Effects of the renin inhibitor A-64662 in monkeys and rats with varying baseline plasma renin activity.

The efficacy of the potent, primate selective renin inhibitor A-64662 was studied in monkeys and rats with varying baseline plasma renin activity (PRA) to elucidate the relationship between PRA and the hypotensive response induced by this compound. The effect of a single bolus of vehicle or A-64662 at 0.001, 0.01, 0.1, 1.0, and 10.0 mg/kg i.v. was compared in 30 normal and 30 salt-depleted, anesthetized monkeys (n = 5/dose). Baseline mean arterial pressure (MAP) was similar among all groups, but baseline PRA was elevated in salt-depleted monkeys. A-64662 induced a comparable dose-related fall in MAP, affecting the magnitude and duration of action, accompanied by inhibition of PRA, the duration of which was dose-related in both the normal and salt-depleted groups. However, the minimum effective doses required to reduce MAP by approximately 10% were 0.01 mg/kg for the salt-depleted monkeys and 0.1 mg/kg for the normal monkeys. In a second study, three consecutive boluses of vehicle or A-64662 at 0.1, 1.0, and 10.0 mg/kg were administered to anephric monkeys, human renin-infused anephric monkeys, and normal monkeys (n = 4/group). A dose of 0.1 mg/kg was ineffective, but the 1.0 mg/kg dose lowered MAP by 11 +/- 3% (mean +/- SE) in the anephric monkeys. The infusion of renin into anephric monkeys restored the efficacy of A-64662 at the 0.1 and 1.0 mg/kg doses to responses comparable to those of the normal monkeys. A-64662 at 10.0 mg/kg caused a similar fall in MAP of 50 to 60% in anephric, renin-infused anephric, and normal monkeys in the absence of detectable PRA.(ABSTRACT TRUNCATED AT 250 WORDS)

Sodium chloride depletion in a cat with fistulated meningomyelocele.

Decreased serum and CSF chloride concentrations were documented in a 5-year-old Manx cat referred for evaluation of anorexia. Inadequate chloride intake coupled with chloride loss through a fistulated meningomyelocele probably caused chloride deficiency. The inciting cause of anorexia was not determined. The cat was treated with 0.9% NaCl solution. Normal serum and CSF chloride concentrations were restored. Lumbar myelography was performed to delineate the meningocutaneous tract, which then was dissected surgically and was ligated. The cat's body attempted to maintain normal CSF chloride concentration even though the serum chloride concentration was decreased markedly. Calculations made on the basis of rate of CSF production, CSF chloride concentration, and duration of anorexia provided supportive evidence for an active transport system for chloride from plasma to CSF.

Electrophysiology of newt skin: responses to salt-depletion, aldosterone, arginine vasotocin and epinephrine.

1. Newts (Taricha granulosa), salt-depleted by 3 weeks' immersion in distilled water, showed significantly higher in vitro integumental short-circuit current (SCC) than control newts immersed in dilute saline. 2. Isolated, in vitro preparations of newt skin responded to aldosterone (10(-6) M), arginine vasotocin (10(-9)-10(-8) M), and epinephrine (10(-7)-10(-5) M) by increasing SCC. 3. The hormonal response of the skin of this salamandrid urodele, as judged from in vitro (Ussing chamber) measurements, is similar to that seen in classical anuran ("frog skin") preparations.

An examination of chronic angiotensin-converting enzyme inhibition in the rat.

We have examined the systemic and renal effects of 2 weeks' administration of angiotensin-converting enzyme inhibition (CEI) to both normal and chronic NaCl-depleted Munich-Wistar rats and focused particularly on the factors contributing to the significant hypotension observed during surgery and anesthesia and the response of renal glomerular hemodynamics under these conditions. At renal micropuncture, mean arterial pressure was decreased in rats receiving CEI on normal and NaCl-depleted diets (72 +/- 5 and 78 +/- 6 mm Hg, p less than 0.01) but nephron filtration rate (sngfr) was well maintained since plasma flow was not altered and glomerular capillary pressure only slightly decreased. Negative Na+ balance in NaCl-depleted CEI rats correlated with decreased awake blood pressures. Under surgery, plasma norepinephrine and epinephrine were not increased in CEI rats in spite of hypotension, and diminished adrenergic responses may contribute to systemic and renal effects observed. Nephron plasma flow and sngfr are remarkably well preserved during CEI in spite of hypotension due to marked afferent arteriolar dilation.

Circadian wheel-running activity of rats under schedules of limited daily access to salt.

Schedules of limited daily access to food result in 'anticipatory' activity preceding each daily feeding. It is well-established that such food-anticipatory activity depends on a food-entrainable circadian timing mechanism. In the present study, we sought to extend the generality of these results by maintaining rats in running wheels under schedules which provided access to salt solutions or to salty food for 2 hr each day. The animals were subjected to dietary, pharmacological and surgical treatments that promote salt appetite. However, we found no evidence for daily salt-anticipatory wheel running activity in any condition.

Multiple factors in the satiation of salt appetite.

There is evidence in the literature that has been taken to show that, unlike hunger and thirst, salt appetite cannot be satiated in the absence of salt taste stimulation. The present study showed that repletion of body sodium in the absence of taste stimulation, that is, by gavage, can diminish subsequent saline intake. The satiating effects of gavage versus drinking of saline were studied at various intervals after repletion. For the first few hours, gastric loading was constantly less satiating than was drinking. But as the interval between gavage and testing was lengthened beyond 4-8 hr, the satiating effect began to increase until by 16 hr it was equal to that of drinking. The specificity of the satiating effect of saline gavage as a function of time between treatment and testing was also studied. There appeared to be a transient nonspecific blocking effect of solutes on solute intake which had a duration of less than 30 min. The satiating effect of saline gavage became specific after that time. The experiment suggests that there are multiple factors involved in the satiation of salt appetite--a taste factor, a short-latency post ingestional factor, and a long-latency postingestional factor.

Salt hunger in the rhesus monkey.

Five rhesus monkeys (Macaca mulatta) were placed on a low-sodium diet and given injections of furosemide in order to promote sodium loss. The results indicated that these methods elicit a substantial and specific salt hunger. Issues surrounding salt hunger are discussed.

Sodium depletion enhances salt palatability in rats.

Sterotyped fixed action patterns (FAPs) are elicited in rats by oral infusions of taste solutions. These taste-elicited FAPs can be classified as either ingestive or aversive. They reflect the palatability of the taste and can be modified by learning and by the physiological state of the animal. These studies demonstrated that when the physiological state of the rat is altered by sodium depletion, the pattern of FAPs elicited by oral infusions of 0.5 M NaCl shifts from a mixture of ingestive and aversive components (while sodium replete) to exclusively ingestive ones (while sodium deplete). This shift in taste reactivity occurred the first time the rats were made sodium deplete. A similar shift was not observed to accompany infusions of 0.01 M HCl, a taste solution that also elicited mixed ingestive and aversive FAPs. This result suggests that the shift in response to NaCl is not due to a general change in ingestive bias or to a general taste deficit. On the basis of the change in FAPs, it is concluded that the palatability of highly concentrated salt solutions increases in sodium-deplete rats. Such a shift in salt palatability may be instrumental in directing the appetitive behavior of the animal.

Saline depletion, pre-renal failure and acute renal failure.

The wide range of diseases that can influence the kidney, either directly or indirectly, all influence water and electrolyte balances according to established 'rules'. There is great scope for helping patients by understanding these rules, and also a great potential to do harm by ignoring them. Careful consideration of simple routine data, and an awareness of the limitations of some indexes and ratios in common use, will usually result in an adequate provisional classification of the patient. This can be used to plan therapeutic trials designed to correct metabolic and electrolytic disturbances, and to organize diagnostic procedures that will establish the cause of any intrinsic renal diseases or the cause of obstructions. Earlier and more frequent use of dialysis and related techniques in management is recommended, as is greater attention to the control of blood glucose, nutrition and electrolyte balance. A general recommendation is that corrections of many deficits should not be excessively rapid.

Inner medullary hemodynamics in chronic salt-depleted dogs.

The effects of chronic salt depletion on medullary hemodynamics remain unknown. In the present study, sodium excretion, renal hemodynamics including papillary plasma flow, measured by the albumin-accumulation technique, and papillary tissue solute content were determined during hydropenia in 13 anesthetized sodium-replete and 10 sodium-depleted dogs. Salt depletion induced a significant rise in plasma renin activity and aldosterone without potassium depletion. Mean arterial pressure, GFR, and renal blood flow were similar in sodium-depleted and sodium-replete dogs. Despite a similar distribution of cortical blood flow (measured by the microsphere method) in the two groups, papillary plasma flow was markedly reduced in sodium-depleted dogs (8.8 +/- 1.7 vs. 22.8 +/- 1.9 ml X min-1 X 100 g-1 in sodium-replete dogs), associated with a significant decrease in renal sodium excretion. Furthermore, papillary osmolality and sodium concentration were significantly greater in sodium-depleted dogs. Ultrastructure examination revealed smooth muscle cells surrounding the efferent arterioles and pericytes with contractile potential encircling descending vasa recta. These results suggest that included in the complex hemodynamic adjustment to chronic sodium depletion is a significant reduction in inner medullary blood flow that may be important in maintaining enhanced papillary solute concentration. In addition, the anatomy of the medullary vasculature is compatible with regional regulation of medullary blood flow.

Relationship of growth depression from salt deficiency and biotin intake to foot pad dermatitis of turkey poults.

Foot pad lesions in turkey poults were visually and microscopically examined in two experiments. Poults with normal growth had a high incidence of foot pad dermatitis. Histology of the foot pads indicated a biotin deficiency. Foot pad dermatitis was infrequent when growth was reduced as a result of lowered dietary salt intake. No histologic evidence of biotin deficiency was found in foot pads of poults fed a diet containing no supplemental salt.

No effect of intrarenal converting enzyme inhibition on canine renal blood flow.

Captopril and teprotide were administered intra-arterially to the kidney and intravenously to inhibit intrarenal and extrarenal converting enzyme (CE), respectively. Captopril was infused at 0.4, 0.8, and 1.6 micrograms . kg-1 . min-1 intra-arterially, and teprotide was given at 0.4 and 0.8 micrograms . kg-1 . min-1 intra-arterially in salt-replete dogs (group 1). Both agents were also given intravenously in the dose of 0.2 mg/kg, known to cause maximal extrarenal CE inhibition. The intra-arterial infusions of the inhibitors had no effect on renal hemodynamics but caused a graded degree of intrarenal CE inhibition. A lesser degree of extrarenal CE inhibition was seen after captopril in these doses. Intravenous administration of captopril and teprotide inhibited extrarenal CE, but only captopril increased renal blood flow (13%). When teprotide was given in a higher dose (group 3, 1.02 mg/kg), it too increased renal blood flow. In salt-deplete dogs (group 2), captopril infused intra-arterially caused a degree of intrarenal CE inhibition comparable with that in the salt-replete dogs but again produced little or no renal hemodynamic changes. When given intravenously in this group, captopril inhibited extrarenal EE and elicited a greater increase in renal blood flow (36%) than in the group 1 dogs. These results indicate that in conscious dogs renal vasodilatation is associated with extrarenal, but not intrarenal, CE inhibition.

[Thyroid weights and iodized salt prophylaxis: a comparative study from autopsy material from the Institute of Pathology, University of Zurich]. / Schilddrüsengewichte und Jodsalzprophylaxe. Vergleichende Untersuchung am Sektionsgut des Instituts für Pathologic der Universität Zürich.

Based on autopsy material from the Institute of Pathology, University of Zürich, thyroid weights and goiter incidence were investigated and the results correlated with goiter prophylaxis. Autopsy protocols of the years 1949/50 adn 1978/79 were reviewed for thyroid weights as well as for age and sex of patients. Average thyroid weights and goiter incidence were determined separately for both sexes and for different age groups. The values for both periods (1949/50) and 1978/79) were compared and related to results reported in the literature. Thirty years ago the mean thyroid weights were very high, although as an effect of goiter prophylaxis with iodized salt, introduced in 1923, the thyroids of younger adults were significantly lighter than those of older groups. 30 years later the thyroids were only half the weight of those in the years 1949/50. Goiter incidence decreased to the same degree. In addition, some preexisting goiters were found to have decreased in size within the 30 year span. The average thyroid weights of adults up to 40 years of age are now largely the same as in regions without endemic goiter. The few remaining goiters may be explained by a still insufficient iodination of table salt. However, other pathogenic factors, e.g. disturbances of hormone synthesis, must also be considered.

Effect of sodium chloride deficiency on basal metabolism in broiler chickens.

1. Male broiler chickens were given a sodium chloride-deficient or NaCl-adequate diet from 7 to 21 d of age in Expt 1 and 28 to 56 d of age in Expt 2. 2. NaCl-deficient chickens had a markedly poorer growth and food conversion efficiency than those given the NaCl-adequate diet. 3. NaCl deficiency was associated with an increase in basal metabolic rate and increases in oxygen consumption, heat production and respiratory quotients were also noted. The glycogen content of chicken livers was also higher. 4. MEasurements of acid-base balance were found to be changed in NaCl-deficient chickens. Values for pH and bicarbonate content in blood plasma were lowered. 5. NaCl deficiency increased the packed cell volume and thyroxine level in blood plasma. Sodium and chloride contents in blood were lowered. 6. Results are discussed in relation to the decreased food conversion in NaCl-deficient chickens.

Salt, diuretics and pregnancy.

This article reviews the homeostasis of water and salt in normal and pre-eclamptic pregnancy. During pre-eclampsia there is a decrease in circulating plasma volume, which the administration of diuretics reduces still further. There is no proof that diuretics have a beneficial effect on prevention or treatment of toxemia of pregnancy. They should thus be regarded as contraindicated, except in cases of cardiac insufficiency and certain renal diseases.

Renin-angiotensin system inhibition in conscious sodium-depleted dogs. Effects on systemic and coronary hemodynamics.

The role of the renin-angiotensin system in the regulation of the systemic and coronary circulations during sodium depletion was studied in conscious normotensive dogs by i.v. administration of teprotide (0.5 mg/kg), an angiotensin-converting enzyme inhibitor, and saralasin (0.05-5 mug/kg per min), an angiotensin-receptor antagonist. Sodium depletion was produced by administering a low sodium diet and furosemide for 5 days. Administration of both teprotide and saralasin lowered systemic arterial blood pressure and total peripheral vascular resistance. Simultaneously, cardiac output increased, but left ventricular end-diastolic pressure, dP/dt, and dP/dt/P did not change significantly. Furthermore, both agents reduced diastolic coronary vascular resistance and increased coronary blood flow, but did not affect myocardial oxygen consumption, left ventricular work, or myocardial efficiency. These systemic and coronary vasodilator effects of teprotide and saralasin, however, were not observed in normal dogs on a regular sodium diet; in this group, the only effect noted was a slight increase in arterial pressure during saralasin infusion. Arterial plasma concentration of norepinephrine did not differ between normal and sodiumdepleted dogs, nor did it change significantly after teprotide administration. These results suggest that, during salt depletion, angiotensin II exerts an active vasoconstrictor action on the systemic and coronary vessels, but has no significant effects on myocardial contractility or energetics. It also appears likely that the increase in cardiac output observed in sodiumdepleted dogs after angiotensin inhibition was caused, at least in part, by the decrease in systemic arterial pressure.