Distinct and complementary roles for [alpha] and [beta] 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 PKC-dependent inhibition of voltage-gated potassium channels. Experimental Approach Patch-clamp...

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Bibliographic Details
Published in:British journal of pharmacology 2016-03, Vol.173 (5), p.870
Main Authors: Jackson, Robert, Brennan, Sean, Fielding, Peter, Sims, Mark W, Challiss, RA John, Adlam, David, Squire, Iain B, Rainbow, Richard D
Format: Article
Language:English
Subjects:
Arteries
Dependence
Depolarization
Electrophysiology
Glucose
Isoenzymes
Microvasculature
Muscle contraction
Muscles
Myocardial infarction
Myocytes
Perfusion
Potassium
Potassium channels (voltage-gated)
Protein kinase C
Rodents
Smooth muscle
Vasoconstriction
Vasoconstrictors
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Summary: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 PKC-dependent 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 PKC-dependent and could be pharmacologically dissected using PKC isoenzyme-specific inhibitors to reveal a PKC[beta]-dependent component of Kv inhibition dominating between 0 and 10 mM glucose with an additional PKC[alpha]-dependent 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 PKC[alpha]/PKC[beta]-mediated components. Conclusions and Implications Our results provide compelling evidence that glucose-induced PKC[alpha]/PKC[beta]-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 PKC 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.
ISSN:0007-1188
1476-5381
DOI:10.1111/bph.13399