Diminution of contractile response by κ-opioid receptor agonists in isolated rat ventricular cardiomyocytes is mediated via a pertussis toxin-sensitive G protein

Wenzlaff, H.; Stein, Birgitt; Teschemacher, H.

doi:10.1007/pl00005265

Cited by 21 publications

(6 citation statements)

References 39 publications

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“…In vitro studies have shown that opioids directly decrease the contractile response of isolated ventricular cardiomyocytes to electrical stimulation [19]. One hypothesis explaining morphine-induced decreased contractility is that morphine induced the increase in generation of free radicals that we measured at baseline.…”

Section: Discussionmentioning

confidence: 84%

Morphine Enhances Doxorubicin-Induced Cardiotoxicity in the Rat

et al. 2014

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Interventions to reduce the cardiotoxicity of doxorubicin are clinically relevant. Pharmacological preconditioning mimicking ischemic preconditioning has been demonstrated with morphine and represents an acceptable clinical intervention. The purpose of this study was to examine if pretreatment in vivo with morphine could reduce doxorubicin-induced cardiotoxicity ex vivo in a rat model. Wistar rats were divided into six groups and pretreated with an intraperitoneal (i.p.) injection of 3 or 10 mg/kg morphine, 1 mg/kg naloxone and saline, 1 mg/kg naloxone and 3 mg/kg morphine or saline, 60 min before excision of the heart. Biochemical indices such as troponin T (TnT) and hydrogen peroxide (H2O2) in effluate were measured together with physiological parameters in Langendorff hearts before and after doxorubicin infusion (2 mg/mL 0.05 mL/min for 45 min). Myocardial content of doxorubicin was measured at the end of infusion. Pretreatment with morphine, irrespective of dosage, produced a significant loss in left ventricular-developed pressure and an increase of TnT and H2O2 in effluate before doxorubicin infusion (p < 0.05). Morphine also produced a significant increase in left ventricular end-diastolic pressure and an increase of TnT and H2O2 in effluate (p < 0.05) at the end of doxorubicin infusion. Naloxone, a non-selective opioid receptor antagonist, abolished the effects of morphine both before and after doxorubicin infusion. Morphine, irrespective of dosage, increased myocardial content of doxorubicin compared to pretreatment with saline (p < 0.05). Pretreatment with morphine is associated with a cardiodepressive effect and enhances cardiotoxicity of doxorubicin measured by increased myocardial accumulation of doxorubicin and physiological and biochemical indices. The negative effects observed in our rat model are abolished by naloxone.

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Section: Discussionmentioning

confidence: 84%

Morphine Enhances Doxorubicin-Induced Cardiotoxicity in the Rat

et al. 2014

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“…Hypoxia decreases Gs activity in both ventricles. From Kacimi et al [ 19 ] release of dynorphins from the heart in hypoxia can activate the kappa opioid receptors and blunt the adrenergic pathway, therefore protecting the heart from too high-energy consumption [ 47 ]. These adaptations of the autonomic control of the heart in hypoxia seem well established even in species genetically adapted to high altitude, such as the guinea pig living on the Altiplano [ 23 ] (Fig.…”

Section: Fig 233mentioning

confidence: 95%

Physiological and Clinical Implications of Adrenergic Pathways at High Altitude

Richalet

2016

Advances in Experimental Medicine and Biology

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The adrenergic system is part of a full array of mechanisms allowing the human body to adapt to the hypoxic environment. Triggered by the stimulation of peripheral chemoreceptors, the adrenergic centers in the medulla are activated in acute hypoxia and augment the adrenergic drive to the organs, especially to the heart, leading to tachycardia. With prolonged exposure to altitude hypoxia, the adrenergic drive persists, as witnessed by elevated blood concentrations of catecholamines and nerve activity in adrenergic fibers. In response to this persistent stimulation, the pathways leading to the activation of adenylate cyclase are modified. A downregulation of β-adrenergic and adenosinergic receptors is observed, while muscarinic receptors are upregulated. The expression and activity of Gi and Gs proteins are modified, leading to a decreased response of adenylate cyclase activity to adrenergic stimulation. The clinical consequences of these cellular and molecular changes are of importance, especially for exercise performance and protection of heart function. The decrease in maximal exercise heart rate in prolonged hypoxia is fully accounted for the observed changes in adrenergic and muscarinic pathways. The decreased heart rate response to isoproterenol infusion is another marker of the desensitization of adrenergic pathways. These changes can be considered as mechanisms protecting the heart from a too high oxygen consumption in conditions where the oxygen availability is severely reduced. Similarly, intermittent exposure to hypoxia has been shown to protect the heart from an ischemic insult with similar mechanisms involving G proteins and downregulation of β receptors. Other pathways with G proteins are concerned in adaptation to hypoxia, such as lactate release by the muscles and renal handling of calcium. Altogether, the activation of the adrenergic system is useful for the acute physiological response to hypoxia. With prolonged exposure to hypoxia, the autonomous nervous system adapts to protect vital organs, especially the heart, against a too high energetic state, via a purely local autoregulation mechanism necessary for the preservation of overall homeostasis.

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“…In convincing in vitro (30) and in vivo (31) studies, negative inotropic effects of -opioid receptor agonists were demonstrated. In our study, nor-BNI pretreatment may have antagonized -opioid receptor mediated negative inotropy.…”

Section: Discussionmentioning

confidence: 96%

??-Opioid Receptor Antagonism Improves Recovery from Myocardial Stunning in Chronically Instrumented Dogs

Hartlage¹,

Theisen²,

Oliveira³

et al. 2006

Anesthesia & Analgesia

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We tested the hypothesis that the selective kappa-opioid receptor antagonist nor-binaltorphimine (nor-BNI) improves recovery from myocardial stunning. Ten dogs were chronically instrumented for measurement of heart rate, left atrial, aortic and left ventricular pressure (LVP), and the maximum rate of LVP increase (LV dP/dt(max)) and decrease (LV dP/dt(max)), coronary blood flow velocity and myocardial wall-thickening fraction. Regional myocardial blood flow was determined with fluorescent microspheres. Catecholamine plasma levels were measured by high-performance liquid chromatography, and beta-endorphin and dynorphin plasma levels by radioimmunoassay. An occluder around the left anterior descending artery (LAD) allowed induction of a reversible LAD-ischemia. Animals underwent two experiments in a randomized crossover fashion on separate days: (a) 10 min LAD-occlusion (control experiment), (b) second ischemic episode 24 h after nor-BNI (2.5 mg/kg IV) (intervention). Dogs receiving nor-BNI showed an increase in wall-thickening fraction, LV dP/dt(max) and LV dP/dt(min) before ischemia and during the whole reperfusion (P < 0.05 versus control experiment). After nor-BNI pretreatment, dynorphin levels increased after induction of ischemia to a peak level of 15.1 +/- 3.6 pg/mL (P < 0.05 versus control experiment). The increase in plasma beta-endorphin during ischemia and early reperfusion was attenuated after nor-BNI. Compared with the control experiment, nor-BNI left global hemodynamics, regional myocardial blood flow, and catecholamine levels unchanged. In conclusion, nor-BNI improves recovery from myocardial stunning after regional myocardial ischemia in chronically instrumented dogs.

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Diminution of contractile response by κ-opioid receptor agonists in isolated rat ventricular cardiomyocytes is mediated via a pertussis toxin-sensitive G protein

Cited by 21 publications

References 39 publications

Morphine Enhances Doxorubicin-Induced Cardiotoxicity in the Rat

Morphine Enhances Doxorubicin-Induced Cardiotoxicity in the Rat

Physiological and Clinical Implications of Adrenergic Pathways at High Altitude

??-Opioid Receptor Antagonism Improves Recovery from Myocardial Stunning in Chronically Instrumented Dogs

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