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Rats with congestive heart failure (CHF) develop ventricular inotropic responsiveness to serotonin (5-HT), mediated through 5-[HT.sub.2A] and 5-[HT.sub.4] receptors. Human ventricle is similarly responsive to 5-HT through 5-[HT.sub.4] receptors. We studied isolated ventricular cardiomyocytes to clarify the effects of 5-HT on intracellular [Ca.sup.2+] handling. Left-ventricular cardiomyocytes were isolated from male Wistar rats 6 wk after induction of postinfarction CHF. Contractile function and [Ca.sup.2+] transients were measured in field-stimulated cardiomyocytes, and L-type [Ca.sup.2+] current ([I.sub.Ca,L]) and sarcoplasmic reticulum (SR) [Ca.sup.2+] content were measured in voltage-clamped cells. Protein phosphorylation was measured by Western blotting or phosphoprotein gel staining. 5-[HT.sub.4]- and 5-[HT.sub.2A]-receptor stimulation induced a positive inotropic response of 33 and 18% (both P < 0.05) and also increased the [Ca.sup.2+] transient (44 and 6%, respectively; both P < 0.05). [I.sub.Ca,L] and SR [Ca.sup.2+] content increased only after 5-[HT.sub.4]-receptor stimulation (57 and 65%; both P < 0.05). Phospholamban [serine.sup.16] (PLB-[Ser.sup.16]) and troponin I phosphorylation increased by 26 and 13% after 5-[HT.sub.4]-receptor stimulation (P < 0.05). 5-[HT.sub.2A]-receptor stimulation increased the action potential duration and did not significantly change the phosphorylation of PLB-[Ser.sup.16] or troponin I, but it increased myosin light chain 2 (MLC2) phosphorylation. In conclusion, the positive inotropic response to 5-[HT.sub.4] stimulation results from increased [I.sub.Ca,L] and increased phosphorylation of PLB-[Ser.sup.16], which increases the SR [Ca.sup.2+] content. 5-[HT.sub.4] stimulation is thus, like [beta]-adrenoceptor stimulation, possibly energetically unfavorable in CHF. 5-[HT.sub.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

Aims: The Na+/K+-ATPase (NKA) α2-isoform is preferentially located in the t-tubules of cardiomyocytes and is functionally coupled to the Na+/Ca2+-exchanger (NCX) and Ca2+ regulation through intracellular Na+ concentration ([Na+]i). We hypothesized that downregulation of the NKA α2-isoform during congestive heart failure (CHF) disturbs the link between Na+ and Ca2+, and thus the control of cardiomyocyte contraction. [ABSTRACT FROM PUBLISHER]

Rats with congestive heart failure (CHF) develop ventricular inotropic responsiveness to serotonin (5-HT), mediated through 5-HT2A 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 (ICa,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-HT2A-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). ICa,L and SR Ca2+ content increased only after 5-HT4-receptor stimulation (57 and 65%; both P < 0.05). Phospholamhan serine16 (PLB-Ser16) and troponin I phosphorylation increased by 26 and 13% after 5-HT4-receptor stimulation (P < 0.05). 5-HT2A-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 ICa,L and increased phosphorylation of PLB-Ser16, which increases the SR Ca2+ content. 5-HT4 stimulation is thus, like β-adrenoceptor stimulation, possibly energetically unfavorable in CHF. 5-HT2A-receptor stimulation, previously studied in acute CHF, induces a positive inotropic response also in chronic CHF, probably mediated by MLC2 phosphorylation. [ABSTRACT FROM AUTHOR]

A correction to the article "Altered Na+/Ca²+-exchanger activity due to downregulation of Na+/K+-ATPase α2-isoform in heart failure," is presented.

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.