Characteristics of histamine tachyphylaxis in canine tracheal smooth muscle

Abstract

Summary In isolated canine tracheal smooth muscle, repeated administrations of histamine result in a rapid reduction in contractile response to about 15% of the initial contraction (tachyphylaxis). Development of this tachyphylaxis is specific inasmuch as: 1) it does not develop to acetylcholine (10⁻⁶ M or 10⁻⁴ M), or serotonin (10⁻⁵ M); and 2) maximally developed histamine tachyphylaxis is not associated with a parallel reduction in response to acetylcholine. Pretreatment with propranolol (10⁻⁵ M) or phentolamine (10⁻⁴ M) does not prevent tachyphylaxis: however, pretreatment with atropine (10⁻⁴ M) does prevent tachyphylaxis in about 50% of the animals tested. Tachyphylaxis to histamine can be reversed in a dose- and time-dependent fashion with prostaglandin synthesis inhibiting agents. The order of potency obtained with such compounds (indomethacin > mefenamic acid > oxyphenbutazone > acetylsalicylic acid) is consistent with potencies for inhibition of prostaglandin synthesis found in the literature. Also, in indomethacin pretreated strips in which tachyphylaxis to histamine was prevented, exogenous addition of PGE₂ (1.42×10⁻¹⁰ M to 2.84×10⁻⁹ M) and PGA₂ in a high concentration (2.9×10⁻⁹ M) are capable of selectively reducing the response to histamine without an effect on acetylcholine-induced contractions. These data suggest that the mechanism of histamine tachyphylaxis in the canine tracheal smooth muscle preparation involves prostaglandin synthesis.