Chien-Hsing Lee1, Zen-Kong Dai2, Cheng-Ting Yen3, Su-Ling Hsieh4, Bin-Nan Wu5. 1. Department of Pharmacology, Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan. 2. Department of Pediatrics, Division of Pediatric Cardiology and Pulmonology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Department of Pediatrics, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan. 3. Department of Pharmacology, Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan. 4. Department of Pharmacy, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan. 5. Department of Pharmacology, Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Lipid Science and Aging Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan. Electronic address: binnan@kmu.edu.tw.
Abstract
BACKGROUND: Diabetes mellitus is a metabolic disorder characterized by chronic hyperglycemia accompanied by impaired vascular and endothelial function. Activation of ATP-sensitive potassium (KATP) 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. METHODS: 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 KATP currents recorded by a whole-cell patch-clamp technique. RESULTS: STZ decreased MA KATP 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 KATP currents, suggesting that vascular KATP 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. CONCLUSION: KMUP-1 prevents STZ impairment of MA reactivity, eNOS levels and KATP channels, and accordingly protects against vascular dysfunction in diabetic rats.
BACKGROUND:Diabetes mellitus is a metabolic disorder characterized by chronic hyperglycemia accompanied by impaired vascular and endothelial function. Activation of ATP-sensitive potassium (KATP) 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 diabeticrats. METHODS: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 KATP currents recorded by a whole-cell patch-clamp technique. RESULTS:STZ decreased MA KATP 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 KATP currents, suggesting that vascular KATP 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. CONCLUSION:KMUP-1 prevents STZ impairment of MA reactivity, eNOS levels and KATP channels, and accordingly protects against vascular dysfunction in diabeticrats.