Distinct and complementary roles for α and β isoenzymes of PKC in mediating vasoconstrictor responses to acutely elevated glucose.

BACKGROUND AND PURPOSE:We investigated the hypothesis that elevated glucose increases contractile responses in vascular smooth muscle and that this enhanced constriction occurs due to the glucose-induced inhibition of voltage-gated potassium channels. EXPERIMENTAL APPROACH:Patch-clamp electrophysiology in rat isolated mesenteric arterial myocytes was performed to investigate the glucose-induced inhibition of voltage-gated potassium (Kv ) current. To determine the effects of glucose in whole vessel, wire myography was performed in rat mesenteric, porcine coronary and human internal mammary arteries. KEY RESULTS:Glucose-induced inhibition of Kv was duanyu1531-dependent and could be pharmacologically dissected using isoenzyme-specific inhibitors to reveal a component of Kv inhibition dominating between 0 and 10 mM glucose with an additional component becoming evident at concentrations greater than 10 mM. These findings were supported using wire myography in all artery types used, where contractile responses to vessel depolarization and vasoconstrictors were enhanced by increasing bathing glucose concentration, again with evidence for distinct and complementary components. CONCLUSIONS AND IMPLICATIONS:Our results provide compelling evidence that glucose-induced duanyu1531α/duanyu1531β-mediated inhibition of Kv current in vascular smooth muscle causes an enhanced constrictor response. Inhibition of Kv current causes a significant depolarization of vascular myocytes leading to marked vasoconstriction. The duanyu1531 dependence of this enhanced constrictor response may present a potential therapeutic target for improving microvascular perfusion following percutaneous coronary intervention after myocardial infarction in hyperglycaemic patients.

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