Modulation of Cardiovascular Function in Primary Hypertension in Rat by SKA-31, an Activator of KCa2.x and KCa3.1 Channels

Abstract

The aim of this study was to investigate the hemodynamic effects of SKA-31, an activator of the small (KCa2.x) and intermediate (KCa3.1) conductance calcium-activated potassium channels, and to evaluate its influence on endothelium-derived hyperpolarization (EDH)-KCa2.3/KCa3.1 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 KCa3.1, KCa2.3, KIR 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, KCa2.3, KCa3.1 and KIR were decreased, while Na+/K+-ATPase expression was increased. Collectively, SKA-31 promoted hypotension and vasodilatation, potentiated agonist-stimulated vasodilation, and maintained KCa2.3/KCa3.1-EDH-response in sMAs of SHR with downstream signaling that involved KIR 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 KCa2.3/KCa3.1 channels such as SKA-31 seem to be a promising avenue in pharmacotherapy of hypertension.

Vasoprotective Endothelial Effects of Chronic Cannabidiol Treatment and Its Influence on the Endocannabinoid System in Rats with Primary and Secondary Hypertension

“…In the mesenteric G3 artery, a greater (about 20%) significance of NO-mediated vasorelaxation in WKY rats and SHR than in DOCA-salt rats was determined. Like in our previous studies, vasodilator prostanoids play a small but constant role in modulating vascular tone independent of the vessel size, especially in normotensive rats [40,41].…”

“…Additionally, we evaluated the expression of the mRNAs of KCNN4 and KCNN3, whose products (the intermediate and small calcium-activated potassium channels K Ca 3.1 and K Ca 2.3, respectively) are thought to mediate endothelium-dependent hyperpolarization (EDH). They play a pivotal role in NO-/PGI 2 -independent endothelium-mediated vasorelaxation in resistance vessels and act as a backup system to maintain endothelial function in situations associated with decreased bioactivity of NO-e.g., in hypertension [40]. We revealed changes dependent on the hypertension model, since both KCNN4 and KCNN3 were downregulated in the aortas and mesenteric G3 arteries of SHR, whereas their expression levels were unchanged in DOCA-salt rats, with the exception of the KCNN4 level being enhanced in aortas.…”

Cannabidiol Ameliorates Monocrotaline-Induced Pulmonary Hypertension in Rats

“…For immunohistochemical analysis, the EnVision method was used according to Kloza et al [ 55 ], using antibodies against von Willebrand factor (vWF) (1:2000, 2 h incubation at room temperature (RT), Polyclonal Rabbit Anti-Human (no cat. A 0082); DakoCytomation, Glostrup, Denmark).…”

Pancreatic Microcirculation Profiles in the Progression of Hypertension in Spontaneously Hypertensive Rats

“… 28 NO, synthesized by eNOS, is an endothelial-derived vasodilator, that maintains microvascular endothelial physiological function via the nitrate–nitrite–NO pathway. 29 It has been reported that the reduction 30 and inactivation 31 of eNOS in hypertensive rats might mediate vasodilatory dysfunction. Consistently, the present study showed a reduction in the amplitudes of NO-independent and NO-dependent endothelial oscillators, together with increased nitrate/nitrite and endothelin-1 levels in SHRs, which may result in a decrease in flow-mediated vasodilation.…”