The effect of acute and chronic administration of cyclosporine on systemic and renal hemodynamics was studied in conscious rats. Infusion of cyclosporine in a dose of 20 mg/kg (Cy 20) resulted in a significant fall in renal blood flow (RBF) (3.4 vs. 6.5 ml/min/g, P less than 0.05) and a rise in renal vascular resistance (RVR) (36.9 vs. 20.6 mm Hg/ml/min/g, P less than 0.05). Infusion of cyclosporine at a dose of 10 mg/kg (Cy 10) did not result in a significant change in RBF or RVR. Both doses of cyclosporine resulted in stimulation of plasma renin activity (PRA) from control values of 5.6 +/- 0.8 ng/ml/hr to 11.6 +/- 2.0 with 10 mg/kg and 26.7 +/- 5.6 with 20 mg/kg. Urinary 6-keto-PGF1 alpha excretion increased from control values of 14.0 +/- 2.0 ng/6 hr to 22.7 +/- 2.2 with 10 mg/kg and 25.0 +/- 2.0 with 20 mg/kg. Similar effects on RBF, RVR, PRA, and 6-keto-PGF1 alpha excretion were seen after chronic administration of cyclosporine (20 mg/kg i.p. for 7 days). Pretreatment of animals with captopril did not prevent the fall in RBF after cyclosporine, suggesting that the vasoconstriction was not mediated by angiotensin II. Animals treated with meclofenamate demonstrated reduction in RBF with 10 mg/kg cyclosporine (4.3 vs. 7.0 ml/min/g, P less than 0.05), suggesting that prostaglandins protect against the vasoconstrictor effect of cyclosporine. Administration of phenoxybenzamine after cyclosporine improved RBF (5.0 vs. 3.4 ml/min/g) and restored RVR to normal. Similarly, renal denervation dramatically reduced the fall in RBF after cyclosporine (innervated right kidney 3.6 vs. denervated left kidney 6.0 ml/min/g, P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

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A B S T R A C T In a previous study we have found that acetylcholine, a renal vasodilator, inhibits fractional and absolute reabsorption of sodium in the proximal tubule of the dog. To delineate whether this effect on proximal tubular sodium reabsorption was related to alterations in renal hemodynamics or to a direct tubular action of the drug, free-flow micropuncture studies were performed in the dog in which the tubular fluid to plasma inulin ratio and nephron filtration rate were determined before and during the administration of a structurally different renal vasodilator, bradykinin. This agent increased sodium excretion from 12 to 96 *Eq/cnin and decreased total kidney filtration fraction from 0.35 to 0.25. However, sodium reabsorption in the proximal tubule of the superficial nephrons was unchanged during bradykinin 'administration.Since it has been shown that a decrease in filtration fraction and presumably peritubular capillary protein concentration will decrease proximal tubular sodium reabsorption, studies were performed to determine whether the fall in total kidney filtration fraction seen with both vasodilators is paralleled by a similar change in the circulation of superficial nephrons. The results of these studies indicate that neither agent altered superficial nephron capillary protein concentration, hematocrit, or filtration fraction.

Studies were performed in the dog to determine the mechanism of the renal functional impairment which follows the administration of the nephrotoxic agent, uranyl nitrate. In the first series of 28 experiments, total renal blood flow was determined with the radioactive microsphere method before and after uranyl nitrate administration, 10 mg/kg. Total blood flow fell from 199 to 121 ml/min 6 hr after administration of uranyl nitrate (P less than 0.001) but was unchanged 48 hr after administration of the drug. Yet the blood urea nitrogen concentration had increased from a control value of 13 to 120 mg/100 ml at 48 hr (P less than 0.001). Since renal blood flow was normal at 48 hr, micropuncture studies were performed to further evaluate the mechanism of the renal impairment. In the first group of nine studies using a 10 mg/kg dose of uranyl nitrate, nephron glomerular filtration rate (GFR) was reduced 37% while total kidney GFR averaged less than 1% of normal. A similar disparity between superficial and total GFR was noted after a 5 mg/kg dose even though urine flow was comparable to values found in normal hydropenic dogs. Proximal tubular transit time and intratubular pressure were normal. The recovery of 3H-inulin injected into the proximal tubule was 97% in normal dogs and 14% in uranyl nitrate dogs (P less than 0.001). Since there was no difference between early and late proximal tubular nephron GFR, it was suggested that the pars recta, the segment most severely involved histologically, was the main site of inulin leak. Scanning electron microscopy revealed an alteration in epithelial architecture which may have accounted, at least in part, for the diminution in nephron GFR. These studies are interpreted to indicate that the impairment in renal function in this model is due to both leakage of filtrate across damaged tubular epithelium and a modest decrease in nephron GFR.

A B S T R A C T Captopril, 5 mg/kg, administered to pregnant rabbits caused a reduction in mean arterial pressure (MAP) from 106±2 to 87±2 mmHg (P < 0.01) without change in cardiac output or renal blood flow.Uterine blood flow fell from 31.9±2.5 to 21.3±3.4 ml/ min (P < 0.01) as uterine vein prostaglandin E series level (PGE) decreased from 127±23 ng/ml to 26±8 ng/ml (P < 0.01). Saralasin also caused a reduction in MAP from 110±5 to 92±4.3 (P < 0.01), a reduction in uterine blood flow from 28.8±1.6 to 21.8±1.7 ml/ min (P < 0.01) as uterine vein PGE decreased from 121.3±14.4 to 63.5±14.2 ng/ml (P < 0.01). Plasma renin activity (PRA) was higher in the uterine vein, 11±3 ng/ml per h, than peripheral vein, 6±1.6 ng/ml per h, (P < 0.05), before Captopril and rose in the uterine vein to 90±19 ng/ml per h (P < 0.01) as peripheral vein PRA rose to 62±15 ng/ml per h (P <0.05) after Captopril. After saralasin uterine vein PRA rose from 4.6±1.5 to 14.8±6.3 ng/ml per h (P < 0.05) and peripheral vein PRA rose from 3.7±1 to 6.5±2.1 (P < 0.05).Reducing MAP with MgSO, from 98±4 to 70±2 (P < 0.01) caused a significant fall in cardiac output from 695±33 to 588±49 (P < 0.01) without change in renal or uterine blood flow. Uterine vein PGE concentration also did not change significantly following MgSO4; 80±22 ng/ml before and 60±27 ng/ml (NS) during the administration of MgSO4.Chronic administration of Captopril in doses of either 2.5 or 5.0 mg/kg per d from the 15th d of gestation caused an 86% fetal mortality at the lower and a 92% fetal mortality at the higher dose of the drug.These experiments point to the importance of uterine PGE synthesis in maintenance of uterine blood flow and fetal survival during pregnancy and suggest that uterine PGE synthesis is dependent upon angioAddress reprint requests to Dr. T.

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