Acute and Chronic Hyperglycemia Enhance Constriction of Retinal Venules to Endothelin-1

Abstract

Purpose : Hyperglycemia, a hallmark of diabetes, is associated with increased retinal fluid filtration, a process heavily influenced by the postcapillary pressure and venous constriction. Although the ocular level of vasoconstrictor endothelin-1 (ET-1) is elevated in hyperglycemia/diabetes, its impact and mechanistic action on venular vasomotor activity in the retina remain unclear. Herein, we characterized the constriction of retinal venules to ET-1 and determined the relative roles of ET-1 receptor subtypes and L-type voltage-operated calcium channels (L-VOCCs) in this vasomotor regulation with and without hyperglycemic insults.

Methods : Retinal venules (<150 µm maximum diameter) were isolated from streptozocin-induced diabetic pigs (2-wk; chronic hyperglycemia: 286 ± 67 mg/dl) or age-matched control pigs (euglycemia: 71 ± 5 mg/dl) and then cannulated and pressurized to 5 cmH₂O for vasoreactivity study. For acute hyperglycemia study, vessels from nondiabetic pigs were exposed intraluminally to high glucose (25 mM ≈ 450 mg/dl) for 2 hr, and normal glucose (5 mM ≈ 90 mg/dl) served as the control.

Results : Retinal venules developed basal tone (constricted to about 90% of maximum diameter), which was not influenced by the glucose level. ET-1 elicited concentration-dependent vasoconstriction that was significantly increased in a similar manner after exposure to acute or chronic hyperglycemia. By contrast, vasoconstriction to L-VOCC agonist Bay K8644 was slightly reduced by hyperglycemia. The L-VOCC inhibitor nifedipine abolished basal tone and vasoconstriction to Bay K8644 but did not alter ET-1-induced vasoconstriction. Vasoconstriction to ET-1 was prevented in the presence of the ET_A receptor antagonist BQ123 but not the ET_B receptor antagonist BQ788 during normal glucose exposure. However, treatment with either BQ123 or BQ788 diminished ET-1-induced vasoconstriction after hyperglycemia.

Conclusions : Retinal venules develop L-VOCC-dependent basal tone but constrict in an L-VOCC-independent manner to ET-1. In the presence of normal glucose, ET-1 elicits ET_A receptor-dependent vasoconstriction. Hyperglycemia appears to enhance ET-1-induced vasoconstriction via activation of both ET_A and ET_B receptors. The ability of hyperglycemia to augment venular constriction to ET-1 might elevate postcapillary pressure and promote retinal tissue edema during diabetic retinopathy.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.