Am. J. Respir. Crit. Care Med., Volume 159, Number 1, January 1999, 165-168

Guinea Pig Airway Hyperresponsiveness Induced by Blockade of the Angiotensin II Type 1 Receptor
Role for Endogenous Nitric Oxide

HIROSHI KANAZAWA, KAZUTO HIRATA, and JUNICHI YOSHIKAWA

First Department of Internal Medicine, Osaka City University Medical School, Osaka, Japan

Losartan is the first angiotensin II type 1 (AT₁) receptor antagonist to become available for the treatment of hypertension. However, recent reports have revealed several cases of losartan-induced bronchoconstriction. We investigated to determine the mechanism of losartan-induced bronchoconstriction, considering in particular the involvement of endogenous nitric oxide (NO). In this study, we examined the effects of losartan on airway obstruction and endogenous NO production using anesthetized guinea pigs and cultured airway epithelial cells. Five minutes after administration of angiotensin II (Ang II), the bronchoconstriction induced by acetylcholine was not changed. In contrast, Ang II in the presence of losartan caused a significant increase in the acetylcholine responsiveness. Pretreatment with L-N -nitroarginine-methylester (L-NAME) potentiated acetylcholine-induced bronchoconstriction 5 min after administration of Ang II, and L-arginine reversed this action of L-NAME on the acetylcholine responsiveness. Moreover, Ang II administration increased NO concentration in expired air (12.5 ± 1.5 ppb for saline, 40 ± 5 ppb for Ang II, p < 0.01), and losartan significantly inhibited Ang II-stimulated NO release (20 ± 3.5 ppb) from guinea pig airway. In cultured airway epithelial cells, Ang II also increased NO release (160 ± 25 nM), and the effect of this Ang II-induced NO release was significantly inhibited by pretreatment with losartan (25 ± 8 nM, p < 0.01). These findings suggest that losartan-induced bronchoconstriction may result from inhibition of endogenous NO release in the airway.

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