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

Jon Arne Kro Birkeland1, Fredrik Swift, Nils Tovsrud

  • 1Institute for Experimental Medical Research, Ullevaal Univ. Hospital, Kirkeveien 166, 0407 Oslo, Norway. j.a.birkeland@medisin.uio.no

American Journal of Physiology. Heart and Circulatory Physiology
|July 31, 2007
PubMed

Insights

Serotonin (5-HT) enhances heart contractility in rats with heart failure via 5-HT(4) and 5-HT(2A) receptors. 5-HT(4) receptor stimulation increases intracellular calcium, while 5-HT(2A) affects action potential duration in heart failure.

Area of Science:

  • Cardiology
  • Pharmacology
  • Molecular Biology

Background:

  • Congestive heart failure (CHF) alters ventricular responsiveness to neurotransmitters.
  • Serotonin (5-HT) has shown inotropic effects mediated by specific receptors in both rat and human ventricles.

Purpose of the Study:

  • To investigate the effects of serotonin (5-HT) on intracellular calcium handling in cardiomyocytes from rats with chronic heart failure.
  • To elucidate the specific roles of 5-HT(2A) and 5-HT(4) receptors in mediating these effects.

Main Methods:

  • Isolated left-ventricular cardiomyocytes from Wistar rats with postinfarction CHF were used.
  • Measurements included contractile function, Ca(2+) transients, L-type Ca(2+) current (I(Ca,L)), sarcoplasmic reticulum (SR) Ca(2+) content, and protein phosphorylation (PLB-Ser(16), troponin I, MLC2).

Main Results:

  • Both 5-HT(4) and 5-HT(2A) receptor stimulation induced positive inotropic responses and increased Ca(2+) transients.
  • 5-HT(4) stimulation uniquely increased I(Ca,L) and SR Ca(2+) content, accompanied by increased PLB-Ser(16) and troponin I phosphorylation.
  • 5-HT(2A) stimulation prolonged action potential duration and increased MLC2 phosphorylation, without significantly altering PLB-Ser(16) or troponin I phosphorylation.

Conclusions:

  • The positive inotropic effect of 5-HT(4) stimulation in CHF is attributed to increased I(Ca,L) and SR Ca(2+) content via PLB-Ser(16) phosphorylation.
  • 5-HT(4) stimulation may be energetically unfavorable in CHF, similar to beta-adrenoceptor stimulation.
  • 5-HT(2A) receptor stimulation contributes to positive inotropy in chronic CHF, likely through MLC2 phosphorylation.

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