Sodium-depleted Subjects Research Articles

Effects of muscimol in the nucleus accumbens shell on salt appetite and sucrose intake: a microstructural study with a comment on the sensitization of salt intake.

Previous work has demonstrated that injections of the γ-aminobutyric acidA (GABAA) agonist muscimol into the nucleus accumbens shell (AcbSh) induce pronounced increases in the intake of solid foods and sucrose solutions, but do not potentiate water intake. In order to clarify the range of situations in which inactivation of the AcbSh potentiates ingestive behavior, we examined the effects of muscimol injections on the intake of a 3% NaCl solution in sodium-depleted animals. Although sodium-depleted subjects avidly consumed this solution, muscimol injections had no effect either on the volume consumed or on a variety of microstructural licking parameters. In contrast, in these same animals, muscimol injections significantly increased licking of a 10% sucrose solution. These results suggest that inactivation of the AcbSh may selectively increase the intake of foods, but not that of other homeostatically relevant ingestates. Examination of microstructural parameters suggested that the effect of muscimol on sucrose intake was not mediated by alterations in the "palatability" of the sucrose solution. We also observed that sodium-depleted subjects displayed significantly larger salt intakes after their second experience with sodium depletion than their first, and microstructural analysis in this case indicated that this sensitization effect was produced in a manner consistent with the animals showing increased "hedonic responsiveness" to the salt solution.

Renal effects of the cyclooxygenase-inhibiting nitric oxide donator AZD3582 compared with rofecoxib and naproxen during normal and low sodium intake

Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase (COX) and can thereby reduce renal function, especially with respect to solute excretion and renal perfusion. AZD3582 [4-(nitrooxy)butyl-(2S)-2-(6-methoxy-2-naphthyl)propanoate] is a COX-inhibiting nitric oxide donator. Donation of nitric oxide by AZD3582 could preserve blood flow and thereby counteract the deleterious effects of COX inhibition in the gastrointestinal tract and possibly in other organ systems, including the kidney. The aim of this single-dose study was to assess the hypothesis that AZD3582 would not adversely affect renal function compared with NSAIDs. In a parallel, randomized, double-blind fashion, a total of 60 healthy subjects (age range, 20-44 years) received 2 single doses of 750 mg AZD3582, 1500 mg AZD3582, 50 mg rofecoxib, 500 mg naproxen, or placebo (n = 12 per group). The first dose was given after a 5-day normal-sodium diet (150 mmol/d), and the second was given after a consecutive 3-day low-sodium diet (10 mmol/d). Urinary sodium excretion during normal sodium intake and glomerular filtration rate (GFR) (assessed by iohexol clearance) during sodium depletion were the primary variables measured. Urinary sodium excretion was reduced in all active treatment groups (maximal reduction of approximately 11 mmol/h during normal sodium intake, P < .05 versus placebo for all groups). GFR was also reduced in all active treatment groups. In sodium-depleted subjects, the mean (SD) maximal reduction in GFR during 0 to 6 hours for 750 mg AZD3582, 1500 mg AZD3582, 50 mg rofecoxib, and 500 mg naproxen was 28.1 mL/min (13.5 mL/min), 33.7 mL/min (23.3 mL/min), 25.2 mL/min (29.2 mL/min), and 41.7 mL/min (30.7 mL/min), respectively, with a statistically significant difference between 500 mg naproxen and placebo. Relative changes in sodium excretion and GFR were similar during normal sodium intake and sodium depletion during active treatment. The renal effects of 750 mg and 1500 mg AZD3582 were similar to those of 500 mg naproxen and 50 mg rofecoxib. Thus the potential for nitric oxide donation to create a renal-sparing agent was not found for AZD3582.

Renin Angiotensin System Antagonists and Anesthesia

R enin angiotensin system (RAS) antagonists, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin II receptor antagonists are increasingly used to treat cardiovascular and other diseases (1–6). These treatments induce a blockade of the RAS that may affect hemodynamics during anesthesia and surgery. In 1978, Miller et al. (7) reported that the RAS is involved in maintaining normal blood pressure during anesthesia. Although anesthesia is not invariably associated with a deleterious hemodynamic event in RAS-blocked patients (8–10), hemodynamic instability, described as unexpected episodes of hypotension, have been reported (11–13). Otherwise, stresses such as surgery or hypotension stimulate the generation of angiotensin II, which induces vasoconstriction (14) to maintain blood pressure but reduces blood flow to organs such as the kidneys and bowels. Accordingly, an angiotensin II-induced reduction in blood flow may contribute to acute renal failure (15) and splanchnic ischemia (16), which are obvious factors in postoperative morbidity (17). RAS blockade with ACE inhibitors decreases some consequences of the stress response on the regional circulation (9,18,19), which may then contribute to body protection. Much of the information regarding the physiology and pathophysiology of the RAS during anesthesia and surgery is based on the effects of ACE inhibitors. Because ACE inhibitors probably act mostly by blocking the RAS, similar effects should be obtained from angiotensin (AT) receptor antagonists. RAS antagonist pharmacology may help us to understand the hemodynamic risk of anesthesia in RAS-blocked patients, to identify predisposing factors, and to determine the potential benefit of RAS antagonists during anesthesia and surgery. Physiology of the RAS Generation of Angiotensin II

Additive Effects of Captopril and Losartan on Blood Pressure in Mildly Sodium-Depleted Normotensives

The lowering of the mean blood pressure (MBP) by a combination of losartan 50mg/captopril 50mg and by, respectively, losartan 50mg and 100mg and Captopril 50mg and 100mg was studied in 10 sodium-depleted normal subjects. A double-blind, randomised, 5-way crossover study design was followed. To induce the mild sodium depletion, each subject took 40mg furosemide orally 12 hours preceding each study session. On each study day the subjects were placed in a semirecumbent position and the MBP and heart rate were monitored at defined intervals over the 8 hours following the administration of the antihypertensive drug. The difference between Captopril 100mg and the combination regimens did not reach statistical significance. The combination of losartan 50mg/captopril 50mg caused a significantly greater maximum baseline-subtracted fall in MBP at 2 hours than did the 50 or 100mg losartan at 6 hours (p < 0.05). In addition, the area under the concentration-time curve from 1 to 8 hours (AUC1–8) for the fall in MBP with the combination was significantly larger than that with the losartan-only regimens.

Pharmacological Demonstration of the Additive Effects of Angiotensin-Converting Enzyme Inhibition and Angiotensin II Antagonism in Sodium Depleted Healthy Subjects

A blockade of the hemodynamic and tissue effects of angiotensin II (Ang II) more complete than that presently achieved with usual daily doses of angiotensin converting enzyme (ACE) inhibitors or type 1 Ang II receptor antagonists has potential advantages and risks. Therefore, it is worthwhile to investigate the biological and the hemodynamic effects of the simultaneous blockade of the renin-angiotensin system (RAS) at the two sites where it can be currently achieved, ACE and type 1 Ang II receptors. To investigate this issue, 2 double-blind randomized crossover studies were performed in a model of mild sodium depletion in normotensive volunteers. They ingested single oral doses of captopril 50 mg, losartan 50 mg, their combination or matched placebos, and in a second study, single oral doses of enalapril 10 mg, enalapril 20 mg and the combination of losartan 50 mg with enalapril 10 mg. The combination captopril 50 mg and losartan 50 mg had additive effects on blood pressure fall and renin release in sodium-depleted normotensive subjects. When compared to enalapril 10 mg and the doubling of its dose, the combination of losartan 50 mg and enalapril 10 mg significantly increased both the area under the time curve of mean blood pressure fall and plasma active renin levels. It did not further decrease plasma aldosterone levels. The conclusion is that a more complete blockade of the RAS can be achieved by concomitant administration of an type 1 Ang 11 receptor antagonist and an ACE inhibitor.

147. Effects of the renin inhibitor SR 43845 on arterial pressure and the renin-angiotensin system in sodium-depleted normal subjects

147. Effects of the renin inhibitor SR 43845 on arterial pressure and the renin-angiotensin system in sodium-depleted normal subjects

147. Effects of the renin inhibitor SR 43845 on arterial pressure and the renin-angiotensin system in sodium-depleted normal subjects

147. Effects of the renin inhibitor SR 43845 on arterial pressure and the renin-angiotensin system in sodium-depleted normal subjects

Selective peripheral dopamine-1 receptor stimulation. Differential responses to sodium loading and depletion in humans.

Dopamine-1 (DA1) receptors in the renal tubules may be involved in the regulation of sodium homeostasis. To test this hypothesis, fenoldopam, a selective DA1 agonist, was infused at 0.05 microgram/kg/min i.v. in 16 normal male subjects in metabolic balance at 300 or 10 meq sodium. Renal function studies were performed by standard p-aminohippurate, inulin, and lithium clearances for three periods: 1) precontrol (2 hours), 2) experimental (3 hours), and 3) postcontrol (2 hours). DA1 receptor stimulation in sodium-loaded individuals increased the following parameters during the experimental period: urine flow rate, from 12.5 +/- 0.4 to 15.5 +/- 0.5 ml/min (p less than 0.05); urinary sodium excretion, from 309 +/- 12 to 489 +/- 18 mu eq/min (p less than 0.001); renal plasma flow, from 631 +/- 19 to 717 +/- 21 ml/min (p less than 0.005); fractional sodium excretion, from 2.2 +/- 0.1% to 3.4 +/- 0.1% (p less than 0.001); fractional lithium excretion, from 26.2 +/- 0.7% to 32.1 +/- 0.8% (p less than 0.005); and distal sodium load, from 10.7 +/- 0.4 to 13.8 +/- 0.5 ml/min (p less than 0.05). The increase in fractional sodium excretion was greater than that of fractional lithium excretion (p less than 0.0001). Distal sodium reabsorption decreased from 78.3 +/- 0.8% to 73.2 +/- 1.1% but the change was not statistically significant. In contrast, sodium-depleted subjects exhibited no significant changes except in renal plasma flow, which rose from 550 +/- 13 to 625 +/- 17 ml/min (p less than 0.0001). Glomerular filtration rate remained unchanged through the entire study. These results indicate that diuretic and natriuretic responses are mediated by DA1 receptors at both proximal and distal tubular sites. Attenuation of the DA1 natriuretic response during sodium depletion suggests a direct inhibition of cellular DA1 mechanisms in the renal tubule or recruitment of nondopaminergic compensatory homeostatic mechanisms within the kidney.

Effects of incremental low-dose infusions of atrial natriuretic factor (ANF) on plasma aldosterone and renin activity in sodium-depleted subjects

Journal Article Effects of incremental low-dose infusions of atrial natriuretic factor (ANF) on plasma aldosterone and renin activity in sodium-depleted subjects Get access S Kleiner, S Kleiner Abt. Endokrinologie, Medizinische Klinik und Poliklinik, Klinikum Steglitz, Freie Universität Berlin Search for other works by this author on: Oxford Academic Google Scholar V Bähr, V Bähr Abt. Endokrinologie, Medizinische Klinik und Poliklinik, Klinikum Steglitz, Freie Universität Berlin Search for other works by this author on: Oxford Academic Google Scholar W Oelkers W Oelkers Abt. Endokrinologie, Medizinische Klinik und Poliklinik, Klinikum Steglitz, Freie Universität Berlin Search for other works by this author on: Oxford Academic Google Scholar Acta Endocrinologica (Norway), Volume 117, Issue 4_Supplement, Apr 1988, Pages S161–S162, https://doi.org/10.1530/acta.0.117S161 Published: 01 April 1988

Converting Enzyme Inhibitors in the Treatment of Hypertension

The renin-angiotensin system has a wide range of physiological actions, and thus interference with the system has attractive therapeutic potential. The orally active angiotensin converting enzyme (ACE) inhibitors have so far been the most successful drugs in this area. They lower arterial pressure both in renovascular and essential hypertension, and their effects are enhanced by concomitant diuretic therapy or dietary salt restriction. Since, in renovascular hypertension, the affected kidney depends on enhanced local generation of angiotensin II to help preserve its function, the circulation and excretory capacity of this kidney may be compromised with ACE inhibition. ACE inhibitors can improve exercise tolerance and diminish cardiac ventricular arrhythmias in patients with heart failure. Because these drugs lower plasma aldosterone, they tend to correct potassium deficiency and hypokalemia, which may have been induced by diuretic treatment. Hypotension can occur with the first dose of ACE inhibitor, especially in sodium-depleted subjects; in patients on prior antihypertensive therapy, particularly if this includes a diuretic; and in the elderly. Not all of the actions of ACE inhibitors are necessarily due to lowering of plasma angiotensin II: accumulation of kinins may be responsible for some of the effects and side effects. Common to all ACE inhibitors are occasional rashes, cough, and, more rarely, angioedema. Apparently peculiar to captopril, and less often seen with the lower doses now employed, are taste disturbance, proteinuria, and marrow depression. ACE inhibitors, should not be used in pregnant women.

Effect of exogenous vasopressin on vasopressin release.

To characterize the influence of extracellular volume status on vasopressin pharmacokinetics, eleven young (aged 19-31 yr) and four old (aged 62-80 yr) subjects received bolus injections of 1 mU/kg Pitressin or synthetic arginine vasopressin following 6 days of sodium depletion (10 meq Na/day) or sodium loading (250 meq Na/day). In six young subjects the rapid decline in plasma vasopressin (pAVP) following the initial peak was interrupted by a second peak 5-30 pg/ml in magnitude 7.5-20 min after injection. In four of these subjects the second peak was larger following sodium depletion as compared with sodium loading. In the elderly a small (4 pg/ml) second peak was present in one sodium-depleted subject. Of five sodium-depleted subjects with central diabetes insipidus, none showed a secondary rise in pAVP. These results indicate that exogenous vasopressin may stimulate the release of endogenous AVP, an effect that appears to be enhanced by sodium depletion and is virtually absent in the elderly. There was no effect of age, volume status, or diabetes insipidus on AVP pharmacokinetics.

Effect of renin-angiotensin system on limb circulation in normal subjects.

It is not known whether the renin-angiotensin-aldosterone (RAA) system contributes to the regulation of the limb circulation in normal human beings. Accordingly, the effect of the angiotensin converting-enzyme inhibitor, captopril, on forearm vascular resistance (FVR) and forearm venous volume (FVV) was studied in nine normal subjects during states of both sodium loading and sodium depletion. All subjects were studied in the supine position and during 60 degrees head-up tilt. By analysis of variance, the combined intervention of sodium depletion and converting-enzyme inhibition was responsible for a decrease in both FVR and mean blood pressure (BP). In sodium-depleted subjects, converting-enzyme inhibition decreased supine mean BP 7.0% and supine FVR 22.8% but did not change FVV. Neither the fall in BP nor the fall in FVR, however, was significantly augmented by tilting from a supine to upright posture. In sodium-loaded subjects, captopril did not alter BP, FVR, or FVV in recumbent or upright positions. Therefore, the RAA system contributes to the maintenance of blood pressure and limb vascular resistance only in sodium-depleted subjects. Limb venous capacitance in normal subjects is not regulated by the RAA system.

Effects of Prostaglandin Synthesis Inhibition on Blood Pressure and Humoral Factors in Exercising, Sodium-deplete Normal Man

A double-blind placebo-controlled study was carried out in 10 sodium-deplete normal men to determine whether prostaglandin synthesis inhibition (PG-inhibition) by indomethacin (150 mg daily for three days plus an additional 50 mg on the morning of the active experiments) affected blood pressure and humoral factors at exercise. Urinary sodium excretion during placebo averaged 39 mEq/24 h. Independent of the level of physical activity, PG-inhibition increased (P less than 0.001) intraarterial systolic pressure by 12 mmHg and mean and diastolic pressure by 5 and 3 mmHg, respectively. Heart rate, body weight and exercise capacity were not significantly changed. Following PG-inhibition plasma 13,14-dihydro-15-keto-prostaglandin F alpha, plasma renin, angiotensin II and aldosterone were reduced (P less than 0.001) to a similar degree at rest and exercise. However, PG-inhibition did not abolish the exercise related stimulation of the plasma renin-angiotensin-aldosterone system. PG-inhibition had no significant effect on the plasma catecholamines nor on the urinary excretion of aldosterone and kallikrein. Twenty-four-h urinary sodium (-15 mEq; P less than 0.01) decreased. In sodium-deplete subjects prostaglandins seem to exert a depressor action on the systemic circulation, and to have a tonic influence on the renin system. Both these effects are similar at rest and exercise. Prostaglandins are probably not involved in the exercise-induced stimulation of the plasma renin-angiotensin-aldosterone system.

Effects of Ketanserin, a New Selective Serotonin Antagonist, on Blood Pressure and the Renin-Aldosterone System in Sodium-Depleted Normal Subjects

Effects of Ketanserin, a New Selective Serotonin Antagonist, on Blood Pressure and the Renin-Aldosterone System in Sodium-Depleted Normal Subjects

Role of the renin-angiotensin system in enhancing the aldosterone response to adenocorticotropin during acute sodium depletion in normal subjects.

The role of the renin-angiotensin system in enhancing aldosterone responsiveness to ACTH during acute sodium depletion was studied in 14 healthy medical students. Acute sodium depletion was achieved by oral treatment with 80 mg furosemide and 200 mg SQ 14,225 for 1 day. The im administration of 250 micrograms alpha ACTH-(1-24) or vehicle was performed at 0800-0900 h both on the day after ad libitum diet (control) and 1 h after the oral administration of 50 mg SQ 14,225 on the day after acute sodium depletion. Treatments with furosemide and SQ 14,225 before both ACTH and vehicle administration induced a reproducible sodium depletion, accompanied by a marked increase in PRA and no significant increase in plasma aldosterone. The administration of ACTH, but not of vehicle, produced significant increases in plasma aldosterone in both control and acute sodium-depleted subjects. However, the ACTH-induced increases in plasma aldosterone and their maximal net and percent increments during acute sodium depletion were significantly greater than control values. It is concluded that angiotensin II does not play an important role in enhancing the aldosterone-stimulating activity of ACTH during acute sodium depletion and that sodium depletion per se may be responsible for this enhancement.

Plasma aldosterone, renin activity, and cortisol responses to heat exposure in sodium depleted and repleted subjects

The effect of 90-min heat exposure (46 degrees C, 35 mbar) on plasma aldosterone (PA) patterns was studied and the respective roles of plasma renin activity (PRA), adrenocorticotropin (ACTH), Na+ and K+ concentrations in the control of PA response were in investigated in eight subjects on a low sodium diet and in five subjects on a high sodium diet. In all subjects, transitory PA increases of varying importance were observed, which were not related to sweat losses (less than 1% bodyweight) or to rectal temperature rise. In sodium-repleted subjects, basal PA and PRA levels as well as heat-induced rises were low (mean PA peak level = 12.62 +/- 1.15 ng/100 ml). They were enhanced by sodium depletion and PA reached a mean peak level of 34.07 +/- 2.73 ng/100 ml. But, in both conditions, the heat-induced PA peaks were 3-times higher than the initial levels. PA correlated with PRA in all but one of the sodium-repleted subjects and in 6 of the 8 sodium-depleted subjects. ACTH release, as measured by plasma cortisol (PC) levels, occurred in those subjects who noted an increased feeling of annoyance and discomfort. Thus, PA correlated positively with PC in 4 sodium-depleted subjects. A high sodium intake improved heat-tolerance. Plasma K+ and Na+ concentrations were not significantly modified by exposure to heat. PA increases can occur without concomitant changes in PRA, PC, K+ or Na+, which suggests that an additional factor may play a role in aldosterone regulation during acute heat exposure.

Effects of angiotensin antagonism at rest and during exercise in sodium-deplete man

Mean intra-arterial pressure (P-), heart rate (HR), cardiac index (CI), total peripheral resistance index (TPRI), and plasma renin activity (PRA), norepinephrine (PNE), and epinephrine (PE) were estimated in five normal male subjects placed on a low-sodium diet for the previous 7 days. Subjects were studied during rest in recumbency and during intravenous infusion of either glucose or saralasin in a) recumbent position, b) sitting position on the bicycle ergometer, and c) during submaximal graded exercise. At rest recumbent saralasin induced pressure changes that were closely related to logPRA. During exercise the increase in P- was significantly lower during saralasin as compared to glucose from 110 W on, related to a greater reduction in TPRI. The increase of PRA during exercise was about three times greater with saralasin as compared to glucose, but the rises in PNE and PE were similar in both series of tests. Angiotensin II may thus have a role in the maintenance of P- in the supine sodium-deplete normal subjects, and stimulation of the renin angiotensin system during physical exercise contributes to a minor extent to the increase in P- in these conditions.

Relative significance of plasma renin activity and concentration in physiologic and pathophysiologic conditions.

Plasma renin activity (PRA) and concentration, measured after acid treatment of the plasma (PRC3.3), were determined on the same plasma samples in different conditions. Log PRA and log PRC3.3 were significantly (P less than 0.001) and similarly related to sodium intake, age, and plasma aldosterone concentration in normal subjects. The correlation coefficient between log PRA and log PRC3.3 was 0.49 in 80 sodium-replete and sodium-deplete normal subjects, and it was 0.84 in 84 hypertensive patients untreated or under treatment with thiazides. On the contrary, during beta adrenergic blockade, PRA decreased significantly (P less than 0.001) by 62% while the changes in PRC3.3 were not significant. At maximal exercise, PRA increased significantly by 168% while the PRC3.3 increase of 24% was not significant. In hypertensive patients with unilateral renal artery stenosis the ipsilateral renal vein/artery ratio was higher for PRA (2.46) than for PRC3.3 (1.56), whereas both ratios on the controlateral side were similar and close to one (1.14 and 1.06). The conditions in which PRA and PRC3.3 determinations are concordant or discordant are discussed.

The relationship of urinary kallikrein activity to renal salt and water excretion.

1. We measured urinary kallikrein (kininogenin) excretion in black and white normotensive subjects during a variety of manipulations of salt and water balance. 2. A large intravenous saline load administered while the subjects were on an unrestricted sodium diet did not significantly change urinary kallikrein activity in either racial group. 3. After several days of dietary sodium restriction both racial groups increased their urinary kallikrein activity. An intravenous water load given then further increased urinary kallikrein activity. White subjects were studied for an additional 24 h period, and urinary kallikrein activity returned to pre-water load values, indicating that the excretion of a water load in sodium-depleted subjects is associated with an increase in kallikrein excretion. 4. Black subjects excreted less kallikrein in the urine than white subjects during the initial 24 h periods of unrestricted dietary sodium intake, but there were no other significant racial differences during the other experimental conditions.

Sensitization of the adrenal cortex to angiotensin II in sodium-deplete man

The effect of sodium depletion on the dose-response relationships of angiotensin II to aldosterone and blood pressure was studied. Arterial plasma angiotensin II and aldosterone and arterial blood pressure were measured before and during the incremental infusion of angiotensin II into sodium-replete and sodium-deplete subjects. Sodium depletion caused a distinct steepening of the angiotensin Il-aldosterone dose-response curves in four of five subjects and a concurrent diminution in the pressor effect of angiotensin II. Administration of angiotensin II did not demonstrably alter the half-life of aldosterone. Sodium depletion did not change the plasma concentrations of sodium or potassium, but it was accompanied by a significant increase in plasma levels of 11-hydroxycorticosteroids and magnesium. The contrasting effects of sodium depletion on the aldosterone and the pressor dose-response curves favored sodium retention. These results are consistent with an important role for the renin-angiotensin system in the control of aldosterone secretion in man.