Pharmacology of the lower urinary tract

Abstract

Pharmacology of the lower urinary tract provides the basis for medical treatment of lower urinary tract symptoms (LUTS). Therapy of LUTS addresses obstructive symptoms (frequently explained by increased prostate smooth muscle tone and prostate enlargement) in patients with benign prostate hyperplasia (BPH) and storage symptoms in patients with overactive bladder (OAB). Targets for medical treatment include G protein-coupled receptors (α1-adrenoceptors, muscarinic acetylcholine receptors, β3-adrenoceptors) or intracellular enzymes (5α-reductase; phosphodiesterase-5, PDE5). Established therapies of obstructive symptoms aim to induce prostate smooth muscle relaxation by α1-blockers or PDE5 inhibitors, or to reduce prostate growth and volume with 5α-reductase inhibitors. Available options for treatment of OAB comprise anitmuscarinics, β3-adrenoceptor agonists, and botulinum toxin A, which improve storage symptoms by inhibition of bladder smooth muscle contraction. With the recent approval of β3-antagonists, PDE inhibitors, and silodosin for therapy of LUTS, progress from basic research of lower urinary tract pharmacology was translated into new clinical applications. Further targets are in preclinical stages of examination, including modulators of the endocannabinoid system and transient receptor potential (TRP) channels.

Keywords: 5 alpha reductase; Alpha1 adrenoreceptor; arginine vasopressors; endocannabinoids; muscarinic receptors; phosphodiesterase; vitamin D.

Figure 1

Pathophysiology and medical therapy of LUTS. Obstructive symptoms are frequently explained by benign prostatic obstruction, due to enhanced prostate smooth muscle tone and prostate enlargement. Both may contribute to urethral obstruction. Application of α₁-blockers or PDE5 inhibitors cause improvement of obstructive symptoms by relaxation of prostate smooth muscle, while beneficial effects of 5α-reductase inhibitors occur by reduction of prostate growth and volume. Storage symptoms (“irritative”) are often caused by an overactive bladder, due to overactivity of detrusor smooth muscle contraction. Consequently, available options for treatment of storage symptoms are based on relaxation and quiescing of bladder smooth muscle tone, by application of muscarinic receptor antagonists, β3-adrenoceptors agonists, or botulinum toxin A

Figure 2

Mechanisms of prostate smooth muscle contraction and assumed connections to the regulation of prostate growth. In contrast to earlier concepts, α₁-adrenoceptors in the prostate are no longer regarded as isolated receptors mediating exclusively contraction. In fact, α₁-adrenoceptors in the prostate are part of a signaling network, where different receptors and non-adrenergic mediators cooperatively regulate prostate smooth muscle tone and growth, leading to benign prostate obstruction. Prostate α₁-adrenoceptors lead to contraction by activation of the IP₃/Ca²⁺/calmodulin pathway, of DAG/protein kinase C, of the RhoA/Rho kinase pathway, and by a JNK-dependent mechanism. At least the Ca²⁺- and Rho kinase-dependent mechanisms are shared by TXA2 receptors, which cause prostate smooth muscle contraction in parallel to α₁-adrenoceptors. In addition, α₁-adrenoceptors share intracellular effectors with hormone receptors and growth factors (e. g. fibroblast growth factor): Stimulation of prostate α₁-adrenoceptors leads to activation of ERK1/2, Akt and transcription factors, which are well known to mediate growth and differentiation

Figure 3

Role of endocannabinoids and TRP channels for regulation of smooth muscle tone in the lower urinary tract. Mechano-afferent signals lead to activation of CB2 receptors and TRP channels (TRPA, TRPV) in sensory neurons. This causes the release of nitric oxide and cyclooxygenase-dependent neurotransmission, finally resulting in smooth muscle relaxation in the detrusor, prostate, and urethra. Consequently, activation of CB2 receptors by Cannabinor or FAAH inhibitors improves LUTS in animal models.