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(Circulation Research. 2005;97:268.)
© 2005 American Heart Association, Inc.

Integrative Physiology

Dual Serotonergic Regulation of Ventricular Contractile Force Through 5-HT_2A and 5-HT₄ Receptors Induced in the Acute Failing Heart

Eirik Qvigstad^*, Ivar Sjaastad^*, Trond Brattelid, Caroline Nunn, Fredrik Swift, Jon Arne Kro Birkeland, Kurt A. Krobert, Geir Øystein Andersen, Ole M. Sejersted, Jan-Bjørn Osnes, Finn Olav Levy, Tor Skomedal

From the Department of Pharmacology (E.Q., T.B., C.N., K.A.K., G.Ø.A., J.-B.O., F.O.L., T.S.), the Center for Heart Failure Research (E.Q., I.S., T.B., C.N., F.S., J.A.K.B., K.A.K., G.Ø.A., O.M.S., J.B.O., F.O.L., T.S.), and the Institute for Experimental Medical Research (I.S., F.S., J.A.K.B., O.M.S.), University of Oslo, Norway; and the Department of Cardiology (I.S., G.Ø.A.), Ullevaal University Hospital, Oslo, Norway.

Correspondence to Finn Olav Levy, Dept of Pharmacology, University of Oslo, PO Box 1057 Blindern, 0316 Oslo, Norway. E-mail f.o.levy{at}medisin.uio.no

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 G_s-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-HT_2A receptor-mediated inotropic response was detected in acute failing ventricle, accompanied by increased 5-HT_2A mRNA levels. Functionally, this receptor dominated over 5-HT₄ receptors that were also induced. The 5-HT_2A 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-HT_2A stimulation. The acute failing rat ventricle is, thus, dually regulated by serotonin through G_q-coupled 5-HT_2A receptors and G_s-coupled 5-HT₄ receptors.

Key Words: serotonin • heart failure • 5-HT_2A receptor • Ca²⁺-calmodulin-dependent myosin light chain kinase • Rho-associated kinase

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