Melatonin alleviates diabetic-induced vascular dysfunction by modulating endothelin-1 receptors (ETA and ETB) reactivity in rat aortic rings.

Melatonin, an indoleamine, has been reported to exert cardiovascular protective effects; however, its influence on endothelin-1 (ET-1)–induced vascular reactivity in diabetic endothelial dysfunction remains incompletely understood. The present study aimed to evaluate the functional effects of melatonin on ET-1–mediated vasoreactivity and the involvement of ETA- and ETB-dependent responses in the aortas of streptozotocin (STZ)-induced diabetic rats. Thoracic aortic rings were isolated from non-diabetic, diabetic, and melatonin-treated diabetic rats (30 mg/kg orally for 14 days) and mounted in an automatic organ bath system. Cumulative concentration–response curves to ET-1 were generated in the presence or absence of acute melatonin preincubation and selective ETA (BQ123) and ETB (BQ788) receptor antagonists. Vascular responses were assessed using maximal contraction (Emax), potency (pD₂), and area under the curve (AUC) as functional outcome measures. Diabetes significantly enhanced ET-1–induced vasoconstriction, evidenced by a leftward shift of the concentration–response curve and increased Emax, indicating augmented vascular reactivity. In non-diabetic aortas, acute melatonin preincubation significantly attenuated ET-1–induced contraction, whereas this inhibitory effect was markedly reduced in diabetic vessels. Chronic melatonin treatment partially normalized ET-1 responsiveness in diabetic aortas, reflected by reduced maximal contraction and altered sensitivity to ETA and ETB receptor antagonism. Functional blockade studies further demonstrated that diabetes impaired ETB-dependent vasodilatory responses, which were partially restored following melatonin administration. In conclusion, this study demonstrates that melatonin improves ET-1–induced vascular dysfunction in experimental diabetes by attenuating exaggerated vasoconstrictor responses and modulating ETA- and ETB-dependent functional pathways. These findings support the use of melatonin as a functional vasoprotective agent and highlight its potential as an adjunct strategy for mitigating diabetic vascular complications.