Effects of PAF on isolated rat airways perfused with blood-free solution.

We examined the mechanism of constriction and muscarinic augmentation of contraction of airway smooth muscle caused by platelet-activating factor (PAF) in airways from 55 Sprague-Dawley rats perfused through the isolated bronchial circulation (BC) and pulmonary circulation (PC) and isometrically in tissue perfusion chambers. Dose-response curves were generated cumulatively by infusing 10(-10) to 10(-7) mol PAF dissolved in Krebs-Henseleit solution buffer containing 4% bovine serum albumin into the BC or PC. The efficacy of PAF in central airways (BC) was approximately twofold greater in increasing lung resistance (RL) than for more peripheral airways perfused by the PC (P less than 0.05). Tachyphylaxis was demonstrated in both BC and PC for preparations in which a second PAF dose-response curve was generated. Bolus injection of 10(-6) mol of the PAF antagonist, CV-6209, plus 10(-7) mol PAF caused 81% reversal of the maximal BC response. The same dose of CV-6209 reversed the response to PAF in the PC by 99.2%. Initial administration of 10(-6) mol CV-6209 with PAF prevented completely contraction elicited by PAF in the BC and PC. Concentration-response studies also were generated isometrically in tissue perfusion chambers from 64 tracheal smooth muscle strips. Maximal contraction elicited by 10(-6) M PAF was blocked completely with 10(-6) M CV-6209. In separate studies, addition of 10(-6) mol CV-6209 to the BC perfusate caused 93% blockade of the RL response to PAF and 100% inhibition when administered in the PC. Prior administration of PAF caused two- to fourfold augmentation of the contractile response to acetylcholine (ACh) within the same preparation; in the presence of CV-6209, the response to ACh was unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)