vapiprost and Disease-Models--Animal

Following the use of deep hypothermic circulatory arrest in cardiac surgery, cerebral blood flow and cerebral oxygen metabolism are impaired. These may result from abnormal cerebral vasospasm. Powerful vasoconstrictors including endothelins and thromboxane A2 could mediate these processes. We investigated possible involvement of these two factors by assessing the effects of (a) phosphoramidon-an inhibitor of endothelin converting enzyme, and (b) vapiprost (GR32191B)-a specific thromboxane A2-receptor antagonist, on the recovery of cerebral blood flow and cerebral oxygen metabolism following deep hypothermic circulatory arrest.. A total of 18 1-week-old piglets were randomised into three groups (n = 6 per group). At induction, the control group received saline; group PHOS received phosphoramidon 30 mg kg-1 intravenously. Group VAP received vapiprost 2 mg kg-1 at induction and at 30 min intervals thereafter. All groups underwent cardiopulmonary bypass cooling to 18 degrees C, exposed to 60 min of deep hypothermic circulatory arrest, rewarmed and reperfused for 1 h. Cerebral blood flow was measured with radio-labeled microspheres: cerebral oxygen metabolism was calculated at baseline before deep hypothermic circulatory arrest and at 1 h of reperfusion and rewarming.. In the control group, cerebral blood flow decreased to 40.2 +/- 2.0% of baseline after deep hypothermic circulatory arrest and cerebral oxygen metabolism decreased to 50.0 +/- 5.5% (P < 0.0005). The responses in group PHOS were similar. In group VAP, cerebral blood flow and cerebral oxygen metabolism were 64.3 +/- 10.6 and 80.1 +/- 9.8% of baseline, respectively, after deep hypothermic circulatory arrest. Thus, treatment with vapiprost significantly improved recovery of cerebral blood flow (P = 0.046) and cerebral oxygen metabolism (P = 0.020) following deep hypothermic circulatory arrest. No such improvement was seen after treatment with phosphoramidon.. Thromboxane A2 mediates impairments in cerebral perfusion and metabolism following deep hypothermic circulatory arrest. These changes were attenuated by blockade of thromboxane A2-receptors using vapiprost. Endothelins are not shown to be involved. Better knowledge of injury mechanisms will enable development of more effective cerebral protection strategies and allow safer application of deep hypothermic circulatory arrest.

Topics: Animals; Animals, Newborn; Biphenyl Compounds; Brain; Cardiopulmonary Bypass; Cerebrovascular Circulation; Confidence Intervals; Disease Models, Animal; Endothelins; Glycopeptides; Heart Arrest, Induced; Heptanoic Acids; Hypothermia, Induced; Metalloendopeptidases; Oxygen; Random Allocation; Receptors, Thromboxane; Reference Values; Swine; Vascular Resistance

The photochemical reaction between rose bengal and light (540 nm) produces thrombotic occlusion in rat coronary artery. We have now developed an experimental myocardial infarction (MI) model by photochemically induced thrombosis (PIT) in rats and investigated the mechanisms responsible for the induction of MI. PIT in the coronary artery induced myocardial ischemia, which was determined by tissue oxygen tension (tpO2), and resulted in MI. Pretreatment with a thromboxane (TX) A2-receptor antagonist, vapiprost, prevented a decrease in myocardial tpO2 and markedly reduced the MI area, although vapiprost inhibited collagen-induced platelet aggregation by 30% ex vivo. An ADP-induced platelet aggregation inhibitor, clopidogrel, also reduced the MI area. In contrast to vapiprost, clopidogrel inhibited collagen-induced platelet aggregation by 90% ex vivo. Pretreatment with a 5-HT2-receptor antagonist, ketanserin, which did not inhibit collagen-induced platelet aggregation ex vivo, prevented the decrease in myocardial tpO2 and reduced the MI area. These results suggest that TXA2, 5-HT and ADP play a role in the induction of MI and that platelet aggregation and other factors induce ischemia in this model.

Topics: Animals; Biphenyl Compounds; Clopidogrel; Coronary Vessels; Disease Models, Animal; Electrocardiography; Heptanoic Acids; Ketanserin; Male; Myocardial Infarction; Oxygen; Platelet Aggregation Inhibitors; Rats; Rats, Sprague-Dawley; Thrombosis; Ticlopidine

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.

Topics: Adjuvants, Pharmaceutic; Animals; Antithrombins; Arginine; Biphenyl Compounds; Disease Models, Animal; Drug Therapy, Combination; Endothelium, Vascular; Femoral Artery; Fibrinolytic Agents; Guinea Pigs; Heptanoic Acids; Indoles; Leukotriene Antagonists; Male; Microscopy, Electron, Scanning; Neutrophils; Pipecolic Acids; Platelet Aggregation Inhibitors; Receptors, Thromboxane; Recombinant Proteins; Sulfonamides; Thrombolytic Therapy; Thrombosis; Tissue Plasminogen Activator

The effect of a thromboxane A2 receptor antagonist (GR32191) on gastrocnemius muscle blood flow, oedema and viability was assessed in a rodent model of 6-h unilateral hindlimb ischaemia and 4-h reperfusion, and the results compared with those in control and normal groups, and in animals undergoing 6-h ischaemia alone. Control animals demonstrated reduced muscle blood flow throughout reperfusion (at 10 min, P < 0.01 versus normal, P not significant versus ischaemia; at 120 min, P < 0.05 versus normal and ischaemia; at 240 min, P < 0.01 versus normal, P not significant versus ischaemia), and the development of muscle oedema (P < 0.01 versus normal and ischaemia) and muscle necrosis (P < 0.01 versus normal and ischaemia). In contrast, the thromboxane A2 receptor antagonist enhanced muscle blood flow (at 10 min, P < 0.01 versus control; at 120 min, P < 0.05 versus control; at 240 min, P < 0.01 versus control) and preserved muscle viability (P < 0.01 versus control; P not significant versus normal and ischaemia). These results indicate that thromboxane A2 is an important mediator of skeletal muscle reperfusion injury and suggest that administration of a thromboxane A2 receptor antagonist may improve limb salvage rates after surgery for acute ischaemia.

Topics: Animals; Biphenyl Compounds; Disease Models, Animal; Edema; Extremities; Heptanoic Acids; Ischemia; Male; Muscles; Rats; Rats, Sprague-Dawley; Receptors, Thromboxane; Reperfusion Injury

We aimed to evaluate a modified tissue-type plasminogen activator, SUN9216, and the combination of SUN9216 and a thromboxane A2 receptor antagonist, vapiprost, in a rat middle cerebral artery thrombosis model.. Under anesthesia, the left middle cerebral artery was observed under an operation microscope without cutting the dura mater via a subtemporal craniotomy. Photoillumination (wave length, 540 nm) was applied to the middle cerebral artery, and then rose bengal (20 mg/kg) was administered intravenously. The reopening of the middle cerebral artery by SUN9216, injected 30 minutes after middle cerebral artery occlusion, was observed under an operation microscope for a 60-minute observation period. Twenty-four hours after the operation, sections of the cerebrum were stained with triphenyltetrazolium chloride, and the area of cerebral infarction was analyzed by a computer.. The combination of SUN9216 and vapiprost caused reopening of the middle cerebral artery in 58.8% of the rats, which was a greater percentage than that achieved with SUN9216 alone (31.6%). In contrast, saline did not cause reopening of the middle cerebral artery during the 60-minute observation period. The area of cerebral infarction in rats reperfused with SUN9216 was significantly reduced compared with that in the control group. The infarction area in rats treated with the combination of SUN9216 and vapiprost was reduced compared with that in rats treated with SUN9216 alone; this was the case whether or not the occlusion was reperfused. There was a significant correlation between the time of reopening of the middle cerebral artery and area of cerebral infarction.. A single injection of SUN9216 was effective in recanalizing the vessel and reducing the area of cerebral infarction.

Topics: Animals; Biphenyl Compounds; Cerebral Infarction; Disease Models, Animal; Drug Combinations; Drug Evaluation, Preclinical; Heptanoic Acids; Intracranial Embolism and Thrombosis; Male; Plasminogen Activators; Rats; Rats, Wistar; Receptors, Thromboxane; Time Factors; Tissue Plasminogen Activator

Non-immunosuppressed rat aortic allografts from DA (RT1av1) to WF (RT1u) strain develop, after a short reversible acute rejection episode, chronic arteriosclerotic changes in the vascular wall, which are indistinguishable from those seen in human allografts during chronic rejection. Incubation of the aortic wall segments in vitro and immunochemical assays demonstrated that the allografts synthesized increased amounts of TxB2, but not 6-keto-PGF1alpha, or LTB4, compared to syngenic or normal aortas. The two major cellular components of the vascular wall, intima and adventitia, were incubated separately after microdissection. TxB2 was produced in the adventitia, whereas most of the 6-keto-PGF1alpha was synthesized in the intima. Administration of a specific TxA2 receptor inhibitor to the recipient rat reduced significantly the proliferation of adventitial inflammatory cells and the intimal smooth muscle cells. Nevertheless, it only delayed but did not inhibit the overall sclerosis of the intima.

Topics: Animals; Biphenyl Compounds; Disease Models, Animal; Graft Rejection; Heptanoic Acids; Prostaglandin Antagonists; Rats; Rats, Inbred Strains; Rats, Inbred WF; Thromboxane B2; Thromboxanes; Transplantation, Homologous

We have already developed an arterial thrombosis model in the rat femoral artery which utilized photochemical reaction between systemically injected rose bengal and transillumination of a green light with 540 nm wave length from the outside of the vessel. In the present study, we applied this model to guinea-pigs in order to produce a more suitable thrombus model for evaluation of antithrombotic drugs which act on the prostaglandin cascade. In the guinea-pigs, the irradiated femoral artery was completely occluded in 7 min after the injection of rose bengal (10 mg/kg) in a similar manner to the rats. The processes of primary endothelial injury and the subsequent formation of thrombus during this manipulation were observed by the electron microscopy. Pretreatment with aspirin and Y-20811, a thromboxane synthetase inhibitor, significantly prolonged the time required for occlusion in the guinea-pigs, while these drugs were ineffective in the rats. The antithrombotic effect of vapiprost, a thromboxane A2 receptor antagonist, was more pronounced in the guinea-pigs than the rats. In conclusion, this model in guinea-pigs is more suitable for evaluating antithrombotic drugs, particularly, the action of which is exerted involving the prostaglandin cascade.

Topics: Animals; Aspirin; Biphenyl Compounds; Disease Models, Animal; Femoral Artery; Fibrinolytic Agents; Guinea Pigs; Heptanoic Acids; Imidazoles; Light; Male; Microscopy, Electron, Scanning; Photochemistry; Platelet Aggregation; Prostaglandins; Rats; Rats, Wistar; Rose Bengal; Thrombosis

ePTFE interposition grafts in the common carotid arteries of 16 adult sheep were used to study the effect of a thromboxane receptor antagonist. Vapiprost (GR 32191, Glaxo research group, London, UK). After insertion of the grafts the sheep were randomised to treatment (n = 8) or control (n = 8). Treatment was given as an intravenous injection with GR 32191 of 1 mg/kg body weight. The flow in one of the two inserted grafts was restricted from normal (190 ml/min) to 25 ml/min. Autologous 111-In labelled platelets and human 125-I labelled fibrinogen were injected intravenously. The radioactivity over each graft was measured for 4 h at two separate points with a gamma scintillation technique. Due to technical complications immediately before the start of the measurements one sheep in each group was excluded from the study. In the treated group three out of seven grafts with restricted flow occluded compared to all seven grafts with a flow reduction in the control group (p less than 0.05). The grafts with unrestricted flow occluded in two of seven in both groups. In the open grafts with unrestricted flow the fibrinogen activity was significantly reduced in the treated group compared to the control group. The platelet activity was not significantly reduced. It is concluded that GR 32191 significantly reduced the fibrinogen uptake as well as graft occlusions of ePTFE grafts in a low flow situation.

Topics: Acute Disease; Animals; Biphenyl Compounds; Blood Vessel Prosthesis; Carotid Arteries; Disease Models, Animal; Female; Graft Occlusion, Vascular; Heptanoic Acids; Male; Polytetrafluoroethylene; Receptors, Prostaglandin; Receptors, Thromboxane; Sheep; Thrombosis