The pharmacological rationale for combining muscarinic receptor antagonists and β-adrenoceptor agonists in the treatment of airway and bladder disease

Abstract

Muscarinic receptor antagonists and β-adrenoceptor agonists are used in the treatment of obstructive airway disease and overactive bladder syndrome. Here we review the pharmacological rationale for their combination. Muscarinic receptors and β-adrenoceptors are physiological antagonists for smooth muscle tone in airways and bladder. Muscarinic agonism may attenuate β-adrenoceptor-mediated relaxation more than other contractile stimuli. Chronic treatment with one drug class may regulate expression of the target receptor but also that of the opposing receptor. Prejunctional β2-adrenoceptors can enhance neuronal acetylcholine release. Moreover, at least in the airways, muscarinic receptors and β-adrenoceptors are expressed in different locations, indicating that only a combined modulation of both systems may cause dilatation along the entire bronchial tree. While all of these factors contribute to a rationale for a combination of muscarinic receptor antagonists and β-adrenoceptor agonists, the full value of such combination as compared to monotherapy can only be determined in clinical studies.

Figure 1

Relaxation of rat bladder strips with passive tension or precontracted with KCl, carbachol, bradykinin or serotonin by the β-adrenoceptor agonist isoprenaline. Note that both the potency and the efficacy of isoprenaline against carbachol were significantly smaller than against all other conditions.

Figure 2

Schematic representation of assumed signal transduction pathways involved in the regulation of smooth muscle contraction by muscarinic and β-adrenergic pathways. AC, adenylyl cyclase; AR, adrenoceptor; DAG, diacylglycerol; IP3, inositol-tris-phosphate; MLC, myosin light chain; PKA, protein kinase A; PKC, protein kinase C; PLC, phospholipase C; PLD, phospholipase D; SR, sarcoplasmic reticulum. Red and green lines and arrows represent pathways activated by muscarinic and β-adrenergic receptors, respectively.

Figure 3

Epac as a novel effector of airway smooth muscle relaxation. Cumulative concentration response curves of the selective Epac activators 8-pCPT-2’-O-Me-cAMP (8-pCPT) and Sp-8-pCPT-2′-O-Me-cAMPS on methacholine (0.3 μm) precontracted guinea pig tracheal open ring preparations in the absence (control) or presence of 100 μm of the selective protein kinase A inhibitor Rp-8-CPT-cAMPS. Results are means ± SEM of 3-8 independent experiments. Stress fiber formation was measured by phalloidin staining in guinea pig airway smooth muscle. Results are expressed as percentage of stress fiber-positive cells relative to the total number of cells. Representative images of 5 experiments are shown. These data demonstrate that cAMP generated upon β-adrenoceptor stimulation may relax airway smooth muscle via the Epac pathway.