ozagrel and Body-Weight

We used rats (the Otsuka Long-Evans Tokushima Fatty strain) as a model of type 2 diabetes to find whether thromboxane (TX) A2 is involved in diabetic nephropathy, and if so, to identify where it is synthesized. We measured urinary excretion of TXB2 and 2,3-dinor-TXB2 in rats up to 60 weeks of age as markers of renal and platelet synthesis of TXA2, respectively. Some diabetic rats were given daily oral doses of OKY-046 (100 mg/kg), a TXA2 synthase inhibitor, starting when they were 10 weeks of age. Healthy Long-Evans Tokushima Otsuka rats served as the controls. Urinary excretion of protein was greater in diabetic rats at 26 weeks than in controls, and the difference increased with age. Urinary excretion of TXB2 by diabetic rats was about 150% that of controls at 14 weeks, and remained at that level. In diabetic rats, urinary excretion of 2,3-dinor-TXB2 increased with age in parallel to increases in proteinuria, but in controls, excretion of these metabolites did not change with age. In diabetic rats, OKY-046 prevented the increase in urinary excretion of both metabolites, and decreased the proteinuria. Histologic examination at 60 weeks showed intraglomerular thrombi in diabetic rats but not in controls. OKY-046 reduced intraglomerular thrombi formation and the score for glomerulosclerosis. When platelet aggregation began, more TXA2 than before was released from the thrombi that formed, and the TXA2 contributed to the progress of nephropathy in this rat model of type 2 diabetes.

Topics: 6-Ketoprostaglandin F1 alpha; Aging; Animals; Blood Glucose; Blood Pressure; Body Weight; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Progression; Enzyme Inhibitors; Glomerular Mesangium; Male; Methacrylates; Prostaglandins; Proteinuria; Rats; Rats, Inbred OLETF; Thrombosis; Thromboxane A2; Thromboxane-A Synthase

We investigated the influence of the vascular and renal thromboxane system on the antihypertensive effects of the alpha 1 adrenoceptor antagonist (alpha 1 blocker) bunazosin in spontaneously hypertensive rats (SHR). SHR were treated for 2 weeks with the alpha 1, blocker bunazosin (0.5 mg/kg body weight/day). The systolic blood pressure immediately declined with bunazosin treatment, and then rose toward the level observed in untreated SHR. This antihypertensive effect was accompanied by a decrease in the ratio of prostacyclin to thromboxane A2 in the vascular wall and the kidney. A subdepressor dose of the thromboxane synthase inhibitor OKY-046 lessened the thromboxane generation during bunazosin treatment, and synergistically potentiated the antihypertensive action of the alpha 1 blocker. Such synergy was also observed between OKY-046 and prazosin, an alternative alpha 1 blocker, but not with amosulalol, an alpha 1 blocker having no quinazoline moiety. alpha 1 blockers with a quinazoline moiety dose-dependently stimulate thromboxane generation in cultured smooth muscle cells from SHR. These data indicate that alpha 1 blockers enhance thromboxane generation in the arterial wall and kidney, thereby contributing to the lessening of the antihypertensive effects observed during alpha 1 blocker treatment.

Topics: Adrenergic alpha-Antagonists; Animals; Antihypertensive Agents; Aorta; Blood Pressure; Body Weight; Cells, Cultured; Drug Synergism; Eicosanoids; Ethanolamines; Kidney; Methacrylates; Muscle, Smooth, Vascular; Prazosin; Quinazolines; Rats; Rats, Inbred SHR; Sodium; Thromboxane-A Synthase; Thromboxanes

Recently, thromboxane synthetase inhibitor has been used for the treatment of preeclampsia. In this study, we investigated the effects of thromboxane synthetase inhibitor (OKY-046) on placental blood flow (measured with clearance of hydrogen gas generated by electrolysis) in normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). The systolic blood pressure of OKY-046-treated SHR (1, 4 and 8 mg/kg) decreased significantly (p < 0.05); however, the systolic blood pressure of WKY did not decrease. The placental blood flow of both OKY-046-treated WKY and SHR did not decrease. We found that OKY-046 has no reducing effect on placental blood flow in rats, and systolic blood pressure of SHR decreases. These data suggest that thromboxane synthetase inhibitor might have a beneficial effect on preeclampsia.

Topics: Animals; Blood Pressure; Body Weight; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Fetus; Hypertension; Methacrylates; Organ Size; Placenta; Pregnancy; Pregnancy Complications, Cardiovascular; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Regional Blood Flow; Systole; Thromboxane-A Synthase

The abdominal aorta of 20 pregnant rabbits was surgically constricted below the renal arteries on the 21st day of pregnancy, producing a stricture that decreased the blood flow by 60%. Four pregnant rabbits underwent sham operation and served as control. The pressor response to angiotensin II (A-II) was assessed by measuring the systolic blood pressure in the ear of rabbits. We intravenously administered 20 mg/kg of OKY-046, a thromboxane A2 (TXA2) synthetase inhibitor (OKY group: n = 13) or saline (n = 7) daily from the 23rd day of pregnancy until the day of delivery. After stricture of the abdominal aorta, the "effective pressor dose" (EPD:nanograms of A-II/kg/min necessary to cause a 20 mmHg rise in systolic pressure) was significantly lower in the saline group than in the control group. On the 27th and 29th day of pregnancy, the EPD in the OKY group was significantly higher than that in the control group. The plasma thromboxane B2 (TXB2) level in the OKY group was significantly lower than that in the saline group on the 27th day. The fetal birth weight in the saline group was significantly lower than that in the control group. These finding suggest that OKY-046 restores the vascular refractoriness induced by A II and suppresses TXA2 synthesis in pregnant rabbits with aortic constriction.

Topics: Angiotensin II; Animals; Aorta, Abdominal; Blood Pressure; Body Weight; Constriction; Female; Methacrylates; Muscle, Smooth, Vascular; Pregnancy; Pregnancy Outcome; Pregnancy, Animal; Prostaglandins; Rabbits; Thromboxane-A Synthase

To examine the effects of endogenous thromboxane A2 on the development of diabetic nephropathy, we administered OKY-046, an inhibitor of thromboxane synthesis, to streptozotocin-induced diabetic rats. Animals were divided into three groups; nondiabetic control, diabetic, and diabetic with OKY-046, and were sacrificed 16 weeks after experimental procedures. The chronic oral administration of OKY-046 to diabetic rats significantly decreased plasma and urinary thromboxane B2 levels. Urinary protein excretion and serum glucose levels were significantly lower in the OKY-046-treated diabetic rats than in the untreated diabetics (60.8 +/- 23.2 vs. 94.1 +/- 33.4 mg/day in the 16th week, p less than 0.05 and 424.4 +/- 93.3 vs. 614.4 +/- 102.3 mg/dl in the 16th week, p less than 0.01, respectively). Platelet aggregation was inhibited by OKY-046. Blood urea nitrogen was unaffected. Ultrastructural examination revealed that the thickness of glomerular basement membrane was markedly thinner in the OKY-046-treated diabetic rats than in the untreated diabetics (197.4 +/- 29.6 vs. 288.6 +/- 46.9 nm, p less than 0.01). These results suggest that thromboxane A2 may play an important role in the development and progression of diabetic nephropathy in rats.

Topics: 6-Ketoprostaglandin F1 alpha; Administration, Oral; Animals; Blood Glucose; Blood Pressure; Blood Urea Nitrogen; Body Weight; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Insulin; Kidney; Male; Methacrylates; Microscopy, Electron; Platelet Aggregation; Proteinuria; Rats; Rats, Inbred Strains; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase

To induce crescentic-type anti-glomerular basement membrane (anti-GBM) nephritis, male Sprague-Dawley rats were immunized with rabbit gamma-globulin in Freund's complete adjuvant following i.v. injection of anti-GBM serum. At the same time, original type anti-GBM nephritis was induced in other rats by anti-GBM serum only. The animals with crescentic-type anti-GBM nephritis showed significantly higher platelet aggregability than that in rats with original-type anti-GBM nephritis at days 5, 10 and 40 after anti-GBM serum administration, respectively. To estimate the antinephritic effect of OKY-046, a thromboxane A synthetase inhibitor, it was given orally to rats at doses of 0.5, 2.5 or 20 mg/kg for 39 days after anti-GBM serum. OKY-046 (20 mg/kg) significantly inhibited the increase in both urinary protein and plasma cholesterol levels (40% and 35% vs. control, respectively). Moreover, when examined by light microscopy, this drug remarkably prevented histological involvement of the glomeruli. OKY-046 at 20 mg/kg had suppressed the hyperaggregability of platelets by 77% by day 40 as compared with the control, but doses of 0.5 and 2.5 mg/kg did not. It is concluded from these data that OKY-046 has beneficial effects on crescentic-type anti-GBM nephritis and may act through inhibition of not only platelet TxA2 but also glomerular TxA2 in its action to prevent histological alterations.

Topics: Acrylates; Animals; Blood Urea Nitrogen; Body Weight; Cholesterol; Glomerulonephritis; Kidney; Kidney Glomerulus; Male; Methacrylates; Platelet Aggregation; Platelet Aggregation Inhibitors; Proteinuria; Rats; Rats, Inbred Strains; Thromboxane-A Synthase; Urodynamics