Abstract
Human adrenomedullin is a potent vasodilator with bronchodilation properties. The effects of adrenomedullin on antigen-induced bronchoconstriction and airway microvascular leakage in guinea-pigs was investigated. The portion of the adrenomedullin molecule possessing these pulmonary active profiles was also examined, using two truncated adrenomedullin molecules: adrenomedullin (1-25) and adrenomedullin (22-52). Four weeks after sensitization with ovalbumin (0.1 mg x k(-1)), the guinea-pigs were anaesthetized and mechanically ventilated. Respiratory resistance, dynamic compliance and arterial blood pressure were monitored. Airway microvascular leakage was evaluated by extravasation of 20 mg x kg(-1) Evans blue into airway interstitial tissue. In order to enhance the pulmonary effects of adrenomedullin, the active production of endogenous nitric oxide was inhibited by coadministration of a nitric oxide synthase inhibitor, L-N(G)-nitroarginine methethyl ester (10 mg x kg(-1)). Intravenous pretreatment with adrenomedullin (10, 30 and 100 microg x mL(-1)) dose-dependently inhibited ovalbumin-induced bronchoconstriction and airway microvascular leakage in all airway segments. Inhaled adrenomedullin (100 microg.mL(-1), 1 min) also significantly inhibited pulmonary changes induced by ovalbumin inhalation (3 mg x mL (-1) , 3 min). These pulmonary profiles of adrenomedullin were enhanced by inhibiting the active production of endogenous nitric oxide. In conclusion, adrenomedullin has inhibitory effects on antigen-induced microvascular leakage and bronchoconstriction in guinea-pigs. These beneficial effects strongly related to its unique ring structure and N-terminal segment, making it a potential anti-asthma.
Highlights
Intravenous pretreatment with adrenomedullin (10, 30 and 100 mg.mL-1) dosedependently inhibited ovalbumin-induced bronchoconstriction and airway microvascular leakage in all airway segments
With no antigen challenge, it was ascertained that the intravenous administration of adrenomedullin (100 mg.kg-1 i.v., n=4) or L-arginine (100 mg.kg-1 i.v., n=5) showed no statistically significant effect on airway microvascular leakage and bronchoconstriction, and L-NG-nitroarginine methethyl ester (L-NAME) (10 mg.kg-1 i.v., n=5) showed no statistically significant effect on bronchoconstriction
As demonstrated in figure 3a and b, the NO synthase inhibitor L-NAME inhibited bronchodilation caused by adrenomedullin, but with no statistical significance
Summary
Intravenous pretreatment with adrenomedullin (10, 30 and 100 mg.mL-1) dosedependently inhibited ovalbumin-induced bronchoconstriction and airway microvascular leakage in all airway segments. The potent inhibitory effects of natriuretic peptides against antigen-induced microvascular leakage and bronchoconstriction in the asthmatic model of guinea-pigs were reported [9]. A previous study has shown that adrenomedullin significantly inhibits acetylcholine- and histamine-induced bronchoconstriction in a dose-dependent fashion [11] These findings suggest that adrenomedullin might have similar effects to ANP on asthmatic changes. A recent study has reported that adrenomedullin augments inducible NO synthesis in interleukin-1b-stimulated rat vascular smooth muscle, partially through a cyclic adenosine monophosphate (cAMP)dependent pathway [16] These facts suggest that adrenomedullin-induced NO production might negate the beneficial effects of adrenomedullin on asthmatic reactions. The second purpose of this study was to investigate whether or not L-NG-nitroarginine methethyl ester (L-NAME), a NO synthase inhibitor, could potentiate the effects of adrenomedullin on antigeninduced microvascular leakage
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