Serotonin responsiveness through 5-HT2A and 5-HT4 receptors is differentially regulated in hypertrophic and failing rat cardiac ventricle.
Cardiac ventricular responsiveness to serotonin appears in rat postinfarction congestive heart failure (CHF), mainly mediated by 5-HT(4) receptors in chronic dilated CHF and 5-HT(2A) receptors in acute CHF. To differentiate between the effects of left ventricular (LV) hypertrophy and failure on 5-HT(2A)- and 5-HT(4)-mediated inotropic serotonin response, male Wistar rats with increasing LV hypertrophy (AB1-3) and failure (ABHF) 6 weeks after banding of the ascending aorta were screened for contractile function in vivo (echocardiography) and ex vivo in LV papillary muscles, and mRNA expression level determined by RT-PCR. Both AB1-3 and ABHF displayed LV hypertrophy and remodelling. In ABHF, systolic LV and left atrial diameter increased and cardiac output decreased compared to AB3. Serotonin induced a positive inotropic response (PIR) in papillary muscles correlated with the degree of hypertrophy reaching a maximum in ABHF. Both 5-HT(2A) and 5-HT(4) receptors contributed to the PIR. The 5-HT(2A) contribution increased with increasing hypertrophy, and the 5-HT(4) contribution increased upon transition to heart failure. No 5-HT(2B)-mediated PIR was observed, consistent with increased 5-HT(2B) mRNA only in non-cardiomyocytes. The 5-HT(2A), 5-HT(2B) and 5-HT(4) mRNA levels increased in AB1-3 and increased further in ABHF compared to AB3, but did not correlate with degree of hypertrophy. 5-HT(2A) mRNA was also increased in LV of terminally failing human hearts. In conclusion, functional 5-HT(2A) and 5-HT(4) receptors are differentially induced in LV hypertrophy and failure. While the 5-HT(2A)-mediated PIR is linearly correlated with the degree of hypertrophy, the 5-HT(4)-mediated PIR seems to increase with LV dilatation, as also seen in postinfarction CHF.
Brattelid
Trond
T
Department of Pharmacology, University of Oslo, Sognsvannsvn. 20, Oslo, Norway.
Qvigstad
Eirik
E
Birkeland
Jon Arne Kro
JA
Swift
Fredrik
F
Bekkevold
Silje V S
SV
Krobert
Kurt A
KA
Sejersted
Ole M
OM
Skomedal
Tor
T
Osnes
Jan-Bjørn
JB
Levy
Finn Olav
FO
Sjaastad
Ivar
I
D000818:Animals; D004452:Echocardiography; D005786:Gene Expression Regulation / Q000187:drug effects*; D006333:Heart Failure / Q000235:genetics*; D006352:Heart Ventricles / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D017379:Hypertrophy, Left Ventricular / Q000235:genetics*; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D009200:Myocardial Contraction / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D044402:Receptor, Serotonin, 5-HT2A / Q000235:genetics* / Q000378:metabolism; D044403:Receptor, Serotonin, 5-HT2B / Q000235:genetics / Q000378:metabolism; D044422:Receptors, Serotonin, 5-HT4 / Q000235:genetics* / Q000378:metabolism; D012701:Serotonin / Q000494:pharmacology*; D014019:Tissue Donors
D012333:RNA, Messenger; D044402:Receptor, Serotonin, 5-HT2A; D044403:Receptor, Serotonin, 5-HT2B; D044422:Receptors, Serotonin, 5-HT4; D012701:Serotonin; D007545:Isoproterenol