Robert E. McCaa

Renin, Aldosterone, Body Fluid Volumes, and the Baroreceptor Reflex in the Development and Reversal of Goldblatt Hypertension in Conscious Dogs

The renal artery to a sole remaining kidney was constricted in unanesthetized dogs while renal arterial pressure was recorded distal to the occluder. Following the constriction, mean arterial blood pressure, which was continuously monitored 24 hours a day for 1 week, exhibited a biphasic increase. The first peak in pressure correlated with a large increase in plasma renin activity; the second peak correlated with an increase in plasma volume brought about by positive sodium and water balances. Renin activity was returning to normal when the second peak occurred. Increased drinking played a major role in the positive water balance. Plasma aldosterone concentration was moderately and transiently increased for only a few hours following the constriction. The experiment was repeated in sinoaortic baroreceptor-denervated dogs; apparently, the baroreceptor reflex significantly slows the time course of the arterial blood pressure increase during the first few days of constriction but does not alter the magnitude of the pressure increase after 1 week. After release of renal artery constriction, mean arterial blood pressure decreased progressively over a 3-day period, during which time significant negative sodium and fluid balance occurred. The slow return of the pressure back to normal correlated highly with a decrease in plasma volume. In the baroreceptor-denervated dogs, the initial fall in arterial blood pressure apparently also resulted at least partly from a decrease in plasma renin activity, but this effect was not observed in the intact dogs because the renin activities in these dogs had already decreased to normal prior to constrictor release. The effects of the baroreceptor reflex on the time course of the pressure decrease did not seem to be as significant as those on the time course of the pressure increase.

The natriuretic and hypotensive effects of potassium.

The chronic effects of potassium loading on sodium balance and related variables were studied in two groups of dogs. The first group was intact except for the presence of indwelling arterial and venous cannulas. On the 1st day, increasing daily potassium intake from a normal level (30 mEq/day) to 200 mEq/day produced a 0.47-mEq increase in plasma potassium with a 56% increase (P > 0.01) in sodium excretion in spite of a 58% increase in plasma aldosterone concentration. After 6 days of potassium loading the cumulative negative sodium balance averaged 44 mF.q while 22Na space decreased 6.7% (P < 0.025). In this group arterial pressure did not change measurably. The same experimental protocol was repeated in a second group of dogs that were chronically adrenalecto-mized and maintained on fixed levels of aldosterone (50 &mgr;g/day) and hydrocortisone (1 mg/day). With aldosterone levels held constant the same increase in potassium intake produced a 1st day increase in potassium concentration of 1.20 mEq/liter and 217% (P < 0.001) increase in sodium excretion. After 5 days of high potassium intake, the cumulative negative sodium balance totaled 84 mEq. Sodium space decreased 7.5% (P < .005) during the course of the 5-day high potassium intake period. Potassium loading caused a fall in mean arterial pressure in this group; pressure fell from the control level of 110 ± 3 mm Hg to 87 ± 4 mm Hg (P < .001) after 3 days of high intake. By the 5th day of the experiment, pressure stabilized at 96 ± 3 mm Hg, 13% less than (P < 0.01) the control level. The results suggest that changes in plasma potassium concentration within physiological limits may have long term effects on sodium balance.

Increased Plasma Aldosterone Concentration In Response to Hemodialysis In Nephrectomized Man

The nephrectomized patient maintained on intermittent hemodialysis while awaiting renal transplantation provides an excellent model for studying the influence of factors other than the renal renin-angiotensin system that play a role in the regulation of plasma aldosterone concentration. Peripheral plasma aldosterone concentrations were determined using a sensitive radioimmunoassay method in nine anephric patients in the recumbent position immediately before and after hemodialysis. Average patient weight fell 1.5 kg following 12 hours of dialysis on the Kiil dialyzer. Plasma sodium concentration decreased from 137 ± 1 (SE) to 132 ± 1 mEq/liter, plasma potassium concentration decreased from 4.8 ± 0.3 to 3.2 ± 0.1 mEq/liter, and the ratio of sodium to potassium increased from 31.3 ± 1.9 to 41.7 ± 0.9. Plasma aldosterone concentration increased from 9.7 ± 1.6 ng/100 ml plasma before dialysis to 17.9 ± 2.1 ng/100 ml plasma after dialysis despite the lack of kidneys to produce renin. Plasma cortisol concentration did not change significantly (17.5 ± 2.0 μg/100 ml plasma to 14.8 ± 1.9 μg/100 ml plasma). These results show that plasma aldosterone concentration increased in anephric patients in response to hemodialysis. This increase occurred without a concomitant increase in plasma cortisol levels, suggesting absence of an adrenocorticotropic hormone response, and was independent of the renal reninangiotensin system.

Role of angiotensin II and potassium in the long-term regulation of aldosterone secretion in intact conscious dogs.

The aldosterone response to long-term infusion of angiotensin II and potassium was studied in intact conscious dogs. Plasma aldosterone concentration (PAC), plasma renin activity (PRA), and plasma cortisol concentration (PCC) were determined by radio-immunoassay. In ten dogs maintained on angiotension II infusion (5 ng/kg min−1) for 14 days, PAC increased from 6.9 ± 2.9 to 18.6 ± 4.7 ng/100 ml plasma (mean ± se) within ten minutes after beginning the infusion, reached a maximum level of 28.3 ± 6.8 ng/100 ml plasma by one hour, and returned to control levels by six hours. PCC increased from 0.6 ± 0.2 to 3.9 ± 1.0/ig/100 ml plasma within one hour after angiotensin II infusion and returned to control levels by six hours. During the next 14 days of angiotensin II infusion, PAC remained at control levels, PRA was undetectable by radioimmunoassay, and mean arterial blood pressure was elevated 29 ± 4 mm Hg above control levels. In ten dogs maintained on KC1 infusion (250 mEq/day) for 15 days, PAC increased from 6.8 ± 2.4 to 13.6 ± 3.4 ng/100 ml plasma within 24 hours, averaged 22.4 ± 4.3 ng/100 ml plasma by 48 hours, and remained elevated for the next 12 days, averaging 21.8 ± 5.6 ng/100 ml plasma. During the next 14 days of KC1 infusion, serum K+ increased from 4.1 ± 0.3 to 4.9 ± 0.5 mEq/L, and PRA decreased from 1.25 ± 0.3 to 0.65 ± 0.2 ng/ml/hr. PCC averaged 0.73 ± 0.4 μg/100 ml plasma in the control samples and failed to change significantly during KC1 infusion. These data indicate that chronic angiotensin II infusion into intact conscious dogs at rates capable of maintaining elevated arterial blood pressure results in a transient increase in aldosterone secretion that lasts only a few hours, while chronic infusion of potassium ions at rates that produce a minor increase in serum K+ results in a sustained increase in aldosterone secretion.

Influence of Acute Stimuli on Plasma Aldosterone Concentration in Anephric Man and Kidney Allograft Recipients

The response of plasma aldosterone concentration to postural variation, adrenocorticotropic hormone (ACTH), and angiotensin II was studied in five kidney allograft recipients and compared with the response observed in the same five subjects during the anephric period. Normal subjects acted as intact controls. After 2 hours of normal ambulation, plasma aldosterone levels increased in normal subjects (6.7 ± 1.6 to 22.9 ± 2.7 ng/100 ml plasma), remained unchanged in anephric patients (4.5 ± 1.0 to 5.2 ± 1.1 ng/100 ml plasma), and increased in kidney allograft recipients (6.8 ± 1.5. to 25.6 ± 1.9 ng/100 ml plasma). After ACTH administration, plasma aldosterone levels increased in normal subjects (7.5 ± 1.8 to 24.3 ± 2.5 ng/100 ml plasma), anephric subjects studied immediately after hemodialysis (16.6 ± 1.6 to 30.0 ± 2.6 ng/100 ml plasma), and kidney allograft recipients (5.0 ± 1.6 to 22.3 ± 1.4 ng/100 ml plasma). After angiotensin II infusion, plasma aldosterone levels increased in normal subjects (7.2 ± 1.8 to 42.5 ± 3.6 ng/100 ml plasma), remained unchanged in anephric subjects (8.6 ± 2.1 to 7.4 ± 1.6 ng/100 ml plasma), and increased in kidney allograft recipients (6.3 ± 1.5 to 40.2 ± 3.1 ng/100 ml plasma). In anephric man after prolonged absence of the renal renin-angiotensin system ACTH increased the rate of aldosterone secretion but angiotensin II had little effect. An intact renal renin-angiotensin system was necessary for increased aldosterone secretion in response to postural variation.

Relative Influence of Acute Sodium and Volume Depletion on Aldosterone Secretion in Nephrectomized Man

Plasma aldosterone concentration can increase in anephric man during hemodialysis despite the lack of kidneys to produce renin. Because the metabolic clearance rate of aldosterone does not change during hemodialysis, aldosterone secretion must increase in response to sodium depletion, volume depletion, or both. This study was designed to determine the relative influence of sodium and volume depletion by ultrafiltration and hemodialysis on plasma aldosterone concentration in anephric man. Fluid (547 ml) was removed from 13 anephric subjects during 4 hours of ultrafiltration in the absence of hemodialysis. Plasma sodium and potassium concentration did not change during ultrafiltration, but total body sodium and potassium decreased. Plasma aldosterone concentration did not change significantly. Each subject was then hemodialyzed for 8 hours. In 5 subjects, an additional liter of fluid was removed without a significant change in plasma sodium concentration. Plasma aldosterone concentration also did not change in response to the reduction in fluid volume. In 8 subjects, an additional liter of fluid was removed, and plasma sodium concentration decreased from 138.5 to 130.0 mEq/liter. Plasma aldosterone concentration increased from 8.3 to 19.6 ng/100 ml plasma. Three additional anephric subjects were hemodialyzed against a dialysate containing 125.0 mEq sodium/liter for 8 hours. Plasma potassium and total body fluid volume were held constant. Plasma sodium concentration decreased from 138.5 to 125.0 mEq/liter, and plasma aldosterone concentration increased from 7.4 to 24.3 ng/100 ml plasma. These data indicate that acute sodium depletion by hemodialysis accompanied by decreased plasma sodium concentration without a change in plasma potassium concentration or fluid volume can stimulate aldosterone secretion independently of the renal renin-angiotensin system.

Stimulation of Aldosterone Secretion by Hemorrhage in Dogs after Nephrectomy and Decapitation

In eight intact, anesthetized dogs the aldosterone secretory rate averaged 13.8 ± 1.9 ng/min (mean ± SE). One hour after nephrectomy and decapitation, the aldosterone secretory rate decreased to 2.3 ± 1.7 ng/min and failed to increase in response to hemorrhage. By 8 hours after surgery, the aldosterone secretory rate had returned to control levels. The serum potassium concentration gradually increased from 3.2 ± 0.5 mEq/liter in the control samples to 5.3 ± 0.5 mEq/liter in the 8-hour samples. Eight hours after nephrectomy and decapitation, the arterial blood pressure was lowered to 70 mm Hg by hemorrhage in six dogs. During the next 3 hours, the aldosterone secretory rate increased from 11.2 ± 2.1 ng/min to 27.3 ± 2.1 ng/min. Associated with the increase in the aldosterone secretory rate following hemorrhage was a further increase in the serum potassium concentration from 5.3 ± 0.5 mEq/liter to 6.8 ± 0.5 mEq/liter. The aldosterone secretory rate did not increase following hemorrhage when the rise in serum potassium concentration was prevented by hemodialysis. These data indicate that normal levels of aldosterone secretion can be maintained in the absence of the renin-angiotensin system and the pituitary secretion of adrenocorticotropic hormone. Also, hemorrhage will greatly enhance aldosterone secretion in the absence of the head and the kidneys but only if the serum potassium concentration is allowed to rise following the hemorrhage.

Role of the Renin-Angiotensin-Aldosterone and Kallikrein-Kinin Systems in the Control of Fluid and Electrolyte Metabolism, Renal Function, and Arterial Blood Pressure

The long-term effects of angiotensin I converting enzyme (kininase II) inhibition with Captopril on fluid and electrolyte metabolism, aldosterone secretion, renal function, and arterial pressure were evaluated in conscious sodium deficient dogs. Plasma aldosterone concentration (PAC), plasma renin activity (PRA), urinary sodium excretion (UNaV), arterial pressure (AP), renal blood flow (RBF), glomerular filtration rate (GFR), blood kinin concentration (BK), urinary kinin excretion (UK), and urinary kallikrein activity (UKA) were determined during long-term inhibition of angiotensin I converting enzyme (kininase II). In response to Captopril administration (20 mg/kg/day) PAC decreased from 38.9 +/- 6.7 to 14.3 +/- 2.3 ng/dl, PRA increased from 3.58 +/- 0.53 to 13.7 +/- 1.6 ng/ml/hr, UNaV increased from 0.65 +/- 0.27 to 6.4 +/- 1.2 mEq/day, AP decreased from 102 +/- 3 to 65 +/- 2 mmHg, RBF increased from 136 +/- 7 to 156 +/- 8 ml/min, GFR decreased from 65 +/- 8 to 36 +/- 7 ml/min, BK increased from 0.17 +/- 0.02 to 0.41 +/- 0.04 ng/ml, UK increased from 7.2 +/- 1.5 to 31.4 +/- 3.2 micrograms/day, and UKA decreased from 23.6 +/- 3.1 to 5.3 +/- 1.2 E.U./day. Aldosterone infusion in sodium deficient dogs maintained on Captopril failed to alter urinary sodium excretion, renal function, or arterial blood pressure. However, angiotensin II infusion (3 ng/kg/min) restored aldosterone secretion, renal function, and arterial blood pressure within three days to levels observed in untreated sodium deficient dogs. The marked alterations in renal function and urinary sodium excretion during angiotensin II infusion indicate that angiotensin II is several times more potent than aldosterone in the long-term control of sodium excretion. Also, our studies demonstrated that the long-term hypotensive and natriuretic actions of inhibitors of angiotensin I converting enzyme (kininase II) are mediated by inhibition of angiotensin II formation.

Effect of sustained hypernatraemia on the renin-aldosterone system in the dog.

1. To determine if increases in plasma sodium concentration P[Na] have any sustained effects of the renin‐aldosterone system, P[Na] was increased in a group of six dogs over a period of 6 days by increasing sodium intake from 10 to 200 mmol per day while a fixed 700 ml per day water intake was maintained along with a continuous i.v. infusion of antidiuretic hormone (ADH) at a rate of 2.4 units per day.