Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 20, Issue 17, Pages -Publisher
MDPI
DOI: 10.3390/ijms20174118
Keywords
SHR; hypertension; SKA-31; K(Ca)3; 1; K(Ca)2; 3-EDH-dilator system; K-IR; Na+; K+-ATP-ase
Funding
- Medical University of Bialystok [N/ST/ZB/18/003/2213, N/ST/ZB/18/004/2213, SUB/2/DN/19/003/2213]
- National Science Centre (Poland) [NCN 2012/05/B/NZ7/03102]
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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 mu M)-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, Ba2+ 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.
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