Epac1 And Epac2 Regulate Airway Smooth Muscle Tone In Mice

Dysfunctional regulation of airway smooth muscle (ASM) tone is a feature of obstructive airway diseases. cAMP-elevating agents, such as β 2 -adrenoceptor agonists, are potent inhibitors of bronchial constriction. Although used clinically for many years, their precise mechanism of action is still under debate. Activation of protein kinase A (PKA) by β 2 -agonists induces ASM relaxation. Next to PKA, activation of the exchange protein directly activated by cAMP (Epac) induces ASM relaxation. We have recently shown that Epac1 and Epac2 are differentially involved in inflammatory and remodeling processes in vivo. Here, we studied the roles of Epac1 and Epac2 in regulating ASM tone. In precontracted rings, isoprenaline dose-dependently reduced methacholine-induced ASM tone by approximately 80 % (pD2-value 7.58±0.22), both effects were reduced but not diminished by the PKA inhibitor Rp, pointing to PKA-independent mechanisms (Emax 63.4±3.5; pD2-value 7.34±0.13). Epac activators dose-dependently reduced methacholine-induced ASM tone (pEC50=4.22±0.12 and 4.30±0.10, respectively). The reduction was 25.2±3.0% and 46.0±1.8% for the highest dose used (300 μM). The effects of the Epac activator9s were unaffected by Rp. Isoprenaline-induced relaxation was not altered in Epac1-/- or Epac2-/- mice. The effects of 8-pCPT were reduced in Epac deficient mice, although to a smaller extent in Epac1-/-. Pharmacological inhibition of Epac1 - to a lesser extent of Epac2 – dose-dependently increased isoprenaline-induced relaxation, effects blunted in Epac deficient mice, confirming the specificity of the Epac inhibitors. Collectively, these data show that Epac1 and Epac2 regulate airway smooth muscle tone in mice by currently unknown mechanisms.