RESEARCH PAPER Insulin induces airway smooth muscle contraction

Background and purpose: Recently, the use of inhaled insulin formulations for the treatment of type I and type II diabetes has been approved in Europe and in the United States. For regular use, it is critical that airway function remains unimpaired in response to insulin exposure. Experimental approach: We investigated the effects of insulin on airway smooth muscle (ASM) contraction and contractile prostaglandin (PG) production, using guinea-pig open-ring tracheal smooth muscle preparations. Key results: It was found that insulin (1 nM-1mM) induced a concentration-dependent contraction that was insensitive to epithelium removal. These sustained contractions were susceptible to inhibitors of cyclooxygenase (indomethacin, 3mM), Rho-kinase (Y-27632, 1mM) and p42/44 MAP kinase (PD-98059, 30mM and U-0126, 3mM), but not of PI-3-kinase (LY-294002,10mM). In addition, insulin significantly increased PGF2a-production which was inhibited by indomethacin, but not Y-27632. Moreover, the FP-receptor antagonist AL-8810 (10mM) and the EP1-receptor antagonist AH-6809 (10mM) strongly reduced insulin-induced contractions, supporting a pivotal role for contractile prostaglandins.