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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