2-methyl-3-(4-(3-pyridinylmethyl)phenyl)-2-propenoic-acid and Disease-Models--Animal

Local intra-arterial infusion of picomole quantities of endothelin-1 induced gastric vascular leakage of radiolabelled albumin. This leakage was partially inhibited by the platelet activating factor (PAF) receptor antagonist WEB 2086 (0.5-2 mg kg-1), but was unaffected by the thromboxane synthase inhibitor OKY 1581 (5 mg kg-1) or by pretreatment with anti-neutrophil serum. These results indicate a partial role of PAF, but demonstrate that neutrophils are not involved in the gastric vascular dysfunction induced by locally administered endothelin-1.

Topics: Animals; Azepines; Capillary Permeability; Disease Models, Animal; Endothelins; Endothelium, Vascular; Gastric Mucosa; Infusions, Intra-Arterial; Isotope Labeling; Male; Methacrylates; Neutrophils; Platelet Activating Factor; Rats; Rats, Wistar; Serum Albumin; Stomach Ulcer; Thromboxane-A Synthase; Triazoles

Ablation of greater than 70% of renal mass in the rat results in hypertension, proteinuria, and glomerular sclerosis of the remnant kidney. Rats with a remnant kidney have increased excretion of thromboxane in the urine when compared with normal rats. Chronic oral administration of OKY 1581, an inhibitor of thromboxane synthesis, in rats with a remnant kidney increases renal blood flow and glomerular filtration rate (GFR), decreases protein and thromboxane excretion in the urine, lowers blood pressure and cardiac index, and improves renal histology. The degree of hypertrophy of the remnant kidney was unaffected by administration of OKY 1581. Calculated values for single nephron plasma flow and GFR were significantly greater in rats with remnant kidneys given OKY 1581 than in rats given saline. Acute i.v. administration of OKY 1581 increased renal plasma flow and GFR in rats with a remnant kidney but not in normal rats or rats with a remnant kidney previously treated with acetylsalicyclic acid. OKY 1581 markedly inhibited platelet aggregation. We suggest that in this model of renal disease platelet aggregation and intraglomerular thrombosis play a key role in the development of glomerulosclerosis. Inhibition of platelet aggregation prevents development of glomerulosclerosis, hypertension, and cardiac hypertrophy. We suggest that hyperperfusion and hyperfiltration per se occurring in remnant glomeruli are not directly responsible for the development of glomerulosclerosis.

Topics: Acrylates; Animals; Blood Pressure; Disease Models, Animal; Female; Glomerular Filtration Rate; Glomerulosclerosis, Focal Segmental; Heart; Kidney; Kidney Diseases; Methacrylates; Nephrectomy; Oxidoreductases; Platelet Aggregation; Rats; Thromboxane B2; Thromboxane-A Synthase

We present a simple method for screening antithrombotic agents. When male Swiss-Webster mice (25-34 g; N = 143) were given an i.v. injection of 0.1 ml of a mixture of collagen (dose, 15 micrograms/mouse) and epinephrine (dose, 1.8 micrograms/mouse), 94% died within 5 min or remained paralyzed for more than 15 min. Examples of the use of the system for the study of antithrombotic agents are given. Solutions of agents were administered to the animals i.p. about 1 hr before the thrombotic challenge. Aspirin (20 mg/kg), OKY-1581 (30 mg/kg) and ethanol (2 gm/kg), administered as single agents in aqueous medium, protected (P less than .01, chi 2 test) 40, 50 and 35% of the animals, respectively. Heparin (150 U/kg) was ineffective. Combinations of ethanol with indomethacin or indobufen provided complete protection, whereas ethanol plus aspirin protected 84% of the animals and ethanol plus OKY-1581 protected 70% of the animals. Dipyridamole alone (3 mg/kg), dipyridamole (1.65 mg/kg) plus ethanol or dipyridamole (1.65 mg/kg) plus aspirin were ineffective. The method appears well suited for screening potential antithrombotic agents which act primarily against platelet thromboembolism.

Topics: Adenosine Triphosphate; Animals; Aspirin; Collagen; Disease Models, Animal; Drug Synergism; Epinephrine; Ethanol; Fibrinolytic Agents; Male; Methacrylates; Mice; Platelet Aggregation; Thromboembolism