Administration of the KCa channel activator SKA-31 improves long-term endothelial function, blood pressure regulation and cardiac performance in rats with type 2 diabetes

Objective

Our goal in the present study was to examine whether long-term administration of the selective K_Ca channel activator SKA-31 would mitigate the development/severity of type 2 diabetes (T2D)-associated cardiovascular (CV) complications in adult male Goto-Kakizaki (GK) rats with spontaneous T2D.

Methods

Adult male T2D GK rats instrumented with radio-telemeters were administered either vehicle or the K_Ca channel activator SKA-31 (10 mg/kg) at ~14 weeks of age by daily intraperitoneal injection for 12 consecutive weeks. In vivo and ex vivo analyses of CV function, immune system status, vascular signaling and metabolic hormones were performed following treatment.

Results

Vehicle-treated T2D GK rats exhibited gradual increases in systolic and diastolic blood pressure, whereas SKA-31 administration led to lower mean arterial pressure, along with improvements in cardiac function (i.e., ejection fraction, fractional shortening) and structure (i.e., end systolic and diastolic volumes), as determined by echocardiography. SKA-31 treatment in vivo further improved vascular endothelial function in small mesenteric arteries, as determined by arterial pressure myography, and increased the protein expression of vasodilatory signaling molecules in the vascular wall. Prolonged SKA-31 treatment did not impair vasodilatory responsiveness in skeletal muscle and coronary arteries, elicit a pro-inflammatory profile in T2D GK rats or produce any adverse histological effects in brain, kidney or liver.

Conclusions

The results of our study demonstrate that low-dose administration of the K_Ca channel activator SKA-31 improved CV function in an established rat model of spontaneous T2D and reveal a potential novel strategy to oppose CV-related morbidity in T2D.