Compromised endothelium-dependent hyperpolarization-mediated dilations can be rescued by NS309 in obese Zucker rats

Objective: NO and a non-NO/prostacyclin EDH mechanism are major contributors of vascular tone and cerebral blood flow. However, the effect of metabolic syndrome on EDH-mediated responses in cerebral vessels remains unknown and may offer another avenue for therapeutic targeting. The purpose of this study was to investigate EDH-dependent responses in cerebral arteries during metabolic syndrome. Methods: EDH-dependent dilations were assessed in MCAs isolated from nondiabetic obese and lean Zucker rats in the presence and absence of NS309, an activator of SK_Ca and IK_Ca channels. IK_Ca channel expression and activity were assessed by western blotting and pressure myography, respectively. Results: EDH-mediated dilations were significantly attenuated in the obese compared to the lean Zucker rat MCA. Luminal delivery of 1 μM NS309 enhanced EDH-mediated responses in lean and obese Zucker cerebral vessels. Both dose-dependent dilations to luminal NS309 and IK_Ca protein expression in pooled cerebral arteries were comparable between the two groups. Conclusions: Our results suggest that pharmacological targeting of IK_Ca channels can rescue EDH-mediated dilations in obese Zucker rat MCAs. Compromised EDH-mediated dilations in obesity are not due to impaired IK_Ca channel expression or activity.