Am. J. Respir. Crit. Care Med.,
Volume 157, Number 2, February 1998, 522-530
The Mechanism by Which Epinastine Stops an
Adenosine Analog from Contracting BDE
Rat Airways
CHRISTOPHER J.
MEADE
Department of Biological Research, Boehringer Ingelheim KG, Ingelheim am Rhein, Germany
Epinastine is an antihistamine and antiallergic drug. The object of this work was to use a rat model of
noncholinergic bronchospasm to identify novel nonantihistamine mechanisms that might contribute to the efficacy of this drug in asthma. Oral epinastine blocked bronchospasm (increase in RL) in BDE
rats induced by the adenosine A3 receptor agonist N 6-2-(4-aminophenyl)ethyladenosine with an ED50
of only 0.47 mg/kg. An intravenous dose of 10 µg/kg epinastine was also effective. In vitro, epinastine
bound 5-HT2a, 5-HT7, and 5-HT3 receptors (Ki values, respectively, 21, 33, and 159 nM). In the in vivo rat model, 5-HT2a antagonist ketanserin, 5-HT7 agonist 5-carboxamidotryptamine, and (to a limited
extent) 5-HT3 antagonist ondansetron could all, like epinastine, block bronchospasm, but the "classic" antihistamine chlorpheniramine was ineffective. Epinastine could not block bronchospasm in the
presence of 1 mg/kg NK2 receptor antagonist L 659877 or 20 µg/kg potassium channel blocker iberiotoxin, suggesting the epinastine was acting on a neurokinin- and potassium channel-mediated mechanism. Epinastine has other modes of action apart from its antihistamine activity that may be
relevant to its use in asthma.
