Inhibition by viozan of extravasation induced in rat trachea by capsaicin is mediated exclusively by β2-adrenoceptors

Abstract

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

Capsaicin‐induced mucus secretion in rat airways assessed in vivo and non‐invasively by magnetic resonance imaging

“… Fozard et al . (2001) demonstrated an increased extravasation of plasma protein tagged with Evans Blue in the rat trachea (from the larynx to the bifurcation) 10 min after i.t.…”

“…In our studies, MRI signals following capsaicin administration were observed in lower parts of the lung that are associated with an increase of mucin concentration in BAL fluid. An explanation for the discrepancy between the current results and those of Fozard et al . (2001) could be the greater density of sensory nerves in upper airways compared to lower ones as demonstrated by Larson et al .…”

“…An increase in plasma extravasation from the rat trachea has been shown with capsaicin administered intratracheally (i.t.) at doses between 3 and 30 μ g kg −1 ( Fozard et al ., 2001 ). Tachykinins may be involved in smooth muscle contraction, vasodilatation, edema, mucus secretion and inflammatory cell activation ( Reynolds et al ., 1997 ).…”

Effect of dopamine receptor agonists on sensory nerve activity: possible therapeutic targets for the treatment of asthma and COPD

“…These in vitro data seem to concur with in vivo data published which demonstrated that D 2 receptor agonists inhibit neuropeptide release from airway sensory nerves (Weyman‐Jones et al ., 1999) and that AR‐C68397AA and the D 2 receptor agonist ropinirole inhibit capsaicin evoked plasma extravasation into the airways in a sulpiride sensitive manner (Trevisani et al ., 2001). In some respects this data is in contrast to that published by Fozard et al . (2001) where inhibition by AR‐C68397AA of plasma extravasation in rat trachea induced by capsaicin was mediated exclusively by β 2 ‐adrenoreceptors.…”

“…In addition, another group have shown an analogue of AR‐C68397AA, AR‐C65116AB, and ropinirole (Dopamine agonist, Eden et al ., 1991) to be effective in the same model and these effects could be blocked by the D 2 receptor antagonist, sulpiride (Trevisani et al ., 2001). In contrast, a recent study by Fozard et al . (2001), using a similar model, has shown the activity of AR‐C68397AA to be due solely to its activity on the β 2 adrenoreceptor and that a dopamine D 2 receptor agonist, quinagolide, was ineffective.…”