Enhancement of thrombolytic efficacy of tissue-type plasminogen activator by adjuvants in the guinea pig thrombosis model.
Reocclusion following thrombolysis is a major limitation of thrombolytic therapy with recombinant tissue-type plasminogen activator (rt-PA). We investigated the effects of vapiprost ((1R-(1 alpha(Z),2 beta,3 beta,5 alpha))-7-(5-((1,1'-biphenyl)-4-yl-methoxy)- 3-hydroxy-2-(1-piperidinyl)cyclopentyl)-4-heptenoic acid, a thromboxane A2 receptor antagonist); argatroban ((2R,4R)-4-methyl-1-[N2-(3-methyl-1,2,3,4-tetrahydro-8-quinolinyl)sulfon yl] - L-arginyl)]-2-piperidine-carboxylic acid, a specific thrombin inhibitor) and MK-886 (3-[1-(4-chlorobenzyl)-3-t-butyl-thio-5-isopropylindol-2-yl]-2,2- dimethylpropanoic acid, a specific leukotriene biosynthesis inhibitor) on the thrombolytic efficacy of rt-PA. The guinea pig femoral artery was thrombotically occluded by photochemical reaction between rose bengal and green light. Thirty min after the occlusion, rt-PA was administered and the time (T1) for reopening of the vessel and the frequency of reocclusion (Fro) 24 h after thrombolysis were monitored. With rt-PA alone, T1 was 28 +/- 7 min (n = 10) and Fro was 70%. T1 was reduced to 9 and 20 min by a combination of rt-PA with vapiprost and argatroban respectively. Fro was reduced by all three adjuvants. Histological observations revealed extensive adherence of polymorphonuclear leucocytes to the damaged endothelium at the site of thrombolysis. It is concluded that thromboxane A2, thrombin and leucocytes are involved in reocclusion after thrombolysis.
Department of Pharmacology, Hamamatsu University School of Medicine, Japan.
H
H
Nishiyama
K
K
Umemura
A R
AR
Saniabadi
Y
Y
Takiguchi
T
T
Uematsu
M
M
Nakashima
D000277:Adjuvants, Pharmaceutic; D000818:Animals; D000991:Antithrombins / Q000008:administration & dosage / Q000494:pharmacology; D001120:Arginine / Q000031:analogs & derivatives; D001713:Biphenyl Compounds / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D005263:Femoral Artery / Q000187:drug effects / Q000473:pathology / Q000601:surgery; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D006168:Guinea Pigs; D006538:Heptanoic Acids / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D020024:Leukotriene Antagonists; D008297:Male; D008855:Microscopy, Electron, Scanning; D009504:Neutrophils / Q000187:drug effects; D010875:Pipecolic Acids / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D013449:Sulfonamides; D015912:Thrombolytic Therapy; D013927:Thrombosis / Q000188:drug therapy*; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D002722:Chlorobenzenes
D000277:Adjuvants, Pharmaceutic; D000991:Antithrombins; D001120:Arginine; D001713:Biphenyl Compounds; D005343:Fibrinolytic Agents; D006538:Heptanoic Acids; D007211:Indoles; D020024:Leukotriene Antagonists; D010875:Pipecolic Acids; D010975:Platelet Aggregation Inhibitors; D017482:Receptors, Thromboxane; D011994:Recombinant Proteins; D013449:Sulfonamides; D010959:Tissue Plasminogen Activator; C060893:MK-886; D002722:Chlorobenzenes; C060013:vapiprost; C031942:argatroban