Appearance of a ventricular 5-HT receptor-mediated inotropic response to serotonin in heart failure

Abstract

Functional ventricular 5-HT(4) receptors are induced by myocardial infarction and CHF of the rat heart. We propose that they are a model for ventricular 5-HT(4) receptors of human failing heart and may play a pathophysiological role in heart failure.

Surprises from a cardiac 5-HT4 TG mouse: spontaneous atrial arrhythmias by endogenous 5-HT of atrial origin? Different mechanism of arrhythmias through 5-HT4 receptors and β-adrenoceptors?

“…Arrhythmias, probably mediated through 5-HT 4 receptors, have also been reported in porcine atrium (Rahme et al 1999). Rat ventricular 5-HT 4 receptor expression and function is induced in rats with ischaemic heart failure but not in normal rats (Qvigstad et al 2005), plausibly by reactivating a phenotype resembling late foetal development (Brattelid et al 2012). Gergs et al (2010) overexpressed human 5-HT 4a receptors in the heart of mice that normally do not express functional cardiac 5-HT 4 receptors.…”

“…Arrhythmias, probably mediated through 5-HT 4 receptors, have also been reported in porcine atrium (Rahme et al 1999). Rat ventricular 5-HT 4 receptor expression and function is induced in rats with ischaemic heart failure but not in normal rats (Qvigstad et al 2005), plausibly by reactivating a phenotype resembling late foetal development (Brattelid et al 2012).Gergs et al (2010) overexpressed human 5-HT 4a receptors in the heart of mice that normally do not express functional cardiac 5-HT 4 receptors. In these transgenic mice 5-HT produced sinoatrial tachycardia, increases in ventricular I Ca,L and Ca 2+ transients, positive inotropic and lusitropic effects in ventricle, associated with phosphorylation of phospholamban (PLB) at Ser16 in ventricular myocytes and Thr 17 in perfused working hearts.…”

“…Constitutive 5-HT 4 receptor activity is, however, unlikely to occur because the reserpineinduced depletion of 5-HT prevented the spontaneous arrhythmias. On the other hand, in addition to the facilitation of 5-HT 4 receptor-mediated cardiostimulation, constitutive activity cannot entirely be ruled out, in clinical (Brattelid et al 2004) and experimental heart failure of ischaemic origin (Qvigstad et al 2005). A more compelling source 5-HT would come from platelets aggregating against a damaged atrial wall (Kaumann 1994).…”

Serotonin increases L-type Ca2+ current and SR Ca2+ content through 5-HT4 receptors in failing rat ventricular cardiomyocytes

“…During the early phase of CHF, the response was mediated through both 5-HT 2A and 5-HT 4 receptors (41). Later, in the chronic phase of CHF, a 5-HT 4 receptor-mediated response appeared more prominent (40). A 5-HT 4 response is also present in ventricular muscle strips from porcine hearts and explanted human CHF hearts (9).…”

“…In the chronic phase, ␤-adrenergic responsiveness is reduced because of ␤ 1 -and ␤ 2 -adrenoceptor desensitization and ␤ 1 -adrenoceptor downregulation (29). Recently, a positive inotropic response (PIR) to serotonin (5-HT) was demonstrated in left-ventricular (LV) papillary muscles from rats with CHF (40). During the early phase of CHF, the response was mediated through both 5-HT 2A and 5-HT 4 receptors (41).…”