The IK‐channel (KCa3.1) activator SKA‐31 dilates resistance arteries and lowers blood pressure independent of connexin40

SKA‐31 (naphtho[1,2‐ d ]thiazol‐2‐ylamine) is a newly developed activator of endothelial IK Ca channels, thereby inducing vasodilation and thus is a candidate for antihypertensive therapy. It is unknown whether IK Ca ‐induced dilation requires gap junctional coupling. We studied effects of SKA‐31 on hemodynamic parameters measured by telemetry and on arteriolar diameters studied by intravital microscopy in mice being deficient for connexin40 globally (Cx40 −/− ) or in the endothelium (Cx40fl:TIE2) as well as in IK Ca −/− and wildtype controls (wt). Superfusion of SKA‐31 dilated arterioles concentration‐dependently in wt and similarly in Cx40fl:TIE2 (up to 45%) independent of NO and prostaglandins. The dilation is mediated by IK Ca since it was abolished in IK Ca −/− . Injection of 30mg/kg SKA‐31 (i.p.) decreased blood pressure in wt, normotensive Cx40fl:TIE2, and hypertensive Cx40 −/− by a similar amount (~21 mmHg) without reducing heart rate. 100mg/kg SKA‐31 lowered pressure more effectively in these mice (~32 mmHg) but also reduced heart rate. We conclude that SKA‐31 specifically activates IK Ca leading to arteriolar dilation and blood pressure reduction in mice including hypertensive mice. We suggest that EDHF mediates this response and that it is independent of Cx40. Thus, the transfer of the hyperpolarization from the endothelium to smooth muscle may not necessarily require myoendothelial coupling in vivo.