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.