Insulin induces airway smooth muscle contraction.
OBJECTIVE
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.


METHODS
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.


RESULTS
It was found that insulin (1 nM-1 microM) induced a concentration-dependent contraction that was insensitive to epithelium removal. These sustained contractions were susceptible to inhibitors of cyclooxygenase (indomethacin, 3 microM), Rho-kinase (Y-27632, 1 microM) and p42/44 MAP kinase (PD-98059, 30 microM and U-0126, 3 microM), but not of PI-3-kinase (LY-294002,10 microM). In addition, insulin significantly increased PGF(2alpha)-production which was inhibited by indomethacin, but not Y-27632. Moreover, the FP-receptor antagonist AL-8810 (10 microM) and the EP(1)-receptor antagonist AH-6809 (10 microM) strongly reduced insulin-induced contractions, supporting a pivotal role for contractile prostaglandins.


CONCLUSIONS
Collectively, the results show that insulin induces guinea-pig ASM contraction presumably through the production of contractile prostaglandins, which in turn are dependent on Rho-kinase for their contractile effects. The data suggest that administration of insulin as an aerosol could result in some acute adverse effects on ASM function.
Schaafsma
D
D
Department of Molecular Pharmacology, University of Groningen, Groningen, The Netherlands. D.Schaafsma@rug.nl
Gosens
R
R
Ris
J M
JM
Zaagsma
J
J
Meurs
H
H
Nelemans
S A
SA
D000818:Animals; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007328:Insulin / Q000494:pharmacology / Q000502:physiology*; D008297:Male; D009119:Muscle Contraction; D009130:Muscle, Smooth / Q000378:metabolism / Q000502:physiology*; D011453:Prostaglandins / Q000096:biosynthesis; D020545:Respiratory Mucosa / Q000502:physiology; D014132:Trachea / Q000378:metabolism / Q000502:physiology*
D007328:Insulin; D011453:Prostaglandins