Increased arginase activity underlies allergen‐induced deficiency of cNOS‐derived nitric oxide and airway hyperresponsiveness
H Meurs, S McKay, H Maarsingh… - British journal of …, 2002 - Wiley Online Library
H Meurs, S McKay, H Maarsingh, MAM Hamer, L Macic, N Molendijk, J Zaagsma
British journal of pharmacology, 2002•Wiley Online LibraryA deficiency of constitutive nitric oxide synthase (cNOS)‐derived nitric oxide (NO), due to
reduced availability of l‐arginine, importantly contributes to allergen‐induced airway
hyperresponsiveness (AHR) after the early asthmatic reaction (EAR). Since cNOS and
arginase use l‐arginine as a common substrate, we hypothesized that increased arginase
activity is involved in the allergen‐induced NO deficiency and AHR. Using a guinea‐pig
model of allergic asthma, we addressed this hypothesis by examining the effects of the …
reduced availability of l‐arginine, importantly contributes to allergen‐induced airway
hyperresponsiveness (AHR) after the early asthmatic reaction (EAR). Since cNOS and
arginase use l‐arginine as a common substrate, we hypothesized that increased arginase
activity is involved in the allergen‐induced NO deficiency and AHR. Using a guinea‐pig
model of allergic asthma, we addressed this hypothesis by examining the effects of the …
- A deficiency of constitutive nitric oxide synthase (cNOS)‐derived nitric oxide (NO), due to reduced availability of L‐arginine, importantly contributes to allergen‐induced airway hyperresponsiveness (AHR) after the early asthmatic reaction (EAR). Since cNOS and arginase use L‐arginine as a common substrate, we hypothesized that increased arginase activity is involved in the allergen‐induced NO deficiency and AHR.
- Using a guinea‐pig model of allergic asthma, we addressed this hypothesis by examining the effects of the specific arginase inhibitor Nω‐hydroxy‐nor‐L‐arginine (nor‐NOHA) on the responsiveness to methacholine of isolated perfused tracheae from unchallenged control animals and from animals 6 h after ovalbumin challenge. Arginase activity in these preparations was investigated by measuring the conversion of L‐[14C]arginine to [14C]urea.
- Airways from allergen‐challenged animals showed a 2 fold (P<0.001) increase in responsiveness to intraluminal (IL) administration of methacholine compared to controls. A similar hyperresponsiveness (1.8 fold, P<0.01) was observed in control airways incubated with the NOS inhibitor Nω‐nitro‐L‐arginine methyl ester (L‐NAME, 0.1 mM, IL), while L‐NAME had no further effect on the airways from challenged animals.
- Remarkably, 5 μM nor‐NOHA (IL) normalized the hyperresponsiveness of challenged airways to basal control (P<0.001), and this effect was fully reversed again by 0.1 mM L‐NAME (P<0.05). Moreover, arginase activity in homogenates of the hyperresponsive airways was 3.5 fold (P<0.001) enhanced compared to controls.
- The results indicate that enhanced arginase activity contributes to allergen‐induced deficiency of cNOS‐derived NO and AHR after the EAR, presumably by competition with cNOS for the common substrate, L‐arginine. This is the first demonstration that arginase is involved in the pathophysiology of asthma.
British Journal of Pharmacology (2002) 136, 391–398; doi:10.1038/sj.bjp.0704725
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