Harold E. Williamson

Furosemide induced release of prostaglandin E to increase renal blood flow.

Summary Levels of PGE in renal venous blood were found to be significantly elevated at the time RBF was increased by furosemide. Following indomethacin, a second dose of furosemide failed to increase RBF and levels of PGE in renal venous blood were not elevated. Levels of PGF and PGA were not affected by furosemide. The increase of PGE in renal venous blood at the time of renal dilation supports the hypothesis that furosemide increases RBF by releasing PGE. An intrarenal action of the released PGE is implied by this mechanism.

Lack of Correlation Between Natriuretic Activity and Inhibition of Renal Na-K-Activated ATPase.

Summary Ethacrynic acid, which is a potent natriuretic in man and dog but inactive in the rat, and furosemide, which is a potent natriuretic in man and dog as well as in the rat, were compared for their ability to inhibit microsomal Na-K-activated ATPase following in vivo administration in the rat. Both agents were found to inhibit the activity of this enzyme. Furosemide produced a significant natriuretic response whereas ethacrynic acid did not. Therefore, no correlation between natriuretic activity and enzyme inhibition could be made with these agents. This study does not rule out a correlation between Na-K-activated ATPase and natriuretic activity but it does question the practice of determining Na-K-activated ATPase in vitro and attempting to relate this to responses in vivo.

EFFECT OF FUROSEMIDE ON RENAL MEDULLARY SODIUM GRADIENT.

Summary Furosemide, 25 mg/kg/hr (25 mg/kg prime) abolished the sodium medullary gradient in the dog kidney. It is concluded that the natruresis produced by furosemide is due, at least in part, to inhibition of sodium reabsorption in the ascending limb of the loop of Henle.

Evidence for an Hepatic Role in the Control of Sodium Excretion

Discussion and Conclusions The increased natriuresis found after a small hypertonic sodium chloride load was infused into anesthetized dogs was found to be greater when the stimulus was administered directly into the hepatic circulation than when it was infused systemically via the femoral vein. In addition, the response appears to be dose-related within limits. At 0.05 ml/kg/min a significant natriuresis was obtained only after portal loading. At double this rate, significant increases in sodium excretion occurred with both routes of administration, but the increase after portal loading was more than 50% greater. At a higher rate of infusion (0.4 ml/kg/min) no difference was observed between routes. It would appear that the liver exerts a modest influence on sodium excretion and that the modest contribution of an hepatic component is obscured by other components of the natriuretic response to saline loading when the load of saline is increased. Data obtained when 5% saline was infused distal to the hepatic circulation into the right atrium indicate no difference from systemic loading. Since an infusion rate was used (0.1 ml/kg/min) which resulted in a difference when infused via the portal vein, these experiments provide additional support for the involvement of the liver in the natriuretic response. Substitution of a 56% sucrose solution, isosmotic with 5% sodium chloride, resulted in no difference between portal and femoral infusion when infused at 0.1 ml/kg/min for 30 min. Thus, the liver would appear to be responsive to an increase in sodium concentration rather than to an increase in osmolality in the portal blood. Daly et al., using similar stimulus parameters, reached similar conclusions by means of a different experimental design. Although our experiments were undertaken because of our reservations to their experimental design, we concur with their conclusion of an hepatic influence on sodium excretion based on our experiments. Additional experiments presented here, which indicate that a dose-related response occurs with increased portal levels of sodium, provide further evidence for the involvement of the liver in the control of sodium excretion.

Inhibition of ethacrynic acid induced increase in renal blood flow by indomethacin.

Abstract Administration of ethacrynic acid induces, after a delay of 2–3 minutes, an increase in renal blood flow. The delay in onset is also present after renal arterial administration. In order to test the possibility that ethacrynic acid might be releasing vasodilating prostaglandins, indomethacin an inhibitor of prostaglandin synthesis was employed. In six dogs the administration of ethacrynic acid, 0.2 mg/kg, via a renal artery increased renal blood flow by 66 ± 22 ml/min. A second dose administered after indomethacin increased renal blood flow only 8 ± 6 ml/min, a decrease of 58 ml/min. In a second series where indomethacin was not administered, the first dose of ethacrynic acid increased renal blood flow by 65 ± 11 ml/min and 43 ± 8 ml/min after a second administration. Thus while some tachyphylaxis occurs after a second administration, the much greater decrease seen after indomethacin implicates prostaglandins in mediating the renal vasodilation produced by ethacrynic acid.

Characteristics of the Antinatriuretic Action of Growth Hormone

Summary The antinatriuretic action of growth hormone (bovine) was studied in adrenalectomized rats. A dose-response relationship and a time sequence were determined for the antinatriuretic action of growth hormone. Actinomycin D was administered prior to the hormone to determine the effect of actinomycin D on growth hormone-induced antinatriuresis. The results indicated that the antinatriuretic response of growth hormone was dose related. It was found that a 2-hr delay in onset of action followed the administration of growth hormone. The duration of antinatriuresis was approximately 4 hr and this was observed between 2 and 6 hr after administration. The data show that actinomycin D administered prior to growth hormone completely blocked the antinatriuretic action of this agent. The blockade by actinomycin D suggests that RNA synthesis is involved in this action of growth hormone. The observed delay in onset of action of growth hormone is also consistent with the suggestion that growth hormone induced antinatriuresis is mediated through RNA synthesis.

Inhibiton of Furosemide Induced Increase in Renal Blood Flow by Indomethacin

Summary The ability of furosemide to increase RBF was found to be significantly inhibited by indomethacin. The implication of this observation is that the dilation of the renal vasculature produced by furosemide is mediated by prostaglandins. Inhibition of the synthesis of these agents by indomethacin inhibits the increase in RBF produced by furosemide.

Stimulation in vivo of Renal RNA-Synthesis by Aldosterone.∗

Summary Spectrophotometric determination of RNA and isotopic determination of the incorporation of uridine 5′-monophosphate H3 into RNA have shown that aldosterone stimulates RNA-synthesis in vivo. This occurs during the time aldosterone exerts its antinatruretic action. Actinomycin D, an inhibitor of RNA-synthesis, blocked both of these effects. These observations are consistent with the hypothesis that the antinatruretic action of aldosterone is mediated via DNA directed synthesis of messenger-RNA which in turn stimulates the synthesis of a protein involved in the transport of sodium.

Ethacrynic acid induced release of prostaglandin E to increase renal blood flow.

Ethacrynic acid administered to anesthetized dogs was found to increase the level of prostaglandin E as determined by radioimmunoassay in renal venous blood at the time when renal blood flow was increased by this agent. No change was found in the renal venous level of prostaglandin F. When ethacrynic acid was administered after treatment with indomethacin, which blocks the increase in renal blood flow induced by the natriuretic agent, no increase in the renal venous level of prostaglandin E was seen. Thus, the dilation of the renal vasculature would appear to be caused by a stimulation of synthesis and release of prostaglandin E by ethacrynic acid.

Effect of furosemide on renal blood flow in the conscious dog.

Summary and Conclusions Furosemide was administered to unanesthetized dogs containing implanted flow transducers and pressure cannulas. The results show that furosemide increased renal blood flow in the conscious animal after an initial decrease, but that the increase in renal flow produced by 1 mg/kg of the drug was less than previously reported values obtained from anesthetized animals. It was observed that initial renal vascular resistance was lower in unanesthetized animals than the values reported for anesthetized animals. Thus, it was concluded that: (1) furosemide does increase renal blood flow in the conscious dog, and (2) the increase in renal flow produced by the drug in conscious animals is less than the increase in renal flow produced by the drug in anesthetized dogs, because initial resistance to renal flow is lower in conscious than in anesthetized animals.