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 bronchoconstriction in patients with asthma, the role of angiotensin II in patients with asthma is unclear. We investigated the effects of two specific antagonists at type 1 and type 2 angiotensin II receptors, candesartan cilexetil (TCV-116) and PD123319, on antigen-induced airway reactions in guinea pigs. Sixty minutes after intraperitoneal administration of candesartan cilexetil (0.1, 1.0, or 10 mg/kg) or PD123319 (30 mg/kg), animals received an antigen challenge. Airway responsiveness to inhaled methacholine was assessed as the dose of methacholine required to produce a 200% increase in the pressure at the airway opening (PC(200)). Differential cell counts in bronchoalveolar lavage fluids (BALF) were measured 24 h after antigen challenge. Candesartan cilexetil did not inhibit antigen-induced bronchoconstriction in sensitized guinea pigs or alter PC(200) in nonsensitized guinea pigs. Antigen inhalation significantly increased bronchoconstrictor responses to methacholine and increased airway accumulation of eosinophils; both responses showed dose-dependent prevention by candesartan but not by PD123319. These results indicate that endogenous angiotensin II promotes antigen-induced airway hyperresponsiveness and eosinophil accumulation by acting at type 1 receptors.
Myou
S
S
The Third Department of Internal Medicine, Kanazawa University School of Medicine, Kanazawa, Japan. myous@p2222.nsk.ne.jp
Fujimura
M
M
Kurashima
K
K
Tachibana
H
H
Watanabe
K
K
Hirose
T
T
D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000941:Antigens / Q000502:physiology*; D001562:Benzimidazoles / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D016084:Bronchoconstriction / Q000187:drug effects*; D016085:Bronchoconstrictor Agents / Q000494:pharmacology; D004804:Eosinophils / Q000187:drug effects; D006168:Guinea Pigs; D007093:Imidazoles / Q000494:pharmacology*; D008297:Male; D016210:Methacholine Chloride / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology*; D012130:Respiratory Hypersensitivity / Q000188:drug therapy* / Q000276:immunology*; D013777:Tetrazoles
D057911:Angiotensin Receptor Antagonists; D000941:Antigens; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D016085:Bronchoconstrictor Agents; D007093:Imidazoles; D011725:Pyridines; D013777:Tetrazoles; D016210:Methacholine Chloride; C073402:PD 123319; C077793:candesartan cilexetil