John R. Gill

Effects of Dietary Sodium and of Acute Saline Infusion on the Interrelationship between Dopamine Excretion and Adrenergic Activity in Man

The effects of dietary sodium and of saline infusion on urinary dopamine and norepinephrine and on the relationship of these catecholamines to adrenergic activity were determined. In seven normal subjects on a 9-meq sodium intake, urinary dopamine and norepinephrine were 136+/-18 (SE) and 37.4+/-5.3 mug/day, respectively. When sodium intake was increased to 209 or 259 meq/day, urinary dopamine increased to 195+/-20 mug/day (P<0.01) whereas urinary norepinephrine decreased to 21.1+/-3.0 mug/day (P<0.01). Infusion of saline in seven subjects increased sodium excretion and urinary dopamine (from 2.18+/-0.22 to 2.79+/-0.19 mug/20 min, P<0.01), but decreased plasma dopamine-beta-hydroxylase by 33% and urinary norepinephrine insignificantly. The clearance of inulin and p-aminohippurate did not change significantly and filtration fraction was the same. The data indicate that an increase in dietary sodium or infusion of saline results in an apparent decrease in adrenergic activity and an increase in urinary dopamine. Dopamine excretion would thus appear to relate inversely to adrenergic activity and to parallel sodium excretion. These findings suggest a possible role for dopamine and norepinephrine in the regulation of renal sodium excretion.

Urinary Kallikrein Excretion in Normal Man: Relationships to Sodium Intake and Sodium-Retaining Steroids

The urinary excretion of kallikrein, a renal enzyme that cleaves the potent vasodilator kinin, kallidin, from kininogen, was measured in normal volunteers by three different assays, one of which was a bioassay. When sodium intake was changed from ad libitum or 109 mEq/day to 9 mEq/day, daily kallikrein excretion increased progressively in every subject to a mean maximal value that was 271% of control by day 7; an increase in sodium intake to 259 mEq/day resulted in the return of kallikrein excretion to control values. Urinary excretion of amylase, a protein with a molecular weight similar to that of kallikrein, did not change when sodium intake was changed, but plasma renin activity and aldosterone excretion changed appropriately. In subjects on a constant-sodium (109 mEq/day), constant-potassium (100 mEq/day) diet, fludrocortisone, 0.5 mg/day for 10 days, increased kallikrein excretion to a mean maximal value that was 203% of control. In subjects on a diet containing 9 mEq sodium/day, elevated kallikrein excretion decreased during treatment with spironolactone, 400 mg/day. Rapid administration of water (1 or 2 liters in 30 minutes, orally) or rapid infusion of 2.4 liters of normal saline did not significantly alter urinary kallikrein excretion despite large changes in urine volume or sodium excretion. Thus, kallikrein excretion appears to be directly related to the effective level of circulating sodium-retaining steroid. The findings are consistent with a role for the kallikrein-kinin system in the renal response to sodium-retaining hormones.

The Kallikrein-Kinin System in Bartter's Syndrome and Its Response to Prostaglandin Synthetase Inhibition

The kallikrein-kinin system was characterized in seven patients with Bartters syndrome on constant metabolic regimens before, during, and after treatment with prostaglandin synthetase inhibitors. Patients with Bartters syndrome had high values for plasma bradykinin, plasma renin activity (PRA), urinary kallikrein, urinary immunoreactive prostaglandin E excretion, and urinary aldosterone; urinary kinins were subnormal and plasma prekallikrein was normal. Treatment with indomethacin or ibuprofen which decreased urinary immunoreactive prostaglandin E excretion by 67%, decreased mean PRA (patients recumbent) from 17.3+/-5.3 (S.E.M.) ng/ml per h to 3.3+/-1.1 ng/ml per h, mean plasma bradykinin (patients recumbent) from 15.4+/-4.4 ng/ml to 3.9+/-0.9 ng/ml, mean urinary kallikrein excretion from 24.8+/-3.2 tosyl-arginine-methyl ester units (TU)/day to 12.4+/-2.0 TU/day, but increased mean urinary kinin excretion from 3.8+/-1.3 mug/day to 8.5+/-2.5 mug/day. Plasma prekallikrein remained unchanged at 1.4 TU/ml. Thus, with prostaglandin synthetase inhibition, values for urinary kallikrein and kinin and plasma bradykinin returned to normal pari passu with changes in PRA, in aldosterone, and in prostaglandin E. The results suggest that, in Bartters syndrome, prostaglandins mediate the low urinary kinins and the high plasma bradykinin, and that urinary kallikrein, which is aldosterone dependent, does not control kinin excretion. The high plasma bradykinin may be a cause of the pressor hyporesponsiveness to angiotensin II which characterizes the syndrome.

Adrenergic Nervous System in Sodium Metabolism: Effects of Guanethidine and Sodium-retaining Steroids in Normal Man*

Increased activity of the sympathetic nervous system (SNS) has been thought to be partly responsible for sodium retention in congestive heart failure, since sympatholytic drugs may increase the renal excretion of sodium in dogs (1) and patients (2) with congestive heart failure. Two other observations support the suggestion that changes in adrenergic activity may produce changes in renal function. Infusions of norepinephrine, the neurohumoral transmitter of the SNS, can decrease the excretion of sodium in normal subjects and in patients with Addisons disease (3). Patients with autonomic insufficiency excrete sodium at supranormal rates during infusions of normal saline (4). In the present investigation, sodium excretion during infusion of saline and during the administration of a sodium-retaining steroid has been studied before andi after sympathetic blockade by guanethidine. The results of these studies provide additional evidence for a role of the SNS in sodium metabolism.

Relation between Urinary Hydroxyproline and Parathyroid Function

With the exception of small amounts in elastin, all the hydroxyproline (OHPr) in the body is found in collagen. Evidence has been presented that the urinary peptide-bound OHPr reflects the metabolism of collagen (2-5) except when the dietary intake of gelatin or collagen is excessive. Since a major body depot of collagen is the matrix of bone, it might be anticipated that under some conditions the rate of OHPr excretion would furnish an index of the turnover of bone matrix. Parathyroid hormone is known to increase bone resorption (6-11). Thus, changes in parathyroid function might be expected to be associated with changes in OHPr excretion. Recently, Klein and Curtiss (12) reported that urinary OHPr first decreased and then increased in rats given parathyroid extract (PTE). Bates, McGowen, and Talmage noted that PTE increased plasma peptide-bound OHPr in rats (13). An elevated urinary excretion of OHPr has been reported in patients with hyperparathyroidism (14-16). The present studies were carried out to examine further the relationship of parathyroid activity to OHPr excretion.

Depression of proximal tubular sodium reabsorption in the dog in response to renal beta adrenergic stimulation by isoproterenol

Water diuresis was produced in anesthetized hypophysectomized, cortisone-treated dogs by infusion of 2.5% dextrose. Alpha adrenergic blockade of the left kidney produced by infusion of phenoxybenzamine in the left renal artery was associated with a significantly (P < 0.05) greater rate of urine flow (V) and free water excretion (C(H2O)) in the left kidney than in the right despite similar glomerular filtration rates (GFR) (17 +/- 1.3 ml/min, left; 18 +/-0.9 ml/min, right). Sodium excretion (U(Na)V) was similar in the two kidneys (3 and 5 muEq/min). When beta adrenergic stimulation of the left kidney was superimposed on alpha blockade by the addition of isoproterenol to the left renal artery infusate, GFR remained unchanged and similar in the two kidneys, as V and C(H2O) increased significantly (P < 0.01) in the left kidney but not in the right. When isoproterenol was discontinued, V and C(H2O) returned towards control in the left kidney and remained unchanged in the right. The ratios of the left kidney to the right during control, isoproterenol, and postcontrol were 1.22, 1.65, and 1.35, respectively, for V and 1.36, 1.90, and 1.44, respectively, for C(H2O). Sodium excretion remained unchanged and similar in the two kidneys throughout the study. The results indicate that blockade of alpha adrenergic activity inhibits the increased proximal tubular sodium reabsorption which anesthesia induces in the dog. Beta adrenergic stimulation appears to decrease proximal tubular sodium reabsorption but does not prevent virtually complete reabsorption of the increased quantity of delivered sodium by the ascending limb of the loop of Henle and the distal tubule. These changes in sodium reabsorption presumably are not associated with changes in colloid osmotic pressure or hydrostatic pressure in the peritubular capillary inasmuch as cortical and non-cortical plasma flow, filtration fraction, and mean arterial pressure in the left kidney were unchanged. Thus, isoproterenol probably produced its effects through a direct action on the renal tubule, possibly through the mediation of the adenyl cyclase system.

Restoration of water diuresis in addisonian patients by expansion of the volume of extracellular fluid.

Although the inability of patients with Addisons disease to excrete a water load is well known, the nature of this defect remains obscure. The effects of changing glomerular filtration rate (GFR) and solute excretion (UosmV) on water excretion in patients with adrenal insufficiency have recently been described (1). While an increase in these two variables leads to an increase in the excretion of water, the improvement is very small compared with that seen with carbohydrate-active steroids. In healthy persons expansion of the volume of extracellular fluid may increase the rate of excretion of solute-free water (CH2o) (2, 3). In patients with Addisons disease, when replacement therapy is stopped, the increase in urinary sodium excretion leads to a depletion of body fluids, and continues despite this depletion. It is possible that depletion of the volume of extracellular fluid (ECF) could limit the rate at which water is excreted. These experiments were designed to explore the effects of contraction and expansion of the volume of ECF on water excretion in adrenal insufficiency.

Role of the sympathetic nervous system in the renal response to hemorrhage

In 12 studies, a femoral artery and vein of a donor dog treated with desoxycorticosterone were connected by tubing to a renal artery and vein of a recipient dog treated with desoxycorticosterone, and the kidney with its nerve supply intact was perfused at femoral arterial pressure. Infusion of normal saline, which contained albumin, from 2.7 to 3.1 g/100 ml, in the donor produced significant natriuresis in a kidney of the donor (from 112 to 532 muEq/min) and in the perfused kidney (from 60 to 301 muEq/min) of the recipient. Increased sodium excretion in the perfused kidney was associated with an increase in the clearances of inulin and para-aminohippurate (P < 0.01) and a decrease in hematocrit of perfusing blood (P < 0.01). Infusion was continued in the donor while recipient was bled 23 ml/kg, with a decrease in mean arterial pressure from 152 to 130 mm Hg. Sodium excretion in perfused kidney decreased from 301 to 142 muEq/min (P < 0.01), whereas sodium excretion in donor was unchanged (506 VS. 532 muEq/min; P > 0.3). Clearance of inulin by perfused kidney was not significantly affected by bleeding (26 +/-SE 2 VS. 25 +/-SE 2; P > 0.2), but the clearance of para-aminohippurate was decreased by bleeding (P < 0.01), so that filtration fraction increased. As the perfused kidney of the recipient dog continued to receive blood from the natriuretic donor dog when the recipient dog was bled, the decrease in sodium excretion that bleeding produced in the perfused kidney was presumably mediated by renal nerves. Thus, an increase in nervous stimuli to the kidney that is not sufficient to decrease glomerular filtration rate can increase the tubular reabsorption of sodium and thereby significantly decrease its excretion. This property of the sympathetic nervous system to affect tubular reabsorption of sodium suggests that an increase in sympathetic activity may constitute an important mechanism for the renal conservation of sodium when intravascular volume is contracted by hemorrhage or other cause.