KMUP-1 protects against streptozotocin-induced mesenteric artery dysfunction via activation of ATP-sensitive...

Diabetes mellitus is a metabolic disorder characterized by chronic hyperglycemia accompanied by impaired vascular and endothelial function. Activation of ATP-sensitive potassium (K_ATP) channels can protect endothelial function against hypertension and hyperglycemia. KMUP-1, a xanthine derivative, has been demonstrated to modulate K⁺-channel activity in smooth muscles. This study investigated protective mechanisms of KMUP-1 in impaired mesenteric artery (MA) reactivity in streptozotocin (STZ)-induced diabetic rats.

Rats were divided into three groups: control, STZ (65 mg/kg, ip) and STZ + KMUP-1 (5 or 10 mg/kg/day, ip). MA reactivity was measured by dual wire myograph. MA smooth muscle cells (MASMCs) were enzymatically dissociated and the K_ATP currents recorded by a whole-cell patch-clamp technique.

STZ decreased MA K_ATP currents in a time-course dependent manner and achieved steady inhibition at day 14. In the MASMCs of STZ-treated rats, KMUP-1 partially recovered the K_ATP currents, suggesting that vascular K_ATP channels were activated by KMUP-1. K⁺ (80 mM KCl)-induced MA contractions in STZ-treated rats were higher than those of control rats. KMUP-1 significantly attenuated STZ-stimulated MA contractions in response to high K⁺, suggesting that KMUP-1 may partly restore the vascular reactivity of MAs. In addition, STZ decreased the expression of endothelial nitric oxide synthase (eNOS) and this effect was reversed by KMUP-1, suggesting that KMUP-1 could improve STZ-induced vascular endothelial dysfunction.

KMUP-1 prevents STZ impairment of MA reactivity, eNOS levels and K_ATP channels, and accordingly protects against vascular dysfunction in diabetic rats.