Opioid receptors mediate inotropic and depressor effects of apelin in rats with 2K1C‐induced chronic renovascular hypertension

Abstract

Apelin receptors (APJ) cross-talk with other G-protein-coupled receptors. However, the role of APJ interaction with opioid receptors (OPR) on the cardiovascular effects of apelin in hypertension is not clear. Renovascular hypertension was induced by placing a Plexiglas clip on the left kidney of rats. After 16 weeks, F13A (an APJ antagonist), naloxone (a general OPR inhibitor), and nor-binaltorphimine dihydrochloride (nor-BNI; a selective inhibitor of KOR) were given prior to injections of apelin at doses of 40 and 60 μg/kg. The arterial systolic/diastolic blood pressure and left ventricular contractility responses were then evaluated. The arterial systolic/diastolic blood pressure in sham and 2K1C rats was 110/71 mm Hg and 171/124 mm Hg, respectively. The hypotensive effects of apelin at both doses were inhibited by F13A and naloxone. Nor-BNI completely inhibited the effects of apelin 40 on arterial pressure, and decreased the effects of 60 μg/kg. KOR inhibition also prevented the compensation for the decrease in the left ventricle +dp/dt max and -dp/dt max caused by apelin 60. The simultaneous inhibition of OPR and APJ reduced arterial pressure and increased cardiac contractility. Findings showed that the OPR, particularly KOR, mediate the inotropic, lusitropic, and depressor effects of apelin. The interaction of the OPR and APJ augments the inotropic and vasodepressor effects of apelin. This interaction may have potential clinical applications in cardiac failure since opioids are currently used in the treatment of myocardial infarction and stroke, and apelin has been introduced as a potential therapeutic agent in cardiovascular complications.

Chronic treatment with apelin, losartan and their combination reduces myocardial infarct size and improves cardiac mechanical function

“…This was also associated with antagonizing the apelin‐induced reduction in AT1R expression (Figure ). Similarly the results of our previous study have shown that kappa opioid receptors mediate and potentiate the impacts of apelin on increasing cardiac contractility through its receptors . The findings of the present study also show that even endogenous apelin has an important effect on conserving mechanical function of the myocardium, as pretreatment with F13A had significantly impaired contractility indices of the heart such as LVDP and + dp/dt max (see Table ).…”

Blockade of Rostral Ventrolateral Medulla Apelin Receptors Does Not Attenuate Arterial Pressure in SHR and L-NAME-Induced Hypertensive Rats

“…Previous studies in other receptor systems have shown compensatory changes in gene expression following injection of gene-specific lenti- or adenoviral constructs ( Chen et al, 2006 ; Blume et al, 2013 ). APJ interacts with other receptors to regulate the cardiovascular system ( Gurzu et al, 2006 ; Rostamzadeh et al, 2017 , 2018 ), and forms heterodimers in vitro with other GPCRs e.g., the angiotensin II receptor ( Chun et al, 2008 ), the kappa opioid receptor ( Li et al, 2012 ), the neurotensin 1 receptor ( Bai et al, 2014a ) and the bradykinin 1 receptor ( Bai et al, 2014b ), to selectively regulate cellular responses mediated by apelin. It is tempting to speculate that the V1a vasopressin receptor (V1aR), a key modulator of cardiovascular regulation ( Japundžić-Žigon, 2013 ), might be capable of forming heterodimers with APJ.…”

Vascular effects of apelin: Mechanisms and therapeutic potential

“…F13A demonstrated dose-dependent inhibition of apelin-induced hypotensive effects, with no effect on Ang II-induced hypertensive effects, indicating selectivity of F13A toward apelin-induced responses (Lee, et al, 2005). F13A also attenuated apelin-induced depressor responses during renovascular hypertension (Rostamzadeh, et al, 2018) and, in isolated rat cerebral arteries, F13A abolished the inhibitory effects of apelin on BK Ca channel function and NO-induced relaxation (Mughal, et al, 2018). Moreover, pressor responses to centrally administered apelin in both normotensive and hypertensive rats are significantly attenuated by pre-treatment with F13A (Zhang, et al, 2014a; Griffiths, et al, 2017).…”

“…In animal models of pulmonary hypertension and diabetes, apelin treatment lowered mean arterial pressure and reduced the levels of vasoconstrictor mediators such as angiotensin-II and endothelin-1 (Akcilar, et al, 2013; Falcao-Pires, et al, 2009). Similarly, intravenous bolus administration of apelin caused a significant reduction in mean pulmonary arterial pressure during acute pulmonary embolism (Feng, et al, 2010), and apelin signaling via APJ – KOR heterodimers caused a depressor response during renovascular hypertension (Yeganeh-Hajahmadi, et al, 2017; Rostamzadeh, et al, 2018). Moreover, by increasing eNOS phosphorylation, apelin reversed the impaired relaxation response to acetylcholine and abrogated abnormal Ang II-induced contractile tone in intrarenal arteries from diabetic mice (Zhong, et al, 2007a).…”