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

Sphingosine-1-phosphate (S1P) induces a transient bradycardia in mammalian hearts through activation of an inwardly rectifying K+ current (IKACh) 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 Gi exclusively, whereas S1P3 activates both Gi and Gq, these results strongly implicate the involvement of mainly Gi. Additional experiments using the IKACh blocker tertiapin demonstrated that IKACh can contribute to the negative inotr...