vapiprost and Kidney-Diseases

To elucidate the role of the vasoconstrictor thromboxane A2(TXA2) in post-obstructive nephropathy, we examined the effect of the TXA2 receptor antagonist GR32191(GR) on renal function and histopathology in the post-obstructed kidney (POK) in rats. Rats pre-treated with 3 or 6 mg/kg i.p. of GR prior to ureteral obstruction and maintained on b.i.d. doses of GR were compared to vehicle-treated and sham-operated controls. Renal hemodynamic, clearance and excretory function were assessed in each kidney following relief of 24 hours of unilateral ureteral obstruction. The histology of each kidney was evaluated. Mean clearances of inulin for the POK were significantly greater in the treated rats (0.42 +/- 0.06 ml/min at 6 mg/kg) than in controls (0.13 +/- 0.04 ml/min) and a dose-response effect was observed (P < 0.05). Paraaminohippurate clearance was increased by > 150% and renal vascular resistance was reduced by 50% in GR treated animals compared with controls (P < 0.05). Histopathologic findings in the untreated POK were typical of early obstruction. In the GR treated groups these changes were much less severe. These data support an important role for TXA2 in the pathogenesis of post-obstructive nephropathy.

Topics: Animals; Biphenyl Compounds; Heptanoic Acids; Kidney; Kidney Diseases; Kidney Function Tests; Male; Rats; Rats, Sprague-Dawley; Receptors, Thromboxane; Ureteral Obstruction

Functional and morphological studies were done in three groups of male Sprague-Dawley rats after removal of the right kidney and infarction of approximately five-sixths of the left. Group 1 received no specific therapy. Group 2 was treated with ticlopidine, 150 mg/kg per os, for 50 days starting 10 days after surgical ablation. Group 3 was given the thromboxane antagonist, GR 32191, 3 mg/kg b.i.d. orally for 50 days, like ticlopidine. Untreated Group 1 rats developed renal insufficiency, systemic hypertension, progressive proteinuria and glomerulosclerosis. In Group 2 treatment with ticlopidine was associated with less severe impairment of renal function. Proteinuria was significantly lower and animals were partially protected from the development of glomerulosclerosis. These animals had significantly prolonged skin bleeding time. In vitro ADP and arachidonic acid (AA)-induced platelet aggregation was inhibited. Systemic blood pressure was significantly lower than in controls. In Group 3 rats GR 32191 failed to influence progressive proteinuria and severity of glomerulosclerosis which were comparable to those in Group 1. Bleeding time was not prolonged, and in vitro platelet aggregation was inhibited only when AA was used as aggregating agent. Systemic blood pressure was not influenced. These studies suggest that a drug like ticlopidine, which has a broad spectrum of pharmacological actions on platelets and platelet-cell interactions, does retard the development of progressive renal injury when nephron number is reduced. Specific blocking of thromboxane A2 (TxA2) biological activity does not influence progressive renal disease in rats with remnant kidney.

Topics: Animals; Biphenyl Compounds; Bleeding Time; Blood Pressure; Hematocrit; Heptanoic Acids; Infarction; Kidney; Kidney Diseases; Kidney Function Tests; Male; Nephrectomy; Platelet Aggregation; Platelet Aggregation Inhibitors; Rats; Rats, Inbred Strains; Thromboxane A2; Ticlopidine