Inhibition by salmeterol of increased vascular permeability and granulocyte accumulation in guinea-pig lung and skin.
1. The long-acting beta 2-adrenoceptor agonist, salmeterol has been evaluated 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 concentration, 0.001-1.0 mg ml-1) routes, inhibited histamine-induced plasma protein extravasation (PPE) into the airway lumen. 3. Inhibition of PPE by salmeterol was long-lasting (greater than 6 h) and was inhibited by prior administration of propranolol (1 mg kg-1, s.c.), indicating an effect mediated by beta-adrenoceptors. 4. Inhaled salbutamol (nebulizer concentration, 0.001-1.0 mg ml-1) also inhibited PPE in guinea-pig lung but, in contrast to salmeterol, this effect was short-lived with substantial 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 (100 micrograms ml-1). Salmeterol, but not salbutamol, inhibited the infiltration of eosinophils into the airway lumen in response to platelet activating factor (100 micrograms 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.), inhibited zymosan-induced granulocyte accumulation and PPE in guinea-pig skin. Lower doses of salmeterol (0.1 and 1 mg kg-1) inhibited PPE, but not granulocyte accumulation.The effects of salmeterol were blocked by prior administration of propranolol (1mgkg-', s.c.). Both salmeterol and salbutamol inhibited histamine-induced PPE in guinea-pig skin.7. Intradermal salmeterol (10-'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 bronchodilator doses in the guinea-pig, inhibits granulocyte accumulation and PPE, possibly by an action on the vasculature. As this profile of activity is not shared by the shorter-acting compound, salbutamol, it would seem that anti-inflammatory activity is associated with beta-adrenoceptor agonism of long duration. The implications of these findings for the use of salmeterol in the treatment of bronchial asthma are discussed.
Department of Peripheral Pharmacology, Glaxo Group Research Limited, Ware, Hertfordshire.
C J
CJ
Whelan
M
M
Johnson
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000420:Albuterol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000494:pharmacology; D001798:Blood Proteins / Q000378:metabolism; D002199:Capillary Permeability / Q000187:drug effects*; D015232:Dinoprostone / Q000494:pharmacology; D006098:Granulocytes / Q000187:drug effects*; D006168:Guinea Pigs; D006632:Histamine / Q000494:pharmacology; D008168:Lung / Q000187:drug effects; D008297:Male; D000068299:Salmeterol Xinafoate; D012867:Skin / Q000187:drug effects
D000318:Adrenergic beta-Agonists; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001798:Blood Proteins; D000068299:Salmeterol Xinafoate; D006632:Histamine; D015232:Dinoprostone; D000420:Albuterol