Article date: January 2007
By: J A K Birkeland, I Sjaastad, T Brattelid, E Qvigstad, E R Moberg, K A Krobert, R Bjørnerheim, T Skomedal, O M Sejersted, J‐B Osnes, F O Levy in Volume 150, Issue 2, pages 143-152
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.
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 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.
DOI: 10.1038/sj.bjp.0706966
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