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ET-1 activates Ca²⁺ sparks in PASMC: local Ca²⁺ signaling between inositol trisphosphate and ryanodine receptors

¹Division of Pulmonary and Critical Care Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland 21224; ²Department of Physiology and Biophysics, College of Medicine, University of South Florida, Tampa, Florida 33612; and ³Department of Cell Biology and Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75390

Submitted 11 March 2003 ; accepted in final form 5 May 2003

Ca⁺ sparks originating from ryanodine receptors (RyRs) are known to cause membrane hyperpolarization and vasorelaxation in systemic arterial myocytes. By contrast, we have found that Ca²⁺ sparks of pulmonary arterial smooth muscle cells (PASMCs) are associated with membrane depolarization and activated by endothelin-1 (ET-1), a potent vasoconstrictor that mediates/modulates acute and chronic hypoxic pulmonary vasoconstriction. In this study, we characterized the effects of ET-1 on the physical properties of Ca²⁺ sparks and probed the signal transduction mechanism for spark activation in rat intralobar PASMCs. Application of ET-1 at 0.1-10 nM caused concentration-dependent increases in frequency, duration, and amplitude of Ca²⁺ sparks. The ET-1-induced increase in spark frequency was inhibited by BQ-123, an ET_A-receptor antagonist; by U-73122, a PLC inhibitor; and by xestospongin C and 2-aminoethyl diphenylborate, antagonists of inositol trisphosphate (IP₃) receptors (IP₃Rs). However, it was unrelated to sarcoplasmic reticulum Ca²⁺ content, activation of L-type Ca²⁺ channels, PKC, or cADP ribose. Photorelease of caged-IP₃ indicated that Ca²⁺ release from IP₃R could cross-activate RyRs to generate Ca²⁺ sparks. Immunocytochemistry showed that the distributions of IP₃Rs and RyRs were similar in PASMCs. Moreover, inhibition of Ca²⁺ sparks with ryanodine caused a significant rightward shift in the ET-1 concentration-tension relationship in pulmonary arteries. These results suggest that ET-1 activation of Ca²⁺ sparks is mediated via the ET_A receptor-PLC-IP₃ pathway and local Ca²⁺ cross-signaling between IP₃Rs and RyRs; in addition, this novel signaling mechanism contributes significantly to the ET-1-induced vasoconstriction in pulmonary arteries.

endothelin; pulmonary arteries; photorelease; pulmonary artery smooth muscle cells; endothelin-1; calcium ion

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