Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Anesthesiology and Operative Intensive Care Medicine, Charité Campus Benjamin Franklin, Hindenburgdamm 30, 12203, Berlin, Germany.
Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Physiology Campus Charité Mitte, Chariteplatz 1, 10117, Berlin, Germany.
Cardiovasc Drugs Ther. 2021 Aug;35(4):733-743. doi: 10.1007/s10557-020-07132-4. Epub 2021 Jan 23.
Myocardial 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.
Volume 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.
In 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.
Opioid 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.
心肌阿片受体在动物和人体中均有表现，似乎与左心室（LV）兴奋-收缩偶联的膜和肌浆网钙通道共存。因此，本研究旨在探讨纳曲酮阻断心脏阿片系统是否会影响容量超负荷诱导心力衰竭的 Wistar 大鼠的心脏功能和神经激素参数。
通过腹主动脉-腔静脉瘘（ACF）诱导 Wistar 大鼠的容量超负荷。通过免疫组织化学鉴定左心室心脏阿片受体，并通过实时聚合酶链反应（RT-PCR）定量其信使核糖核酸（mRNA）及其内源性配体 mRNA。通过微量泵持续输注阿片受体拮抗剂纳曲酮或载体（每组 5 只大鼠），在 ACF 诱导后 28 天评估血流动力学和体液参数。假手术动物作为对照。
在 ACF 大鼠中，μ、δ 和 κ 阿片受体与左心室心肌细胞中的电压门控 L 型 Ca2+通道共定位。慢性纳曲酮治疗 ACF 大鼠可降低中心静脉压（CVP）和左心室舒张末期压（LVEDP），改善收缩和舒张左心室功能。同时，ACF 期间升高的大鼠脑钠肽（rBNP-45）和血管紧张素-2 血浆浓度在纳曲酮治疗后显著降低。平行地，慢性纳曲酮显著降低 μ、δ 和 κ 阿片受体 mRNA，同时与对照组相比，增加内源性阿片肽 mRNA。
纳曲酮阻断阿片受体可改善 LV 功能，降低 rBNP-45 和血管紧张素-2 血浆水平。同时，纳曲酮导致阿片受体 mRNA 下调和内源性阿片肽固有张力升高，可能反映了心脏阿片系统在容量超负荷期间对心脏的潜在抑制作用。
