Thomas F. Ferris

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 muEq/min 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. In contrast, a decrease in capillary protein concentration, hematocrit, and filtration fraction was consistently demonstrated during the intrarenal infusion of 7.5-15 ml/min of Ringer's solution while an increase in these parameters occurred during the i.v. administration of norepinephrine, 60 mug/min. In the Ringer's infusion studies, both fractional and absolute sodium reabsorption in the proximal tubule were decreased concomitant with the fall in capillary protein concentration and hematocrit. THIS DATA SUGGESTS THAT: (a) the hemodynamic effect of renal vasodilatation is not the same in the circulation of all nephrons; (b) the inhibitory effect of acetylcholine on proximal tubular sodium reabsorption is due to a direct tubular action; (c) a decrease in capillary protein concentration and/or hematocrit does decrease proximal tubular sodium reabsorption; (d) although proximal reabsorption of sodium is unchanged in the superficial nephrons during bradykinin administration, a decrease in reabsorption may be present in deeper nephrons in which filtration fraction is decreased.

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(4) 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 MgSO(4); 80+/-22 ng/ml before and 60+/-27 ng/ml (NS) during the administration of MgSO(4). 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 angiotensin II. Synthesis of uterine renin and PGE may be necessary for maintenance of uterine blood flow and fetal survival during pregnancy.

To further evaluate the mechanism of the oliguria of acute renal failure, a model was utilized in which intense and prolonged vasoconstriction produced the unilateral cessation of urine flow. The radioactive microsphere method was used to measure total and regional blood flow before and after the intrarenal infusion of norepinephrine, 0.75 mug/kg/min, for 2 h in the dog. In the control kidney, renal blood flow increased 32% 48 h after norepinephrine in association with a fall in the fractional distribution of flow to the outer cortex. In the experimental kidney, total renal blood flow fell from 190 ml/min before norepinephrine to 116 ml/min at 48 h (P < 0.025) with a uniform reduction in cortical blood flow. After the administration of 10% body wt Ringer's solution, there was a marked redistribution of flow to inner cortical nephrons in both the control and experimental kidney. In addition, there was a marked increase in total blood flow in both kidneys. On the experimental side, flow rose to 235 ml/min, a value greater than in either the control period (P < 0.05) or at 48 h after norepinephrine (P < 0.001). However, in spite of this marked increase in blood flow, there was essentially no urine flow from the experimental kidney. In separate studies, the animals were prepared for micropuncture. In all studies, the surface tubules were collapsed, and there was no evidence of tubular obstruction or leakage of filtrate. Over 99% of the 15-muM spheres were extracted in one pass through the experimental kidney. An analysis of the forces affecting filtration suggested that an alteration in the ultrafiltration coefficient may be responsible, at least in part, for the anuria in this model. In this regard, transmission and scanning electron microscopy revealed a marked abnormality in the epithelial structure of the glomerulus. It is suggested that a decrease in glomerular capillary permeability may be present in this model of acute renal failure.