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


METHODS
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.


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 microM) increased by 36% and the response to 5-HT (10 microM) decreased by 57% in MI(int) compared to MI(pl). mRNA levels for ANP, 5-HT(4(b)) and 5-HT(2A) receptors, MHCbeta, and the MHCbeta/MHCalpha -ratio were not significantly changed in MI(int) compared to MI(pl).


CONCLUSIONS
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.
Birkeland
J A K
JA
Institute for Experimental Medical Research, University of Oslo, Oslo, Norway.
Sjaastad
I
I
Brattelid
T
T
Qvigstad
E
E
Moberg
E R
ER
Krobert
K A
KA
Bjørnerheim
R
R
Skomedal
T
T
Sejersted
O M
OM
Osnes
J-B
JB
Levy
F O
FO
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D002302:Cardiac Output / Q000187:drug effects; D006333:Heart Failure / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D007211:Indoles / Q000627:therapeutic use*; D007545:Isoproterenol / Q000494:pharmacology; D008168:Lung / Q000187:drug effects / Q000473:pathology; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009929:Organ Size / Q000187:drug effects; D010880:Piperidines / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D011943:Receptors, Adrenergic, beta / Q000502:physiology; D044422:Receptors, Serotonin, 5-HT4 / Q000096:biosynthesis; D058832:Serotonin 5-HT4 Receptor Antagonists; D015854:Up-Regulation; D016277:Ventricular Function, Left / Q000187:drug effects; D020257:Ventricular Remodeling / Q000187:drug effects
D000318:Adrenergic beta-Agonists; D007211:Indoles; D010880:Piperidines; D012333:RNA, Messenger; D011943:Receptors, Adrenergic, beta; C096919:SB 207266; D058832:Serotonin 5-HT4 Receptor Antagonists; D044422:Receptors, Serotonin, 5-HT4; D007545:Isoproterenol