A pharmacologic activator of endothelial KCa channels enhances coronary flow in the hearts of type 2 diabetic rats

Ramesh C. Mishra, Heike Wulff, William C. Cole, Andrew P. Braun

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Endothelial dysfunction is a common early pathogenic event in patients with type 2 diabetes (T2D) who exhibit cardiovascular disease. In the present study, we have examined the effect of SKA-31, a positive modulator of endothelial Ca2+-activated K+ (KCa) channels, on total coronary flow in isolated hearts from Goto-Kakizaki rats, a non-obese model of T2D exhibiting metabolic syndrome. Total coronary flow and left ventricular developed pressure were monitored simultaneously in isolated, spontaneously beating Langendorff-perfused hearts. Acute administrations of bradykinin (BK) or adenosine (ADO) increased coronary flow, but responses were significantly blunted in diabetic hearts at 10-12 and 18-20weeks of age compared with age-matched Wistar controls, consistent with the presence of endothelial dysfunction. In contrast, SKA-31 dose-dependently (0.01-5μg) increased total coronary flow to comparable levels in both control and diabetic rat hearts at both ages. Flow responses to sodium nitroprusside were not different between control and diabetic hearts, suggesting normal arterial smooth muscle function. Importantly, exposure to a sub-threshold concentration of SKA-31 (i.e. 0.3μM) rescued the impaired BK and ADO-evoked vasodilatory responses in diabetic hearts. Endothelial KCa channel activators may thus help to preserve coronary flow in diabetic myocardium.

Original languageEnglish (US)
Pages (from-to)364-373
Number of pages10
JournalJournal of Molecular and Cellular Cardiology
Volume72
DOIs
StatePublished - 2014

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Bradykinin
Adenosine
Type 2 Diabetes Mellitus
Calcium-Activated Potassium Channels
Nitroprusside
Ventricular Pressure
Smooth Muscle
Myocardium
Cardiovascular Diseases
naphtho(1,2-d)thiazol-2-ylamine
Isolated Heart Preparation

Keywords

  • Coronary circulation
  • Endothelium
  • Type 2 diabetes
  • Vasodilation

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine
  • Medicine(all)

Cite this

A pharmacologic activator of endothelial KCa channels enhances coronary flow in the hearts of type 2 diabetic rats. / Mishra, Ramesh C.; Wulff, Heike; Cole, William C.; Braun, Andrew P.

In: Journal of Molecular and Cellular Cardiology, Vol. 72, 2014, p. 364-373.

Research output: Contribution to journalArticle

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