-dependent sustained ligand-activated preconditioning (SLP), assessing duration of protection, opioid receptor involvement, additivity with conventional responses, and signaling underlying preischemic induction of the phenotype. Male C57BL/6 mice were treated with morphine (75-mg subcutaneous pellet) for 5 days followed by morphine-free periods (0, 3, 5, or 7 days) before ex vivo assessment of myocardial tolerance to 25-min ischemia/45-min reperfusion. SLP substantially reduced infarction (by ϳ50%) and postischemic contractile dysfunction (eliminating contracture, doubling force development). Cardioprotection persisted for 5 to 7 days after treatment. SLP was induced specifically by ␦-receptor and not -or -opioid receptor agonism, was eliminated by ␦-receptor and nonselective antagonism, and was additive with adenosinergic but not acute morphine-or PC-triggered protection. Cotreatment during preischemic morphine exposure with the phosphoinositide-3 kinase (PI3K) inhibitor wortmannin, but not the protein kinase A (PKA) inhibitor myristoylated PKI-(14-22)-amide, prevented induction of SLP. This was consistent with shifts in total and phospho-Akt during the induction period. In summary, data reveal that SLP triggers sustained protection from ischemia for up to 7 days after stimulus, is ␦-opioid receptor mediated, is induced in a PI3K-dependent/PKA-independent manner, and augments adenosinergic protection. Mechanisms underlying SLP may be useful targets for manipulation of ischemic tolerance in young or aged myocardium.

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Section: Discussionmentioning

confidence: 99%

Sustained Ligand-Activated Preconditioning via δ-Opioid Receptors

Peart¹,

Hoe²,

Gross³

et al. 2010

J Pharmacol Exp Ther

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“…10 Likewise, both hibernationinduction trigger and DADLE have been shown to similarly improve protection in animal models of multiorgan block autoperfusion 12 or cardioplegic arrest. 13 …”

Section: Endogenous Mediators Of Natural Hibernationmentioning

confidence: 99%

Opening of Potassium Channels

et al. 1999

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Background-The tolerance of hibernating mammals to cold hypoxia is related to a factor similar to agonists of ␦-opioid receptors. This study was designed to assess whether activation of these receptors could reproduce the protection conferred by ischemic preconditioning and whether such cardioprotection was similarly mediated by an opening of ATP-sensitive potassium (K ATP ) channels. Methods and Results-Thirty-two isolated rat hearts were arrested with and stored in Celsior at 4°C for 5 hours before being reperfused for 2 hours. They were divided into 4 equal groups. Group 1 hearts served as controls. In group 2, ischemic preconditioning was elicited by two 5-minute global ischemia periods interspersed with 5 minutes of reperfusion before arrest. In group 3, hearts were pharmacologically preconditioned with a 15-minute infusion of the ␦-opioid receptor agonist D-Ala2-D-Leu5-enkephalin (DADLE; 200 mol/L). In group 4, the protocol was similar to group 3 except that infusion of DADLE was preceded by infusion of the K ATP blocker glibenclamide (50 mol/L). The salutary effects of both forms of preconditioning were primarily manifest as a better preservation of diastolic function, a reduced myocardial edema, and reduced creatine kinase leakage. This protection was abolished by administration of glibenclamide before DADLE. Conclusions-These data suggest that activation of ␦-opioid receptors improves recovery of cold-stored hearts to a similar extent as ischemic preconditioning, most likely through an opening of K ATP channels. This provides a rationale for improving the preservation of hearts for transplantation by pharmacologically duplicating the common pathway to natural hibernation and preconditioning. (Circulation. 1999;99:3079-3085.)

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“…Decreases in cardiac mass as well as electrophysiological changes have also been observed in healthy humans during periods of prolonged inactivity and/or during space travel [29,30,36]. Although it has been reported that circulating proteins such as "hibernation induction trigger" and "hibernation-specific protein" complex (HPc) may play an important role in conserving cardiac form and function in hibernating mammals, the physiological mechanisms of the heart that aid in the prevention of ischemic tissue damage during overwintering have not been fully characterized [3,16,18].…”

Section: Introductionmentioning

confidence: 99%

Extreme Respiratory Sinus Arrhythmia Enables Overwintering Black Bear Survival—Physiological Insights and Applications to Human Medicine

Laske

Harlow

Garshelis

et al. 2010

J. of Cardiovasc. Trans. Res.

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American black bears survive winter months without food and water while in a mildly hypothermic, hypometabolic, and inactive state, yet they appear to be able to return to near-normal systemic function within minutes of arousal. This study's goal was to characterize the cardiovascular performance of overwintering black bears and elicit the underlying mechanisms enabling survival. Midwinter cardiac electrophysiology was assessed in four wild black bears using implanted data recorders. Paired data from early and late winter were collected from 37 wild bears, which were anesthetized and temporarily removed from their dens to record cardiac electrophysiological parameters (12-lead electrocardiograms) and cardiac dimensional changes (echocardiography). Left ventricular thickness, primary cardiac electrophysiological parameters, and cardiovascular response to threats ("fight or flight" response) were preserved throughout winter. Dramatic respiratory sinus arrhythmias were recorded (cardiac cycle length variations up to 865%) with long sinus pauses between breaths (up to 13 s). The accelerated heart rate during breathing efficiently transports oxygen, with the heart "resting" between breaths to minimize energy usage. This adaptive cardiac physiology may have broad implications for human medicine.

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Use of “Natural” Hibernation Induction Triggers for Myocardial Protection

Cited by 86 publications

References 17 publications

Sustained Ligand-Activated Preconditioning via δ-Opioid Receptors

Sustained Ligand-Activated Preconditioning via δ-Opioid Receptors

Opening of Potassium Channels

Extreme Respiratory Sinus Arrhythmia Enables Overwintering Black Bear Survival—Physiological Insights and Applications to Human Medicine

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