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Luke B. Potts, Yi Ren, Guangrong Lu, Enoch Kuo, Ellen Ngo, Lih Kuo, Travis W. Hein; Constriction of Retinal Arterioles to Endothelin-1: Requisite Role of Rho Kinase Independent of Protein Kinase C and L-Type Calcium Channels. Invest. Ophthalmol. Vis. Sci. 2012;53(6):2904-2912. doi: 10.1167/iovs.12-9542.
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Although endothelin-1 (ET-1) is a potent vasoconstrictor peptide implicated in several retinal pathologies, the underlying mechanism of vasoconstriction is understood incompletely. We addressed this issue by assessing the contributions of extracellular calcium (Ca2+), L-type voltage-operated calcium channels (L-VOCCs), Rho kinase (ROCK), and protein kinase C (PKC) to ET-1-induced constriction of porcine retinal arterioles, all of which have been implicated commonly in vascular smooth muscle contraction.
Porcine retinal arterioles (∼50–100 μm) were isolated for vasomotor study and molecular assessment of ROCK isoforms.
Isolated arterioles developed stable basal tone at 55 cmH2O luminal pressure and constricted to ET-1 (0.1 nM) with a 40 ± 6% reduction in resting diameter in 20 minutes. In the absence of extraluminal Ca2+, arterioles lost basal tone and failed to constrict to ET-1. Although L-VOCC inhibitor nifedipine reduced basal tone and blocked vasoconstriction to PKC activator PDBu, vasoconstriction to ET-1 was unaffected. The broad-spectrum PKC inhibitor Gö-6983 abolished vasoconstriction to PDBu, but did not alter ET-1-induced vasoconstriction or basal tone. Incubation of arterioles with ROCK inhibitor H-1152 abolished basal tone and vasoconstrictions to ET-1 and PDBu. Both ROCK1 and ROCK2 isoforms were expressed in the retinal arteriolar wall.
Extracellular Ca2+ entry via L-VOCCs and basal ROCK activity play important roles in the maintenance of basal tones of porcine retinal arterioles. ET-1-induced constriction is mediated by extracellular Ca2+ entry independent of L-VOCCs and by ROCK activation without the involvement of PKC. However, direct PKC activation can cause vasoconstriction via L-VOCC and ROCK signaling.
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