Although apelin g kg shows
Although apelin 60μg/kg shows negative (early) and positive (late) inotropic effects, since ERK1/2 phosphorylation starts at the min 5 of administration , ERK1/2 phosphorylation mediate positive inotropic effects of apelin 60μg/kg.
After the simultaneous inhibition of KOR and APJ the phosphorylation of ERK1/2 reduced significantly (Fig. 7B). This finding also emphasized that KOR and APJ heterodimer mediated ERK1/2 phosphorylation in response to apelin. It is possible that after inhibition of KORs with nor-BNI, changes in conformation of heterodimer permit to F13A to bind with APJ and inhibit ERK1/2 phosphorylation. However, despite reduction in pERK1/2 the cardiac contractility did not decrease (Figs. 3B and 5B). This finding show that apelin probably increase cardiac contractility through another pathway as mentioned above. The findings that suppression of PKC signaling potently inhibited the inotropic and lusitropic effects of apelin in both doses (Figs. 3B, 4F and 5B) imply that PKC pathway is more important route for apelin cardiac effects. It is probable that excess pERK1/2 may mediate negative inotropic effects. This inference needs more investigation to verify.
Conclusion Results of the present study indicated that the fccp of KORs increases in the hypertrophic heart exposed to increase in pressure load. KORs and APJ form heterodimer in the heart of rat and the level of heterodimerization increases under renovascular hypertension. Both doses of apelin normalized the level of heterodimerization, and the level of pERK1/2 that was reduced under hypertension. These changes may participate in pathophysiology of heart dysfunction in renovascular hypertension, the condition in which apelin level is lower than normal . Apelin may be a therapeutic goal to reconstruct the impairment in inotropic and lusitropic responses of the hypertrophied heart in these conditions.
Introduction Apelin and its receptor, APJ, are widely expressed throughout the cardiovascular system (Kleinz & Davenport, 2004; Kleinz, Skepper, & Davenport, 2005). This expression pattern has prompted considerable interest in the roles of apelin and APJ receptors in cardiovascular health and disease (Kalea & Batlle, 2010). Indeed, several clinical trials are evaluating the potential benefits of apelin and novel APJ receptor agonists in treating various cardiovascular disorders. A growing body of knowledge continues to shed new light on the apelinergic system, including the discovery of novel endogenous APJ receptor ligands (e. g. Elabela/Toddler) (Chng, Ho, Tian, & Reversade, 2013; Pauli et al., 2014), synthetic analogs (e.g. E339-3D6, ML-233, MM07) (Brame et al., 2015; Iturrioz et al., 2010; Khan et al., 2010) and receptor antagonists (e.g. F13A, ML221) (Lee et al., 2005; Maloney et al., 2012). With regard to the apelinergic system in blood vessels, there are several features involved in apelin-APJ signaling that make it a potential, but challenging target for drug discovery: (1) apelin has multiple effects on vasomotor tone (Maguire, Kleinz, Pitkin, & Davenport, 2009; Mughal, Sun, & O'Rourke, 2018; Salcedo et al., 2007), (2) APJ receptors are expressed in the intimal and medial layers of the blood vessel wall, and possibly on cells in the adventitia as well (Kleinz, Skepper, & Davenport, 2005; Mughal, Sun, & O'Rourke, 2018; Pope, Roberts, Lolait, & O'Carroll, 2012), (3) APJ receptors are associated with multiple G-protein subunits (Hashimoto et al., 2006; Kang et al., 2013; Szokodi et al., 2002), and (4) apelin may act via central nervous system mechanisms to regulate peripheral vascular function (Kagiyama et al., 2005; Zhang, Yao, Raizada, O'Rourke, & Sun, 2009). The present review summarizes the current state of knowledge regarding the vascular effects of apelin, with an emphasis on the regulation of vasomotor tone, as well as novel pharmacologic agents that interact with APJ receptors in blood vessels.