Involvement of gap junction, calcium and potassium channels in Urotensin II reactivity in diabetic rat isolated aorta.

Abstract

Background: Urotensin II (U-II) is one of the most potent endogenous vasoconstrictors, with its vascular effects tightly regulated by endothelial function and ion channel activity. The impact of diabetes mellitus on the signalling mechanisms underlying U-II-induced vascular reactivity remains insufficiently understood.

Objective: This study systematically investigated how diabetes alters U-II-induced vasoconstriction by dissecting the contributions of endothelial integrity, potassium channel subtypes, calcium influx, and gap junction communication in the thoracic aorta of normoglycemic and streptozotocin-induced diabetic rats.

Methods: Isolated aortic rings with intact or denuded endothelium were exposed to cumulative concentrations of U-II (1 0 ^-11-1 0 -8 M). Pharmacological inhibitors-including L-NAME (NOS inhibitor), indomethacin (COX inhibitor), TEA (Kv channel blocker), BaCl₂ (Kir channel blocker), clotrimazole (IKCa channel blocker), nifedipine (L-type Ca²⁺ channel blocker), and GAP27 (gap junction inhibitor) were employed to delineate mechanistic pathways.

Results: Endothelial removal significantly potentiated U-II-induced contractions in both non-diabetic and diabetic vessels, affirming the critical modulatory role of endothelium-derived vasodilators. Diabetic vessels exhibited marked reductions in maximal contraction (Emax) and sensitivity (pD₂) to U-II. In non-diabetic aorta, Kir and IKCa channel blockade robustly suppressed U-II-induced contraction, whereas these effects were diminished or reversed in diabetic tissue, indicating functional channel dysregulation. L-NAME potentiated U-II responses selectively in diabetes, implicating impaired nitric oxide bioavailability. Strikingly, nifedipine enhanced U-II-mediated contraction in diabetic rats, suggesting maladaptive remodelling of calcium influx. GAP27 reduced U-II responses, with a more pronounced inhibitory effect in diabetic vessels, highlighting disease-specific alterations in gap junction signalling.

Conclusion: Diabetes markedly impairs urotensin II-induced vascular contractility by disrupting Kir and IKCa potassium channel function, alongside distinct changes in calcium channels, gap junctions, and prostanoids. Restoring Kir and IKCa  may offer an effective therapeutic strategy to reverse vascular dysfunction in diabetic vascular myopathy.