Isbogrel

We investigated an effect of ureteral obstruction on a progressive immune complex glomerulonephritis in murine lupus erythematosus. Unilateral ureteral obstruction for 8 days significantly decreased the expanded glomerular mesangial area, as measured by computer-assisted morphometry (4.44 +/- 0.33 x 10(-4) mm2 to 3.60 +/- 0.34 x 10(-4) mm2, P < .05), and reduced the staining for IgG, C3, and extracellular matrix components, whereas the nephritis was exacerbated in the contralateral non-obstructed kidney. The renal concentration of prostaglandin E2 (PGE2) and 6-keto-prostaglandin F1alpha (6-keto-PGF1alpha) in the obstructed kidneys 8 days after obstruction significantly exceeded that of kidneys in sham-operated controls (344.2 +/- 83.9 pg/mg tissue protein vs 50.0 +/- 27.5 pg/mg tissue protein, P < .01; 71.9 +/- 11.4 pg/mg tissue protein vs 9.5 +/- 2.3 pg/mg tissue protein, P < .01), whereas thromboxane B2 (TxB2) levels were similar in the two groups (33.9 +/- 4.5 pg/mg tissue protein vs 31.3 +/- 2.6 pg/mg tissue protein). Next, an experiment was performed to evaluate the role of renal eicosanoids in the amelioration in the immune complex glomerulonephritis after ureteral obstruction. Treatment with the cyclooxygenase inhibitor indomethacin abolished the decrease in mesangial area induced by ureteral obstruction (7.7% +/- 6.9%). CV-4151, a thromboxane synthetase inhibitor, had no effect on the decrease in mesangial area (-25.8% +/- 6.8%, P < .05). We conclude that unilateral ureteral obstruction quickly decreased the mesangial expansion in immune complex glomerulonephritis, and vasodilatory eicosanoids such as PGE2 and PGI2 at least partly contribute to the amelioration of glomerular histology.

The purpose of this study was to determine whether thromboxane A2 (TXA2) is involved in the development of ventricular arrhythmias produced by coronary artery occlusion. Ventricular arrhythmias were induced by coronary artery occlusion in 66 male Sprague-Dawley rats. Rats were separated into 4 groups, and saline (n = 19) or CV4151 (a TXA2 synthetase inhibitor)(10 mg/kg, n = 14; 30 mg/kg, n = 15; or 100 mg/kg, n = 18) was injected intravenously 5 min before coronary artery occlusion. The antiarrhythmic effect of CV4151 was assessed in terms of the number of ventricular premature complexes (VPCs), the combined duration of ventricular tachycardia (VT) and ventricular fibrillation (Vf), the incidence of Vf, and the mortality rate within 30 min after occlusion. The total number of VPCs was as follows; control: 1789 +/- 330 beats: 10 mg/kg group: 1289 +/- 302 beats: 30 mg/kg group: 1008 +/- 229 beats: 100 mg/kg group: 986 +/- 275 beats, with no significant differences between groups. The incidence of Vf was significantly reduced in the 30 mg/kg and 100 mg/kg groups, as was the combined duration of VT and Vf and the mortality rate. Our results indicate that the TXA2 synthetase inhibitor CV4151 reduces the incidence of lethal arrhythmias induced by coronary artery occlusion in rats.