Priming interactions between platelet activating factor and histamine in the in vivo microcirculation

To elucidate whether priming exists between platelet-activating factor (PAF) and histamine in the microcirculation, we measured the clearance of FITC-dextran 150 in response to the topical applications of substimulatory concentrations of PAF and histamine. Maximal priming by PAF was observed when a 5-min interval separated the applications of 10^-9M PAF and 10^-6M histamine. The mean (± SEM) clearance resulting from this sequence of agonist administration was 7529 ± 659 nl·2 h^-1·g^-1, representing a 4.5-fold enhancement in FITC-dextran 150 clearance compared with that evoked by 10^-6M histamine alone (1664 ± 397 nl·2 h^-1·g^-1). Lowering the PAF priming dose to 10^-11M, or reversing the order of agonist addition to the microcirculation, resulted in diminished but significant responses of 3545 ± 1143 and 4467 ± 1170 nl·2 hr^-1·g^-1, respectively. Coapplication of PAF and histamine or increasing the time interval between the agonists to 15 min greatly reduced the responses to 1906 ± 678 and 2770 ± 837, respectively. The PAF receptor antagonist WEB 2086 (2 mg/kg i.v.), the H₁ blocker pyrilamine (10 mg/kg i.v.), and leukocyte depletion with cyclophosphamide (150 mg/kg i.p.) completely abolished the PAF priming effect. In addition, the 5-lipoxygenase inhibitor RG 5901 (1 or 10 mg/kg i.v.) produced a two-thirds attenuation in PAF priming. We conclude that 1) PAF has the ability to prime the in vivo microvascular actions of histamine in both a concentration and time-dependent fashion; 2) this primed response is receptor mediated; and 3) histamine can prime the microcirculation for enhanced responses to PAF. Our data also demonstrate that leukocytes and the release of leukotrienes participate in PAF priming.