Chronic Naltrexone Therapy Is Associated with Improved Cardiac Function in Volume Overloaded Rats

Lukas Dehe,Mehdi Shakibaei,Shaaban A Mousa,Helmut Habazettl,Mohammed Shaqura,Michael Nordine,Michael Schäfer,Helena Schluchter,Petra Von Kwiatkowski,Sascha Treskatsch

doi:10.1007/s10557-020-07132-4

Abstract

PurposeMyocardial opioid receptors were demonstrated in animals and humans and seem to colocalize with membranous and sarcolemmal calcium channels of the excitation–contraction coupling in the left ventricle (LV). Therefore, this study investigated whether blockade of the cardiac opioid system by naltrexone would affect cardiac function and neurohumoral parameters in Wistar rats with volume overload-induced heart failure.MethodsVolume overload in Wistar rats was induced by an aortocaval fistula (ACF). Left ventricular cardiac opioid receptors were identified by immunohistochemistry and their messenger ribonucleic acid (mRNA) as well as their endogenous ligand mRNA quantified by real-time polymerase chain reaction (RT-PCR). Following continuous delivery of either the opioid receptor antagonist naltrexone or vehicle via minipumps (n = 5 rats each), hemodynamic and humoral parameters were assessed 28 days after ACF induction. Sham-operated animals served as controls.ResultsIn ACF rats mu-, delta-, and kappa-opioid receptors colocalized with voltage-gated L-type Ca2+ channels in left ventricular cardiomyocytes. Chronic naltrexone treatment of ACF rats reduced central venous pressure (CVP) and left ventricular end-diastolic pressure (LVEDP), and improved systolic and diastolic left ventricular functions. Concomitantly, rat brain natriuretic peptide (rBNP-45) and angiotensin-2 plasma concentrations which were elevated during ACF were significantly diminished following naltrexone treatment. In parallel, chronic naltrexone significantly reduced mu-, delta-, and kappa-opioid receptor mRNA, while it increased the endogenous opioid peptide mRNA compared to controls.ConclusionOpioid receptor blockade by naltrexone leads to improved LV function and decreases in rBNP-45 and angiotensin-2 plasma levels. In parallel, naltrexone resulted in opioid receptor mRNA downregulation and an elevated intrinsic tone of endogenous opioid peptides possibly reflecting a potentially cardiodepressant effect of the cardiac opioid system during volume overload.

Highlights

With an increasing life expectancy throughout the world, patients undergoing surgery will be inherently older and exhibit a greater prevalence of heart failure (CHF)
Double immunofluorescence demonstrated that Mu-Opioid Receptor (MOR), Delta-Opioid Receptor (DOR), and KOR were abundantly expressed in the left ventricular myocardium of rats with aortocaval fistula (ACF)-induced volume overload (Fig. 1a, d, and g)
Using quantitative real-time polymerase chain reaction (RT-PCR) for detection of messenger ribonucleic acid (mRNA) expression our results show that MOR, DOR, and KOR mRNAs were expressed in the left ventricular myocardium of all three groups (Fig. 3a, c, and e)

Summary

Introduction

With an increasing life expectancy throughout the world, patients undergoing surgery will be inherently older and exhibit a greater prevalence of (congestive) heart failure (CHF). An activation of this intrinsic cardiac opioid system in volume-overloaded rat hearts was detected, reflected by an upregulation of delta- and kappa-opioid receptor expression and their respective endogenous ligand peptide precursors [5, 7]. In this context, acute infusion of kappaopioid receptor agonists acutely provoked an augmented negative inotropic and lusitropic response in the failing ex vivo perfused hamster heart [11]. Shortterm systemic delta-opioid receptor inhibition increased cardiac output and improved left ventricular performance in dogs with CHF [12]

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Conclusion