These model findings highlight the importance of structural features in rotor dynamics and suggest that regions of fibrosis may anchor fibrillatory rotors. Increasing extent of fibrosis and scar may eventually convert fibrillation to excitable gap reentry. Such macro-reentry can then be eliminated by extending the obstacle or by external stimuli that penetrate the excitable gap.
The molecular pharmacology of the G protein-coupled receptors for sphingosine 1-phosphate (S1P) provides important insight into established and new therapeutic targets. A new, potent bitopic S1P 3 antagonist, SPM-354, with in vivo activity, has been used, together with S1P 3 -knockin and S1P 3 -knockout mice to define the spatial and functional properties of S1P 3 in regulating cardiac conduction. We show that S1P 3 is a key direct regulator of cardiac rhythm both in vivo and in isolated perfused hearts. 2-Amino-2-[2-(4-octylphenyl)ethyl] propane-1,3-diol in vivo and S1P in isolated hearts induced a spectrum of cardiac effects, ranging from sinus bradycardia to complete heart block, as measured by a surface electrocardiogram in anesthetized mice and in volume-conducted Langendorff preparations. The agonist effects on complete heart block are absent in S1P 3 -knockout mice and are reversed in wild-type mice with SPM-354, as characterized and described here. Homologous knockin of S1P 3 -mCherry is fully functional pharmacologically and is strongly expressed by immunohistochemistry confocal microscopy in Hyperpolarization Activated Cyclic Nucleotide Gated Potassium Channel 4 (HCN4)-positive atrioventricular node and His-Purkinje fibers, with relative less expression in the HCN4-positive sinoatrial node. In Langendorff studies, at constant pressure, SPM-354 restored sinus rhythm in S1P-induced complete heart block and fully reversed S1P-mediated bradycardia. S1P 3 distribution and function in the mouse ventricular cardiac conduction system suggest a direct mechanism for heart block risk that should be further studied in humans. A richer understanding of receptor and ligand usage in the pacemaker cells of the cardiac system is likely to be useful in understanding ventricular conduction in health, disease, and pharmacology.
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