title: Effects of first and second generation antihistamines on muscarinic induced mucus gland cell ion transport.
abstract: BACKGROUND
  The first generation antihistamines, such as diphenhydramine, are fairly potent muscarinic antagonists in addition to being H1 selective antihistamines. The antimuscarinic action is often not desirable since it is in part responsible for the drying of secretions in the airways and the sedative effect. We therefore examined a number of antihistamines for antimuscarinic effects on ion transport by mucus gland cells isolated from the airways of swine. Enzymatically isolated airway mucus gland cells were purified utilizing density gradients and grown in culture on porous inserts (Millicell HA) at an air interface. Cells grown in this manner maintain phenotype and polarity. Transport of ions, as short-circuit current measured under voltage-clamp, was measured in response to acetylcholine (ACh) or histamine applied to the serosal side of the gland cell layers. Concentration-response relationships for ACh or histamine were generated in the presence and absence of various drugs. The potencies against muscarinic receptor activation were estimated using the dose-ratio method of Schild.
  
  
  RESULTS
  Three known muscarinic antagonists were used to validate the system. Atropine had a pA2 of 9.4 +/- 0.1 (n = 9). 4-DAMP and methoctramine had pA2 values of 8.6 +/- 0.1 and 5.6 +/- 0.1, respectively (n = 12, 11) all consistent with inhibition of an M3 subtype muscarinic receptor. The rank order of potency of the antihistamines against the inhibition of M3 receptors was desloratadine = diphenhydramine > hydroxyzine (pA2; 6.4, 6.2, 4.8, respectively). pA2 values for fexofenadine, loratadine and cetirizine were not determined since they had no effect on the cholinergic response at the highest drug concentrations tested (10, 10 and 100 microM, respectively). The pA2 values for the antihistamines against the histamine response could not be calculated, but the estimates of the rank order of potency were estimated to be desloratadine > cetirizine approximate to hydroxyzine > fexofenadine > loratadine > diphenhydramine.
  
  
  CONCLUSIONS
  The rank order of selectivity for histamine receptors over muscarinic receptors was estimated to be cetirizine approximate to fexofenadine > loratadine > desloratadine > or = hydroxyzine > or = diphenhydramine.
authors.affiliation: Department of Pharmacology and Toxicology, University of Mississippi Medical Center, 2500 N. State St., Jackson, MS 39216, USA. huliu@pharmacology.umsmed.edu
authors.forename: Huiling
authors.initials: H
authors.lastname: Liu
authors.forename: Jerry M
authors.initials: JM
authors.lastname: Farley
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D005088:Exocrine Glands / Q000187:drug effects* / Q000378:metabolism; D006634:Histamine H1 Antagonists / Q000494:pharmacology*; D017136:Ion Transport / Q000187:drug effects*; D008297:Male; D009093:Mucus / Q000378:metabolism; D018727:Muscarinic Antagonists / Q000494:pharmacology*; D011968:Receptors, Histamine / Q000187:drug effects*; D011976:Receptors, Muscarinic / Q000187:drug effects*; D013552:Swine; D014132:Trachea / Q000187:drug effects* / Q000378:metabolism
chemical_list: D006634:Histamine H1 Antagonists; D018727:Muscarinic Antagonists; D011968:Receptors, Histamine; D011976:Receptors, Muscarinic