β-Adrenoceptor-Mediated Relaxation of Carbachol-Pre-Contracted Mouse Detrusor

Propping, Stefan; Newe, Manja; Lorenz, Kristina; Wirth, Manfred P.; Ravens, Ursula

doi:10.1159/000369075

Cited by 11 publications

(5 citation statements)

References 21 publications

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“…Based on the clinical trials and in vivo assays done, systemic doses have been used without toxicity in humans (up to 20 mg/kg), rodents (0.5 or 1 mg/kg) or rhesus monkeys (0.1 μg/kg). ICI, nowadays, is mainly used as control of β-blockers's specificity in physiological processes such us control of heart and vascular tone and SNC and muscular signaling [37][38][39][40] . Finally, ICI has been also used in cancer research showing a role in cell proliferation and signalling regulation 41,42 .…”

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confidence: 99%

The β2-adrenergic receptor antagonist ICI-118,551 blocks the constitutively activated HIF signalling in hemangioblastomas from von Hippel-Lindau disease

Cuesta

Albiñana

Gallardo-Vara

et al. 2019

Sci Rep

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One of the major consequences of the lack of a functional VHL protein in von Hippel-Lindau disease, a rare cancer, is the constitutive activation of the HIF pathway. This activation ends up in the generation of Central Nervous System (CNS) Hemangioblastomas among other tumours along the lifespan of the patient. Nowadays, only surgery has been proven efficient as therapy since the systemic attempts have failed. Propranolol, a non-specific β1-and β2-adrenergic receptor antagonist, was recently designated as the first therapeutic (orphan) drug for VHL disease. Nevertheless, its β1 affinity provokes the decrease in blood pressure, being not recommended for low or regular blood pressure VHL patients. In order to overcome the β1-drawback, the properties of a high specific β2-adrenergic receptor blocker named ICI-118,551 have been studied. ICI-118,551 was able to decrease Hemangioblastomas cell viability in a specific manner, by triggering apoptosis. Moreover, ICI-118,551 also impaired the nuclear internalization of HIF-1α in Hemangioblastomas and hypoxic primary endothelial cells, reducing significantly the activation of HIF-target genes and halting the tumour-related angiogenic processes. In this work, we demonstrate the therapeutical properties of ICI-118,551 in VHL-derived CNS-Hemangioblastoma primary cultures, becoming a promising drug for VHL disease and other HIF-related diseases. Von Hippel-Lindau (VHL) disease is an autosomal dominant inherited genetic disorder with an incidence of 1 per 36,000 individuals in the general population and is considered as a rare disease or rare cancer 1,2. Patients with VHL disease harbour a single mutation allele in the tumour suppressor gene VHL (3p25-p26). VHL protein (pVHL) controls the cytoplasmic levels of the Hypoxia Inducible Factor (HIF) complex. In normoxic conditions, pVHL binds to the previously hydroxylated prolyl residues of HIF-1α and HIF-2α, being ubiquitinated and targeted to the proteasome for rapid degradation. When patients suffer a spontaneous inactivation or loss of the second wild-type VHL allele (loss of heterozygosity), either there is no expression of the pVHL or the mutated form is not functional 3,4. Therefore, in the absence of functional pVHL, HIF-1α and HIF-2α subunits accumulate within the cytoplasm and translocate to the nucleus, triggering the hypoxia program by targeting hypoxia responsive genes, which are normally silenced in normoxia 5. HIF-1α and HIF-2α are involved in cell proliferation, angiogenesis, extracellular matrix degradation, vascular tone, and erythropoiesis, among other processes. Hence, cells from VHL tumours have a constitutively active HIF program (a pseudo-hypoxic state) due to the absence of functional pVHL 6,7. As a consequence of this pseudo-hypoxic state, the clinical manifestations of the disease include multiple benign and malignant tumours that appear throughout the lifespan of the patient: retinal hemangioblastoma,

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confidence: 99%

The β2-adrenergic receptor antagonist ICI-118,551 blocks the constitutively activated HIF signalling in hemangioblastomas from von Hippel-Lindau disease

Cuesta

Albiñana

Gallardo-Vara

et al. 2019

Sci Rep

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“…Speciesdependent differences in β-adrenergic detrusor relaxation may be imparted by divergent expression patterns of receptor subtypes, and by differences in ligand-receptor interactions (Cernecka et al, 2015;Dale et al, 2014). β-Adrenergic relaxation of human detrusor tissues has been widely attributed to β 3 , whereas β-adrenergic relaxation of detrusor tissues from mice is predominantly mediated by β 2 (Propping et al, 2016;Propping et al, 2015;Wuest et al, 2009). Data are available from wildtype and β 2 -adrenoceptor knockout mice, but obviously not from β 3 -adrenoceptor knockout mice.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Full Smooth Muscle Contraction in Isolated Human Detrusor Tissues by Mirabegron Is Limited to Off-Target Inhibition of Neurogenic Contractions

Huang

Tamalunas

Waidelich

et al. 2022

J Pharmacol Exp Ther

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Mirabegron is used for treatment of storage symptoms in overactive bladder (OAB), caused by spontaneous bladder smooth muscle contractions. However, owing to limitations in available studies using human tissues central questions are still unresolved, including mechanisms underlying improvements by mirabegron and its anticontractile effects in the detrusor. Here, we assessed concentration-dependent mirabegron effects on contractions of human detrusor tissues in frequence-response curves and concentration-response curves for different cholinergic and non-cholinergic agonists. Detrusor tissues were sampled from patients undergoing radical cystectomy. Contractions were induced by electric field stimulation (EFS), and by cumulative concentrations of cholinergic agonists, endothelin-1 and the thromboxane A 2 analog U46619. EFS-induced contractions were inhibited using 10 µM mirabegron, but not using 1 µM. Inhibition by 10 µM mirabegron was resistant to the β 3adrenergic antagonist L-748,337. Concentration-dependent contractions by carbachol were not inhibited by 1 µM or 10 µM mirabegron. Concentration response curves for methacholine were slightly right-shifted by 10 µM, but not 1 µM mirabegron. Concentration-dependent contractions by endothelin-1 or U46619 were not changed by mirabegron. In contrast, the muscarinic antagonist tolterodine right-shifted concentration response curves for carbachol and methacholine, and inhibited EFS-induced contractions. In conclusion, inhibition of neuogenic contractions in isolated detrusor tissues by mirabegron requires concentrations highly exceeding known plasma levels during standard dosing and the known K i values for β 3 -adrenoceptors. Full contractions by cholinerigc agonists, endothelin-1 and U46619 are not affected by therapeutic concentrations of mirabegron. Improvements of storage symptoms are most likely not imparted by inhibition of β 3 -adrenoceptors in the bladder wall itself.

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“…Characterization of mice: the WT and β 2 -AR KO mice had average body weights of 29 ± 3 g for WT ( n = 55) and 28 ± 4 g for β 2 -AR KO mice ( n = 49). Strips of mouse urinary bladder were dissected as described previously ( Propping et al, 2015a , b ). Muscle strips with an intact mucosal layer (mean weight WT mice 2.9 ± 1.6 mg, n = 75 strips; β 2 -AR KO mice 2.4 ± 1.8 mg, n = 74, P = 0.26) were mounted in an organ bath filled with 5 ml of modified Tyrode solution of the following composition (in mM): NaCl 126.9, KCl 5.4, MgCl 2 1.05, CaCl 2 1.8, NaH 2 HPO 4 0.45, NaHCO 3 22, EDTA 0.04, ascorbic acid 0.2, glucose 5.6.…”

Section: Methodsmentioning

confidence: 99%

β-Adrenoceptor-mediated Relaxation of Urinary Bladder Muscle in β2-Adrenoceptor Knockout Mice

et al. 2016

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Background and Objective: In order to characterize the β-adrenoceptor (AR) subtypes involved in agonist-stimulated relaxation of murine urinary bladder we studied the effects of (-)-isoprenaline and CL 316,243 on tonic contraction and spontaneous contractions in detrusor strips of wild-type (WT) and β2-AR knockout (β2-AR KO) mice.Materials and Methods: Urinary bladders were isolated from male WT and β2-AR KO mice. β-AR subtype expression was determined with quantitative real-time PCR. Intact muscle strips pre-contracted with KCl (40 mM) were exposed to cumulatively increasing concentrations of (-)-isoprenaline or β3-AR agonist CL 316,243 in the presence and absence of the subtype-selective β-AR blockers CGP 20712A (β1-ARs), ICI 118,551 (β2-ARs), and L748,337 (β3-ARs).Results: Quantitative real-time PCR confirmed lack of β2-AR expression in bladder tissue from β2-AR KO mice. In isolated detrusor strips, pre-contraction with KCl increased basal tone and enhanced spontaneous activity significantly more in β2-AR KO than in WT. (-)-Isoprenaline relaxed tonic tension and attenuated spontaneous activity with similar potency, but the concentrations required were two orders of magnitude higher in β2-AR KO than WT. The concentration-response curves (CRCs) for relaxation were not affected by CGP 20712A (300 nM), but were shifted to the right by ICI 118,551 (50 nM) and L748,337 (10 μM). The -logEC50 values for (-)-isoprenaline in WT and β2-AR KO tissue were 7.98 and 6.00, respectively, suggesting a large receptor reserve of β2-AR. (-)-CL 316,243 relaxed detrusor and attenuated spontaneous contractions from WT and β2-AR KO mice with a potency corresponding to the drug’s affinity for β3-AR. L743,337 shifted the CRCs to the right.Conclusion: Our findings in β2-AR KO mice suggest that there is a large receptor reserve for β2-AR in WT mice so that this β-AR subtype will mediate relaxation of tone and attenuation of spontaneous activity under physiological conditions. Nevertheless, upon removal of this reserve, β3-AR can also mediate murine detrusor relaxation.

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β-Adrenoceptor-Mediated Relaxation of Carbachol-Pre-Contracted Mouse Detrusor

Cited by 11 publications

References 21 publications

The β2-adrenergic receptor antagonist ICI-118,551 blocks the constitutively activated HIF signalling in hemangioblastomas from von Hippel-Lindau disease

The β2-adrenergic receptor antagonist ICI-118,551 blocks the constitutively activated HIF signalling in hemangioblastomas from von Hippel-Lindau disease

Inhibition of Full Smooth Muscle Contraction in Isolated Human Detrusor Tissues by Mirabegron Is Limited to Off-Target Inhibition of Neurogenic Contractions

β-Adrenoceptor-mediated Relaxation of Urinary Bladder Muscle in β2-Adrenoceptor Knockout Mice

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