Steroid and Antihistamin Synergize to Inhibit Rat’s Tracheal Smooth Muscle Contractility and Its Possible Mechanisms

Chronic obstructive airway disease (COAD), including asthma and chronic obstructive pulmonary disorder (COPD), has become one of the most prevalent diseases and is increasing throughout the world. Airway remodeling is a classic feature, which is characterized by changes in the airway tissue architecture, including increased extracellular matrix deposition and airway smooth muscle accumulation. Major drug classes used in COAD encompass bronchodilators and anti-inflammatory drugs, which suppress inflammation in the airways. Prednisolone (Kidsolone) is an anti-inflammatory drug that is mainly used for patients with chronic obstructive airway diseases (COAD), such as asthma and chronic obstructive pulmonary diseases (COPD). The major action was to switch off multiple activated inflammatory genes that code for cytokines, chemokines, adhesion molecules, inflammatory enzymes, and receptors. In addition, in vitro studies indicated that glucocorticoids inhibited proliferation of airway smooth muscle cells, indicating that they can also alter airway smooth muscle contractile properties. But the direct effect of glucocorticoids on smooth muscle tension was not fully explored. H1-antihistamines (ex. Xyzal) were widely used in clinic to control allergic symptoms. However, some authors held their concern that H1-antihistamines might not be ideal for asthma patients with acute exacerbations. H1-antihistamines had drying effects on the airways and could contribute to mucous retention and increase airway obstruction. Therefore, the H1-antihistamines were not the first choice of drug in treating acute asthma attack. The coexistence of AR with asthma was widely recognized by clinicians. We had found that sole use of glucocorticoids had no direct effect on the trachea tension. The effects of glucocorticoids were mainly through the genomic pathway, which need hours to days. On the contrary, high doses of H1-antihistamines can relax the trachea smooth muscle directly. Recently, we also found a surprisingly synergistic effect of Kidsolone can work with Xyzal to dramatically relax the trachea smooth muscle within minutes. However, the mechanisms were not fully explored. In this study, we tested the effectiveness of Kidsolone and Xyzal on isolated rat trachea submersed in Kreb’s solution in a muscle bath. Changes in tracheal contractility in response to the application of parasympathetic mimetic agents were measured. The following assessments of the drug were performed: (1) effect on tracheal smooth muscle resting tension; (2) effect on contraction caused by 10-6 M methacholine; (3) effect of the drug on electrical field stimulation (EFS) induced tracheal smooth muscle contractions. We will also use different kinds of rat, including wild type, H1-receptor-deficient or M3-receptor-knockout rat to confirm what kind of receptors were responsible for that non-genomic response. We will also test cycloheximide and RU486 (the antagonist of glucocorticoids) to see its effect on trachea tension. Finally, we will investigate the relationship of this non-genomic response with Na+/H+ pump, intra-cellular calcium level, activation of adenylated cyclase, phospholipase C (PLC), protein kinase C (PKC), phosphatidylinositol 4,5-bisphosphate (PIP2), inositol-1,4,5-trisphosphate (IP3) and RhoA kinase.