Paradoxal effect of salbutamol in an in vitro model of bronchoprotection.
Salbutamol-induced hyperresponsiveness to acetylcholine was investigated in human and guinea-pig isolated airways and cultured human airway smooth muscle cells. Salbutamol (10(-7)-10(-5) m) inhibited contractions induced by low concentrations of acetylcholine (10(-8)-10(-7) m) but potentiated contractions induced by higher concentrations of acetylcholine (10(-5)-10(-3) m). Pretreatment with the calcium channel antagonist nicardipine suppressed salbutamol-induced hyperresponse. Stimulation of cultured human airway smooth muscle cells with salbutamol (10(-6) m) amplified intracellular calcium concentration rise induced by acetylcholine (10(-5) m). Propranolol (10(-7) m), a beta1- and beta2-adrenoceptor antagonist, and ICI 118551 (10(-7)-10(-6) m), a beta2-adrenoceptor antagonist, suppressed the inhibitory effect of salbutamol but did not inhibit the hyperresponse on high concentrations of acetylcholine. In contrast, higher concentration of propranolol (10(-6) m) inhibited salbutamol-induced hyperreactivity. Effects of salbutamol were not affected by atenolol, a beta1-adrenoceptor blocker. Salbutamol-induced hyperresponsiveness is mediated through a mechanism involving calcium channel activation.
Girodet
P O
PO
Laboratoire de Pharmacologie Respiratoire, Université Victor Segalen Bordeaux 2, 33076 Bordeaux, France.
Berger
P
P
Martinez
B
B
Marthan
R
R
Advenier
C
C
Molimard
M
M
D000109:Acetylcholine / Q000037:antagonists & inhibitors / Q000633:toxicity*; D000420:Albuterol / Q000008:administration & dosage / Q000627:therapeutic use*; D000818:Animals; D016084:Bronchoconstriction / Q000187:drug effects; D001993:Bronchodilator Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006168:Guinea Pigs; D006801:Humans; D009119:Muscle Contraction / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects*; D014132:Trachea / Q000187:drug effects; D014665:Vasodilator Agents / Q000037:antagonists & inhibitors / Q000633:toxicity*
D001993:Bronchodilator Agents; D014665:Vasodilator Agents; D000109:Acetylcholine; D000420:Albuterol