SummaryAntimuscarinic side-effects, which include dry mouth, tachycardia, thickening of mucus possibly sedation, of the antihistamines limited the usefulness of these drugs. The advent of newer agents has reduced the sedative effect of the antihistamine. The data presented here show that one of the newest antihistamines, desloratadine, and a first generation drug, diphenhydramine, are both competitive inhibitors of muscarinic receptor mediated slowing of the heart as measured using a Langendorff preparation. Both agents have apparent sub-micromolar affinities for the muscarinic receptor. Two other agents, cetirizine and fexofenadine, do not interact with muscarinic receptors in the heart at the concentrations used in this study. Structural similarities of the drugs suggest that substitution of a group with a high dipole moment or charge on the side chain nitrogen decreases the binding with muscarinic receptors. We conclude that of the compounds tested fexofenadine and cetirizine have little or no interaction with muscarinic receptors.The newest antihistamines, desloratadine, fexofenadine and cetirizine, are metabolites of the older antihistamines, loratadine, terfenadine and hydroxyzine [1]. All these compounds are selective H1-histamine receptor antagonists. The newer agents also cause less drowsiness than first generation antihistamines (e.g., diphenhydramine) [2]. In addition, the newest compounds do not interact with HERG channels in the heart to cause a prolonged QT syndrome as did terfenadine, the parent compound of fexofenadine [3,4].Another potential interaction of antihistamines with cardiac function is at receptors involved in modifying heart rate and contraction. The first generation compounds were known to be competitive inhibitors of muscarinic receptors [5] and caused tachycardia by impairing vagal tone on the heart and xerostomia by inhibiting muscarinic stimulation of salivary function. Desloratadine is reported to inhibit muscarinic receptors at submicromolar concentrations [6] and therefore could potentially interact on the heart through inhibition of M2-muscarinic receptors. In this report we examine the interaction of antihistamines with muscarinic receptor-induced reduction of cardiac function in a working rat heart model using a Langendorff apparatus.
Methods
LangendorffFemale Sprague-Dawley rats weighing 300-350 g were used in these experiments. They were housed within the animal facility of University of Mississippi Medical center, and supplied with standard chow and water ad libitum. All experimental procedures were approved by the institutional animal care and use committee.The basic procedures are similar to those used by Vergely et al. [7]. Rats were anesthetized with phenobarbital sodium (65 mg/kg body wt., i.p.),