Effects of first and second generation antihistamines on muscarinic induced mucus gland cell ion transportReportar como inadecuado




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BMC Pharmacology

, 5:8

First Online: 24 March 2005Received: 22 September 2004Accepted: 24 March 2005

Abstract

BackgroundThe 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.

ResultsThree 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 μM, 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 ≈ hydroxyzine > fexofenadine > loratadine > diphenhydramine.

ConclusionThe rank order of selectivity for histamine receptors over muscarinic receptors was estimated to be cetirizine ≈ fexofenadine > loratadine > desloratadine ≥ hydroxyzine ≥ diphenhydramine.

Electronic supplementary materialThe online version of this article doi:10.1186-1471-2210-5-8 contains supplementary material, which is available to authorized users.

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Autor: Huiling Liu - Jerry M Farley

Fuente: https://link.springer.com/







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