Inhibition of thromboxane synthesis ameliorates the progressive kidney disease of rats with subtotal renal ablation (renal ABSTRACTAblation of >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.

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We examined the in vitro production of PGE2, 6-keto PGF1 alpha and TxB2 by isolated glomeruli from rats fed a low (6% casein) or a high (40% casein) protein diet for approximately eight weeks. Glomeruli from high protein-fed rats produced significantly greater amounts of PGE2, 6-keto PGF1 alpha and TxB2 under basal conditions and in response to the addition of 100 nM angiotensin II (Ang II) than glomeruli from low protein-fed rats. To elucidate the mechanisms by which greater protein intake enhanced the glomerular production of eicosanoids, we explored phospholipase (A2 and C) and cyclooxygenase activity in glomeruli isolated from low- or high-protein fed rats. PE-specific PLA2 activities were significantly increased in glomeruli from rats fed a high protein diet when compared to a low protein diet. On the other hand, PC-specific PLA2 activities were significantly decreased in glomeruli from rats fed a high protein diet. No significant difference in PIP2-PLC activities was detected between glomeruli of the two dietary groups. The cyclooxygenase content and activity was significantly greater in glomeruli from rats fed a high protein diet than in glomeruli from rats fed a low protein diet. Glomeruli of rats fed a 50/50 mixture of the diets (23% casein) had amounts and activity of cyclooxygenase and activities of PE-specific PLA2 intermediate between those of high and low protein-fed animals. In conclusion, increased synthesis of eicosanoids by glomeruli from rats fed a high protein diet may be mediated by increases in the amount and activity of cyclooxygenase coupled with enhanced activity of PE-specific PLA2.

SUMMARY The present study examines effects of administration of OKY 046, an inhibitor of thromboxane synthesis, for 100 days on systemic blood pressure and renal function in spontaneously hypertensive rats and in normotensive control rats. Untreated spontaneously hypertensive rats had higher values for thromboxane excretion in the urine and higher values for blood pressure than did normotensive control rats. Administration of OKY 046 decreased systolic and mean arterial blood pressure and urinary excretion of thromboxane and protein in spontaneously hypertensive rats. Administration of OKY 046 decreased thromboxane excretion in the urine of normotensive control rats but had no effect on blood pressure or protein excretion. Renal function, as assessed by the clearances of inulin and p-aminohippuric acid, was greater in spontaneously hypertensive rats treated with OKY 046 than in those receiving vehicle alone. In normotensive control rats, OKY 046 administration did not affect renal function. These results suggest that increased renal synthesis of thromboxane may play a role in the pathogenesis of the elevated blood pressure of spontaneously hypertensive rats. (Hypertension 8: 1113(Hypertension 8: -1120(Hypertension 8: , 1986 KEY WORDS * hypertension • thromboxane • renal function • renal pathology M ECHANISMS responsible for development and maintenance of hypertension in spontaneously hypertensive rats (SHR) are still incompletely understood, yet the kidney is known to play a primary role in the development of hypertension. In the developmental phase of hypertension, SHR retain sodium, and this may contribute to the development of hypertension.12 This enhanced sodium-retaining capacity in young SHR may be caused by an increase in renal sympathetic nerve activity. 34The kidney has a high capacity to synthesize prostaglandins and thromboxane A 2 . However, the contribution of these compounds, particularly thromboxane, to the renal function and the pathogenesis of hypertension in SHR remains to be elucidated. Shibouta et al. 3 ' 6 demonstrated enhanced thromboxane A 2 synthesis in isolated kidneys from 6-week-old SHR in response to

A B S T R A C T Acetazolamide, an inhibitor of the enzyme carbonic anhydrase, increased the urinary excretion of cyclic AMP in normal and parathyroidectomized rats. The increase was greater in rats with intact parathyroid glands than in parathyroidectomized rats. This rise in the urinary excretion of cyclic AMP was not due to an increase in urine flow or a change in urine pH. Furosemide caused an increase in urine flow, but did not affect the excretion of cyclic AMP or phosphate. Alkalinization of the urine with bicarbonate did not increase the urinary excretion of phosphate or cyclic AMP. Acetazolamide increased the production of cyclic AMP by rat renal cortical slices in vitro. This effect was dose-dependent. Acetazolamide also stimulated the activity of renal cortical adenyl cyclase in a dose-dependent manner but had no effect on the activity of cyclic nucleotide phosphodiesterase. The pattern of urinary excretion of cyclic AMP and phosphate after administration of acetazolamide was similar to that observed in rats given parathyroid hormone. It is suggested that acetazolamide stimulates the renal production of cyclic AMP by activating adenyl cyclase and that this may be the mechanism by which this inhibitor of carbonic anhydrase produces phosphaturia.