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James Tumelty, Kevin Hinds, Peter Bankhead, Neil J. McGeown, C. Norman Scholfield, Tim M. Curtis, J. Graham McGeown; Endothelin 1 Stimulates Ca2+-Sparks and Oscillations in Retinal Arteriolar Myocytes via IP3R and RyR-Dependent Ca2+ Release. Invest. Ophthalmol. Vis. Sci. 2011;52(6):3874-3879. doi: 10.1167/iovs.10-6029.
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To investigate endothelin 1 (Et1)–dependent Ca2+-signaling at the cellular and subcellular levels in retinal arteriolar myocytes.
Et1 responses were imaged from Fluo-4–loaded smooth muscle in isolated segments of rat retinal arteriole using confocal laser microscopy.
Basal [Ca2+]i, subcellular Ca2+-sparks, and cellular Ca2+-oscillations were all increased during exposure to Et1 (10 nM). Ca2+-spark frequency was also increased by 90% by 10 nM Et1. The increase in oscillation frequency was concentration dependent and was inhibited by the EtA receptor (EtAR) blocker BQ123 but not by the EtB receptor antagonist BQ788. Stimulation of Ca2+-oscillations by Et1 was inhibited by a phospholipase C blocker (U73122; 10 μM), two inhibitors of inositol 1,4,5-trisphosphate receptors (IP3Rs), xestospongin C (10 μM), 2-aminoethoxydiphenyl borate (100 μM), and tetracaine (100 μM), a blocker of ryanodine receptors (RyRs).
Et1 stimulates Ca2+-sparks and oscillations through EtARs. The underlying mechanism involves the activation of phospholipase C and both IP3Rs and RyRs, suggesting crosstalk between these Ca2+-release channels. These findings suggest that phasic Ca2+-oscillations play an important role in the smooth muscle response to Et1 within the retinal microvasculature and support an excitatory, proconstrictor role for Ca2+-sparks in these vessels.
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