Adrenomedullin inhibits ovalbumin-induced bronchoconstriction and airway microvascular leakage in guinea-pigs.
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.
Ohbayashi
H
H
Internal Medicine II, Nagoya University School of Medicine, Japan.
Suito
H
H
Yoshida
N
N
Ilto
Y
Y
Kume
H
H
Yamaki
K
K
D053607:Adrenomedullin; D000818:Animals; D016084:Bronchoconstriction / Q000187:drug effects*; D001993:Bronchodilator Agents / Q000494:pharmacology*; D015740:Calcitonin Gene-Related Peptide / Q000494:pharmacology; D002199:Capillary Permeability / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006168:Guinea Pigs; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D010047:Ovalbumin; D010455:Peptides / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000494:pharmacology*
D001993:Bronchodilator Agents; D004791:Enzyme Inhibitors; D010455:Peptides; D014665:Vasodilator Agents; D053607:Adrenomedullin; D010047:Ovalbumin; D015740:Calcitonin Gene-Related Peptide; D019331:NG-Nitroarginine Methyl Ester