Natriuresis induced by localized perfusion within the third cerebral ventricle of sheep.

Push-pull perfusion was performed at four different sites in the third cerebral ventricle of conscious sheep. The recovery of the infused solution was 75-90%, suggesting a localized change in the ionic composition and osmolality restricted to a relatively small area in the cerebrospinal fluid (CSF). Sodium and potassium excretion and urine flow were studied before, during, and after perfusion of 200, 150, and 100 mM Na-CSF. Localized perfusion in the anterior dorsal third ventricle (AD3V) of 200 mM Na-CSF caused an increase in sodium and potassium excretion, in urine flow, and a decrease in free water clearance. Perfusion of 200 mM Na-CSF at the other three perfusion sites, i.e., anterior ventral third ventricle, posterior dorsal third ventricle, and posterior ventral third ventricle, did not influence sodium excretion and urine flow. Perfusions with 150 and 100 mM Na-CSF did not cause any change in sodium, potassium excretion, or urine flow at any of the four perfusion sites. These results suggest that sensors sensitive to changes of sodium concentration are located close to the ventricular surface in the anterior dorsal part of the third cerebral ventricle. When stimulated with increased sodium concentration they will initiate increased sodium excretion.

Efferent role of ADH in CNS-induced natriuresis.

Ventriculocisternal perfusion (VCP) of artificial cerebrospinal fluid (CSF) was performed in pentobarbital-anesthetized dogs. Renal function was studied in protocols consisting of a 1-h experimental period in which the animals received either CSF with an elevated sodium concentration (300 mM, high Na) via VCP or antidiuretic hormone (ADH) intravenously, bracketed by 1-h control and recovery periods. High Na VCP caused an increase in plasma ADH measured by radioimmunoassay (to 176% of control) that coincided with a natriuresis (to 180% of control). In a second set of experiments, these changes in endogenous ADH were mimicked experimentally with intravenous infusions of synthetic ADH in animals receiving continuous VCP with normal sodium artificial CSF. The dose-response relationship between log ADH and urinary sodium excretion for the intravenous ADH experiments was not different from the relationship for those experiments in which ADH was elevated as a consequence of high Na VCP. These results suggest that ADH causes part, if not all, the natriuresis induced by high Na VCP.

Localization of the cerebroventricular receptors involved in CNS-induced natriuresis.

Ventriculocisternal perfusion (VCP) or localized "push-pull" perfusion (PPP) was performed in pentobarbital-anesthetized dogs. Renal function was studied in protocols consisting of a 1-h experimental period bracketed by 1-h control and recovery periods. The animals were perfused with artificial cerebral spinal fluid (CSF) throughout the protocol but the sodium concentration was elevated (300 mM, high Na) during the experimental period. In the first series of experiments, prior to VCP, petroleum jelly plugs were injected into either the ventral third ventricle (V3V) or other brain regions. When petroleum jelly plugs were injected into the V3V prior to VCP, they prevented perfusates from reaching this area, as determined by subsequent dye perfusion. These V3V plugs blocked the natriuresis and ADH response otherwise induced by high Na VCP. In the second series of experiments, the anterior portion of the V3V (AV3V) was perfused by means of PPP. In some of the PPP experiments a V3V plug was also injected to ensure restriction of the stimulus to the AV3V. PPP of the AV3V with high Na CSF at 50 microliter/min did not induce a natriuresis (either with or without a V3V plug). However, when the high Na CSF was perfused at a very high rate (100 microliter/min) and the stimulus was not restricted to the AV3V by a V3V plug, a natriuresis did occur. These results suggest that the ventricular surface where high Na CSF acts to cause natriuresis and increased ADH secretion is within the V3V region but not in the AV3V.

CNS-induced natriuresis and renal hemodynamics in conscious rats.

Sodium excretion was studied following experimental elevation of cerebrospinal fluid (CSF) sodium in heterozygous and homozygous (DI) Brattleboro rats given exogeneous antidiuretic hormone. Sodium excretion increased 4.5-fold in heterozygous and 3.5-fold in DI rats. The natriuresis in both groups was rapid in onset and occurred with a simultaneous kaliuresis. Blood pressure increased approximately 10 mmHg in the heterozygous but not in the DI rats. Accordingly, increased blood pressure may contribute to the natriuresis but is not the sole mechanism. Plasma renin concentration did not change in the DI rats during high Na CSF infusion, and chronic bilateral renal denervation did not abolish the natriuresis. Glomerular filtration rate increased during the high Na period in both the intact and renally denervated rats. These data provide evidence that a natriuretic mechanism exists that is not mediated by changes in antidiuretic hormone, renal nerve activity, mean arterial pressure, aldosterone, or angiotensin II, and thus may be due to another circulating substance or natriuretic hormone. This hormone may act totally or in part by increasing glomerular filtration rate.

Effect of parathyroid hormone on renin secretion.

The ability of parathyroid hormone (PTH) to increase renin secretion was investigated in pentobarbital-anesthetized dogs. An intravenous infusion of bovine PTH 1-34, at the dose of 0.028 microgram/kg-1 min-1 increased renin secretion by 149% (501 +/- 105 to 1249 +/- 309 ng hr-1 min-1); renin secretion returned to control values during the recovery period. In order to determine whether PTH acted directly on the kidney to increase renin secretion, PTH was infused into the right renal artery at doses of 0.0014 to 0.0028 microgram/kg-1 min-1 and renin secretion from the right kidney was compared to that from the left (control) kidney. Renin secretion from the right (PTH-infused) kidney was not greater than control values for that kidney or different from the renin secretory rate of the left (control) kidney. In contrast, the excretion rates of both phosphate and sodium from the right kidney were greater than control values and from the excretion rates of the left kidney. These data suggest that PTH, while acting directly on the kidney to increase phosphate and sodium excretion, does not elevate renin secretion by a direct renal action.

Osmoregulatory thirst in sheep is disrupted by ablation of the anterior wall of the optic recess.

Ablation of the organum vasculosum of the lamina terminalis (OVLT) and adjacent midline tissue in the anterior wall of the optic recess of the third ventricle resulted in greatly reduced water drinking to intracarotid infusion of hypertonic NaCl in sheep. Daily food and water intake and angiotensin II drinking were not consistently reduced by these lesions. Tissue in or close to the OVLT is probably involved in osmotically induced water-drinking.

Role of sodium concentration of the cerebrospinal fluid in the salt appetite of sheep.

The role of sodium concentration of the cerebrospinal fluid (CSF[Na]) in the initiation and/or satiation of Na appetite of Na-deplete or Na-replete sheep was investigated. Slow infusion (1 ml/h) into a lateral brain ventricle of an artificial sheep CSF solution was begun 0-60 min prior to and continued until the end of the Na access period (30-120 min). In Na-deficient sheep, increasing CSF[Na] caused a decrease in Na intake. In both Na-deficient and Na-replete sheep, decreasing CSF[Na] caused an increase in Na intake. The appetite was observed within 25 min of beginning infusion, which represents the most rapid induction of Na appetite yet observed. In Na-replete sheep, the appetite induced by decreasing CSF[Na] was predominantly for Na-containing solutions. A decrease in CSF[Na] of only 4-6 mmol/l was sufficient to induce Na appetite. The results derived by use of different Na, saccharide, or urea containing artificial CSF solutions suggest that there are sensors within the neuropil that respond to change of [Na] and influence salt appetite. They can be accessed by inducing change in [Na] of cerebroventricular CSF.

Multiple short-term effects of lead on the renin-angiotensin system.

We previously demonstrated that lead (3 mg/kg iv) sharply raises PRA in dogs. In the present study, the short-term effects of the same dose of lead on renin secretion, hepatic removal of renin, and arterial AII levels were measured in anesthetized dogs. Despite large increases in PRA in all nine lead-treated dogs, renin secretion increased in only three out of nine lead-treated animals (those with the lowest baseline renin secretion). Hepatic extraction of renin was eliminated by lead, and so total hepatic removal of renin became zero by 2 or 3 hr after lead administration. Finally, despite large increases in PRA, AII levels did not rise after lead. The linear relationship of AII to PRA seen in animals not treated with lead was changed, so that after lead, AII levels were disproportionately low for the corresponding level of PRA. It is concluded that lead may increase renin secretion in animals otherwise unstimulated to secrete but that the major mechanism for the short-term rise in PRA after lead is elimination of hepatic removal of renin; further, lead prevents AII from rising proportionately with PRA, presumably by inhibiting angiotensin-converting enzyme.

Dose-response relation of CSF sodium and renal sodium excretion, and its absence in homozygous Brattleboro rats.

Constant intraventricular infusion (3.3--6.6 microliters/min) of artificial cerebrospinal fluid with sodium concentrations of 100, 150, 200, 250, 300, and 350 mM produced a linear dose-related change in renal sodium excretion in conscious, unrestrained Sprague-Dawley rats. The periventricular receptors stimulated were able to evoke substantial changes in body sodium balance; the 350 mM Na CSF produced an estimated 14% deficit in the content of Na in the extracellular fluid over a 5-hour infusion period. This is the first demonstration of such a dose-response relation over a wide range of CSF Na concentration (above and below normal) in conscious animals. Both the dose-response relation, and the magnitude of the effects, suggests an important physiologic role for this control mechanism. The natriuresis in response to 300 mM sodium infusion was identical in Long-Evans Brattleboro rats heterozygous for diabetes insipidus (DI), and in Sprague-Dawley rats, but was completely absent in homozygous animals. Although the experimental methods (conscious unrestrained rats) precluded simultaneous evaluation of efferent pathways other than antidiuretic hormone (ADH), the evidence from the DI rats suggests that ADH may be the efferent pathway for the response.

Nonpressor mechanisms in CNS-induced natriuresis.

Ventriculocisternal perfusion was performed in pentobarbital-anesthetized dogs. Perfusion of high Na (300 mM NaCl) artificial cerebrospinal fluid (CSF) (E) for 2 h was preceded by 2 h of control (C) and was followed by 2 h of recovery (R) during which normal (150 mM NaCl) artificial CSF was perfused. A time-control group was perfused with normal artificial CSF throughout C, E, and R. High sodium perfusion resulted in a marked natriuresis in each of nine animals and suppression of plasma renin activity. Theere were no simultaneous changes in mean arterial pressure, glomerular filtration rate, or renal plasma flow. Sodium excretion and plasma renin activity showed a slight gradual rise in the time-control group, but no significant differences were observed between the C and E periods; sodium excretion and plasma renin activity were similar in the high Na and time-control groups during C and R, but significantly different during E. It is concluded that when CSF sodium is elevated by perfusing artificial CSF, the resulting natriuresis and suppression of plasma renin activity are not caused by hemodynamic changes.

Effect of parathyroid hormone on plasma renin activity and sodium excretion.

The interaction between parathyroid hormone (PTH) and the renin-angiotensin system was evaluated in pentobarbital-anesthetized dogs. An intravenous infusion of bovine PTH (1-34) for 1 h was accompanied by a 57% increase (13.7-21.6 ng/ml per h) in plasma renin activity (PRA) which returned toward control levels during the recovery period. Sodium and phosphate excretion also increased. Second the endogenous secretion of PTH was stimulated by infusion of citrate into the blood supply of the thyroparathyroid glands to determine if the stimulatory effect on renin occurred with endogenous secretion of PTH. Phosphate excretion increased, which confirmed PTH secretion. There was a significant rise (57%) in both PRA (6.1-9.8 ng/ml per h) and sodium excretion, the magnitude of the sodium response modulating the increase in PRA. Blood pressure remained constant. In a third set of experiments, thyrocalcitonin was infused intravenously and had no effect on PRA. These data indicate that both exogenous and endogenous PTH can elevate PRA and increase sodium excretion. The sodium effect is probably the result of inhibition of proximal sodium reabsorption by PTH. The mechanism by which PTH elevates PRA is not known.

Psychosocial stimuli and human plasma renin activity.

The effects of several types of acute psychosocial stimuli on plasma renin activity (PRA) were studied in normotensive healthy subjects. Puzzle-solving produced an increase in blood pressure but no significant change in PRA, although two of seven subjects did respond with large increases in PRA. Watching a disturbing movie also raised blood pressure, but did not alter PRA. In contrast, a combination of novelty, fear, and/or anticipation did constitute a significant stimulus for renin secretion; this was evidenced by the fact that naive subjects (who were not told in advance what to expect) had significantly higher PRAs on the first day of the 2-day puzzle-solving study. PRA on this day correlated strongly with anxiety proneness, as did the decrease from day 1 to day 2. We conclude that meaningful psychosocial stimuli can enhance renin secretion in susceptible individuals.