title: RP 58802B, a long-acting beta 2-adrenoceptor agonist: assessment of antiasthma activity in the guinea-pig in vivo.
abstract: We have examined the protective actions of RP 58802B, a novel beta 2-adrenoceptor agonist, administered by the inhaled and oral routes in the anaesthetized and conscious guinea-pig against bronchospasm induced by histamine or antigen (ovalbumin). We have also examined the effects of RP 58802B on airway reactivity and inflammatory cell infiltration in platelet-activating factor (PAF) (aerosol)-induced bronchial hyperreactivity and on PAF (tracheal instillation)-induced microvascular leakage in the guinea-pig. Nebulized RP 58802B produced a rapid onset and long lasting inhibition of histamine-induced bronchospasm in the anaesthetized guinea-pig (EC50 = 3.2 +/- 0.9 micrograms/ml; duration greater than 90 min). Given orally, RP 58802B (5 mg/kg, 60 min before challenge) produced a greater than three-fold shift to the right of the dose-response curve and depressed the maximum response to histamine by 39 +/- 11%. Increasing the concentration to 25 mg/kg had no futher effect. Similar protection was still seen 4 h after oral dosing. In conscious guinea-pigs, RP 58802B (5 or 25 mg/kg, p.o. 60 min before challenge) significantly attenuated antigen-induced dyspnoea with the time to severe dyspnoea increasing from 170 +/- 32 to 325 +/- 32 s at the higher dose of drug. RP 58802B (10 or 25 mg/kg, p.o. 60 min before exposure to PAF) prevented the development of bronchial hyperreactivity. Although PAF-induced bronchial hyperreactivity was not accompanied by an increase in the number of pulmonary eosinophils, RP 58802B (25 mg/kg p.o.) reduced the numbers of eosinophils recovered by lavage. RP 58802B (10 mg/kg p.o.) significantly inhibited PAF-induced microvascular leakage into guinea-pig lung. These data suggest that RP 58802B, in addition to being a potent and long acting bronchodilator, may have a prophylactic role in preventing bronchial hyperreactivity and in reducing plasma exudation into the lungs.
mesh_terms: D000280:Administration, Inhalation; D000284:Administration, Oral; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000420:Albuterol / Q000494:pharmacology; D000758:Anesthesia; D000818:Animals; D000941:Antigens / Q000008:administration & dosage; D001249:Asthma / Q000188:drug therapy* / Q000503:physiopathology; D001562:Benzimidazoles / Q000494:pharmacology*; D001980:Bronchi / Q000187:drug effects / Q000378:metabolism; D016535:Bronchial Hyperreactivity / Q000139:chemically induced / Q000188:drug therapy; D001992:Bronchoalveolar Lavage Fluid / Q000378:metabolism; D016084:Bronchoconstriction / Q000187:drug effects / Q000502:physiology; D003911:Dextrans / Q000493:pharmacokinetics; D004983:Ethanolamines / Q000494:pharmacology*; D016650:Fluorescein-5-isothiocyanate / Q000493:pharmacokinetics / Q000031:analogs & derivatives; D006168:Guinea Pigs; D006632:Histamine / Q000494:pharmacology; D008297:Male; D010972:Platelet Activating Factor / Q000494:pharmacology; D013997:Time Factors; D014132:Trachea / Q000187:drug effects / Q000378:metabolism
chemical_list: D000318:Adrenergic beta-Agonists; D000941:Antigens; D001562:Benzimidazoles; D003911:Dextrans; D004983:Ethanolamines; D010972:Platelet Activating Factor; C015219:fluorescein isothiocyanate dextran; D006632:Histamine; C078396:RP 58802B; D016650:Fluorescein-5-isothiocyanate; D000420:Albuterol