An indomethacin-sensitive contraction induced by beta-antagonists in guinea pig airways.
Beta-adrenergic receptor (beta-AR) antagonists have been associated with increased airway reactivity in asthmatics and potentiation of contractile stimuli in animal models. In the present study, using an in vitro model of tracheal preparations from guinea pigs, we show that the beta-AR antagonists propranolol and pindolol induce a smooth muscle contraction. A prerequisite for this contraction is that the airway preparations have been pre-treated with an beta-AR agonist. Our data show that the contractile effect of beta-AR antagonists is not a simple consequence of reversing the agonist-induced relaxation. Furthermore, the effect seems to be mediated through interaction with beta2-ARs since the response is stereo-selective, and the selective beta1-AR receptor antagonist atenolol did not induce any contractile response. SQ 29,546, a thromboxane A2 antagonist; MK 886, a lipoxygenase inhibitor; and indomethacin, a cyclooxygenase inhibitor significantly inhibited the contractions of the tracheal preparations induced with propranolol or pindolol. We put forward the hypothesis that the contractile effect of the beta-AR antagonist is a consequence of their inverse agonist activity, which is only evident when the receptor population have a higher basal activity. Our results indicate a novel additional explanation for the known side effect, bronchoconstriction, of beta-AR antagonist.
Johansson
Fredrik
F
Department of Medicine and Care, Faculty of Health Sciences, Linköping University, Sweden.
Andersson
Rolf G G
RG
Lindström
Eva
E
Svensson
Samuel S
SS
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology*; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects* / Q000502:physiology; D014132:Trachea / Q000187:drug effects* / Q000502:physiology
D000319:Adrenergic beta-Antagonists; D007213:Indomethacin