Effects of treatment with a 5-HT4 receptor antagonist in heart failure

Background and purpose: Positive inotropic responses (PIR) to 5-hydroxytryptamine (5-HT) are induced in the left ventricle (LV) in rats with congestive heart failure (CHF); this is associated with upregulation of the G(s)-coupled 5-HT4 receptor. We investigated whether chronic 5-HT4 receptor blockade improved cardiac function in CHF rats. Experimental approach: Rats were given either the 5-HT4 antagonist SB207266 (0.5 mg kg(-1) 24h(-1); MIint) or placebo (MIpl) through mini-osmotic pumps for 6 weeks subsequent to induction of post-infarction CHF. In vivo cardiac function and ex vivo responses to isoprenaline or 5-HT were evaluated using echocardiography and isolated LV papillary muscles, respectively. mRNA levels were investigated using real-time quantitative RT-PCR. Key results: LV diastolic function improved, with 4.6% lower LV diastolic diameter and 24.2% lower mitral flow deceleration in MIint compared to MIpl. SB207266 reduced LV systolic diameter by 6.1%, heart weight by 10.2% and lung weight by 13.1%. The changes in posterior wall thickening and shortening velocity, cardiac output, LV systolic pressure and (dP/dt)(max), parameters of LV systolic function, did not reach statistical significance. The PIR to isoprenaline (10 mu M) increased by 36% and the response to 5-HT (10 mu M) decreased by 57% in MIint compared to MIpl. mRNA levels for ANP, 5-HT4(b) and 5-HT2A receptors, MHC beta, and the MHC beta/MHC alpha-ratio were not significantly changed in MIint compared to MIpl. Conclusions and implications: Treatment with SB207266 to some extent improved in vivo cardiac function and ex vivo myocardial function, suggesting a possible beneficial effect of treatment with a 5-HT4 receptor antagonist in CHF.