The influence of DOCA-salt hypertension and chronic administration of the FAAH inhibitor URB597 on KCa2.3/KCa3.1-EDH-type relaxation in rat small mesenteric arteries

Kloza, Monika; Baranowska-Kuczko, Marta; Malinowska, Barbara; Karpińska, Olga; Harasim-Symbor, Ewa; Kasacka, Irena; Kozłowska, Hanna

doi:10.1016/j.vph.2017.10.001

Cited by 9 publications

(8 citation statements)

References 49 publications

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“…In hypertension, under reduced bioavailability of NO, and when vasorelaxation is impaired, EDH-type dilatation is an important compensatory dilator system [1]. This finding is in line with research using the experimental model of acquired angiotensin II-induced, deoxycorticosterone acetate-salt (DOCA-salt) hypertension in SHR and SHRSP [11,38,45,46] respectively.…”

Section: Discussionsupporting

confidence: 54%

“…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%

“…Male SHR and WKY rats were anaesthetized with pentobarbitone sodium (300 µM/kg i.p.). Two mm long segments of the third-order mesenteric arteries (small mesenteric arteries, sMAs) were prepared mounted in a Mulvany-Halpern-type wire myograph (Multi Wire Myograph System DMT 620 M, Danish Myo Technology, Aarhus, Denmark) as described previously [11].…”

Section: Methodsmentioning

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: Discussionsupporting

confidence: 54%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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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“…Interestingly, it was enhanced in DOCA-salt hypertension but reduced in SHR. The reactivity of the CBD-mediated relaxation by endothelium removal in DOCA-salt but not in SHR argues for its possible crucial role in compensatory mechanisms in secondary hypertension, like DOCA-salt [48]. Similarly, despite comparable values of enhanced blood pressure in both models of hypertension in comparison with respective controls secondary [25] and primary [49,50] hypertension enhanced and reduced the vasodilator responses to methanadamide and/or anandamide in rat sMAs and/or the mesenteric vascular bed, respectively; endocannabinoids levels were lower in SHR and higher in DOCA-salt ( [51]; one should keep in mind that CBD is antagonist of anandamide degradation), pressor responses of MAs to periarterial nerve stimulation and to exogenous noradrenaline infusion were higher in SHRs and lower or without change in DOCA-salt, respectively [52].…”

Section: Influence Of Hypertension On the Cannabidiol-mediated Vasorementioning

confidence: 99%

Vasodilatory effects of cannabidiol in human pulmonary and rat small mesenteric arteries: modification by hypertension and the potential pharmacological opportunities

Baranowska-Kuczko¹,

Kozłowska²,

Kloza³

et al. 2020

Journal of Hypertension

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Objective: Cannabidiol (CBD) has been suggested as a potential antihypertensive drug. The aim of our study was to investigate its vasodilatory effect in isolated human pulmonary arteries (hPAs) and rat small mesenteric arteries (sMAs). Methods: Vascular effects of CBD were examined in hPAs obtained from patients during resection of lung carcinoma and sMAs isolated from spontaneously hypertensive (SHR); 11-deoxycorticosterone acetate (DOCA-salt) hypertensive rats or their appropriate normotensive controls using organ bath and wire myography, respectively. Results: CBD induced almost full concentration-dependent vasorelaxation in hPAs and rat sMAs. In hPAs, it was insensitive to antagonists of CB 1 (AM251) and CB 2 (AM630) receptors but it was reduced by endothelium denudation, cyclooxygenase inhibitors (indomethacin and nimesulide), antagonists of prostanoid EP 4 (L161982), IP (Cay10441), vanilloid TRPV1 (capsazepine) receptors and was less potent under KCl-induced tone and calciumactivated potassium channel (K Ca) inhibitors (iberiotoxin, UCL1684 and TRAM-34) and in hypertensive, overweight and hypercholesteremic patients. The time-dependent effect of CBD was sensitive to the PPARg receptor antagonist GW9662. In rats, the CBD potency was enhanced in DOCA-salt and attenuated in SHR. The CBDinduced relaxation was inhibited in SHR and DOCA-salt by AM251 and only in DOCA-salt by AM630 and endothelium denudation. Conclusion: The CBD-induced relaxation in hPAs that was reduced in hypertensive, obese and hypercholesteremic patients was endothelium-dependent and mediated via K Ca and IP, EP 4 , TRPV1 receptors. The CBD effect in rats was CB 1-sensitive and dependent on the hypertension model. Thus, modification of CBD-mediated responses in disease should be considered when CBD is used for therapeutic purposes.

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Regulation of ion channels in the microcirculation by mineralocorticoid receptor activation

Chambers

Dorrance

2020

Current Topics in Membranes

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The influence of DOCA-salt hypertension and chronic administration of the FAAH inhibitor URB597 on KCa2.3/KCa3.1-EDH-type relaxation in rat small mesenteric arteries

Cited by 9 publications

References 49 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

Vasodilatory effects of cannabidiol in human pulmonary and rat small mesenteric arteries: modification by hypertension and the potential pharmacological opportunities

Regulation of ion channels in the microcirculation by mineralocorticoid receptor activation

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