Biological responses to liposome-encapsulated hemoglobin (LEH) are improved by a PAF antagonist

Liposome-encapsulated hemoglobin (LEH) is an experimental oxygen-carrying blood substitute. Previous studies in our laboratory with hydrogenated soy lecithin-based LEH indicated that while this solution maintained some physicochemical and oxygen-carrying properties of red blood cells, it evoked several transient (30-120 min) untoward biological responses, such as hypertension, tachycardia, thrombocytopenia, hemoconcentration, and elevation of plasma thromboxane B2 (TXB2). Such biochemical, hematological, and hemodynamic derangements are also produced by platelet-activating factor (PAF). The purpose of this study was to test the biological responses to administration of a newly produced synthetic distearoyl phosphatidylcholine-based LEH (s-DSPC-LEH) in the normal conscious rat (n = 6-11) and to examine the role of PAF in these processes. Systemic (IV) administration of S-DSPC-LEH caused transient hypotension (-23 +/- 8 mmHg, P less than 0.05), bradycardia (-24 +/- 11 bpm, P less than 0.05) followed by tachycardia (+62 +/- 21 bpm, P less than 0.05), decreased cardiac index (217 +/- 21 ml/min/kg, P less than 0.01), increased peripheral resistance (0.570 +/- 0.003 mmHg/ml/min/kg, P less than 0.01), transient leukocytosis (+6,870 +/- 1,801/microliters, P less than 0.05), hemoconcentration (+5.2 +/- 0.4%, P less than 0.01), thrombocytopenia (-160 +/- 18 X 10(3)/microliters, P less than 0.01), and increase in plasma TXB2 (45.0 +/- 1.9 pg/100 microliters, P less than 0.01). Separate infusion of the liposome vehicle or free hemoglobin, the two components of s-DSPC-LEH, did not evoke any consistent responses. Administration of the PAF antagonist BN 50739 (10 mg/kg, i.p.) 30 min prior to LEH prevented the hemodynamic changes and hemoconcentration induced by s-DSPC-LEH. These data suggest that hemoglobin/phospholipid interactions might account for the transient side effects of s-DSPC-LEH, possibly through interactions with blood elements and the resultant production of PAF and TXA2. Furthermore, PAF antagonists incorporated into or co-administered with LEH might enhance its biological applications.