The pressor effect of sodium-volume expansion is calcium mediated.

To investigate the calcium dependence of salt-induced hypertension we concurrently measured blood pressure and serum ionized calcium in conscious normotensive female dogs undergoing five infusions: 1) sodium chloride (0.9%) 2) calcium chloride (10 mg/kg), 3) combined sodium chloride and calcium chloride, 4) nicardipine (1 micrograms/kg/min), and 5) combined sodium chloride and calcium chloride in the presence of nicardipine. While saline and calcium chloride infusions individually did not affect blood pressure, saline combined with calcium chloride significantly and consistently raised mean arterial pressure (MAP) (delta MAP = 7 +/- 2 mm Hg, P less than .001 v baseline). Serum ionized calcium (Caio) levels increased within the normal range with the infusion of calcium alone (1.32 +/- 0.03 to 1.48 +/- 0.01 mmol/L, P less than .005). Extracellular Caio rose less with the combined NaCl-CaCl2 infusion (delta Caio 0.10 +/- 0.01 v 0.16 +/- 0.02 mmol/L, P less than .02). The difference in calcium elevations could not be attributed to volume expansion alone, since saline infusion itself did not affect serum ionized calcium (1.32 +/- 0.3 to 1.31 +/- 0.01 mmol/L, P = NS). Furthermore, nicardipine prevented the pressor effect of the combined saline-calcium infusion. (delta MAP = -2 +/- 3 v 7 +/- 2 mm Hg, P less than .001), and restored the rise in extracellular Caio to that seen with the nonpressor calcium infusion (delta Caio 0.15 +/- 0.01 mmol/L v 0.16 +/- 0.02 mmol/L, P = NS). Altogether, these data demonstrate that the rise in blood pressure and ionized calcium following an acute infusion of sodium and calcium chloride are interdependent.(ABSTRACT TRUNCATED AT 250 WORDS)     

Antihypertensive and hypotensive effects of atrial natriuretic factor in men

Synthetic atrial natriuretic factor (ANF) was administered in ascending doses (0.03, 0.20, 0.45 microgram/kg/min) to eight mildly essential hypertensive men on high (200 mEq/day) or low (10 mEq/day) sodium diets. Responses of blood pressure, heart rate, urinary volume and electrolyte excretion, renin, and aldosterone were measured. For the entire group, ANF lowered blood pressure and increased heart rate during the 0.20 and 0.45 microgram/kg/min infusions, and the antihypertensive effect of the peptide persisted for at least 2 hours after the infusions ended. Four patients (2 at 0.20 microgram/kg/min and 2 at 0.45 microgram/kg/min) experienced sudden bradycardia and hypotension at the end of or shortly after completion of ANF infusion. Renal excretion of water, sodium, chloride, calcium, and phosphorus increased in a dose-dependent fashion in response to infused ANF. Patients on the 200 mEq/day sodium diet had greater increases in urinary volume (11.1 +/- 2.8 vs 3.0 +/- 2.0 ml/min; p less than 0.05), sodium (870 +/- 134 vs 303 +/- 27 microEq/min; p less than 0.05), and chloride (801 +/- 135 vs 176 +/- 75 microEq/min; p less than 0.02) compared with patients on the low sodium diet. The apparent direct suppressive effect of a 0.03 microgram/kg/min infusion of ANF on renin and aldosterone levels was overcome at higher doses by counterregulation provoked by the depressor action. Renin was slightly (-12%) suppressed during the 0.03 microgram/kg/min infusion of ANF but increased at the 0.20 (+50%) and 0.45 microgram/kg/min (+90%; p less than 0.03) rates. Aldosterone declined significantly during the 0.03 microgram/kg/min infusion (-45%; p less than 0.01) of ANF but not during the two higher dose infusions.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of intrarenal angiotensin II blockade on renal function in conscious dogs.

The effects of intrarenal infusion of 1-sar-8-ala angiotension II (P 113) and a converting enzyme inhibitor, SQ 20881, at doses that did not affect systemic blood pressure (2.0 mug/kg per min) were studied in conscious, uninephrectomized dogs. In dogs receiving approximately equal to 5 mEq/day of sodium, intrarenal infusion of P 113 increased renal blood flow (RBF) from 219.8 +/- 32.3 to 282.7 +/- 20.0 ml/min (P less than 0.004), and with intrarenal SQ 20881 infusion from 215.3 +/- 14.2 to 278.0 +/- 22.2 ml/min (p less than 0.005). In sodium-restricted dogs (approximately equal to 5 mEq/day), glomerular filtration rate (GFR) also increased with intrarenal P 113 infusion from 57.9 +/- 5.7 to 66.3 +/- 6.6 ml/min (P less than 0.05), and with SQ 20881 infusion from 43.1 +/- 2.1 to 55.7 +/- 4.5 ml/min (P less than 0.01). Dogs on approximately equal to 5 mEq/day of sodium showed significant increases in plasma renin activity (PRA) with intrarenal infusion of the peptides, unmasking a negative feedback inhibition of renin release by angiotensin II. No increases in RBF, GFR, or PRA were seen with infusion without inhibitors, or in dogs give P 113 or SQ 20881 while on approximately equal to 80 mEq/day of sodium. In addition, angiotensin II inhibition increased sodium excretion during sodium restriction. These findings suggest that intrarenal angiotensin II is intimately involved in renal responses to sodium restriction which result in conservation of sodium and water.     

Des-1-Asp-angiotensin II. Possible intrarenal role in homeostasis in the dog.

The relative effects of des-a-Asp-angiotensin 3I and angiotensin II on renal function, including renin secretion, were investigated in normal and sodium-depleted dogs. Intrarenal arterial infusion of the heptapeptide fragment into normal dogs at a rate which was calculated to increase blood levels by only 7 ng/100 ml decreased renal blood flow from 254 +/- 9 ml/min to 220 +/- 12 and 219 +/- 12 ml/min (P less than 0.01 for both values) after 10 and 30 minutes of infusion, respectively; renin secretion decreased from 502 +/- 214 ng/min to 253 +/- 109 and 180 +/- 53 ng/min (P less than 0.05 for both values). Infusion of angiotensin II at the same rate decreased renal blood flow from 251 +/- 26 ml/min to 224 +/- 22 and 220 +/- 16 ml/min (P less than 0.01 and 0.025, respectively) and decreased renin secretion from 374 +/- 25 ng/min to 166 +/- 76 and 131 +/- 37 ng/min (P less than 0.025 for both values). Neither peptide significantly changed mean arterial blood pressure, creatinine clearance, or excreted sodium in these dogs. Infusion of des-1-Asp-angiotensin II into sodium-depleted dogs decreased renin secretion from 1094 +/- 211 ng/min to 768 +/- 132 and 499 +/- 31 ng/min (P less than 0.025 for both values) after 10 and 30 minutes of infusion. Angiotensin II infusion decreased renin secretion from 1102 +/- 134 to 495 +/- 235 and 502 +/- 129 ng/min in these dogs (P less than 0.05 and 0.025, respectively). Neither peptide significantly altered renal blood flow, arterial blood pressure, creatinine clearance, or excreted sodium in the sodium-depleted dogs. The data demonstrated that these two peptides have similar effects on the renin secretory mechanism and the vascular receptor at the level of the renal arterioles.     

Responses to a saline load in gonadotropin-releasing hormone antagonist-pretreated premenopausal women receiving progesterone or estradiol-progesterone therapy

The effects of estradiol (E(2)) and progesterone (P(4)) on fluid and sodium regulation may have important clinical implications with respect to cardiovascular and renal disease as well as reproductive syndromes such as preeclampsia and ovarian hyperstimulation syndrome. We tested the hypothesis that sodium excretion is reduced in response to a sodium load during combined P(4)-E(2) treatment, but P(4) administration alone has little effect on sodium regulation. Fifteen women (22 +/- 2 yr) used a GnRH antagonist to suppress endogenous E(2) and P(4) for 9 d; for d 4-9, eight subjects used P(4) (200 mg/d), and seven subjects used P(4) with E(2) (two E(2) patches, 0.1 mg/d each). On d 3 and 9, isotonic saline (0.9% NaCl) was infused [120 min at 0.1 ml/kg body weight (BW).min], followed by 120 min of rest. Compared with GnRH antagonist alone, P([P4]) increased from 1.6 +/- 0.8 to 9.4 +/- 2.3 ng/ml (5.1 +/- 2.5 to 29.9 +/- 7.3 nmol/liter, P < 0.05) in the P(4) treated group, with no change in P([E2]). In the P(4)-E(2) treated group P([P4]) increased from 1.6 +/- 0.5 to 6.7 +/- 0.6 ng/ml (5.1 +/- 1.6 to 21.3 +/- 1.6 nmol/liter, P < 0.05 and P([E2]) increased from 17.9 +/- 6.3 to 200 +/- 41 pg/ml (65.7 +/- 23 to 734.6 +/- 150.0 pmol/liter, P < 0.05). Before isotonic saline infusion, renal sodium and water excretion were similar under all conditions, but during isotonic saline infusion, cumulative sodium excretion was lower in the P(4)-E(2) treated women (34.1 +/- 5.1 mEq) compared with GnRH antagonist (50.2 +/- 11.4 mEq). Sodium excretion was unaffected by P(4) treatment (48.0 +/- 8.2 and 41.2 +/- 5.1 mEq, for GnRH antagonist and P(4)). Compared with GnRH antagonist alone, P(4)-E(2) treatment increased distal sodium reabsorption and transiently decreased proximal sodium reabsorption, whereas P(4) treatment did not alter either distal or proximal sodium reabsorption. Before isotonic saline infusion, the plasma aldosterone (Ald) concentration was greater during P(4) treatment (153 +/- 25 pg/ml; 3883 +/- 1102 pmol/liter) and P(4)-E(2) treatment (242 +/- 47 pg/ml; 6373 +/- 1390 pmol/liter) than during their respective GnRH antagonist alone treatments [96 +/- 13 and 148 +/- 47 pg/ml (2598 +/- 475 and 3284 +/- 973 pmol/liter) for P(4) and combined P(4)-E(2), respectively]. Compared with GnRH antagonist alone treatments, preisotonic saline infusion plasma renin activity was greater only with P(4)-E(2) treatment, whereas the plasma atrial natriuretic peptide concentration was lower only with P(4) treatment. Isotonic saline infusion suppressed plasma Ald under all conditions, but decreased plasma renin activity only with P(4)-E(2) treatment (average decrease, 1.3 +/- 0.5 ng/ml angiotensin I.h; P < 0.05). In summary, we found that P(4)-E(2) treatment decreased sodium excretion via either renin-angiotensin-Ald system stimulation or direct effects on kidney tubules. P(4) treatment at these plasma concentrations had no independent effect on the renal response to acute sodium loading. These data suggest that E(2) is the more powerful reproductive hormone involved in sodium retention relative to P(4), and that estrogen-induced up-regulation of P(4) receptors is required for the effects of P(4) on sodium regulation.     

Histamine-induced paradoxical growth hormone response to thyrotropin-releasing hormone in normal men

GH responses to TRH occur in patients with certain diseases, such as acromegaly, severe liver disease, uremia, and mental disorders, and presumably reflect disruption of normal hypothalamic control of GH secretion. Since histamine (HA) inhibits hypothalamic stimulation of GH secretion, we investigated the combined effect of HA receptor activation and TRH administration on GH secretion in normal men. Eight men were given 4-h infusions of the following: saline, HA, HA plus mepyramine (Me; and H1-antagonist), HA plus cimetidine (C; an H2-antagonist), and C alone. TRH (200 micrograms) was injected iv 2 h after the start of each infusion. HA alone or in combination with either antagonist had no effect on basal or TRH-stimulated TSH secretion and no effect on basal GH secretion. However, when TRH was injected during H1 stimulation by HA plus C, GH secretion increased significantly [from 0.7 +/- 0.1 to 7.1 +/- 1.8 (+/- SEM) ng/ml; P less than 0.01] in seven of eight subjects. This GH response was reproducible and did not occur when saline was administered instead of TRH. A smaller and delayed GH response to TRH occurred during infusions of HA alone (from 0.8 +/- 0.1 to 4.9 +/- 1.0 ng/ml; P less than 0.05). No effect of TRH on GH secretion occurred during the infusion of saline (1.2 +/- 0.3 ng/ml), HA plus Me (0.9 +/- 0.1 ng/ml), or C (2.2 +/- 1.0 ng/ml). There was a significant increase in GH secretion after cessation of the infusions of HA (from 3.4 +/- 1.1 to 7.5 +/- 2.2 ng/ml) and HA plus Me (from 0.8 +/- 0.1 to 5.1 +/- 1.8 ng/ml). This rebound in GH secretion might indicate an inhibitory effect of TRH during H2-receptor stimulation. This concept is supported by the significantly smaller GH response to TRH during HA infusion than during HA plus C infusion (P less than 0.01). The study indicates that H1-receptor stimulation induces a stimulatory effect of TRH on GH secretion in normal men and that H2-receptor stimulation possibly induces an inhibitory effect of TRH on GH secretion.     

Dopamine affects angiotensin II-induced steroidogenesis by altering clearance of the peptide in man

Infusion of dopamine is reported to reduce the response of aldosterone to infused angiotensin II in sodium-deplete but not sodium-replete man. Six normal male subjects were infused with angiotensin II in graded doses (2, 4 and 8 ng/kg per min) with or without dopamine (1.0 microgram/kg per min) during both dietary sodium repletion and depletion. The responses of both aldosterone and 18-hydroxycorticosterone to infusion of angiotensin II appeared to be reduced by dopamine in sodium-deplete, but not sodium-replete, subjects. However, when the relationships between plasma concentrations of angiotensin II and corticosteroid were examined it was evident that plasma concentrations of angiotensin II were lower when dopamine was infused concurrently with the peptide (P less than 0.05). In a second study, six sodium-deplete males were infused with angiotensin II at a constant rate (6 ng/kg per min) while dopamine (or placebo) was given in graded doses (0.5, 1 and 5 micrograms/kg per min). Renal plasma flow was estimated from total body clearance of para-aminohippuric acid. Overall, angiotensin II concentrations were lower during dopamine infusion compared with those during infusion of placebo (63.2 +/- 9.7 (S.E.M.) vs 92.3 +/- 6.4 pmol/l; P less than 0.01) and this was associated with a 40% increase in effective renal plasma flow (627 +/- 68 vs 451 +/- 15 ml/min; P less than 0.05); there again appeared to be a reduced aldosterone response during combined angiotensin II/dopamine infusion compared with that during infusion of angiotensin II alone (1003 +/- 404 vs 1225 +/- 146 pmol/l; 0.05 less than P less than 0.1).(ABSTRACT TRUNCATED AT 250 WORDS)     

Dopaminergic suppression of angiotensin II-induced aldosterone secretion in man: differential responses during sodium loading and depletion

Previous studies have shown that aldosterone secretion may be inhibited by dopaminergic mechanisms in man. Dopamine does not inhibit aldosterone responses to angiotensin II in sodium-replete normal subjects. Since sodium deficiency is associated with a reduction in renal dopamine formation, we investigated the effect of dopamine on angiotensin II-induced aldosterone secretion in the sodium-depleted state. Six normal subjects in balance at 10 mEq sodium intake (UNaV 17 +/- 2 meq/24 hr) received dopamine 4 micrograms/kg/min or vehicle for 210 minutes on two consecutive days. After 60 minutes of the dopamine or vehicle infusion, the subjects received successive 30-minute infusions of angiotensin II in increasing doses of 0.5, 1, 2, 4 and 6 picomol/kg/min. Control plasma aldosterone concentrations before vehicle or dopamine were 15 +/- 3 (mean 1 +/- SE) and 25 +/- 3 ng/dL, respectively. Aldosterone responses to angiotensin II were greater with vehicle than dopamine at angiotensin II doses of 4 and 6 picomol/kg/min (P less than 0.025). The slope of angiotensin-aldosterone dose-response curve was steeper with vehicle (0.33) than with dopamine (0.16), P less than 0.01. Serum prolactin concentrations were lower with dopamine (1.6 +/- 0.8 ng/mL) than with vehicle (6.4 +/- 1.2 ng/mL, P less than 0.05) by 120 minutes of infusion and remained suppressed with dopamine for the remainder of the dopamine infusion. Diastolic blood pressure was higher (P less than 0.05) with vehicle than with dopamine at angiotensin II doses of 2, 4, and 6 picomol/kg/min. Dopamine administration was associated with an increase in plasma cortisol concentration from 90 to 150 minutes of infusion (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Acute Cardiovascular and Metabolic Effects of Acetate in Men

We studied the potential contribution of acetate to the cardiovascular effects of ethanol in 12 healthy male volunteers. Sodium acetate, or sodium chloride in control experiments, was infused i.v. at the rate of 0.033 mEq/kg/min for 60 min. Left ventricular function was examined by M-mode echocardiography and systolic time intervals during infusion and for 60 min thereafter. Blood acetate rose during infusion from 0.19 +/- 0.02 (mean +/- SEM) to a maximum of 0.99 +/- 0.08 mmol/liter. Changes in serum free fatty acids, glycerol, and ketone bodies indicate that acetate inhibited peripheral lipolysis. The volume of urine excreted during the acetate experiment (305 +/- 37 ml) was significantly larger (p less than 0.01) than during the chloride experiment (181 +/- 21 ml). Left ventricular function did not differ between the experiments during the infusions even though at 45 min heart rate was increased by acetate (7%; p less than 0.01, between infusions). After the infusion period, at 75 min the treatment by acetate increased cardiac output from the baseline by 17% (p less than 0.05, between infusions), and decreased peripheral arterial resistance (19%, p less than 0.05), and diastolic blood pressure (10%, p less than 0.01). Circumferential fiber shortening velocity was increased during the acetate experiment maximally by 7% (p less than 0.01) from the baseline at 120 min. These data indicate that acetate is an arterial vasodilator and a mild diuretic and may slightly improve myocardial performance in the concentrations encountered during ethanol metabolism in men.     

Effect of baroreceptor denervation on the inhibition of renin release by vasopressin

Previous studies have suggested that the inhibition of renin secretion by acute administration of vasopressin in conscious dogs results from a reflex reduction in renal nerve activity. In the present investigation, this hypothesis was tested by studying the effect of total baroreceptor denervation or selective low pressure baroreceptor denervation on the suppression of PRA by vasopressin in conscious, chronically prepared dogs. In eight sham-operated dogs, a 45-min infusion of vasopressin (2.0 ng/kg.min, iv) decreased PRA from 10.5 +/- 1.9 to 5.9 +/- 1.0 ng/ml.3 h (P less than 0.01). Mean arterial pressure did not change (110 +/- 10 to 107 +/- 7 mm Hg), but heart rate decreased from 84 +/- 9 to 69 +/- 8 beats/min (P less than 0.05). In contrast, vasopressin infusion failed to significantly decrease PRA in seven sinoaortic/cardiac denervated dogs (9.5 +/- 1.7 to 7.4 +/- 2.0 ng/ml.3 h), although decreases did occur in three of the dogs. Mean arterial pressure increased from 104 +/- 5 to 125 +/- 6 mm Hg (P less than 0.01), but heart rate did not change (112 +/- 4 to 107 +/- 5 beats/min). When renal perfusion pressure was maintained at the preinfusion level in three sinoaortic/cardiac denervated dogs, vasopressin infusion failed to decrease PRA (2.3 +/- 0.6 to 2.4 +/- 0.6 ng/ml.3 h). In six cardiac denervated dogs, vasopressin infusion decreased PRA from 5.3 to 0.9 to 3.1 +/- 0.7 ng/ml.3 h (P less than 0.01). Results obtained with two lower doses of vasopressin (0.5 and 1.0 ng/kg.min) were generally similar to the responses observed during infusion at 2.0 ng/kg.min. Angiotensin II (5.0 ng/kg.min) suppressed PRA in all groups of dogs. These experiments demonstrate that the inhibition of renin secretion by acute administration of vasopressin in conscious dogs is prevented by total baroreceptor denervation, but not by denervation of the low pressure baroreceptors alone. These results suggest that the suppression of renin release by vasopressin is a reflex response resulting from activation of the high pressure baroreceptors.     

beta-Endorphin stimulates plasma renin and aldosterone release in normal human subjects

To determine the effect of beta-endorphin on the renin-angiotensin-aldosterone system, human synthetic beta-endorphin (0.3, 1.0, and 3.0 micrograms/kg X min) was infused iv in normal subjects. Each dose was administered for 30 min, and a control infusion of 5% dextrose and water was given on another day. Ten subjects were studied recumbent and in balance while ingesting a 10-meq Na+ diet. Plasma renin activity (PRA), plasma aldosterone (PA), and plasma cortisol (F) were measured basally and every 30 min for 210 min. The increments in PRA and PA above basal significantly (P less than 0.05) increased (3.1 +/- 1.2 ng/ml X h and 12.2 +/- 5.3 ng/dl, respectively; P less than 0.05) at the end of the beta-endorphin infusion. beta-Endorphin also significantly (P less than 0.01) suppressed F levels. Since in the low salt study, beta-endorphin suppressed F release while stimulating renin secretion, an additional five subjects were pretreated with dexamethasone (0.5 mg every 6 h) and were studied in balance while ingesting a 200-meq Na+ diet to suppress the renin-angiotensin system. Significant (P less than 0.025) increments in PRA (2.1 +/- 0.7 ng/ml X h) and PA (4.1 +/- 1.7 ng/dl) levels above basal were again found during the sequential dose infusion of beta-endorphin (0.3, 1.0, and 3.0 micrograms/kg X min). However, PA elevations were sustained for at least 120 min after the beta-endorphin infusion was stopped despite a drop in PRA 90 min earlier. In additional studies, an attempt was made to define the minimal effective dose of beta-endorphin by 60-min infusions (0.03, 0.1, and 0.3 micrograms/kg X min) in subjects on a 200-meq Na+ diet who were dexamethasone pretreated. The PRA and PA levels rose significantly (P less than 0.05) above basal at the 0.3 micrograms/kg X min dose, but not at the 0.03 or 0.1 micrograms/kg X min dosage levels. There were no changes in blood pressure or potassium during either the 10 or 200-meq Na+ studies. Thus, beta-endorphin stimulates aldosterone release in vivo. However, the underlying mechanisms are complex, since renin levels also increased. The data suggest that the early aldosterone rise may be secondary to an increase in renin release, but renin cannot account for the sustained postinfusion elevations of aldosterone.     

Stimulation of renin by acute selective chloride depletion in the rat.

To determine whether acute chloride depletion per se stimulates renin, we produced selective chloride depletion without sodium depletion in rats by peritoneal dialysis (PD) against 0.15 M NaHCO3 or 0.15 M NaNO3. Control rats were dialyzed against 0.15 M NaCl. Plasma renin activity (PRA) was measured before (PRA1) and 105 minutes after (PRA2) PD. Plasma volume was expanded after PD by infusion of salt-free albumin and was measured immediately after PRA2 by [131I]albumin. In experiment 1, rats were prepared on a normal diet. PRA2 (7.0 +/- 1.0 ng/ml per hr, mean +/- SEM) was increased (P less than 0.05) over PRA1 (4.7 +/- 0.7 ng/ml per hr) in Cl-depleted but not in control rats (PRA1 = 5.3 +/- 0.7, PRA2 = 6.1 +/- 0.7, P = NS). In experiment 2, to produce greater chloride depletion, all rats were prepared for 2 weeks on a low salt diet. PRA2 (47 +/- 5 ng/ml per hr) was increased as compared to PRA1 (24 +/- 2 ng/ml per hr, P less than 0.005) in the Cl-depleted group but not in the control group (PRA1 = 24 +/- 3, PRA2 = 27 +/- 6 ng/ml per hr, P = NS). Serum potassium and final plasma volume were slightly but not significantly lower than controls in these Cl-depleted rats. To exclude an additive effect of these two stimuli for renin, in experiment 2a we infused chloride-depleted rats with three times as much albumin as controls and with KHCO3, 100 mEq/liter. Despite volume expansion and potassium loading, PRA2 (41 +/- 6 ng/ml per hr) was significantly elevated as compared to PRA1 (25 +/- 4 ng/ml per hr, P less than 0.01). Since acute metabolic alkalosis also was present in all Cl-depleted renin-stimulated rats, an additional group (2b) was dialyzed against 0.15 M NaNO3; final plasma arterial pH (7.43) was not different from controls (7.42). Nevertheless, PRA2 levels again were higher (36 +/- 6 ng/ml per hr, P less than 0.05) as compared to PRA1 (23 +/- 4 ng/ml per hr). In all experiments, arterial blood pressure, glomerular filtration rate, and filtered sodium load were not different. Free water reabsorption was lower in Cl-depleted than in control rats. We conclude that acute selective chloride depletion per se is a potent stimulus for renin release.     

Increase in plasma concentrations of atrial natriuretic peptide during infusion of hypertonic saline in conscious newborn calves

Plasma concentrations of atrial natriuretic peptide (ANP), plasma renin activity (PRA), plasma concentrations of aldosterone, urine flow rate and sodium and potassium excretion were studied in two groups of four conscious 3-day-old male calves, infused with hypertonic saline or vehicle. Hypertonic saline infusion (20 mmol NaCl/kg body weight) was accompanied by a progressive rise in plasma concentrations of ANP (from 16.5 +/- 0.2 pmol/l at time 0 to 29.3 +/- 3.0 pmol/l at 30 min; P less than 0.05) and by a gradual decrease in PRA (from 1.61 +/- 0.23 nmol angiotensin I/l per h at time 0 to 0.54 +/- 15 nmol angiotensin I/l per h at 90 min; P less than 0.05); there was no change in the plasma concentration of aldosterone. Within the first 2 h of the 24-h urine collection period there was a marked rise in urine flow rate and sodium excretion in treated calves when compared with control animals (66.0 +/- 8.3 vs 15.9 +/- 1.2 ml/kg body weight per 2 h (P less than 0.05) and 6.7 +/- 1.3 vs 0.4 +/- 0.02 mmol/kg body weight per 2 h (P less than 0.01) respectively). During the following 22 h, urinary water and sodium excretion remained at significantly high levels. Thus, in the conscious newborn calf, changes in plasma ANP levels and urinary water and sodium excretion during hypertonic saline infusion are compatible with the hypothesis that endogenous ANP participates, at least in part, in the immediate diuretic and natriuretic renal response induced by the sodium overload.     

Effect of sodium balance and calcium channel blocking drugs on blood pressure responses

To study the role of calcium movements in mediating the effects of sodium chloride on the response of blood pressure to angiotensin II (ANG II), we infused ANG II before and after giving calcium channel blocking drugs (nifedipine and diltiazem) and calcium infusions to normal subjects during high and low sodium intakes. ANG II was also in nine patients with essential hypertension eating a low sodium diet. In preliminary studies, the effects of nifedipine, 20 mg p.o., on blood pressure and plasma renin activity were determined. Sensitivity to infused ANG II was calculated as the slope of the linear regression of the increase in diastolic blood pressure (DBP) expressed as a function of the ANG II infusion rate (mm Hg/ng ANG II/kg/min). During intake of a high sodium diet (Na, 200 mEq/day) both drugs significantly (p less than 0.05) reduced ANG II sensitivity, while on a low sodium diet (10 mEq Na), neither drug reduced ANG II sensitivity. There was a significant (p less than 0.001) inverse correlation between the initial ANG II-DBP sensitivity and the change in sensitivity induced by the calcium channel blocking drugs in normal subjects (r = -0.78) and in hypertensive patients (r = -0.70). Five hypertensive patients had greater than normal ANG II-DBP sensitivity that was significantly (p less than 0.05) reduced by nifedipine. Calcium infusion did not affect the ANG II-DBP sensitivity on either diet. The results suggest that in normal subjects increased DBP responses to ANG II, induced by an increase in sodium intake, are partially mediated by increased extracellular to intracellular calcium movements, since they are blocked by the structurally different calcium channel blocking drugs nifedipine and diltiazem. In hypertensive patients on a low sodium diet, increased DBP responses to ANG II infusion were blocked by nifedipine, indicating they are at least partly mediated by increased extracellular to intracellular calcium flux.     

Inhibition of sympathoadrenal activity by atrial natriuretic factor in dogs

In six conscious, trained dogs, maintained on a normal sodium intake of 2 to 4 mEq/kg/day, sympathetic activity was assessed as the release rate of norepinephrine and epinephrine during 15-minute i.v. infusions of human alpha-atrial natriuretic factor. Mean arterial pressure (as a percentage of control +/- SEM) during randomized infusions of 0.03, 0.1, 0.3, or 1.0 microgram/kg/min was 99 +/- 1, 95 +/- 1 (p less than 0.05), 93 +/- 1 (p less than 0.01), or 79 +/- 6% (p less than 0.001), respectively, but no tachycardia and no augmentation of the norepinephrine release rate (up to 0.3 microgram/kg/min) were observed, which is in contrast to comparable hypotension induced by hydralazine or nitroglycerin. The release rate of epinephrine (control, 6.7 +/- 0.6 ng/kg/min) declined immediately during infusions of atrial natriuretic factor to a minimum of 49 +/- 5% of control (p less than 0.001) during 0.1 microgram/kg/min and to 63 +/- 5% (0.1 greater than p greater than 0.05) or 95 +/- 13% (not significant) during 0.3 or 1.0 microgram/kg/min. Steady state arterial plasma concentrations of atrial natriuretic factor were 39 +/- 10 pg/ml (n = 6) during infusions of saline and 284 +/- 24 pg/ml (n = 6) and 1520 +/- 300 pg/ml (n = 9) during 0.03 and 0.1 microgram/kg/min infusions of the factor.(ABSTRACT TRUNCATED AT 250 WORDS)     

Trials for simplified hypertonic saline test

Hypertonic saline test is indispensable for the evaluation of posterior pituitary function. However the test is not simple, including water loading, urine sampling and at least 45 min of hypertonic saline infusion, mostly because the test relies on urinary osmolality as an index of ADH secretion. The object of this study is try to simplify the test by directly measuring plasma ADH concentration before and after 10 min of hypertonic saline infusion. Intravenous infusion of hypertonic saline (5% NaCl, 0.24 ml/kg/min, for 10 min) was performed on normal subjects, patients with diabetes insipidus and patients with renal failure under chronic hemodialysis. Venous blood samples were obtained seriously including just before and after 10 min of the infusion. ADH was extracted from plasma using Sep-Pak C18 column and assayed by specific RIA. Minimum sensitivity of the assay was 0.25 pg/ml. The hypertonic saline infusion resulted in an increase of plasma osmolality by about 8 mOsm/kg H2O and plasma sodium concentration by 4 mEq/l. Plasma ADH increased from 0.77 +/- 0.09 to 3.42 +/- 0.73 pg/ml (m +/- SE, n = 8, p less than 0.01) in normal subjects of ad lib. water drinking and from 0.55 +/- 0.33 to 2.34 +/- 0.33 (m +/- SE, n = 4, p less than 0.05) in water loaded normal subjects (20 ml/kg of water, 60 min before hypertonic saline infusion).(ABSTRACT TRUNCATED AT 250 WORDS)     

Renal function and effective beta-blockade in cirrhosis with ascites. Relationship with baseline sympathoadrenergic tone

Renal function, plasma norepinephrine, renin activity (PRA) and aldosterone were determined in 17 cirrhotics with ascites, before and after effective beta-blockade (resting heart rate reduction greater than or equal to 20%) induced by oral propranolol. The drug lowered PRA (from 2.86 +/- 0.96 (S.E.) to 1.86 +/- 0.7 ng/ml/h; P less than 0.005) and plasma aldosterone (from 309.0 +/- 59.2 to 202.6 +/- 26.7 pg/ml; P less than 0.005). As expected, plasma norepinephrine (PNC) increased from 90.7 +/- 12.2 to 176.8 +/- 43 ng/l (P less than 0.01) in the 10 patients with normal basal values ('normal-PNC' group), but it decreased in 6 of the 7 patients with basal sympathoadrenergic hypertone ('high-PNC' group; mean value from 352.6 +/- 37.8 to 273 +/- 39.3 ng/ml (P = 0.06). Glomerular filtration rate and filtered sodium load did not change in the group as a whole and in 'normal-PNC' cirrhotics (from 83.2 +/- 7.1 to 81.4 +/- 7.8 ml/min, and from 11.63 +/- 0.96 to 11.45 +/- 1.14 mmol/min), but rose in 'high-PNC' patients (from 60.7 +/- 9.1 to 109.3 +/- 27.2 ml/min, and from 8.39 +/- 1.31 to 15.47 +/- 3.95 mmol/min; P less than 0.05). Renal sodium excretion increased from 2.45 +/- 0.75 to 3.16 +/- 1.01 mmol/h (P less than 0.01) in the group as a whole. Such an increase, however, was confined to 'high-PNC' cirrhotics. In this group, the tubular rejection fraction did not change and post-beta-blockade sodium excretion was correlated with the filtered sodium load (Rs = 0.83; P less than 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of physiological levels of atrial natriuretic peptide on hormone secretion: inhibition of angiotensin-induced aldosterone secretion and renin release in normal man

Large doses of atrial natriuretic peptide (ANP) inhibit renin and aldosterone secretion in normal man, but the effect of physiological levels is unknown. We, therefore, studied the effect of a low infusion rate of alpha-human ANP (alpha hANP; 0.5 microgram/min for 180 min) on the plasma corticosteroid response to graded physiological doses of angiotensin II (0.5, 1.0, 2.0, and 4.0 ng/kg X min, each for 30 min) and ACTH (6.25, 12.5, 25, and 50 mIU, each for 30 min) in six normal men eating a low salt diet (10 mmol sodium and 100 mmol potassium daily). The angiotensin II and ACTH infusions were given from 0900-1100 h on separate days, during which randomized infusions of placebo or alpha hANP were given from 0800-1100 h according to a single blind protocol. Plasma immunoreactive ANP levels were less than 10 pmol/L on the placebo day compared to 30-50 pmol/L during the alpha hANP infusions, and were not altered by either ACTH or angiotensin II. Compared with the control observations, there was no significant change in arterial pressure or heart rate during either the alpha hANP or angiotensin II infusions. ACTH infusions evoked an incremental response in plasma aldosterone and cortisol, and the dose-response relationship was unaltered by alpha hANP. In contrast, while an incremental and significant increase in plasma aldosterone in response to angiotensin II occurred with the placebo infusion, no significant increase occurred in response to angiotensin during the alpha hANP infusion. The slope of the angiotensin II/aldosterone regression line was significantly less during all alpha hANP infusions compared to that during the placebo infusion (P less than 0.02). In addition, on the ACTH infusion day significant suppression of both PRA (P less than 0.05) and plasma angiotensin II (P less than 0.008) occurred during the alpha hANP infusion compared to that during the placebo infusion, whereas PRA was equally suppressed by angiotensin II in the presence or absence of alpha hANP. alpha hANP also increased urine volume [176 +/- 31 (+/- SEM) vs. 113 +/- 19 mL/mmol creatinine with placebo; P less than 0.03] and sodium excretion (2.14 +/- 0.48 vs. 0.58 +/- 0.22 mmol/mmol creatinine with placebo; P less than 0.004) on the ACTH infusion days. With angiotensin II, urine volume was also significantly increased by alpha hANP (150 +/- 27 vs. 81 +/- 15 mL/mmol creatinine with placebo; P less than 0.03), and urine sodium excretion doubled.(ABSTRACT TRUNCATED AT 400 WORDS)     

Effect of pressor agents on blood pressure, plasma renin activity and plasma aldosterone concentration in essential hypertension.

The responses of blood pressure, plasma renin activity (PRA) and plasma aldosterone concentration (PAC) to infusion of either angiotensin II (10 ng/Kg/min) or norepinephrine (100 ng/Kg/min) were observed in 25 patients with essential hypertension. The difference in modes of response between low renin essential hypertension and normal or high renin essential hypertension was analyzed. For comparison, 5 patients with Conn's syndrome, 4 with renovascular hypertension, and 5 normotensive subjects were also studied. Following infusion of antiotensin II the changes in diastolic blood pressure (DBP) were +24+/-3.0 mmHg in low renin essential hypertension and +25+/-3.1 mmHg in normal or high renin essential hypertension in PRA -0.28+/-0.06 ng/ml/h in low renin essential hypertension and -0.69+/-0.02 mg/ml/h in order and in PAC +3.7+/-1.4 and +7.6+/-1.8 ng/100 ml respectively. There was a significant difference in magnitude of response in PRA between the 2 groups of essential hypertension (p less than 0.05). Norepinephrine induced rise in DBP with decreases both in PRA and PAC. The mean changes in DPB were +6+/-1.4 mmHg in low renin essential hypertension and +16+/-2.2 mmHg in another and the pressor response in the later was significantly greater (p less than 0.01). The changes in PRA were -0.14+/-0.07 ng/ml/h in low renin essential hypertension and -0.67+/-0.26 ng/ml/h in normal or high renin essential hypertension, and in PAC -4.9+/-1.3 and -3.3+/-1.9 ng/100 ml respectively. The greater fall in PRA in normal or high renin essential hypertension was observed but the difference between the 2 groups of essential hypertension was not significant. The changes in PAC did not parallel the changes in PRA. Angiotensin II indcued essentially similar effects on blood pressure in both groups but the greater feedback inhibition of PRA was produced by this peptide in normal or high renin essential hypertension than in low renin essential hypertension. Norepinephrine induced significantly greater pressor effect in normal or high renin essential hypertension. The adopted dose of norepinephrine suppressed both PRA and PAC and a tendency to the greater fall in PRA was observed in normal or high renin essential hypertension. There was no difference in responses of PAC to both agents between the 2 groups of essential hypertension.     

Prostaglandins: modulators of renal function and pressor resistance in chronic liver disease.

Prostaglandins may modulate renal function and play a role in the hyperreninism and angiotensin pressor resistance of chronic liver disease. To study this possibility, we evaluated 12 patients with alcoholic cirrhosis and ascites. Urine immunoassayable prostaglandin E in 5 female patients was 3.3 +/- 0.5 micrograms/day [normal, 0.3 +/- 0.1 (SE)], renin was 14.6 +/- 3.7 ng/ml.h, and aldosterone was 76 +/- 19 ng/dl. After either indomethacin (200 mg) or ibuprofen (2000 mg) for 1 day, urine immunoassayable prostaglandin E fell to 0.8 +/- 0.4 micrograms/day, renin to 8.0 +/- 2.4 ng/mol.h, and aldosterone to 54 +/- 14 ng/dl (all P less than 0.01). Pressor sensitivity increased dramatically, and creatinine clearance transiently fell from 73 +/- 10 to 32 +/- 7 cc/min (P less than 0.01). Because a primary effect on renin might explain the renal impairment, an additional study used propranolol to lower renin activity. Renal function was unaltered by propranolol. We conclude that prostaglandins play a supportive role in maintaining renal function and are involved in the hyperreninism and pressor resistance of patients with liver disease.