A B S T R A C T Observations were made on the relation of the renin-angiotensin-aldosterone system and renal hemodynamic function to sodium balance in 43 pregnant dogs. Daily balance studies revealed that about 30-40% of ingested sodium was retained during the last half of pregnancy; during the same period, potassium balance was also positive but to a lesser extent. For groups of pregnant dogs, plasma renin activity (n = 14) and aldosterone secretion (n = 19) were significantly higher than normal; however, in some animals one or both functions were normal even though sodium retention was present. In contrast, plasma renin substrate concentration was consistently elevated during pregnancy in seven dogs. In a group of nine dogs in which both aldosterone secretion and plasma renin activity were measured, aldosterone secretion was elevated in the three dogs with the highest values for plasma renin activity; in two of the remaining six animals aldosterone secretion was elevated but plasma renin activity was normal or only slightly increased. The sequestration of sodium and water into the uterine contents was defined quantitatively in this study but evidence was lacking to support the idea that such changes led to renin release. The glomerular filtration rate (GFR) was significantly elevated throughout pregnancy but a significant decrease from the high level of mid-pregnancy occurred during the last half of pregnancy; this decrease in GFR probably contributed to the sodium retention. Administration of a large dose of deoxycorticosterone acetate (DOCA) to dogs in late pregnancy produced marked sodium retention but "escape" from the sodium-retaining steroid occurred. The data demonstrate that although increased activity of the renin-angiotensin-aldosterone system was frequently present during pregnancy, a normal rate of aldosterone secretion occurred. This finding and the observed "es-

A striking increase in the plasma renin level occurred in dogs with low output right heart failure secondary to tricuspid insufficiency and pulmonic stenosis and in three of five animals with high output failure produced by a large arteriovenous fistula. When dogs with a small arteriovenous fistula were given daily injections of DOCA, the renal sodium "escape" phenomenon occurred. In these animals, the level of plasma renin was suppressed during DOCA administration both during the initial period of sodium retention and also later when sodium balance was normal or negative. In contrast, when dogs with a larger arteriovenous fistula but without evidence of cardiac failure were given DOCA, they retained sodium and developed signs of congestive heart failure. However, in these animals with congestion and ascites, in contrast to-the dogs that developed spontaneous high output failure, the plasma renin was low. Renin-substrate was unaltered in all of the experimental situations studied except for the decrease observed in dogs with low output right heart failure, la these animals, it seems likely that decreased renin-substrate was secondary to hepatic congestion and liver damage. The renin-angiotensin system does not seem to be related to the "escape" phenomenon, and renin does not appear to be the factor that makes the kidney unusually responsive to mineralocorticoids. Thus, in experimental heart failure the reninangiotensin system was activated, but in the congestive syndrome produced by DOCA the plasma renin level was suppressed. ADDITIONAL KEY WORDSrenin-angiotensin system arteriovenous fistula desoxycorticosterone sodium balance renin-substrate tricuspid insufficiency and pulmonic stenosis high output failure conscious dogs• Hypersecretion of aldosterone is common in edematous states (1-12). Many patients with congestive heart failure have increased secretion and excretion of aldosterone (1, 3-7), but patients with edema also have normal rates of secretion, of this hormone (8-10). Experimental heart failure in dogs is regularly accompanied by an increase in aldosteroneFrom the Departments of Physiology and Surgery, University of Missouri School of Medicine, Columbia, Missouri 6520X.This investigation was supported in part by U. S. Public Health Service Research Grant HE 10612-01 from the National Heart Institute.Dr. Johnston is Research Fellow, National Heart Foundation of Australia.Accepted for publication December 10, 1967. secretion and a high plasma level of aldosterone (2,11,12). The increase in plasma aldosterone in heart failure also results from a decrease in the metabolic clearance of aldosterone by the Ever (4, 9, 13). The present study relates the participation of the reninangiotensin system in experimental heart failure to sodium balance and to the known hypersecfetion of aldosterone. This investigation is also concerned with the role of the renin-angiotensin system in the "escape" phenomenon (14-15). Normal humans or animals given large quantities of a mineralocorticoid retain sodium for only ...

Hepatic blood flow, hepatic extraction of renin, and hepatic clearance of renin were compared in normal conscious dogs, in dogs with constriction of the thoracic inferior vena cava (as a model of low-output heart failure), and in dogs with an aortic-caval fistula (high-output heart failure). Both "failure" preparations showed marked sodium retention. Renin was measured by methods described previously and expressed as nanograms of angiotensin produced during incubation per milliliter of plasma. Hepatic plasma flow was determined by the sodium sulfobromophthalein method. The dogs with low-output heart failure had a marked reduction in hepatic plasma flow, while those with high-output failure showed no significant change in this flow. Plasma renin was significantly elevated in both models of heart failure. Dogs with low-output failure had an increase (P<.05) in hepatic renin extraction from a normal value of 19.8% to 33.4%, while those with high-output failure showed a decrease in hepatic renin extraction to 11.9% (P<.01). The hepatic clearance of renin in low-output failure (104 ml/ min) was the same as the average normal value of 104 ml/min, while clearance of renin by the liver in high-output failure was reduced to 51 ml/min (P<.001). The data provide evidence that the decreased metabolism of renin contributes substantially to the increased plasma level of renin in experimental high-output heart failure. ADDITIONAL KEY WORDS hepatic extraction of renin sodium retention thoracic inferior vena caval constriction aortic-caval fistula plasma renin hepatic blood flow chronic venous congestion• In congestive heart failure, in decompensated cirrhosis of the liver, and in their experimental counterparts, elevated plasma renin levels (1-7) have been causally related in increased aldosterone secretion. The exact mechanisms which lead to an elevated plasma renin have not been clearly defined. Haecox, et al. (8) have demonstrated in anesthetized dogs that significant extraction or inactivation of renin is brought about by the liver. In view of the hepatic congestion associated with right heart failure, it was decided to investigate the role of the hepatic metabolism of renin in the elevated plasma renin levels found in experimental heart failure. Hepatic blood flow, hepatic renin extraction, and the hepatic clearance of renin were measured in normal conscious dogs and in conscious dogs with either constriction of the thoracic inferior vena cava or an aortic-caval fistula.Constriction of the thoracic inferior vena cava was used to produce a model of lowoutput heart failure. Although such animals are not in true congestive heart failure, it has been demonstrated that the salt and

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