Dual serotonergic regulation of ventricular contractile force through 5-HT2A and 5-HT4 receptors induced in the acute failing heart.
Cardiac responsiveness to neurohumoral stimulation is altered in congestive heart failure (CHF). In chronic CHF, the left ventricle has become sensitive to serotonin because of appearance of Gs-coupled 5-HT4 receptors. Whether this also occurs in acute CHF is unknown. Serotonin responsiveness may develop gradually or represent an early response to the insult. Furthermore, serotonin receptor expression could vary with progression of the disease. Postinfarction CHF was induced in male Wistar rats by coronary artery ligation with nonligated sham-operated rats as control. Contractility was measured in left ventricular papillary muscles and mRNA quantified by real-time reverse-transcription PCR. Myosin light chain-2 phosphorylation was determined by charged gel electrophoresis and Western blotting. Ca2+ transients in CHF were measured in field stimulated fluo-4-loaded cardiomyocytes. A novel 5-HT2A receptor-mediated inotropic response was detected in acute failing ventricle, accompanied by increased 5-HT2A mRNA levels. Functionally, this receptor dominated over 5-HT4 receptors that were also induced. The 5-HT2A receptor-mediated inotropic response displayed a triphasic pattern, shaped by temporally different activation of Ca2+-calmodulin-dependent myosin light chain kinase, Rho-associated kinase and inhibitory protein kinase C, and was accompanied by increased myosin light chain-2 phosphorylation. Ca2+ transients were slightly decreased by 5-HT2A stimulation. The acute failing rat ventricle is, thus, dually regulated by serotonin through Gq-coupled 5-HT2A receptors and Gs-coupled 5-HT4 receptors.
Department of Pharmacology, University of Oslo, PO Box 1057 Blindern, 0316 Oslo, Norway.
Eirik
E
Qvigstad
Ivar
I
Sjaastad
Trond
T
Brattelid
Caroline
C
Nunn
Fredrik
F
Swift
Jon Arne Kro
JA
Birkeland
Kurt A
KA
Krobert
Geir Øystein
GØ
Andersen
Ole M
OM
Sejersted
Jan-Bjørn
JB
Osnes
Finn Olav
FO
Levy
Tor
T
Skomedal
D000208:Acute Disease; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002147:Calmodulin / Q000037:antagonists & inhibitors / Q000502:physiology; D024722:Cardiac Myosins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006333:Heart Failure / Q000503:physiopathology*; D047908:Intracellular Signaling Peptides and Proteins; D020935:MAP Kinase Signaling System; D008297:Male; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac / Q000378:metabolism; D018994:Myosin Light Chains / Q000378:metabolism; D009219:Myosin-Light-Chain Kinase / Q000037:antagonists & inhibitors / Q000502:physiology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D044402:Receptor, Serotonin, 5-HT2A / Q000235:genetics / Q000502:physiology*; D044422:Receptors, Serotonin, 5-HT4 / Q000235:genetics / Q000502:physiology*; D012701:Serotonin / Q000494:pharmacology; D054460:rho-Associated Kinases
D002147:Calmodulin; D047908:Intracellular Signaling Peptides and Proteins; D018994:Myosin Light Chains; D012333:RNA, Messenger; D044402:Receptor, Serotonin, 5-HT2A; C107184:myosin light chain 2; D044422:Receptors, Serotonin, 5-HT4; D012701:Serotonin; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D011493:Protein Kinase C; D009219:Myosin-Light-Chain Kinase; D024722:Cardiac Myosins; D002118:Calcium