Type 1 angiotensin II receptor antagonism reduces antigen-induced airway reactions

Although the renin-angiotensin system is activated in patients with asthma during severe acute attacks and angiotensin II has been shown to cause bron choconstriction in patients with asthma, the role of angiotensin II in pati ents with asthma is unclear. We investigated the effects of two specific an tagonists at type 1 and type 2 angiotensin II receptors, candesartan cilexe til (TCV-116) and PD-123319, on antigen-induced airway reactions in guinea pigs. Sixty minutes after intraperitoneal administration of candesartan cil exetil (0.1, 1.0, or 10 mg/kg) or PD123319 (30 mg/kg), animals received an antigen challenge. Airway responsiveness to inhaled methacholine was assess ed as the dose of methacholine required to produce a 200% increase in the p ressure at the airway opening (PC200). Differential cell counts in bronchoa lveolar ravage fluids (BALF) were measured 24 h after antigen challenge. Ca ndesartan cilexetil did not inhibit antigen-induced bronchoconstriction in sensitized guinea pigs or alter PC200 in nonsensitized guinea pigs. Antigen inhalation significantly increased bronchoconstrictor responses to methach oline and increased airway accumulation of eosinophils; both responses show ed dose-dependent prevention by candesartan but not by PD123319. These resu lts indicate that endogenous angiotensin II promotes antigen-induced airway hyperresponsiveness and eosinophil accumulation by acting at type 1 recept ors.