Ro 25-1553: a novel, long-acting vasoactive intestinal peptide agonist. Part II: Effect on in vitro and in vivo models of pulmonary anaphylaxis.
Studies were conducted to compare the effect of native vasoactive intestinal peptide (VIP), Ro 25-1553 (a cyclic peptide analog of VIP) and salbutamol (a beta2-adrenoceptor agonist) on antigen-induced pathophysiological effects in the guinea pig. Ro 25-1553 and salbutamol (0.01-1.0 microM) prevented antigen-induced contractions of the guinea pig trachea in vitro with IC50 values of 0.07 and 0.05 microM, respectively. VIP (0.01-1.0 microM) had no effect on antigen-induced tracheal contractions. Aerosolized Ro 25-1553 and salbutamol were equipotent in preventing antigen-induced increases in guinea pig lung resistance (IC50 value = 0.0001%), whereas aerosolized VIP (0.1%) was ineffective. Ro 25-1553 (0.1-100 micrograms), instilled intratracheally 2 min before the antigen challenge of buffer-perfused lungs from sensitized guinea pigs, produced a dose-dependent inhibition of bronchoconstrictor, vasoconstrictor and edemagenic responses, whereas intratracheal VIP (100 micrograms) had no effect. Intratracheal salbutamol (0.1-100 micrograms) inhibited antigen-induced responses in a manner comparable to Ro 25-1553. Lung inflammation was assessed as leukocyte accumulation in bronchoalveolar lavage fluid after the antigen provocation. Aerosolized antigen-induced bronchoalveolar lavage eosinophilia (13-fold increase over saline controls) at 6 hr after challenge was prevented in a concentration-dependent manner by pretreatment with nebulized Ro 25-1553 and salbutamol, but not by pretreatment with native VIP. These results indicate that Ro 25-1553 suppresses various pathophysiological features associated with pulmonary anaphylaxis and asthma, including airway reactivity, edema formation and granulocyte accumulation.(ABSTRACT TRUNCATED AT 250 WORDS)
O'Donnell
M
M
Department of Bronchopulmonary Research, Hoffmann-La Roche, Inc., Nutley, New Jersey.
Garippa
R J
RJ
Rinaldi
N
N
Selig
W M
WM
Tocker
J E
JE
Tannu
S A
SA
Wasserman
M A
MA
Welton
A
A
Bolin
D R
DR
D000420:Albuterol / Q000494:pharmacology; D000707:Anaphylaxis / Q000517:prevention & control*; D000818:Animals; D000941:Antigens; D001249:Asthma / Q000188:drug therapy; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D001993:Bronchodilator Agents / Q000494:pharmacology*; D004195:Disease Models, Animal; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008171:Lung Diseases / Q000517:prevention & control*; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D010456:Peptides, Cyclic / Q000494:pharmacology*; D010477:Perfusion; D014660:Vasoactive Intestinal Peptide / Q000819:agonists* / Q000031:analogs & derivatives* / Q000494:pharmacology
D000941:Antigens; D001993:Bronchodilator Agents; D010456:Peptides, Cyclic; C089777:Ro 25-1553; D014660:Vasoactive Intestinal Peptide; D000420:Albuterol