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.
Department of Neurology, Uniformed Services University of the Health Sciences, Bethesda, Maryland.
R
R
Rabinovici
A S
AS
Rudolph
T L
TL
Yue
G
G
Feuerstein
D000818:Animals; D001381:Azepines / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D001802:Blood Substitutes / Q000009:adverse effects* / Q000494:pharmacology; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D004347:Drug Interactions; D006439:Hemodynamics / Q000187:drug effects; D006454:Hemoglobins / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use; D007958:Leukocyte Count / Q000187:drug effects; D008081:Liposomes / Q000009:adverse effects; D008297:Male; D010100:Oxygen / Q000097:blood; D010713:Phosphatidylcholines; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors*; D010976:Platelet Count / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D013929:Thromboxane B2 / Q000097:blood; D014230:Triazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*
D001381:Azepines; D001802:Blood Substitutes; D006454:Hemoglobins; D008081:Liposomes; D010713:Phosphatidylcholines; D010972:Platelet Activating Factor; D014230:Triazoles; C064509:BN 50739; D013929:Thromboxane B2; C010942:1,2-distearoyllecithin; D010100:Oxygen