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Effects of treatment with a 5‐HT 4 receptor antagonist in heart failure
Author(s) -
Birkeland J A K,
Sjaastad I,
Brattelid T,
Qvigstad E,
Moberg E R,
Krobert K A,
Bjørnerheim R,
Skomedal T,
Sejersted O M,
Osnes JB,
Levy F O
Publication year - 2007
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0706966
Subject(s) - medicine , heart failure , cardiology , ventricle , cardiac function curve , endocrinology , diastole , blood pressure
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‐HT 4 receptor. We investigated whether chronic 5‐HT 4 receptor blockade improved cardiac function in CHF rats. Experimental approach: Rats were given either the 5‐HT 4 antagonist SB207266 (0.5 mg kg −1 24h −1 ; MI int ) or placebo (MI pl ) 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 MI int compared to MI pl . 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 MI int compared to MI pl . mRNA levels for ANP, 5‐HT 4(b) and 5‐HT 2A receptors, MHCβ, and the MHC β /MHC α ‐ratio were not significantly changed in MI int compared to MI pl . 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‐HT 4 receptor antagonist in CHF. British Journal of Pharmacology (2007) 150 , 143–152. doi: 10.1038/sj.bjp.0706966