Inhibition by viozan of extravasation induced in rat trachea by capsaicin is mediated exclusively by beta 2-adrenoceptors.
The mechanism by which 2(3H)-benzothiazolone, 4-hydroxy-7-[2-[[2-[[3-(2-phenylethoxy)propyl]-sulphonyl]ethyl]amino]ethyl]-monohydrochloride (AR-C68397AA; viozan), a dual dopamine D2/beta2-adrenoceptor agonist which has shown promise in the treatment of chronic obstructive pulmonary disease (COPD), inhibits the extravasation of plasma protein induced by capsaicin in the tracheas of Brown Norway rats has been re-evaluated. Viozan (10-30 microg/kg given intratracheally; i.t.) inhibited dose-dependently the extravasation of plasma protein tagged with Evans Blue into rat trachea induced by capsaicin (10 microg/kg i.t.). Similar effects were seen with the selective beta2-adrenoceptor agonist, salbutamol (3-10 microg/kg i.t.), but the selective dopamine D2 receptor agonist, quinagolide (10-30 microg/kg i.t.), was inactive. The effects of viozan and salbutamol were abolished by propranolol (3 mg/kg) given intraperitoneally (i.p.) but unaffected by sulpiride (3 mg/kg i.p.). Thus, in c,ontrast to claims in the literature, a functional response to dopamine D2 receptor activation in a preclinical model of oedema arising from sensory nerve fibre activation in the rat lung could not be demonstrated. Moreover, no qualitative difference could be demonstrated between the response to a dual D2/beta2-adrenoceptor agonist and a selective beta2-adrenoceptor agonist. The observations call into question whether a dual D2/beta2-adrenoceptor agonist such as viozan would bring added benefit over established selective beta2-adrenoceptor agonists in the therapy
Fozard
J R
JR
Research Department, Novartis Pharma AG, Basel, Switzerland. john_r.fozard@pharma.novartis.com
Baur
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F
Wolber
C
C
Collingwood
S P
SP
D058666:Adrenergic beta-2 Receptor Agonists; D058672:Adrenergic beta-2 Receptor Antagonists; D000318:Adrenergic beta-Agonists / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001798:Blood Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D002211:Capsaicin / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005119:Extravasation of Diagnostic and Therapeutic Materials / Q000378:metabolism* / Q000517:prevention & control*; D007274:Injections, Intraperitoneal; D007442:Intubation, Intratracheal; D008297:Male; D011433:Propranolol / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D011914:Rats, Inbred BN; D018343:Receptors, Adrenergic, beta-2 / Q000502:physiology*; D013469:Sulpiride / Q000008:administration & dosage / Q000494:pharmacology; D013844:Thiazoles / Q000008:administration & dosage / Q000494:pharmacology*; D014132:Trachea / Q000187:drug effects* / Q000502:physiology
D058666:Adrenergic beta-2 Receptor Agonists; D058672:Adrenergic beta-2 Receptor Antagonists; D000318:Adrenergic beta-Agonists; D001798:Blood Proteins; D018343:Receptors, Adrenergic, beta-2; D013844:Thiazoles; D013469:Sulpiride; D011433:Propranolol; C116267:sibenadet; D002211:Capsaicin