CONTRACTILE RESPONSES OF GUINEA-PIG TRACHEA TO OXYBARBITURATES AND THIOBARBITURATES

To determine what mechanisms are involved in barbiturate-induced tracheal constriction and whether a relationship exists between barbiturate structure and the ability of the barbiturate to induce constriction, we compared the effects of thiamylal, thiopental, methohexital, pentobarbital, and phenobarbital at increasing airway tone in an intact guinea pig tracheal preparation in the presence and absence of cyclooxygenase and thromboxane synthetase inhibition. Whole tracheas were suspended between two cannulas in 50-ml tissue baths and perfused at a constant flow rate with Krebs-Henseleit solution. The contractile responses were assessed by measuring the pressure differential between the tracheal inlet and outlet ports. Barbiturates were added to the bath of each trachea, which was washed between each drug. Each drug was added to produce final bath concentrations of 10(-6), 10(-5), 10(-4), 10(-3), and 3 x 10(-3) M. Tracheas were also pretreated with meclofenamate (10(-6) M) (a cyclooxygenase inhibitor) and UK 37,248 (10(-8) to 10(-5) M) and OKY 046 (10(-9) to 10(-6) M) (thromboxane synthetase inhibitors), and the thiamylal protocol was repeated. All data were normalized to a concentration of carbachol (2 x 10(-6) M) that has been shown to produce maximum constriction in this preparation. Thiamylal and thiopental produced constriction beginning at 10(-4) M and reached a maximum at 10(-3) M (P < 0.0001). Methohexital, pentobarbital, and phenobarbital did not produce any significant change in airway tone. Pretreatment with meclofenamate (10(-6) M), UK 37,248 (5 x 10(-5) M), and OKY 046 (10(-6) M) prevented thiamylal-induced tracheal constriction. We conclude that thiobarbiturates, but not oxybarbiturates, constrict guinea pig tracheas in concentrations similar to those achieved in vivo. This constriction is mediated by thromboxane.