These authors contributed equally to this work.
Effects of treatment with a 5-HT4 receptor antagonist in heart failure
Article first published online: 29 JAN 2009
2007 British Pharmacological Society
British Journal of Pharmacology
Volume 150, Issue 2, pages 143–152, January 2007
How to Cite
Birkeland, J. A. K., Sjaastad, I., Brattelid, T., Qvigstad, E., Moberg, E. R., Krobert, K. A., Bjørnerheim, R., Skomedal, T., Sejersted, O. M., Osnes, J.-B. and Levy, F. O. (2007), Effects of treatment with a 5-HT4 receptor antagonist in heart failure. British Journal of Pharmacology, 150: 143–152. doi: 10.1038/sj.bjp.0706966
- Issue published online: 29 JAN 2009
- Article first published online: 29 JAN 2009
- (Received June 28, 2006, Revised September 4, 2006, Accepted September 16, 2006)
- congestive heart failure;
- 5-HT4 receptor blockade;
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 Gs-coupled 5-HT4 receptor. We investigated whether chronic 5-HT4 receptor blockade improved cardiac function in CHF rats.
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.
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 μM) increased by 36% and the response to 5-HT (10 μM) decreased by 57% in MIint compared to MIpl. mRNA levels for ANP, 5-HT4(b) and 5-HT2A receptors, MHCβ, and the MHCβ/MHCα -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.
British Journal of Pharmacology (2007) 150, 143–152. doi:10.1038/sj.bjp.0706966