Pharmacological Modulation of Mucosa-Related Impairment of β-Adrenoceptor-Mediated Relaxation in Human Detrusor

Abstract

Objectives: The mucosa of human detrusor strips impairs catecholamine-induced relaxation. In order to elucidate which signal transduction pathways are involved in this cross talk between the mucosa and detrusor, we have studied the effects of several pharmacological agonists and antagonists on noradrenaline-mediated relaxation in intact and mucosa-denuded detrusor strips. Patients and Methods: Strips of detrusor tissue were obtained from patients who had undergone cystectomy for bladder cancer and were set up for force measurement. KCl- or carbachol-precontracted strips were relaxed with increasing concentrations of noradrenaline in the absence and in the presence of nitric oxide synthase inhibitor, L-NAME; P2X-receptor antagonist, PPADS; ET_A-receptor antagonist, BQ-123; ET_B-receptor antagonist, BQ-788; cyclooxygenase inhibitor, diclofenac; AT₁-receptor antagonist, candesartan; and NK₁-receptor antagonist, L-703,606. Results: In intact strips, KCl-stimulated force was enhanced by all blockers; carbachol-stimulated force increased with L-703,606. In denuded strips, only L-NAME augmented the KCl-stimulated contraction. Noradrenaline relaxed the precontracted detrusor strips to a significantly larger extent and at lower concentrations in denuded than in intact strips. L-NAME, PPADS and BQ-123/BQ-788 had little effect on noradrenaline-induced relaxation, whereas diclofenac, candesartan and L-703,606 sensitized intact carbachol-stimulated detrusor strips to noradrenaline-induced relaxation. Conclusion: Inhibition of the noradrenaline-induced relaxation of precontracted human detrusor strips by the mucosa is attenuated by diclofenac, candesartan and L-703,606 suggesting the involvement of prostanoids, angiotensin and neurokinin pathways. Further experiments are required to unravel the exact mechanisms.

Modulation of lower urinary tract smooth muscle contraction and relaxation by the urothelium

“…Relaxing effects of catecholamines are blunted by the presence of the urothelium in the human bladder (Otsuka et al, 2008, Propping et al, 2013, Propping et al, 2015b and are mediated via β2-adrenoceptors (Propping et al, 2013). A similar effect was seen in mouse bladder, and the urothelium reduced the sensitivity of KCl pre-contracted tissues to β-adrenoceptor-induced relaxation to isoprenaline, again via β2-adrenoceptors, although at high concentrations of isoprenaline there was a minor involvement of β3-adrenoceptors (Propping et al, 2015a).…”

“…A similar effect was seen in mouse bladder, and the urothelium reduced the sensitivity of KCl pre-contracted tissues to β-adrenoceptor-induced relaxation to isoprenaline, again via β2-adrenoceptors, although at high concentrations of isoprenaline there was a minor involvement of β3-adrenoceptors (Propping et al, 2015a). Whilst in human bladder this inhibitory effect on relaxations was seen in tissues pre-contracted with KCl and carbachol (Propping et al, 2015b), the same authors showed in mouse bladder that the urothelium did not inhibit relaxations if the tissues were pre-contracted with carbachol (Propping et al, 2015a). The rat bladder urothelium does not appear to influence smooth muscle relaxation to β3-adrenoceptor agonists (Kullmann et al, 2011).…”

“…However, in the human bladder angiotensin and neurokinin pathways may also be involved (Propping et al, 2015b), and in the pig bladder neck BK channels may play a role (Ribeiro et al, 2014). Thus, the nature of the urothelium-derived agents that have been shown to modulate smooth muscle in the lower urinary tract appear to be complex and are still far from being understood.…”

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

“…The pH was 7.4. All drugs were obtained from the same sources and dissolved either in distilled water of dimethyl sulfoxide as in our previous study ( Propping et al, 2015c ). The DMSO concentration in the bath did not exceed 0.3%.…”