Hexamethylene Diisocyanate Causes Contraction of Canine Tracheal Smooth Muscles through Activation of Muscarinic Receptors

Abstract

Background: Asthma caused by occupational exposure to hexamethylene diisocyanate (HDI) is well known; however, the exact pathogenic mechanisms remain unclear. Methods: Experiments were performed using a standard canine tracheal smooth muscle (CTSM) strip preparation in an isolated bath to determine the effect of HDI on tracheal smooth muscle contraction. HDI concentration-response curves were constructed and the effects of different receptor antagonists on HDI-induced smooth muscle contraction were determined. To determine whether HDI and acetylcholine (ACh) bind to a common muscarinic receptor, ACh concentration-response curves in the absence or presence of HDI and concentration-response curves for HDI and ACh in the presence or absence of atropine were plotted. Results: HDI caused contraction of CTSM, with a threshold concentration of 10^–7 M. The EC₅₀ (HDI concentration that produced 50% of the maximal response) was 6.2 ± 0.7 × 10^–7 M and the maximal contractile response (174 ± 55 g/g of tissue) occurred at a concentration of 5.0 ± 0.8 × 10^–6 M. Atropine, a muscarinic blocker, significantly inhibited HDI-induced contractile responses. HDI shifted the ACh concentration-response curve to the right. The mean pA₂ for atropine against ACh (8.93 ± 0.27) was not significantly different from that against HDI (8.03 ± 0.12). Conclusions: Our results indicated that HDI causes contraction of CTSM through the activation of muscarinic receptors. Direct stimulation of muscarinic receptors by HDI may play an important role in HDI-induced asthma.

Acetaldehyde Induces Histamine Release from Human Airway Mast Cells to Cause Bronchoconstriction

“…Eleven agents, 10 –5 M pyrilamine (an antihistamine H 1 receptor blocking agent; Sigma, St. Louis, Mo., USA), 10 –6 M pranlukast (a cysteinyl leukotriene receptor antagonist; Ono Pharmaceutical, Osaka, Japan), 10 –6 M seratrodast (a thromboxane A 2 synthetase inhibitor; Takeda Chemical Industries, Osaka), 10 –6 M atropine (an anti-cholinergic drug; Sigma), 10 –8 M neostigmine (an anticholinesterase; Sigma), 10 –5 M verapamil (a calcium channel blocking agent; Wako Chemicals, Osaka), 10 –6 M phentolamine (an α-adrenergic blocking agent; Sigma), 10 –6 M prazosin (an α-adrenergic blocking agent; Sigma), 10 –6 M propranolol (a β-adrenergic blocking agent, Sigma), 10 –6 M isoproterenol (a β 2 -adrenergic receptor stimulant; Wako Chemicals) and 10 –6 M cimetidine (a H 2 receptor blocking agent; Wako Chemicals) were tested. The concentration of each agent selected in these experiments was based on our previous studies [7, 8]. Each agent was dissolved in Krebs-Henseleit solution, and this process was not associated with any change in the acid-base balance of the buffer.…”