The influence of nebivolol on the activity of BRL 37344 — the β3‐adrenergic receptor agonist, in the animal model of detrusor overactivity

Abstract

Aims The cardiotoxic effects of antimuscarinics constitute a significant restriction in their application in elderly people. Overactive bladder syndrome pharmacotherapy using compounds with cardioprotective properties would seem an ideal solution. The main goal of the study was to assess the impacts of nebivolol (NEB) on the activity of BRL 37344 — β3‐adrenergic receptor (β3AR) agonist, in the animal model of detrusor overactivity. As both these substances can impact on the cardiovascular system, their effect on the parameters of this system and diuresis was also examined. Methods Retinyl acetate (RA; 0.75%) solution was used to induce detrusor overactivity in female Wistar rats. BRL and/or NEB were administered intra‐arterially during cystometry in a single dose (2.5 or 5, 0.05 or 0.1 mg/kg, respectively). In addition, a 24 hours measurement of heart rate, blood pressure, and urine production was carried out. Results NEB (0.05 mg/kg) and BRL (2.5 mg/kg) monotherapy proved to have no influence on the cystometric parameters of animals with RA‐induced detrusor overactivity. NEB at 0.1 mg/kg resulted in a drop in the detrusor overactivity index, similarly to BRL at 5 mg/kg. Coadministration of NEB and BRL, both at ineffective doses, decreased the detrusor overactivity index and ameliorated the nonvoiding contractions. β3AR stimulation proved to induce tachycardia and hypertension. NEB at 0.05 mg/kg proved to ameliorate detrusor overactivity and have preventive properties against adverse cardiovascular effects of the β3AR agonist. Conclusions The combined application of the β3AR agonist and NEB may improve detrusor overactivity without affecting the heart rate, blood pressure, and urine production.

The Urogynecology Section of the Polish Society of Gynecologists and Obstetricians guidelines on the management of non-neurogenic overactive bladder syndrome in women

“…However, the limitations and side effects of pharmacotherapy are the reasons why the search for new solutions continues. Animal studies are conducted to find new drugs to treat the OAB syndrome [19,36,[77][78][79][80]. Preclinical studies lead to the development of new drugs, which may in time find applications in clinical practice [16,77].…”

A Novel Alternative in the Treatment of Detrusor Overactivity? In Vivo Activity of O-1602, the Newly Synthesized Agonist of GPR55 and GPR18 Cannabinoid Receptors

“…To perform the surgery procedures, the animals' general anesthesia was induced by using intraperitoneal injections of xylazine (15 mg/kg, Sedazin, Biowet) and ketamine hydrochloride (75 mg/kg, Ketanest, Pfizer) [30,63], which do not affect micturition in female rats [76]. The anesthetized animals were subjected to catheterization of the urinary bladder from the external urethral orifice with a polyethylene catheter.…”

“…Next, through a vertical midline incision (approximately 10 mm) the abdominal wall was opened and a double lumen catheter was inserted via the bladder apex (dome) and fixed with 6-0 absorbable suture. In the same surgical session, in order to administer the examined drug and vehicle directly into the vascular bed, and to measure the cardiovascular system parameters (i.e., heart rate and mean blood pressure), the carotid artery was cannulated [30,63,74,132].…”

“…A force displacement transducer (FT03C, Grass Technologies, West Warwick, RI, USA) linked to a fluid collector was used to measure micturition volumes. Additionally, cystometry profiles (cystometrograms) were recorded continuously with a Grass polygraph (Model 7E, Grass Technologies, West Warwick, RI, USA) [30,133]. During the cystometry procedure, the following parameters were evaluated: the area under the pressure curve (AUC, cmH 2 O/sec), the basal pressure (BP, cmH 2 O), the bladder compliance (BC, mL/cmH 2 O), the bladder contraction duration (BCD, s), the inter-contraction interval (ICI, s), the micturition voiding pressure (MVP, cmH 2 O), the post-void residual (PVR, mL), the relaxation time (RT, s), the threshold pressure (TP, cmH 2 O), the voided volume (VV, mL), the voiding efficiency (VE, %), the volume threshold (VT, mL), the detrusor overactivity index (DOI, cmH 2 O/mL), the non-voiding contractions amplitude (ANVC, cmH 2 O), the non-voiding-contractions frequency (FNVC, times/filling phase), and the volume threshold to elicit NVC (VTNVC, %) [30,74,79,132].…”

“…Pre-clinical studies conducted in the recent years have led to the discovery of new potential targets for OAB pharmacotherapy, such as Rho-kinase (ROCK) [19,20], nerve-growth factor (NGF) [21,22], K + channels (ATP-sensitive channels-K ATP , and calcium channels-K Ca ) [23], serotoninergic (5-HT 1A , 5-HT 2 , 5-HT 3 , and 5-HT 4 ) [24], dopaminergic (D 1 -D 5 ) [25,26], β 3 -adrenergic [27][28][29][30], vitamin D 3 [31,32], kinin (B1 and B2) [33], oestrogen [34], opioid (µ, δ, and κ) [35,36], purinergic receptors (P 2 X 1 and P 2 X 3 ), transient receptor potential vanilloid 1 (TRPV 1 ) and 4 (TRPV 4 ) [37,38], tachykinin (NK1 and NK2) [39], glutamatergic (NMDA and AMPA) [40], γ-aminobutyric acid (GABA A and GABA B ) [41,42], corticotropin-releasing factor (CRF) [43], and cannabinoid receptors (CB1, CB2, and GPR55) [44][45][46]. All these possibilities of pharmacotherapy for DO/OAB have limitations.…”