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This Article Full Text Full Text (PDF) All Versions of this Article: 293/4/H2367    most recent 01375.2006v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via ISI Web of Science (1) Citing Articles via Google Scholar Google Scholar Articles by Birkeland, J. A. K. Articles by Sjaastad, I. Search for Related Content PubMed PubMed Citation Articles by Birkeland, J. A. K. Articles by Sjaastad, I.

Serotonin increases L-type Ca²⁺ current and SR Ca²⁺ content through 5-HT₄ receptors in failing rat ventricular cardiomyocytes

¹Institute for Experimental Medical Research, ²Department of Cardiology, Ullevaal University Hospital, ³Department of Pharmacology, and ⁴Center for Heart Failure Research, University of Oslo, Oslo, Norway

Submitted 17 December 2006 ; accepted in final form 26 July 2007

Rats with congestive heart failure (CHF) develop ventricular inotropic responsiveness to serotonin (5-HT), mediated through 5-HT_2A and 5-HT₄ receptors. Human ventricle is similarly responsive to 5-HT through 5-HT₄ receptors. We studied isolated ventricular cardiomyocytes to clarify the effects of 5-HT on intracellular Ca²⁺ handling. Left-ventricular cardiomyocytes were isolated from male Wistar rats 6 wk after induction of postinfarction CHF. Contractile function and Ca²⁺ transients were measured in field-stimulated cardiomyocytes, and L-type Ca²⁺ current (I_Ca,L) and sarcoplasmic reticulum (SR) Ca²⁺ content were measured in voltage-clamped cells. Protein phosphorylation was measured by Western blotting or phosphoprotein gel staining. 5-HT₄- and 5-HT_2A-receptor stimulation induced a positive inotropic response of 33 and 18% (both P < 0.05) and also increased the Ca²⁺ transient (44 and 6%, respectively; both P < 0.05). I_Ca,L and SR Ca²⁺ content increased only after 5-HT₄-receptor stimulation (57 and 65%; both P < 0.05). Phospholamban serine¹⁶ (PLB-Ser¹⁶) and troponin I phosphorylation increased by 26 and 13% after 5-HT₄-receptor stimulation (P < 0.05). 5-HT_2A-receptor stimulation increased the action potential duration and did not significantly change the phosphorylation of PLB-Ser¹⁶ or troponin I, but it increased myosin light chain 2 (MLC2) phosphorylation. In conclusion, the positive inotropic response to 5-HT₄ stimulation results from increased I_Ca,L and increased phosphorylation of PLB-Ser¹⁶, which increases the SR Ca²⁺ content. 5-HT₄ stimulation is thus, like -adrenoceptor stimulation, possibly energetically unfavorable in CHF. 5-HT_2A-receptor stimulation, previously studied in acute CHF, induces a positive inotropic response also in chronic CHF, probably mediated by MLC2 phosphorylation.

contractile apparatus; excitation-contraction coupling; inotropic agents; ion pumps; phosphorylation