Prolonged Administration of the KCa Channel Activator SKA‐31 Improves Cardiac Function and Blood Pressure in Type 2 Diabetic Goto‐Kakizaki Rats

Abstract

Endothelial dysfunction represents an independent risk factor contributing to the onset and progression of cardiovascular complications (e.g. hypertension, cardiomyopathy, stroke) in patients with Type 2 Diabetes (T2D). It is further predicted that reduction/reversal of endothelial dysfunction will mitigate T2D‐associated cardiovascular deficits. Small‐ and intermediate‐conductance, Ca2+‐activated K+ channels (KCa2.3 and KCa3.1, respectively) are prominently expressed in the vascular endothelium, and pharmacologic activators of these channels (e.g. SKA‐31) induce robust vasodilation upon acute application to isolated resistance arteries and intact animals. However, the effects of prolonged, in vivo administration of a KCa activator on the cardiovascular system have not been examined to date. In our current study, we have hypothesized that daily administration of SKA‐31 (10 and 30 mg/kg, I.P. injection) to male, non‐obese Type 2 Diabetic Goto‐Kakizaki rats (T2D GK, 14 weeks of age) for 12 weeks would oppose the development of diabetes‐related cardiac dysfunction. Echocardiographic analyses revealed that left ventricular (LV) ejection fraction, stroke volume and fractional shortening all significantly declined over time in vehicle‐treated rats, but remained at pre‐trial levels in animals administered either 10 or 30 mg/kg SKA‐31 for 12 weeks (n = 5–6/group). Chronic blood pressure measurements over the same period via radiotelemetry further revealed that SKA‐31 treatment lowered mean arterial pressure, compared with vehicle treated animals, with effects observed on both systolic and diastolic pressures (n = 5–6/group). To determine if the observed improvements in cardiac performance may be due to direct changes in the responsiveness of the coronary vasculature, isolated hearts from vehicle and SKA‐31 treated T2D GK rats were mounted in a Langendorff perfusion system under constant pressure (n ≥ 3/group). We observed that endothelium‐dependent, agonist‐evoked increases in coronary flow were similar in hearts from vehicle and SKA‐31 treated animals, as was baseline LV developed pressure. Histological staining of isolated hearts revealed differing levels of LV collagen content in the 3 treatment groups. In summary, these results indicate that prolonged SKA‐31 administration in T2D GK rats can improve cardiac function, which likely occur via both direct and indirect effects.Support or Funding InformationThis study was supported by research funding to APB from the Canadian Institutes of Health Research (MOP‐142467) and the Natural Sciences and Engineering Research Council of Canada (RGPIN‐2017‐04116), and to HW from the National Institutes of Health (R21 NS101876).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.