title: TPI 1020, a novel anti-inflammatory, nitric oxide donating compound, potentiates the bronchodilator effects of salbutamol in conscious guinea-pigs.
abstract: Inhaled corticosteroids are regularly co-administered with beta(2)-adrenoceptor agonists. This study evaluates in conscious guinea-pigs the bronchodilator effect, alone or combined with salbutamol, of TPI 1020, a novel anti-inflammatory corticosteroid and nitric oxide (NO) donor derived from budesonide. Guinea-pigs received inhaled histamine (3 mM) and specific airway conductance (sG(aw)) measured. Responses to histamine were measured before and on the next day 15 min after a 15 min inhalation of vehicle, salbutamol, TPI 1020, budesonide, the NO-donor, S-nitroso-N-acetylpenicillamine (SNAP), or combinations of these drugs. Salbutamol and TPI 1020 caused concentration-dependent bronchodilatation measured as inhibition of histamine-induced bronchoconstriction. TPI 1020-induced bronchodilatation was blocked by the guanylyl cyclise inhibitor, ODQ, indicating cGMP-dependence through released NO. While salbutamol at 80 microM did not exert significant bronchodilatation, significant inhibitions were observed when co-administered with TPI 1020, 0.11 and 0.33 mM. The combined effects of TPI 1020 and salbutamol lasted significantly longer than either drug alone. Inhaled budesonide was a weak bronchodilator and when co-administered with salbutamol there was enhanced bronchodilatation. Addition of the NO-donor, SNAP (0.1 mM), to the budesonide/salbutamol combination, also improved the inhibition of histamine-induced bronchoconstriction. This study has shown that TPI 1020 potentiates the bronchodilator activity of salbutamol, and their combination lasted longer than either drug administered individually. Both the corticosteroid and NO-releasing activities of TPI 1020 appear to be required for the potentiation of salbutamol. Combination of TPI 1020 with a beta(2)-adrenoceptor agonist may therefore be useful against acute bronchoconstriction episodes in asthma, and may offer an opportunity for reducing doses of inhaled beta(2)-adrenoceptor agonists.
authors.affiliation: Division of Pharmacology, Welsh School of Pharmacy, Cardiff University, Cathays Park Campus, Cardiff, Wales, UK.
authors.forename: Dawn L
authors.initials: DL
authors.lastname: Turner
authors.forename: Nicolay
authors.initials: N
authors.lastname: Ferrari
authors.forename: William R
authors.initials: WR
authors.lastname: Ford
authors.forename: Emma J
authors.initials: EJ
authors.lastname: Kidd
authors.forename: Luc
authors.initials: L
authors.lastname: Paquet
authors.forename: Paulo
authors.initials: P
authors.lastname: Renzi
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Broadley
mesh_terms: D000280:Administration, Inhalation; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000420:Albuterol / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001249:Asthma / Q000188:drug therapy; D016084:Bronchoconstriction / Q000187:drug effects; D001993:Bronchodilator Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D019819:Budesonide / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D003243:Consciousness; D006152:Cyclic GMP / Q000494:pharmacology / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D006168:Guinea Pigs; D006632:Histamine / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D009569:Nitric Oxide / Q000494:pharmacology / Q000627:therapeutic use; D020030:Nitric Oxide Donors / Q000494:pharmacology / Q000627:therapeutic use; D018343:Receptors, Adrenergic, beta-2 / Q000627:therapeutic use; D026423:S-Nitroso-N-Acetylpenicillamine / Q000494:pharmacology
chemical_list: D000318:Adrenergic beta-Agonists; D000893:Anti-Inflammatory Agents; D001993:Bronchodilator Agents; C492926:NCX 1020; D020030:Nitric Oxide Donors; D018343:Receptors, Adrenergic, beta-2; D009569:Nitric Oxide; D019819:Budesonide; D026423:S-Nitroso-N-Acetylpenicillamine; D006632:Histamine; D006152:Cyclic GMP; D000420:Albuterol