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Prolonged Infusions of Angiotensin II and Norepinephrine and Blood Prolonged Infusions of Angiotensin II and Norepinephrine and Blood Pressure, Electrolyte Balance, and Aldosterone and Cortisol Secretion in Normal Man and in Cirrhosis with Ascites Richard P. Ames, … , Alfred M. Sicinski, John H. Laragh J Clin Invest. 1965;44(7):1171-1186. https://doi.org/10.1172/JCI105224. Research Article Find the latest version: https://jci.me/105224/pdf Journal of Clinical Investigation Vol. 44, No. 7, 1965 Prolonged Infusions of Angiotensin II and Norepinephrine and Blood Pressure, Electrolyte Balance, and Aldos- terone and Cortisol Secretion in Normal Man and in Cirrhosis with Ascites * RICHARD P. AMES,t ABRAHAM J. BORKOWSKI,4 ALFRED M. SICINSKI,§ AND JOHN H. LARAGH || (From the Department of Medicine, College of Physicians & Surgeons, Columbia University and the Presbyterian Hospital, New York, N. Y.) A series of renal-adrenal interactions involving If angiotensin plays a major role in the control of the pressor peptide angiotensin may control so- aldosterone secretion, 1) it should stimulate aldos- dium balance and blood pressure in normal man terone secretion in nonpressor or mildly pressor (1). Evidence for this is derived from numerous doses since most examples of secondary aldos- experiments in man (2-4) and animals (5-17). teronism are not accompanied by arterial hyper- We propose a mechanism whereby the kidney, tension; 2) aldosterone should be stimulated se- when its perfusion is threatened, releases renin. lectively since hyperaldosteronism is not usually Renin liberates angiotensin from a specific circu- accompanied by increased cortisol secretion; and lating globulin. Angiotensin, in turn, stimulates 3) aldosterone stimulation should continue as the secretion of aldosterone by the adrenal cortex. long as hyperangiotensinemia obtains because the Angiotensin and aldosterone, by increasing ar- pathological secretion of aldosterone is persistent. terial pressure and renal sodium retention, help At present we have not shown that angiotensin restore renal perfusion, thus compensating the meets these requirements. In fact, the literature system. provides both positive and negative opinions for Although it has been demonstrated repeatedly each proposal (1, 3, 16-22). We have examined that infused angiotensin stimulates the secretion of the influences of prolonged infusions of angiotensin aldosterone and causes renal retention of sodium, on arterial pressure, on the selectivity and per- we do not know if the release of endogenous angio- sistence of the stimulation of aldosterone, and on tensin is normally associated with the release of electrolyte balance. These observations were com- aldosterone. Most of our speculation concerning pared with similar studies using the pressor agent angiotensin as a trophic hormone for aldosterone norepinephrine. Our subjects were normal vol- is derived from studies of the pathological hyper- unteers and patients with cirrhosis and ascites, a secretion of aldosterone. Angiotensin is impli- disease involving a typical form of secondary cated in disorders such as malignant hypertension aldosteronism. (1, 2) and the edematous states of cirrhosis, Methods nephrosis, and heart failure (18) because they are usually associated with-renal damage and hyper- We studied seven normal volunteers and eleven pa- tension or abnormal renal electrolyte behavior. tients with cirrhosis. The diagnosis of cirrhosis was de- termined from pertinent findings of the history and * Submitted for publication August 19, 1964; accepted physical and laboratory examinations. It was confirmed March 18, 1965. This work was supported by grants histologically in seven patients. Ten of the patients with H-1275 and H-5741 from .the U. S. Public Health Serv- cirrhosis had ascites; one had completed a spontaneous ice and by the Fleitas Fund. diuresis. Because this latter patient (no. 3) was in clini- t Fellow of the New York Heart Association. cal remission and had corrected the abnormalities of elec- t Fellow of the Polachek Foundation. trolyte and aldosterone metabolism usually associated with § Fellow of the Rockefeller Foundation. ascites formation, she was grouped with the normal sub- 11 Address requests for reprints to Dr. John H. Laragh, jects. One hypertensive patient with uncomplicated dis- Dept. of Medicine, College of Physicians & Surgeons, ease of 12 years known duration was also studied. In Columbia University, New York, N. Y. 10032. all instances full explanation of the nature of the study 1171 1172 AMES, BORKOWSKI, SICINSKI, AND LARAGH was given, and the full cooperation of the subjects was an elevation to 150/100; nonpressor is a minimal eleva- obtained. tion in both systolic and diastolic pressure. Throughout The studies were conducted on the metabolism ward the study patients were permitted limited ambulation and where all subjects received a constant daily diet of lavatory privileges, since infusions were made through known electrolyte content. All subjects received the a 12-foot tube. Metabolic ward technics and the proce- control diet for at least 6 days before study. Normal dures for the routine analysis of plasma and urinary elec- patients were maintained on either normal or low sodium trolytes have been described elsewhere (2). Many of diets, the electrolyte composition of which is given in our basal aldosterone secretory rates were obtained by Table I. 24-hour infusions of 5% dextrose without added pressor All subjects received infusions of angiotensin and agent. norepinephrine in 5% dextrose solution at a rate of ap- Aldosterone secretory rates were determined by an proximately 0.5 ml per minute, held constant by a Bow- isotope dilution technic. 7 or 1, 2, tritium-labeled aldos- man pump. Sphygmomanometric blood pressures were terone was obtained from the U. S. Public Health Serv- recorded at 1-hour intervals during the day and 2-hour ice (SA, 20 and 100 ptc per /Ag). Each batch was checked intervals at night. We have defined pressor infusions as for purity and stability at monthly intervals by a) addition TABLE I Effect of 8- to 24-hour infusions of angiotensin or norepinephrine on sodium balance and aldosterone and cortisol secretion in normal-subjects Urinary sodium Aldosterone Cortisol Blood pressurel excretion secretion secretion Subjects and conditions* Dose Control Exp. Control Exp. Control Exp. Control Exp. mm Hg mEq/day pEqlday mg/day Normal subjects-AngiotensinsAg/min Diet, 70-100 mEq sodium, 120 mEq potassium 1 1.7 124/73 157/98 60 15 135 452 18.8 15.6 2 0.43 122/80 140/91 65 38 226 1,300 26.5 27 3 0.56 105/60 124/77 70 7.0 151 650 22.9 24.3 41 1.8 104/55 141/86 60 8.3 184 556 20 41.5 5 1.7 108/65 150/102 82 67 189 958 18 27 Diet, 70 mEq sodium, 190 mEq potassium 5 1.4 102/65 165/105 83 151 170 1,039 5 1.9 110/70 177/106 75 276 19 34 Diet, 8-18 mEq sodium, 120 mEq potassium 6 0.21 90/64 108/80 17 20 234 439 6 0.21 94/65 98/66 4.8 2.2 358 771 6 2.1 88/58 143/93 1.7 6.8 383 776 7 0.16 110/75 113/72 9.5 3.3 472 463 7 0.34 105/70 125/80 6.2 4.6 215 464 7t 1.9 110/65 150/98 4.9 2.9 323 667 7 2.2 116/60 145/100 8.0 26 520 1,083 7t 2.6 114/80 137/96 1.2 3.3 487 698 Normal subjects-Norepinephrine Diet, 70-100 mEq sodium, 120 mEq potassium 1 13.9 124/73 150/85 50 115 166 207 18.8 23.8 5 7.0 115/70 165/94 66 120 151 18 19.3 8 7.0 118/75 139/82 108 125 9.5§ 13§ Diet, 8-18 mEq sodium, 120 mEq potassium 6 11.1 94/65 138/88 11 60 358 182 7 25.6 116/60 162/87 2.8 33 7t 26.7 110/65 163/88 13 14 413 452 7t 29.4 105/70 170/90 4.4 1.7 520 566 * An interval of several days separated the repeated studies of Subjects 5 to 7. Five and two weeks of the constant regimen elapsed before the final studies of Subjects 6 and 7. t Blood pressure measurements are 24-hour means. Infusion less than 24 hours. I Excretory rate. ANGIOTENSIN, ALDOSTERONE, SODIUM BALANCE, AND BLOOD PRESSURE 1173 TABLE II Effect of 8- to 24-hour infusions of angiotensin or norepinephrine on sodium balance, and aldosterone and cortisol secretion in patients with cirrhosis and ascites Urinary sodium Aldosterone Cortisol Blood pressure excretion secretion secretion Patients and conditions Dose Control Exp. Control Exp. Control Exp. Control Exp. g/mmin mm Hg mEq/day ;sEq/day mg/day Angiotensin Diet, 7-18 mEq sodium, 120 mEq potassium 10* 1.0 120/60 120/65 0.3 0.3 1,560 1,368 11* 1.2 110/65 150/80 38 45 157 108 12 0.47 90/60 110/70 1.8 8.1 177 367 12 2.4 98/65 135/88 1.0 90 1,098 965 5.4 12.2 13* 19.0 100/60 152/84 0.6 116 941 772 13* 2.4 95/65 114/69 3.8 .1 967 928 13* (postshunt) 6.8 96/66 147/82 0.7 180 14* 5.3- 115/80 125/95 25 2.1 85 439 14 4.9 115/80 150/90 2.5 87 85 582 15 0.12 120/70 120/70 0.1 0.3 360 797 15 6.7 124/60 182/92 0.6 334 16* 2.4 110/70 127/85 0.1 2.8 1,027 1,866 16* 8.3 100/70 142/90 0.2 37 2,243 1,846 16* 12.1 100/60 142/94 0.3 64 2,443 2,780 17 3.6 134/76 140/79 2.0 6.0 583 1,119 8.1 13.5 18 0.6 110/60 130/65 0.4 0.6 309 358 18 7.1 105/55 166/79 0.4 170 121 92 18* 17.3 104/60 168/98 2.0 501 122 117 6 41 19 4.6 90/60 102/71 0.5 0.4 Same diet + dexamethasone, 3 mg daily 12* 2.7 97/65 155/89 1.3 270 325 536 <1 1 18* 4.0 124/75 165/85 0.2 2.8 131 366 <1 0.7 Diet, 12 mEq sodium, 190 mEq potassium, and dexamethasone, 3 mg daily 17 4.7 116/75 146/85 2.7 2.8 723 1,058 Norepinephrine Diet, 7-18 mEq sodium, 120 mEq potassium 10* 14.8 120/65 160/80 0.3 0.5 1,560 1,368 12 33.0 98/66 146/90 0.3 3.0 850 487 13* 22.2 98/60 145/78 0.7 0.5 781 465 15 12.9 120/60 149/63 0.4 3.6 1,085 1,089 15 39.4 120/75 187/76 0.3 54 1,964 2,165 16* 33.3 110/72 132/80 0.6 7 2,243 649 17* 8.3 116/60 148/73 3.0 5 1,013 695 18 19.7 104/60 168/72 0.7 39 219 178 6 11.5 19 14.3 90/60 143/94 0.8 4 176t 118t * Infusion less than 24 hours.
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