Enhanced function of inhibitory presynaptic cannabinoid CB1 receptors on sympathetic nerves of DOCA–salt hypertensive rats

Toczek, Marek; Schlicker, Eberhard; Grzęda, Emilia; Malinowska, Barbara

doi:10.1016/j.lfs.2015.03.022

Cited by 16 publications

(28 citation statements)

References 46 publications

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“…However, hypertension‐induced ventricular changes are accompanied by modifications of atrial function (Pluteanu et al , ). In contrast to the reduced effects and expression of cardiac CB 1 receptors in DOCA‐salt reported here, we have found in the same model up‐regulation of vascular CB 1 receptors and CB 1 receptor‐mediated vasodilatation (Baranowska‐Kuczko et al, ) and enhanced inhibition of sympathetic noradrenaline release (Toczek et al, ) in resistance vessels. This suggests that these receptors may play a protective role in hypertension.…”

Section: Discussioncontrasting

confidence: 95%

Chronic inhibition of fatty acid amide hydrolase by URB597 produces differential effects on cardiac performance in normotensive and hypertensive rats

Pędzińska-Betiuk

Weresa

Toczek

et al. 2017

British J Pharmacology

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Section: Discussioncontrasting

confidence: 95%

Chronic inhibition of fatty acid amide hydrolase by URB597 produces differential effects on cardiac performance in normotensive and hypertensive rats

Pędzińska-Betiuk

Weresa

Toczek

et al. 2017

British J Pharmacology

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“…The left femoral vein was cannulated for the intravenous (i.v.) administration of drugs [58]. Each animal was injected with SKA-31 in increasing doses (1, 3, 10 mg/kg) or respective vehicles at a volume of 0.5 mL/kg (1, 3 mg/kg) or 1 mL/kg (10 mg/kg).…”

Section: Methodsmentioning

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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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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“…Their up-regulation, shown by the higher expression level and their involvement in methanandamide-induced relaxation and potential protective role, has been previously demonstrated in sMAs isolated from primary [49] and secondary [25] hypertensive rats. Moreover, the enhancement and a potential protective effect of CB 1 receptor-mediated presynaptic inhibition of the sympathetic nerve endings innervating resistance vessels of pithed rats was noticed in DOCA-salt hypertension [54] but not in SHR [55]. In contrast to hPAs, in rat sMAs, AM251 reduced CBD's potency, suggesting that CBD might rather act directly at CB 1 receptors in this vascular bed.…”

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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Enhanced function of inhibitory presynaptic cannabinoid CB1 receptors on sympathetic nerves of DOCA–salt hypertensive rats

Cited by 16 publications

References 46 publications

Chronic inhibition of fatty acid amide hydrolase by URB597 produces differential effects on cardiac performance in normotensive and hypertensive rats

Chronic inhibition of fatty acid amide hydrolase by URB597 produces differential effects on cardiac performance in normotensive and hypertensive rats

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

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