Protamine-induced pulmonary hypertension in heparinized monkeys and pigs is inhibited by the thromboxane receptor antagonist SQ 30,741.
When protamine reverses heparin anticoagulation a small fraction of patients develops pulmonary hypertension. This response is variably expressed in other species and thromboxane may be one of its mediators. We have compared the pulmonary vascular responses of pigs and monkeys to protamine (3 mg/kg, i.v.) administered 15 min after heparin (300 U/kg, i.v.). The role of thromboxane A2/prostaglandin H2 (TxA2/PGH2)-receptor activation in this response was investigated with the selective TxA2/PGH2-receptor antagonist, SQ 30,741, at a dose (1 mg/kg, i.v.) shown to inhibit U-46,619-induced pulmonary vasoconstriction by greater than or equal to 99%. SQ 30,741 or vehicle (1.5 ml saline) was given 2 min before protamine in Yucatan minipigs (n = 6-7) and African green monkeys (n = 8-9). In saline-treated monkeys and pigs, protamine increased pulmonary vascular resistance (131 +/- 46 and 478 +/- 18%, respectively) primarily by increasing pulmonary artery pressures (54 +/- 19 and 166 +/- 42%, respectively). In pigs only, pulmonary artery flow was also reduced by 33 +/- 9%. These responses peaked within 1 to 3 min and returned to baseline in approximately 5 (monkey) and approximately 15 (pig) min. In monkeys and pigs pretreated with SQ 30,741 the increases in pulmonary vascular resistance (17 +/- 4 and 16 +/- 9%, respectively, p less than 0.05) and pulmonary artery pressure (10 +/- 3 and 16 +/- 9%, respectively, p less than 0.05) were significantly inhibited. SQ 30,741 also accelerated reversal of established hypertension in pigs when given 1 min after protamine. However, transient reductions in circulating monkey leukocytes (approximately 70%) and platelets (approximately 16%) were unaffected by SQ 30,741.(ABSTRACT TRUNCATED AT 250 WORDS)
Schumacher
W A
WA
Department of Pharmacology, Squibb Institute for Medical Research, Princeton, NJ 08543-4000.
Heran
C L
CL
Ogletree
M L
ML
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002522:Chlorocebus aethiops; D004347:Drug Interactions; D006493:Heparin / Q000494:pharmacology; D006976:Hypertension, Pulmonary / Q000139:chemically induced* / Q000503:physiopathology / Q000517:prevention & control; D007700:Kinetics; D008168:Lung / Q000098:blood supply; D011450:Prostaglandin Endoperoxides, Synthetic / Q000037:antagonists & inhibitors / Q000494:pharmacology; D044262:Prostaglandin H2; D011463:Prostaglandins H / Q000037:antagonists & inhibitors; D011479:Protamines / Q000494:pharmacology / Q000633:toxicity*; D011651:Pulmonary Artery / Q000503:physiopathology; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors / Q000502:physiology; D017482:Receptors, Thromboxane; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D013552:Swine; D013556:Swine, Miniature; D013928:Thromboxane A2 / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors* / Q000494:pharmacology / Q000627:therapeutic use; D014655:Vascular Resistance / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects
D011450:Prostaglandin Endoperoxides, Synthetic; D011463:Prostaglandins H; D011479:Protamines; D011982:Receptors, Prostaglandin; D017482:Receptors, Thromboxane; D044244:Receptors, Thromboxane A2, Prostaglandin H2; C054215:SQ 30741; D044262:Prostaglandin H2; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D006493:Heparin