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The aim of this study was to investigate the hemodynamic effects of SKA-31, an activator of the small ( K Ca 2.x ) and intermediate ( K Ca 3.1 ) conductance calcium-activated potassium channels, and to evaluate its influence on endothelium-derived hyperpolarization (EDH)- K Ca 2.3 / K Ca 3.1 type relaxation in isolated endothelium-intact small mesenteric arteries (sMAs) from spontaneously hypertensive rats (SHRs). Functional in vivo and in vitro experiments were performed on SHRs or their normotensive controls, Wistar-Kyoto rats (WKY). SKA-31 (1, 3 and 10 mg/kg) caused a brief decrease in blood pressure and bradycardia in both SHR and WKY rats. In phenylephrine-pre-constricted sMAs of SHRs, SKA-31 (0.01-10 µM)-mediated relaxation was reduced and SKA-31 potentiated acetylcholine-evoked endothelium-dependent relaxation. Endothelium denudation and inhibition of nitric oxide synthase (eNOS) and cyclooxygenase (COX) by the respective inhibitors l -NAME or indomethacin, attenuated SKA-31-mediated vasorelaxation. The inhibition of K Ca 3.1 , K Ca 2.3 , K IR and Na + /K + -ATPase by TRAM-34, UCL1684, Ba 2+ and ouabain, respectively, reduced the potency and efficacy of the EDH-response evoked by SKA-31. The mRNA expression of eNOS, prostacyclin synthase, K Ca 2.3 , K Ca 3.1 and K IR were decreased, while Na + /K + -ATPase expression was increased. Collectively, SKA-31 promoted hypotension and vasodilatation, potentiated agonist-stimulated vasodilation, and maintained K Ca 2.3 / K Ca 3.1 -EDH-response in sMAs of SHR with downstream signaling that involved K IR and Na + /K + -ATPase channels. In view of the importance of the dysfunction of endothelium-mediated vasodilatation in the mechanism of hypertension, application of activators of K Ca 2.3 / K Ca 3.1 channels such as SKA-31 seem to be a promising avenue in pharmacotherapy of hypertension., Competing Interests: The authors declare that there are no conflicts of interest.