Cj. Whelan et M. Johnson, INHIBITION BY SALMETEROL OF INCREASED VASCULAR-PERMEABILITY AND GRANULOCYTE ACCUMULATION IN GUINEA-PIG LUNG AND SKIN, British Journal of Pharmacology, 105(4), 1992, pp. 831-838
1. The long-acting beta(2)-adrenoceptor agonist, salmeterol has been e
valuated for its anti-inflammatory effects in the guinea-pig lung and
skin. 2. Salmeterol, administered in bronchodilator doses to conscious
guinea-pigs by both oral (0.01-1.0 mg kg-1) and inhaled (nebulizer co
ncentration, 0.001-1.0 mg ml-1) routes, inhibited histamine-induced pl
asma protein extravasation (PPE) into the airway lumen. 3. Inhibition
of PPE by salmeterol was long-lasting (> 6 h) and inhibited by prior a
dministration of propranolol (1 mg kg-1, s.c.), indicating an effect m
ediated by beta-adrenoceptors. 4. Inhaled salbutamol (nebulizer concen
tration, 0.001 - 1.0 mg ml-1) also inhibited PPE in guinea-pig lung bu
t, in contrast to salmeterol, this effect was short-lived with substan
tial loss of activity 2 h after administration. 5. Inhaled salmeterol
(0.1 mg ml-1) and salbutamol (1.0 mg ml-1) inhibited the accumulation
of neutrophils in guinea-pig lung in response to lipopolysaccharide (1
00-mu-g ml-1). Salmeterol, but not salbutamol, inhibited the infiltrat
ion of eosinophils into the airway lumen in response to platelet activ
ating factor (100-mu-g ml-1). These effects of salmeterol were blocked
by prior administration of propranolol (5 mg kg-1, s.c.), indicating
that they were also beta-adrenoceptor-mediated. 6. Oral salmeterol (10
mg kg-1, p.o.), but not salbutamol (10 and 100 mg kg-1, p.o.), inhibi
ted zymosan-induced granulocyte accumulation and PPE in guinea-pig ski
n. Lower doses of salmeterol (0.1 and 1 mg kg-1) inhibited PPE, but no
t granulocyte accumulation. The effects of salmeterol were blocked by
prior administration of propranolol (1 mg kg-1, s.c.). Both salmeterol
and salbutamol inhibited histamine-induced PPE in guinea-pig skin. 7.
Intradermal salmeterol (10(-8) mol per site), but not salbutamol, was
also effective in inhibiting zymosan-induced granulocyte accumulation
and PPE in guinea-pig skin. 8. It is concluded that salmeterol, at br
onchodilator doses in the guinea-pig, inhibits granulocyte accumulatio
n and PPE, possibly by an action on the vasculature. As this profile o
f activity is not shared by the shorter-acting compound, salbutamol, i
t would seem that anti-inflammatory activity is associated with beta-a
drenoceptor agonism of long duration. The implications of these findin
gs for the use of salmeterol in the treatment of bronchial asthma are
discussed.