Effects of captopril and enalapril on sodium excretion and blood pressure in sodium-deficient dogs.

Inhibition of angiotensin I-converting enzyme (ACE) (kininase II) provides a powerful new method for evaluating the role of the renin-angiotensin-aldosterone and kallikrein-kinin systems in the control of aldosterone secretion, renal function, and arterial blood pressure. This study compares the effects of long-term administration of a sulfhydryl inhibitor, captopril, with a nonsulfhydryl inhibitor, enalapril (1-[N-[1-(ethoxycarbonyl-3-phenylpropyl]-L-alanyl]-L-proline), in conscious sodium-deficient dogs. Plasma aldosterone concentration (PAC), plasma renin activity (PRA), urinary sodium excretion (UNaV), arterial pressure (AP), blood kinins (BK), urinary kinins (UK), and urinary kallikrein activity (UKA) were determined during long-term inhibition of ACE in sodium-deficient dogs. 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 . h), UNaV increased from 0.65 +/- 0.27 to 6.4 +/- 1.2 meq/day, AP decreased from 102 +/- 3 to 65 +/- 2 mm Hg, 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 EU/day. Quantitatively similar changes in AP, UNaV, and PAC were observed in sodium-deficient dogs in response to long-term enalapril administration (4 mg/(kg X day]. In sodium-deficient dogs maintained on captopril or enalapril for several days, angiotensin II (AngII) infusion (3 ng/(kg X min] restored PAC, UNaV, and AP to levels observed in untreated sodium-deficient dogs. These data indicate that the long-term hypotensive and natriuretic actions of inhibitors of ACE are mediated by inhibition of AngII formation and that the renin-angiotensin system plays an essential role in regulating aldosterone secretion, renal function, and AP during sodium deficiency.

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. 2. P[Na] rose from 137.3 +/- 2.0 to 153.6 +/- 6.5 mmol/l during the high intake period. Plasma potassium concentration, 22Na space, and mean arterial pressure all remained near control levels in response to Na loading. 3. Plasma renin activity (PRA) averaged 1.0 +/- 0.1 ngAI/ml per hour on the final low Na day and fell transiently to 0.6 +/- 0.2 ngAI/ml per hour on the first day of sodium loading. For the duration of the study it remained at the control level. Plasma aldosterone concentration fell from the low Na level of 15.4 +/- 2.4 ng/100 ml to 10.5 +/- 1.5 ng/100 ml on the final day of high Na intake. 4. We conclude that increases in P[Na] in the absence of concomitant changes in P[K], 22Na space and MAP do not have a sustained effect on control of renin release but may exert a negative effect on aldosterone secretion.

Lack of prolonged effect of antidiuretic hormone on the renin-aldosterone system in the dog.

1. The effects of maximally antidiuretic, subpressor antidiuretic hormone (ADH) administration of the renin-aldosterone system were studied in dogs during 4 days of continuous intravenous infusion of ADH at a rate of 0.067 mU/kg per min. Water intake was limited to 700 ml/day to avoid changes in fluid volume status. 2. At the conclusion of the four-day study, plasma sodium concentration had fallen from 140.3 +/- 0.8 to 137.2 +/- 2.0 mmol/l, plasma potassium concentration, 22Na space, and mean arterial pressure remained within the control ranges. 3. Neither plasma renin activity nor plasma aldosterone concentration showed any tendency to change in response to the ADH infusion. 4. The results indicate that physiological levels of ADH have no prolonged, direct effect on the renin-aldosterone system.

Regulation of aldosterone biosynthesis during sodium deficiency. Evidence for an essential role of the pituitary gland.

The aldosterone response to adrenocorticotropic hormone (ACTH) and angiotensin II (AII) was evaluated in patients with pituitary insufficiency before and after dietary sodium restriction (10 mEq Na+/day for 12 days). On normal sodium intake, plasma aldosterone concentration and plasma cortisol concentration failed to change from control levels in response to a single injection of ACTH or to a continuous 1-hour infusion of AII in patients with pituitary insufficiency. In response to dietary sodium restriction for 12 days, plasma renin activity (PRA) increased fivefold in patients with pituitary insufficiency, while plasma aldosterone concentration failed to increase significantly, averaging 11.0 +/- 3.1 before and 12.3 +/- 3.7 ng/dl (ns, p greater than 0.05) after sodium deficiency. Although aldosterone secretion failed to increase during sodium deficiency, the patients came into balance at 10 mEq without a significant change in arterial blood pressure (BP). In sharp contrast to the lack of aldosterone response to ACTH before sodium deficiency, plasma aldosterone concentration increased markedly from 12.9 +/- 3.3 to 156 +/- 17.3 ng/dl (p less than 0.001) in response to ACTH after sodium deficiency. Although the adrenal glomerulosa cells were markedly sensitive to ACTH during sodium deficiency, they remained almost totally refractory to AII since aldosterone secretion failed to increase significantly in response to continuous infusion of a pressor dose of AII for 1 hour. Replacement therapy with ACTH gel for 3 months in patients with pituitary insufficiency failed to restore a normal aldosterone response to either ACTH or AII. These data demonstrate that some non-ACTH pituitary factor(s) is essential for a normal aldosterone response to ACTH, AII, and sodium deficiency.

Role of the renin-angiotensin system in potassium control.

To determine the importance of the renin-angiotensin system in control of plasma potassium concentration and excretion, potassium control was studied in two groups of dogs in response to a 20-fold increase in sodium intake (from 10 to 200 meq/day). Group I was intact whereas group II lacked feedback control of the renin-angiotensin system, which was eliminated by continuous infusion of 10 ng . kg-1 . min-1 angiotensin II. This rate of infusion reduced endogenous plasma renin activity (PRA) to undetectable levels throughout the study. The sodium forcing did not result in measurable changes in plasma potassium concentration or excretion in group I, in which PRA fell to 40% and plasma aldosterone concentration (PAC) to 60% of the low sodium levels. In group II the same sodium forcing produced a 12% decrease in plasma potassium concentration and a 79% increase in urinary potassium excretion. PAC also fell to 60% of the low sodium level in group II. The results demonstrate the importance of the renin-angiotensin system as a link between the nephron and the zona glomerulosa that is essential in controlling plasma potassium concentration and excretion during changes in sodium balance.

Overview of the role of angiotensin inhibitors in delineating the function of the renin-angiotensin system.

In conscious sodium-deficient dogs, beta-adrenergic blockade with propranolol and angiotensin II receptor blockade with an angiotensin II inhibitory analogue reduced arterial blood pressure and increased urinary sodium excretion significantly, but the hypotensive and natriuretic response was considerably greater during inhibition of angiotensin I converting enzyme with captopril. Angiotensin II infusion (3 ng/kg/min) into sodium-deficient dogs maintained on captopril administration restored arterial blood pressure, urinary sodium excretion, and plasma aldosterone concentration to levels that existed in untreated sodium-deficient dogs. This indicates that the hypotensive and natriuretic actions of captopril are due to the inhibition of angiotensin II formation and not to the accumulation of the vasodepressor peptide, bradykinin.

Response of arterial blood pressure, plasma renin activity and plasma aldosterone concentration to long-term administration of captopril in patients with severe, treatment-resistant malignant hypertension.

1. The response of arterial blood pressure, plasma renin activity and plasma aldosterone concentration to inhibition of angiotensin I converting enzyme (kininase II) with captopril has been studied in patients with severe, treatment-resistant, malignant hypertension. 2. Nine patients with a past history of severe hypertension, supine diastolic blood pressure greater than 120 mmHg before conventional antihypertensive therapy and resistant to conventional antihypertensive therapy were studied. 3. Captopril administration resulted in a marked decrease in arterial blood pressure and plasma aldosterone concentration and an increase in plasma renin activity. 4. Although arterial blood pressure remained significantly below the values observed during the control period, pressure did tend to increase again after 3 days. Addition of hydrochlorothiazide kept arterial pressure significantly below pretreatment control values.

Effect of an angiotensin converting enzyme inhibitor (SQ 14,225) on beta-adrenergic and angiotensin-induced thirsts.

The effect of acute administration of SQ 14,225, a new angiotensin converting enzyme inhibitor, on the drinking response of female rats administered either isoprenaline, angiotensin I, or angiotensin II was studied during 2 h after treatment. Administration of isoprenaline (25 micrograms/kg body wt) was accompanied by a significant increase in water intake when compared with saline-treated controls. Acute administration of a constant dose of isoprenaline (25 micrograms/kg body wt) and increasing doses of SQ 14,225 (5--50 mg/kg) was accompanied by a dose-related, linear decrease in water intake. Acute administration of either angiotensin I or angiotensin II (200 micrograms/kg body wt) was accompanied by a significant increase in water intake. The dipsogenic response to angiotensin II was not affected by acute administration of 35 mg SQ 14,225/kg body wt. However, at the same dose of SQ 14,225, angiotensin I-induced thirst was attenuated. Since isoprenaline-induced and angiotensin I-induced, but not angiotensin II-induced, thirsts are blocked by SQ 14,225, the results suggest that isoprenaline-induced thirst is mediated by way of the renin--angiotensin system.

Hypertension in dogs during antidiuretic hormone and hypotonic saline infusion.

Experimental hypertension was produced in 7 dogs by continuously infusing suppressor amounts of antidiuretic hormone (ADH) and hypotonic saline after renal mass had been surgically reduced to 30% of normal. Data were collected during 9 days of control measurements, 14 days of ADH and saline infusion, and then 3 days of saline infusion to 1) determine the chronic effects of ADH on arterial pressure and 2) determine whether hypertension could be maintained during hyponatremia. During the period of ADH infusion, arterial pressure increased to hypertensive levels while plasma sodium concentration decreased almost 20 meq/1. Also, during the ADH infusion period, the dogs demonstrated decreases in heart rate, plasm potassium concentration, plasma renin activity, and plasma aldosterone concentration. Fluid volume expansion was evidenced by sustained increases in blood volume and sodium space. We conclude that when renal function is compromised, subpressor amounts of ADH can contribute to the development of hypertension, probably due to its fluid-retaining properties and in spite of the attendant hyponatremia.

Essential role of mean circulatory filling pressure in salt-induced hypertension.

Experimental hypertension was produced in nine dogs by continuously infusing isotonic saline after renal mass had been surgically reduced to approximately 30% normal. Data were collected during 8 days of base-line measurements and 13 days of saline infusion to determine the cause of the initial increase in cardiac output observed in this type of hypertension and to measure other variables possibly important in the pathogenesis of hypertension. During the infusion period, these dogs demonstrated an increase in arterial pressure to hypertensive levels, transient increases in blood volume, sodium space, and cardiac output, initially depressed then subsequently elevated total peripheral resistance, and decreases in plasma renin activity and plasma aldosterone concentration. The mean circulatory filling pressure increased 4.7 Torr by day 3 and was still elevated 2 Torr at the end of the 2nd wk of infusion. We conclude that the initial increase in cardiac output in salt-loading hypertension is due to elevated fluid volumes and the associated increase in mean circulatory filling pressure.

Subpressor angiotensin infusion, renal sodium handling, and salt-induced hypertension in the dog.

We studied the combined effect of subpressor amounts of angiotensin and long-term sodium chloride infusion on arterial pressure in 16 dogs for periods of 2--8 weeks. In dogs receiving 3.5 liters of isotonic NaCl daily, but no angiotensin, the arterial pressure increased an average of only 3 mm Hg. When angiotensin was infused continuously at a rate of 5 ng/kg per min (a rate too small to cause an observable immediate increase in pressure, subsequent infusion of 3.5 liters of saline daily then increased the pressure by 39 mm Hg. The urinary output of sodium increased to the same extent in both instances, that is, there was no extra sodium loss because of the elevated pressure. This suggests that the angiotensin significantly blocked the normal "pressure natriuresis" usually seen with such large increases in pressure. However, the plasma aldosterone levels during angiotensin infusion were not found to be different from those in the absence of angiotensin. Therefore, we have suggested that the tendency of the kidneys to retain sodium under the influence of angiotensin was probably caused mainly by a direct effect of angiotensin on the kidney itself. Such a direct renal sodium-retaining effect also could be a contributing factor in the marked hypertension that results from salt administration in the presence of small amounts of angiotensin.