Sufficient retinal perfusion is essential for maintaining normal vision ( 1). The retinal microcirculation supplies oxygen and nutrients to and removes metabolic wastes from the inner two-thirds of the metabolically active retinal tissue. Treatments targeting these vascular molecules may lessen retinal complications in early diabetes. Diabetes activates p38 MAPK and NHE1, which cause enhanced venular constriction to ET-1. In conclusion, extracellular Ca 2+ entry and activation of JNK, independent of ERK and PKC, mediate constriction of retinal venules to ET-1. Diabetes (after 2 weeks) enhanced venular constriction to ET-1, which was insensitive to PD98059 and Gö 6983 but was prevented by NHE1 inhibitor cariporide, SB203580, and SP600125.
ET-1–induced vasoconstriction was abolished in the absence of extracellular Ca 2+ and sensitive to c-Jun N-terminal kinase (JNK) inhibitor SP600125 but unaffected by extracellular signal–regulated kinase (ERK) inhibitor PD98059, p38 kinase inhibitor SB203580, or broad-spectrum PKC inhibitor Gö 6983. Retinal venules were isolated from control pigs and pigs with streptozocin-induced diabetes for in vitro studies. We examined roles of sodium-hydrogen exchanger 1 (NHE1), protein kinase C (PKC), mitogen-activated protein kinases (MAPKs), and extracellular calcium (Ca 2+) in retinal venular constriction to ET-1 and the impact of diabetes on these signaling molecules. However, mechanisms contributing to ET-1–induced constriction of retinal venules are incompletely understood. Diabetes elevates endothelin-1 (ET-1) in the vitreous and enhances constriction of retinal venules to this peptide.
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