title: Endothelium dependent hyperpolarization-type relaxation compensates for attenuated nitric oxide-mediated responses in subcutaneous arteries of diabetic patients.
abstract: Diabetes impairs endothelium-dependent relaxations. The present study evaluated the contribution of different endothelium-dependent relaxing mechanisms to the regulation of vascular tone in subcutaneous blood vessels of humans with Type 2 diabetes mellitus. Subcutaneous arteries were isolated from tissues of healthy controls and diabetics. Vascular function was determined using wire myography. Expressions of proteins were measured by Western blotting and immunostaining. Endothelium-dependent relaxations to acetylcholine were impaired in arteries from diabetics compared to controls (P = 0.009). Acetylcholine-induced nitric oxide (NO)-mediated relaxations [in the presence of an inhibitor of cyclooxygenases (COX; indomethacin) and small and intermediate conductance calcium-activated potassium channel blockers (UCL1684 and TRAM 34, respectively)] were attenuated in arteries from diabetics compared to controls (P < 0.001). However, endothelium-dependent hyperpolarization (EDH)-type relaxations [in the presence of indomethacin and the NO synthase blocker, l-NAME] were augmented in arteries from diabetics compared to controls (P = 0.003). Endothelium-independent relaxations to sodium nitroprusside (NO donor) and salbutamol (β-adrenoceptor agonist) were preserved, but those to prostacyclin were attenuated in diabetics compared to controls (P = 0.017). In arteries of diabetics, protein expressions of endothelial NO synthase, prostacyclin synthase and prostacyclin receptors were decreased, but those of COX-2 were increased. These findings suggest that in human diabetes, the impairment of endothelium-dependent relaxations is caused by a diminished NO bioavailability; however, EDH appears to compensate, at least in part, for this dysfunction.
authors.affiliation: Pharmacology Vascular Laboratory, School of Medical Sciences, Universiti Sains Malaysia, Health Campus, Kota Bharu, Malaysia.
authors.forename: Siti Safiah
authors.initials: SS
authors.lastname: Mokhtar
authors.affiliation: Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Vanhoutte
authors.affiliation: Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: Susan Wai Sum
authors.initials: SW
authors.lastname: Leung
authors.affiliation: Department of Orthopaedic, School of Medical Sciences, Universiti Sains Malaysia, Health Campus, Kota Bharu, Malaysia.
authors.forename: Mohd Imran
authors.initials: MI
authors.lastname: Yusof
authors.affiliation: Reconstructive Sciences Unit, School of Medical Sciences, Universiti Sains Malaysia, Health Campus, Kota Bharu, Malaysia.
authors.forename: Wan Azman
authors.initials: WA
authors.lastname: Wan Sulaiman
authors.affiliation: Reconstructive Sciences Unit, School of Medical Sciences, Universiti Sains Malaysia, Health Campus, Kota Bharu, Malaysia.
authors.forename: Arman Zaharil
authors.initials: AZ
authors.lastname: Mat Saad
authors.affiliation: School of Health Sciences, Universiti Sains Malaysia, Health Campus, Kota Bharu, Malaysia.
authors.forename: Rapeah
authors.initials: R
authors.lastname: Suppian
authors.affiliation: Pharmacology Vascular Laboratory, School of Medical Sciences, Universiti Sains Malaysia, Health Campus, Kota Bharu, Malaysia. Electronic address: aidakb@usm.my.
authors.forename: Aida Hanum Ghulam
authors.initials: AH
authors.lastname: Rasool
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001682:Biological Availability; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide / Q000378:metabolism*; D055815:Young Adult
chemical_list: D009569:Nitric Oxide
keywords: Diabetes; Endothelial dysfunction; Endothelium-dependent hyperpolarization; Nitric oxide; Subcutaneous artery