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This Article Full Text Full Text (PDF) All Versions of this Article: 294/2/H736    most recent 00316.2007v1 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 Google Scholar Google Scholar Articles by Landeen, L. K. Articles by Giles, W. R. Search for Related Content PubMed PubMed Citation Articles by Landeen, L. K. Articles by Giles, W. R.

Mechanisms of the negative inotropic effects of sphingosine-1-phosphate on adult mouse ventricular myocytes

¹Department of Bioengineering, University of California, San Diego, La Jolla, California; and ²Department of Kinesiology, University of Calgary, Calgary, Alberta, Canada

Submitted 13 March 2007 ; accepted in final form 12 November 2007

Sphingosine-1-phosphate (S1P) induces a transient bradycardia in mammalian hearts through activation of an inwardly rectifying K⁺ current (I_KACh) in the atrium that shortens action potential duration (APD) in the atrium. We have investigated probable mechanisms and receptor-subtype specificity for S1P-induced negative inotropy in isolated adult mouse ventricular myocytes. Activation of S1P receptors by S1P (100 nM) reduced cell shortening by 25% (vs. untreated controls) in field-stimulated myocytes. S1P₁ was shown to be involved by using the S1P₁-selective agonist SEW2871 on myocytes isolated from S1P₃-null mice. However, in these myocytes, S1P₃ can modulate a somewhat similar negative inotropy, as judged by the effects of the S1P₁ antagonist VPC23019. Since S1P₁ activates G_i exclusively, whereas S1P₃ activates both G_i and G_q, these results strongly implicate the involvement of mainly G_i. Additional experiments using the I_KACh blocker tertiapin demonstrated that I_KACh can contribute to the negative inotropy following S1P activation of S1P₁ (perhaps through G_iβ subunits). Mathematical modeling of the effects of S1P on APD in the mouse ventricle suggests that shortening of APD (e.g., as induced by I_KACh) can reduce L-type calcium current and thus can decrease the intracellular Ca²⁺ concentration ([Ca²⁺]_i) transient. Both effects can contribute to the observed negative inotropic effects of S1P. In summary, these findings suggest that the negative inotropy observed in S1P-treated adult mouse ventricular myocytes may consist of two distinctive components: 1) one pathway that acts via G_i to reduce L-type calcium channel current, blunt calcium-induced calcium release, and decrease [Ca²⁺]_i; and 2) a second pathway that acts via G_i to activate I_KACh and reduce APD. This decrease in APD is expected to decrease Ca²⁺ influx and reduce [Ca²⁺]_i and myocyte contractility.

calcium; contraction; cell shortening; inhibitory G protein; acetylcholine-sensitive potassium; myocyte