Pharmacologic targeting of endothelial Ca<sup>2+</sup>-activated K<sup>+</sup> channels: A strategy to improve cardiovascular function

John, Cini Mathew; Khaddaj‐Mallat, Rayan; George, Grace; Kim, Taeyeob; Mishra, Ramesh; Braun, Andrew P.

doi:10.1080/19336950.2018.1454814

Cited by 12 publications

(11 citation statements)

References 86 publications

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“…Similar observations have also been reported in murine cremaster muscle arterioles [16] and carotid arteries [13] where SKA-31-induced EDH was wholly dependent on K Ca 3.1 activation. In agonist-induced EDH responses and in vasodilation of resistance arteries induced by Ach, K Ca 3.1 was the predominant K Ca channel reportedly involved [7,11,12,47]. However, our results are in opposition to the findings that K Ca 2.3 plays the main role in the EDH-mediated response in superior mesenteric arteries in SHRSP [38] and in SMAs of angiotensin II-induced hypertension and in SHR [45,48].…”

Section: Discussionmentioning

confidence: 99%

“…Pharmacological activation of the K Ca 3.1 and K Ca 2.3 channels could improve endothelium dysfunction and BP regulation thereby representing novel targets for antihypertensive drugs [10,11,12]. The K Ca 3.1 and K Ca 2.x channel activator SKA-31 (naphtho (1,2-d)thiazol-2-ylamine) exhibits excellent pharmacokinetic properties such as long half-life (12 h), no toxicity, and low plasma protein binding in rodents [13].…”

Section: Introductionmentioning

confidence: 99%

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

Kloza

Baranowska-Kuczko

Toczek

et al. 2019

IJMS

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Kloza

Baranowska-Kuczko

Toczek

et al. 2019

IJMS

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“…We and others have reported that endothelium-dependent, agonist-evoked vasodilation can be augmented in the presence of a low or threshold concentration of a KCa channel activator, such as SKA-31 [28,32,33]. This treatment strategy can further mitigate endothelial dysfunction associated with type 2 diabetes [28,33] and we speculate that it occurs via a pharmacological “priming” or sensitization of endothelial KCa channel activity and EDH-type signaling [53]. In small mesenteric arteries from both SHRs and Wistar rats, SKA-31 treatment augmented ACh, but not BK, induced vasodilation (Figure 1), consistent with the putative sensitization of this GPCR signaling pathway in these vessels.…”

Section: Discussionmentioning

confidence: 72%

Pharmacological Targeting of KCa Channels to Improve Endothelial Function in the Spontaneously Hypertensive Rat

Khaddaj‐Mallat¹,

John²,

Mishra³

et al. 2019

IJMS

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Systemic hypertension is a major risk factor for the development of cardiovascular disease and is often associated with endothelial dysfunction. KCa2.3 and KCa3.1 channels are expressed in the vascular endothelium and contribute to stimulus-evoked vasodilation. We hypothesized that acute treatment with SKA-31, a selective activator of KCa2.x and KCa3.1 channels, would improve endothelium-dependent vasodilation and transiently lower mean arterial pressure (MAP) in male, spontaneously hypertensive rats (SHRs). Isolated vascular preparations exhibited impaired vasodilation in response to bradykinin (i.e., endothelial dysfunction) compared with Wistar controls, which was associated with decreased bradykinin receptor expression in mesenteric arteries. In contrast, similar levels of endothelial KCa channel expression were observed, and SKA-31 evoked vasodilation was comparable in vascular preparations from both strains. Addition of a low concentration of SKA-31 (i.e., 0.2–0.3 μM) failed to augment bradykinin-induced vasodilation in arteries from SHRs. However, responses to acetylcholine were enhanced. Surprisingly, acute bolus administration of SKA-31 in vivo (30 mg/kg, i.p. injection) modestly elevated MAP compared with vehicle injection. In summary, pharmacological targeting of endothelial KCa channels in SHRs did not readily reverse endothelial dysfunction in situ, or lower MAP in vivo. SHRs thus appear to be less responsive to endothelial KCa channel activators, which may be related to their vascular pathology.

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“…The K Ca channels are important effectors in the control of vascular tone and blood pressure [ 33 ]. They mediate membrane hyperpolarization in response to elevations of intracellular Ca 2+ and thus counteract SM contractility [ 34 ].…”

Section: Diversity Of K + Channels In Huamentioning

confidence: 99%

Clinical Importance of the Human Umbilical Artery Potassium Channels

Lorigo

Oliveira

2020

Cells

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Potassium (K+) channels are usually predominant in the membranes of vascular smooth muscle cells (SMCs). These channels play an important role in regulating the membrane potential and vessel contractility—a role that depends on the vascular bed. Thus, the activity of K+ channels represents one of the main mechanisms regulating the vascular tone in physiological and pathophysiological conditions. Briefly, the activation of K+ channels in SMC leads to hyperpolarization and vasorelaxation, while its inhibition induces depolarization and consequent vascular contraction. Currently, there are four different types of K+ channels described in SMCs: voltage-dependent K+ (KV) channels, calcium-activated K+ (KCa) channels, inward rectifier K+ (Kir) channels, and 2-pore domain K+ (K2P) channels. Due to the fundamental role of K+ channels in excitable cells, these channels are promising therapeutic targets in clinical practice. Therefore, this review discusses the basic properties of the various types of K+ channels, including structure, cellular mechanisms that regulate their activity, and new advances in the development of activators and blockers of these channels. The vascular functions of these channels will be discussed with a focus on vascular SMCs of the human umbilical artery. Then, the clinical importance of K+ channels in the treatment and prevention of cardiovascular diseases during pregnancy, such as gestational hypertension and preeclampsia, will be explored.

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Pharmacologic targeting of endothelial Ca²⁺-activated K⁺ channels: A strategy to improve cardiovascular function

Cited by 12 publications

References 86 publications

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

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

Pharmacological Targeting of KCa Channels to Improve Endothelial Function in the Spontaneously Hypertensive Rat

Clinical Importance of the Human Umbilical Artery Potassium Channels

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Pharmacologic targeting of endothelial Ca2+-activated K+ channels: A strategy to improve cardiovascular function

Cited by 12 publications

References 86 publications

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

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

Pharmacological Targeting of KCa Channels to Improve Endothelial Function in the Spontaneously Hypertensive Rat

Clinical Importance of the Human Umbilical Artery Potassium Channels

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Pharmacologic targeting of endothelial Ca²⁺-activated K⁺ channels: A strategy to improve cardiovascular function