Mechanisms of l-alpha-lysophosphatidylinositol-induced relaxation in human pulmonary arteries

Karpińska, Olga; Baranowska-Kuczko, Marta; Malinowska, Barbara; Kloza, Monika; Kusaczuk, Magdalena; Gęgotek, Agnieszka; Golec, Paweł; Kasacka, Irena; Kozłowska, Hanna

doi:10.1016/j.lfs.2017.11.020

Cited by 13 publications

(16 citation statements)

References 39 publications

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“…ML193 also blocks pro-nociceptive effects of LPI and LPI-evoked depolarisation of neurons from a brain region, the periaqueductal grey [15], reinforcing previous data linking GPR55 to pain perception [16,17]. CID16020046 has been used to understand the role of GPR55 in the cardiovascular system [12,18,19], in atherosclerosis and intestinal inflammation [20][21][22], and in brain [23]. CID16020046 has extended the association of GPR55 to cancer, blocking LPI-evoked angiogenesis in ovarian carcinoma and migration of breast cancer cells [24,25].…”

Section: Introductionsupporting

confidence: 66%

Structure-Activity Relationship of the GPR55 Antagonist, CID16020046

Brown¹,

Castellano-Pellicena²,

Haslam³

et al. 2018

Pharmacology

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Background/Aims: CID16020046 blocks the effect of the lipid lysophosphatidylinositol (LPI) at its receptor, GPR55. CID16020046 and another antagonist, ML193, have been used to investigate GPR55-mediated effects of LPI on cells, tissues, and in vivo. Here we describe the structure-activity relationship of CID16020046. Methods: Yeast or human cells were engineered to express GPR55 or control receptors. Cells were pretreated with a test agent before agonist challenge. Functional responses were quantified by yeast gene-reporter or calcium imaging. Results: Three substituents around the central pyrazololactam core of CID16020046 are each tolerant to substitution without abolishing GPR55 activity. Analogues of CID16020046 with potency at GPR55 ranging >1,000-fold are described, including several lacking activity up to the top concentration tested. One analogue, compound 1 (GSK875734A), has approximately 50-fold greater potency than CID16020046 in an inverse agonist assay. CID16020046, ML193 and 2 further antagonists (ML191 and ML192) all block the effect of a surrogate agonist at human GPR55. ML193, CID16020046 and several other examples of the pyrazololactam chemotype were also shown to antagonise rat GPR55. Conclusion: These data confirm the utility of CID16020046 and ML193 as tools to investigate the physiological role of GPR55, and offer starting points for GPR55 antagonists with optimised pharmacokinetic or other properties.

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Section: Introductionsupporting

confidence: 66%

Structure-Activity Relationship of the GPR55 Antagonist, CID16020046

Brown¹,

Castellano-Pellicena²,

Haslam³

et al. 2018

Pharmacology

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“…After a stable level of tone was maintained, CRCs were generated by the cumulative application of CBD or its vehicle. To determine the mechanisms of the vasorelaxant effects of CBD, tissues were pretreated for 30 min with either the following antagonists or inhibitors (the respective concentrations are given in parentheses): AM251 (1 mmol/l; cannabinoid CB 1 receptor antagonist); AM630 (1 mmol/l; cannabinoid CB 2 receptor antagonist); O-1918 (10 mmol/l; antagonist of endothelium-dependent relaxation to cannabinoids; see Discussion); capsazepine (1 mmol/l; vanilloid TRPV1 receptor antagonist), Cay10441 (10 mmol/l; prostanoid IP receptor antagonist) [19]; RN1734 (20 mM; vanilloid TRPV4 receptor antagonist) [26]; L161982 (1 mmol/l; prostanoid EP 4 receptor antagonist); nimesulide (10 mmol/l; cyclooxygenase COX-2 inhibitor); sodium diethyldithiocarbamate trihydrate (DETCA; 300 mmol/l; SOD inhibitor) [16]; indomethacin (INDO; 10 mmol/l; cyclooxygenase COX-1/COX-2 inhibitor); N v -nitro-L-arginine methyl ester (L-NAME; 300 mmol/l, nitric oxide synthase inhibitor); and UCL1684 (0.1 mmol/l), TRAM-34 (10 mmol/ l), and iberiotoxin (0.1 mmol/l), which are small (K Ca 2.3), intermediate (K Ca 3.1) and large (K Ca 1.1) conductance Ca 2þactivated K þ channel blockers (K Ca ), respectively [27]. To assess the contribution of PPARg activation, experiments were performed in the presence of the PPARg antagonist GW9662 (1 and 10 mmol/l) [5,28] added 10 min prior to precontraction.…”

Section: Vasorelaxation Studymentioning

confidence: 99%

“…Rat sMAs were isolated from hypertensive SHR, DOCA-salt and normotensive WKY and SHAM animals (pooled from six rats from each group). The RNA isolation and Cnr1 and Cnr2 gene expression analysis were performed according to methodology previously described [27,29]. Tissue samples were immediately flash-frozen in liquid nitrogen and stored at À 80 8C.…”

Section: Rna Isolation and Gene Expression Analysismentioning

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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“…In that study, we showed that CBD fully relaxed isolated human pulmonary arteries [ 7 ]. The similarly strong relaxation of human and rat pulmonary arteries (hPAs, rPAs) caused by other exo- (abnormal-cannabidiol) and endocannabinoids (anandamide, virodhamine, 2-arachidonyl glycerol and l-alpha-lysophosphatidylinositol [ 9 , 10 , 11 , 12 , 13 , 14 ]) led to suggestions about the potential therapeutic significance of cannabinoids in PAH treatment [ 15 ]. In addition, CBD can modify endocannabinoid levels as a result of inhibition of fatty acid amide hydrolase (FAAH), an enzyme responsible for degradation of anandamide or other endocannabinoids, and/or its interaction with the anandamide membrane transporter.…”

Section: Introductionmentioning

confidence: 99%

Cannabidiol Ameliorates Monocrotaline-Induced Pulmonary Hypertension in Rats

Sadowska

Baranowska-Kuczko

Gromotowicz-Popławska

et al. 2020

IJMS

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Cannabidiol (CBD) is known for its vasorelaxant (including in the human pulmonary artery), anti-proliferative and anti-inflammatory properties. The aim of our study was to examine the potential preventive effect of chronic CBD administration (10 mg/kg/day for three weeks) on monocrotaline (MCT)-induced pulmonary hypertension (PH) rats. PH was connected with elevation of right ventricular systolic pressure; right ventricle hypertrophy; lung edema; pulmonary artery remodeling; enhancement of the vasoconstrictor and decreasing vasodilatory responses; increases in plasma concentrations of tissue plasminogen activator, plasminogen activator inhibitor type 1 and leukocyte count; and a decrease in blood oxygen saturation. CBD improved all abovementioned changes induced by PH except right ventricle hypertrophy and lung edema. In addition, CBD increased lung levels of some endocannabinoids (anandamide, N-arachidonoyl glycine, linolenoyl ethanolamide, palmitoleoyl ethanolamide and eicosapentaenoyl ethanolamide but not 2-arachidonoylglycerol). CBD did not affect the cardiopulmonary system of control rats or other parameters of blood morphology in PH. Our data suggest that CBD ameliorates MCT-induced PH in rats by improving endothelial efficiency and function, normalization of hemostatic alterations and reduction of enhanced leukocyte count determined in PH. In conclusion, CBD may be a safe, promising therapeutic or adjuvant therapy agent for the treatment of human pulmonary artery hypertension.

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Mechanisms of l-alpha-lysophosphatidylinositol-induced relaxation in human pulmonary arteries

Cited by 13 publications

References 39 publications

Structure-Activity Relationship of the GPR55 Antagonist, CID16020046

Structure-Activity Relationship of the GPR55 Antagonist, CID16020046

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

Cannabidiol Ameliorates Monocrotaline-Induced Pulmonary Hypertension in Rats

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