The cardiac ventricular 5-HT4 receptor is functional in late foetal development and is reactivated in heart failure.

A positive inotropic responsiveness to serotonin, mediated by 5-HT(4) and 5-HT(2A) receptors, appears in the ventricle of rats with post-infarction congestive heart failure (HF) and pressure overload-induced hypertrophy. A hallmark of HF is a transition towards a foetal genotype which correlates with loss of cardiac functions. Thus, we wanted to investigate whether the foetal and neonatal cardiac ventricle displays serotonin responsiveness. Wistar rat hearts were collected day 3 and 1 before expected birth (days -3 and -1), as well as day 1, 3, 5 and 113 (age matched with Sham and HF) after birth. Hearts from post-infarction HF and sham-operated animals (Sham) were also collected. Heart tissue was examined for mRNA expression of 5-HT(4), 5-HT(2A) and 5-HT(2B) serotonin receptors, 5-HT transporter, atrial natriuretic peptide (ANP) and myosin heavy chain (MHC)-α and MHC-ß (real-time quantitative RT-PCR) as well as 5-HT-receptor-mediated increase in contractile function exvivo (electrical field stimulation of ventricular strips from foetal and neonatal rats and left ventricular papillary muscle from adult rats in organ bath). Both 5-HT(4) mRNA expression and functional responses were highest at day -3 and decreased gradually to day 5, with a further decrease to adult levels. In HF, receptor mRNA levels and functional responses reappeared, but to lower levels than in the foetal ventricle. The 5-HT(2A) and 5-HT(2B) receptor mRNA levels increased to a maximum immediately after birth, but of these, only the 5-HT(2A) receptor mediated a positive inotropic response. We suggest that the 5-HT(4) receptor is a representative of a foetal cardiac gene program, functional in late foetal development and reactivated in heart failure.

Serotonin responsiveness through 5-HT2A and 5-HT4 receptors is differentially regulated in hypertrophic and failing rat cardiac ventricle.

Cardiac ventricular responsiveness to serotonin appears in rat postinfarction congestive heart failure (CHF), mainly mediated by 5-HT(4) receptors in chronic dilated CHF and 5-HT(2A) receptors in acute CHF. To differentiate between the effects of left ventricular (LV) hypertrophy and failure on 5-HT(2A)- and 5-HT(4)-mediated inotropic serotonin response, male Wistar rats with increasing LV hypertrophy (AB1-3) and failure (ABHF) 6 weeks after banding of the ascending aorta were screened for contractile function in vivo (echocardiography) and ex vivo in LV papillary muscles, and mRNA expression level determined by RT-PCR. Both AB1-3 and ABHF displayed LV hypertrophy and remodelling. In ABHF, systolic LV and left atrial diameter increased and cardiac output decreased compared to AB3. Serotonin induced a positive inotropic response (PIR) in papillary muscles correlated with the degree of hypertrophy reaching a maximum in ABHF. Both 5-HT(2A) and 5-HT(4) receptors contributed to the PIR. The 5-HT(2A) contribution increased with increasing hypertrophy, and the 5-HT(4) contribution increased upon transition to heart failure. No 5-HT(2B)-mediated PIR was observed, consistent with increased 5-HT(2B) mRNA only in non-cardiomyocytes. The 5-HT(2A), 5-HT(2B) and 5-HT(4) mRNA levels increased in AB1-3 and increased further in ABHF compared to AB3, but did not correlate with degree of hypertrophy. 5-HT(2A) mRNA was also increased in LV of terminally failing human hearts. In conclusion, functional 5-HT(2A) and 5-HT(4) receptors are differentially induced in LV hypertrophy and failure. While the 5-HT(2A)-mediated PIR is linearly correlated with the degree of hypertrophy, the 5-HT(4)-mediated PIR seems to increase with LV dilatation, as also seen in postinfarction CHF.