Regulation of renin release by calcium and ammonium ions in normal man.

The effect of infusing calcium chloride, magnesium sulfate, sodium lactate, and ammonium chloride on renin secretion was compared to equimolar infusions of hypotonic and normal saline in sodium-deplete normal subjects. The infusion of 75 mEq of ammonium chloride for 60 min in 6 normal, sodium-deplete subjects suppressed plasma renin activity significantly (P less than 0.01) from 4.4 +/- 0.8 to 2.1 +/- 0.2 ng/ml/h, an effect comparable to that produced by normal saline. Sodium lactate (75 mEq sodium/hr) also significantly reduced renin levels at 20-30 min (P less than 0.01). The infusion of 1/3 normal saline (25 mEq sodium/h for 2 h) produced a significant reduction (P less than 0.01) in plasma renin activity (from control levels of 5.2 +/- 0.8 to 3.1 +/- 0.6 ng/ml/h at 90 min). On the other hand, comparable infusions of 50 mEq of magnesium sulfate over 2 h had no effect on renin release (4.6 +/- 0.8 to 4.6 +/- 0.9 ng/ml/h at 2 h), while the infusion of calcium chloride produced an intermediate reduction (5.2 +/- 1.2 to 3.7 +/- 0.8 ng/ml/h at 2 h (P less than 0.05). The observed effects of the hydrogen and calcium ions on suppressing renin release may be secondary to their known actions on renal sodium excretion. Since the infusions of calcium and hydrogen ions both result in an increased delivery of sodium to the distal segment of the nephron, the results may reflect the regulation of renin by the macula densa, a sensitive intrarenal sensor of renal tubular sodium.     

Interrelationships between the renin-angiotensin-aldosterone and calcium homeostatic systems.

Blood pressure is affected by both sodium and calcium intake. To determine if there is an interaction between the regulatory mechanisms for these two cations, eight normal male volunteers received the following 1-h infusions on three different days: 1) angiotensin II (AII), 2) the synthetic 1-34 amino terminal fragment of human PTH [hPTH(1-34)], and 3) AII and hPTH(1-34) together. Blood samples were obtained at t = 0 and every 20 min during each infusion and urine was collected for 3 h both before and after the start of each infusion. Infusion of AII produced an increase in intact PTH from 18 +/- 2 to 31 +/- 4 ng/L (P < 0.05), most likely in response to a small decrease in serum ionized calcium (1.25 +/- 0.01 to 1.23 +/- 0.01 mmol/L, P < 0.05). Urinary excretion of calcium was unchanged. Infusion of hPTH(1-34) at 200 U/h increased N-terminal PTH levels (18 +/- 3 to 268 +/- 42 ng/L, P < 0.05), decreased tubular reabsorption of phosphate (0.92 +/- 0.03 to 0.82 +/- 0.11, P < 0.05), and increased urinary cAMP (0.18 +/- 0.02 to 0.53 +/- 0.05 nmol/L of glomerular filtrate, P = 0.0001). hPTH(1-34) infusion suppressed endogenous intact PTH (18 +/- 3 to 14 +/- 2 ng/L, P < 0.005) and increased PRA from 0.14 +/- 0.02 to 0.32 +/- 0.05 ng/(L.s) (P < 0.05) without a change in serum ionized calcium which suggests direct effects of hPTH(1-34) on the parathyroid glands and the juxtaglomerular apparatus. The effects of AII and hPTH(1-34) were antagonistic with little change in serum ionized calcium, intact PTH, or PRA when both were infused together. These interrelationships between the major hormonal systems controlling sodium and calcium homeostasis suggest a mechanism underlying the close association of calcium and sodium in the regulation of blood pressure.     

The effects of synthetic human secretin on calcium carbonate solubility in human bile

This study sought to determine the effects of synthetic human secretin on ionized calcium and carbonate concentrations in human hepatic bile. Five patients with a nasobiliary drain in the right hepatic duct were studied. Three basal samples of bile were collected, each over a 15-minute period. Synthetic human secretin was then infused IV at 0.05 micrograms.kg-1.h-1 for 45 minutes followed by 0.5 micrograms.kg-1.h-1 for 45 minutes. Bile was sampled over 15-minute periods. To document return to baseline conditions, two further samples of bile were obtained over 15-minute periods 2 hours after the infusion was terminated. Bile acid concentration was determined by an enzymatic method; pH and PCO2 were measured with an automated analyzer. Total calcium was determined by inductively coupled plasma emission spectrometry and ionized calcium by an ion-specific electrode. Bicarbonate and carbonate concentrations were calculated using Henry's law and the Henderson-Hasselbalch equation. The fraction of bile sampled by the catheter was determined by Indocyanin Green recovery at the end of the experiment. Secretin caused an increase in bile flow and bicarbonate output. Bicarbonate concentrations increased from 26 +/- 3 mmol/L to 41 +/- 3 mmol/L (P less than 0.05), and chloride concentrations decreased. Mean bile acid concentrations declined significantly from 14.6 +/- 2 mmol/L to 4.7 +/- 1 mmol/L (P less than 0.05). Ionized calcium concentrations decreased from 0.7 +/- 0.005 mmol/L to 0.5 +/- 0.02 mmol/L (P less than 0.05) while pH increased significantly from 7.44 +/- 0.06 to 7.6 +/- 0.04 (P less than 0.05). Carbonate concentrations increased significantly from 0.15 +/- 0.02 mmol/L to 0.26 +/- 0.03 mmol/L, and the ion product for calcium carbonate increased significantly from 0.099 +/- 0.002 (mmol/L)2 to 0.135 +/- 0.015 (mmol/L)2 (P less than 0.05). Synthetic human secretin augments the ion product of calcium and carbonate in human hepatic bile, increasing the tendency for calcium carbonate precipitation.     

Sodium bicarbonate infusion test: a new method for evaluating parathyroid function

We have developed a new test for estimating the secretory capacity of parathyroid hormone (PTH) from the parathyroid gland. Sodium bicarbonate solution [8.4% (w/v); 35 ml/m(2) body surface area] was infused for 2 min, and blood samples for the determination of plasma ionized calcium, plasma PTH (intact, midregion, carboxy-terminus) and related parameters were serially obtained. In 8 healthy volunteers, the mean (+/-SE) plasma ionized calcium fell promptly and significantly (from 1.21 +/- 0.01 to 1.11 +/- 0.01 mmol/L) after the sodium bicarbonate infusion. The mean (+/-SE) plasma intact PTH increased promptly and significantly, by more than four fold (42.3 +/- 4.2 to 182.4 +/- 34.7 pg/ml), and then gradually returned to basal levels. In patients with partial hypoparathyroidism who have detectable basal plasma levels of PTH, the absolute increment in PTH levels was much less, and in the plasma obtained from patients with complete hypoparathyroidism, absolutely no response was observed. Plasma obtained from patients diagnosed with primary hyperparathyroidism (parathyroid adenoma or hyperplasia) has high basal PTH levels. The response to the sodium bicarbonate infusion in these patients was markedly blunted (less than a two-fold increase in all cases examined). No significant adverse effects were observed during the procedure. Therefore, the sodium bicarbonate infusion test is a simple and sensitive method to stimulate PTH release, and is clinically useful for evaluating parathyroid gland function.     

Estrogen replacement decreases the set point of parathyroid hormone stimulation by calcium in normal postmenopausal women

Estrogens decrease serum total and ionized calcium (Ca) concentrations in postmenopausal women with or without primary hyperparathyroidism, but cause little or no increase in serum PTH suggesting a modification of the relationship between the two. In order to define this relationship, we studied the effect of conjugated estrogens on total and ionized serum Ca and serum PTH concentrations in five normal postmenopausal women, before and after 3, 11, and 23 weeks of therapy. Dynamic tests of parathyroid gland function, based on 2-h iv infusions of CaCl2 and NaEDTA, were performed at each time. Total and ionized serum Ca and carboxylterminal PTH were measured every 15 min during the infusions, and parathyroid function was evaluated by a nonlinear 4-parameter mathematical model. Estrogen therapy caused decreases in serum total [2.36 +/- 0.04 (SD) mmol/L, baseline vs. 2.19 +/- 0.05 mmol/L, 23 weeks, P less than 0.005) and ionized calcium (1.27 +/- 0.01 mmol/L, baseline vs. 1.21 +/- 0.02 mmol/L, 23 weeks, P less than 0.005]; the decreases were evident at 3 weeks and persisted for the duration of the study. Serum PTH concentrations did not change (8.94 +/- 1.84 pmol/L, baseline vs. 8.98 +/- 2.38 pmol/L, 23 weeks). Three parameters of the parathyroid function, the maximal response to hypocalcemic stimulation, the nonsuppressible fraction of circulating PTH, and the slope of PTH on calcium at the set point were not affected by estrogen treatment. The fourth parameter, the set point of PTH stimulation by serum total calcium (2.16 +/- 0.04 mmol/L, baseline vs. 1.97 +/- 0.07 mmol/L, 23 weeks, P less than 0.0166) or by serum ionized Ca (1.19 +/- 0.04 mmol/L, baseline vs. 1.12 +/- 0.03 mmol/L, 23 weeks, P less than 0.01), was decreased by estrogen treatment. This was evident at the earliest time point studied and persisted thereafter. The decrease in ionized Ca set point only explained 40% of the decrease in total calcium set point, the remaining 60% being related to hemodilution of plasma protein during therapy. We conclude that estrogen replacement can influence parathyroid function in postmenopausal women by resetting the set point of PTH stimulation by ionized Ca. This in turn could contribute to the estrogen-induced changes in their Ca balance.     

A comparison of the in vivo biochemical responses to exogenous parathyroid hormone-(1-34) [PTH-(1-34)] and PTH-related peptide-(1-34) in man.

PTH-related peptide (PTHrP) is one of the etiological factors associated with hypercalcemia of malignancy in humans and rodents. In both in vivo and in vitro animal systems its actions mimic those of PTH; however, its bioactivity in humans has not previously been assessed. Therefore, we compared the actions of the synthetic human (h) analogs hPTHrP-(1-34) and hPTH-(1-34) when given by iv infusion to 15 healthy subjects, aged 25 +/- 3 yr. Three 12-h test infusions were given to each subject in the order: hPTH-(1-34) at a dose of 8 pmol/kg.h, an equimolar dose (8 pmol/kg.h) of PTHrP-(1-34) (low dose), and a 10-fold higher dose (80 pmol/kg.h) of hPTHrP-(1-34) (high dose). PTH infusion resulted in significant increases from basal values in serum total ionized calcium, urinary phosphate and cAMP, and serum 1,25-dihydroxyvitamin D3 [1,25-(OH)2d3]. No significant increases from basal values in any of these variables were observed during low dose PTHrP infusion. However, a 10-fold higher dose of PTHrP significantly increased serum calcium from 2.36 +/- 0.07 to 2.63 +/- 0.16 mmol/L (P less than 0.003), ionized calcium from 1.22 +/- 0.03 to 1.39 +/- 0.09 mmol/L (P less than 0.003), urinary phosphate from 0.21 +/- 0.19 to 0.31 +/- 0.16 mmol/L glomerular filtrate (P less than 0.05), urinary cAMP from 37 +/- 18 to 53 +/- 28 nmol/L glomerular filtrate (P less than 0.01), and serum 1,25-(OH)2D3 from 29.8 +/- 12.1 to 46.0 +/- 20.3 pmol/L (P less than 0.01). For each variable these changes were statistically equivalent to the increases observed during PTH infusion. The molar concentrations of circulating immunoreactive PTH-(1-34) and PTHrP-(1-34) (at the higher dose) achieved during infusion were at a ratio of 1:3. These results suggest that the in vivo actions of synthetic hPTHrP-(1-34) are comparable to those of hPTH-(1-34), but its biological activity after infusion may be less than that of hPTH-(1-34). Moreover, the increased concentrations of serum 1,25-(OH)2D3 observed with administration of hPTHrP-(1-34) are unlike the changes seen in hypercalcemia of malignancy in which levels of this vitamin D metabolite are frequently depressed.     

Lower serum ionized calcium and abnormal calciotropic hormone levels in preeclampsia.

Relative hypocalciuria has been reported in women with preeclampsia. However, there has been no systematic explanation for this finding. We measured serum and urinary calcium and serum calciotropic hormones in third trimester women with preeclampsia (n = 12, gestational hypertension and proteinuria) and with normotensive pregnancies (n = 24) to try to explain these changes. We confirmed that the women with preeclampsia have a relative hypocalciuria (2.9 +/- 0.7 vs. 6.5 +/- 0.2 mmol/day, P less than 0.01). Preeclamptic women also had lower serum ionized calcium than normotensive third trimester pregnant women (1.20 +/- 0.01 vs. 1.26 +/- 0.01 mmol/L, P less than 0.02). Intact PTH levels were significantly higher in preeclamptic women (29.9 +/- 4.3 vs. 15.4 +/- 1.3 ng/L, P less than 0.01) and a significant inverse relationship was observed between PTH and both urine calcium (r = -0.60, P less than 0.0001) and serum ionized calcium (r = -0.36, P less than 0.05). We measured vitamin D metabolites in a subgroup of both normotensive and preeclamptics. Preeclamptic and normotensive pregnant women had equivalent levels of 25-hydroxyvitamin D [25(OH)D]; however, preeclamptics had significantly lower 1,25-dihydroxyvitamin D [1,25-(OH)2D] levels (172.1 +/- 18.5 vs. 219.6 +/- 12.7 pmol/L, P less than 0.05). Lower 1,25-(OH)2D may contribute to suboptimal intestinal absorption of calcium during a time of increased calcium demand resulting in lower ionized calcium, increased PTH, and hypocalciuria in preeclampsia. Abnormalities in calcium homeostasis may contribute to the increased vascular sensitivity documented in preeclampsia.     

The modulation of circulating parathyroid hormone immunoheterogeneity in man by ionized calcium concentration.

Twenty normal individuals received 2-h iv infusions of CaCl2 and Na2 ethylenediamine tetra-acetate, with sampling every 15 min. PTH was measured by means of an intact hormone assay (I) and two carboxylterminal assays structured to react mostly with mid (M) or late (L) carboxylterminal fragments. A mathematical model was used to fit the sigmoidal relationship between ionized calcium (CA++) and PTH values. The influence of Ca++ on circulating PTH immunoheterogeneity was assessed via changes in L/I, M/I, and M/L ratios. Results are reported as means +/- SD. Response to hypocalcemia was highest with M (57.8 +/- 26.4 pmol/L, P less than 0.005 vs. L or I) and higher with L (20.1 +/- 5.6 pmol/L; P less than 0.0005 vs. I) than with I (14.1 +/- 6.4 pmol/L). L/I, M/I, and M/L decreased from 2.43 +/- 0.56 to 1.54 +/- 0.19 (P less than 0.0005), 8.44 +/- 2.38 to 4.36 +/- 4.07 (P less than 0.0005), and 3.49 +/- 0.71 to 2.86 +/- 0.76 (P less than 0.005), respectively, during Na2 ethylenediamine tetra-acetate infusion. Nonsuppressible PTH was again higher with M (13.7 +/- 4.8 pmol/L; P less than 0.0005 vs. L or I) and higher with L (2.8 +/- 0.7 pmol/L, P less than 0.0005 vs. I) than with I (0.5 +/- 0.3 pmol/L). L/I, M/I, and M/L ratios increased from 2.47 +/- 0.97 to 5.35 +/- 2.09 (P less than 0.0005), 8.90 +/- 3.10 to 29.56 +/- 14.89 (P less than 0.0005), and 3.62 +/- 0.90 to 5.30 +/- 1.91 (P less than 0.005) during CaCl2 infusion. The set-point for PTH stimulation by calcium was similar for M (1.15 +/- 0.035 mmol/L) and L (1.175 +/- 0.041 mmol/L) but significantly higher with the I assay (1.184 +/- 0.31 mmol/L; P less than 0.0005 vs. M). The M/I, L/I, and M/L ratio set-points were similar at 1.28 +/- 0.01, 1.27 +/- 0.01, and 1.29 +/- 0.02 mmol/L. Thus, even if proportionately more intact PTH and less carboxylterminal fragments are produced and secreted during hypocalcemia, the latter still predominate in the circulation. Furthermore, at high calcium values, secretion of fragments is less well inhibited than that of intact hormone. The lower secretion and higher ratio set-points suggest that the secretion and intracellular degradation of PTH have different sensitivities to inhibition by calcium.     

Potassium depletion exacerbates essential hypertension

OBJECTIVE: To determine the effect of potassium depletion on blood pressure in patients with essential hypertension. DESIGN: Double-blind, randomized, crossover study, with each patient serving as his or her own control. SETTING: Clinical research center at a university hospital. PATIENTS: Twelve patients with hypertension. INTERVENTIONS: Patients were placed on 10-day isocaloric diets providing a daily potassium intake of either 16 mmol or 96 mmol. The intake of sodium (120 mmol/d) and other minerals was kept constant. On day 11 each patient received a 2-litre isotonic saline infusion over 4 hours. MEASUREMENTS: Blood pressure; urinary excretion rates for sodium, potassium, calcium, and phosphorous; glomerular filtration rate; renal plasma flow; and plasma levels of vasoactive hormones. MAIN RESULTS: With low potassium intake, systolic blood pressure increased (P = 0.01) by 7 mm Hg (95% CI, 3 mm Hg to 11 mm Hg) and diastolic pressure increased (P = 0.04) by 6 mm Hg (CI, 1 mm Hg to 11 mm Hg), whereas plasma potassium concentration decreased (P less than 0.001) by 0.8 mmol/L (CI, 0.4 to 1.0 mmol/L). In response to a 2-litre isotonic saline infusion, the mean arterial pressure increased similarly on both diets but reached higher levels on low potassium intake (115 +/- 2 mm Hg compared with 109 +/- 2 mm Hg, P = 0.03). Potassium depletion was associated with a decrease in sodium excretion (83 +/- 6 mmol/d compared with 110 +/- 5 mmol/d, P less than 0.001). Plasma renin activity and plasma aldosterone concentrations also decreased in patients during low potassium intake, but concentrations of arginine vasopressin and atrial natriuretic peptide, glomerular filtration rate, and renal plasma flow were unchanged. Further, low potassium intake increased urinary excretion of calcium and phosphorus and of plasma immunoreactive parathyroid hormone levels. CONCLUSION: Dietary potassium restriction increases blood pressure in patients with essential hypertension. Both sodium retention and calcium depletion may contribute to the increase in blood pressure during potassium depletion.     

The effect of hypermagnesaemia on serum immunoreactive calcitonin levels in normal human subjects

The effect of hypermagnesaemia on serum levels of immunoreactive calcitonin was studied in normal human subjects. After iv administration of magnesium sulphate over 120 min, the mean (+/- SEM) serum magnesium concentration rose from the baseline level of 0.9 +/- 0.1 to 2.6 +/- 0.3 mmol/l (P less than 0.01), and thereafter remained higher than the baseline level. The magnesium infusion caused a significant increase in serum immunoreactive calcitonin levels (P less than 0.01). The rise in serum magnesium concentration was accompanied by a significant decrease in the concentrations of corrected serum calcium and whole blood ionized calcium (P less than 0.01, P less than 0.01 respectively). Our results suggest that hypermagnesaemia causes an increase in serum immunoreactive calcitonin levels in normal human subjects despite a decrease in the concentrations of corrected serum calcium and whole blood ionized calcium.     

Hypocalcemia and parathyroid hormone responsiveness in diabetes mellitus: a tri-sodium-citrate clamp study.

The aim of this study was to elucidate the diabetic hypocalcemia and PTH responsiveness, investigated by measuring blood ionized calcium and serum intact parathyroid hormone (S-PTH(1-84)) concentrations, before and during an induced and maintained controlled hypocalcemia. In 15 patients with insulin-dependent diabetes mellitus and 19 healthy volunteers the blood ionized calcium concentration was lowered by about 0.20 mmol/l and maintained at this level by blood ionized calcium controlled tri-sodium-citrate infusion. In patients vs controls, baseline measurements averaged for blood ionized calcium (mmol/l) 1.18 +/- 0.08 vs 1.24 +/- 0.03 (p less than 0.01), for S-magnesium (mmol/l) 0.73 +/- 0.07 vs 0.81 +/- 0.07 (p less than 0.01) and for S-PTH (1-84) (pmol/l) 3.0 +/- 1.0 vs 3.1 +/- 1.0 (p greater than 0.75). During the clamp, S-PTH (1-84) peaked to comparable maximums after 5-10 min in both groups and then declined to constant concentrations two to three times above their control levels. In conclusion, we found a diabetic hypocalcemia and hypomagnesemia, though baseline levels of PTH and PTH responsiveness were normal. This may be taken to indicate a mild shift downwards in the set-point for PTH secretion in patients with insulin-dependent diabetes mellitus.     

Insulin resistance in multiple aspects of intermediary metabolism in myotonic dystrophy

The responses of circulating intermediary metabolites to a low-dose incremental insulin infusion (basal, 0.005, 0.01, and 0.05 U.kg-1.h-1) were examined in eight ambulant subjects with the multisystem disorder, myotonic dystrophy. Eight healthy subjects matched for age, gender, and body mass index served as controls. Oral glucose tolerance (75 g) was normal in all subjects. Basal (postabsorptive) hyperinsulinemia was observed in the subjects with myotonic dystrophy (8.4 +/- 2.0 v 2.3 +/- 0.2 mU/L, P less than .01) with increased basal C-peptide levels. Basal blood glycerol (0.09 +/- 0.02 v 0.05 +/- 0.01 mmol/L, P less than .05), lactate (1.14 +/- 0.12 v 0.77 +/- 0.07 mmol/L, P less than .02), and pyruvate (0.08 +/- 0.01 v 0.05 +/- 0.01 mmol/L, P less than .02) were also elevated in these subjects. During the incremental insulin infusion, circulating insulin (F = 8.2, P less than .02) and C-peptide (F = 5.1, P less than .05) levels were significantly higher in the myotonic subjects. Despite the hyperinsulinemia, circulating concentrations of lactate (F = 9.8, P less than .01), pyruvate (7.8, P less than .02), and glycerol (F = 7.5, P less than .02) were also higher in the subjects with myotonic dystrophy, providing prima facie evidence of insulin resistance in the regulation of these metabolites. During the highest insulin rate, isotopically determined metabolic clearance rate of glucose was significantly lower in the myotonic subjects (3.6 +/- 0.4 v 5.5 +/- 0.7 mL.kg-1.min-1, P less than .05), indicating impaired peripheral glucose metabolism.(ABSTRACT TRUNCATED AT 250 WORDS)     

Corticotropin-releasing activity of gastrin-releasing peptide in normal men

Gastrin-releasing peptide (GRP; mammalian bombesin) exerts several functions within the hypothalamus and is a putative regulator of pituitary hormone secretion. We investigated the effect of GRP on the secretion of pituitary hormones and cortisol in normal men. GRP was infused iv as primed infusions of 0.12 pmol/kg BW. min for 30 min (GRP I) and 1.50 pmol/kg. min for an additional 30 min (GRP II). GRP dose-dependently stimulated ACTH secretion compared with the effect of saline [net change in ACTH (delta ACTH) before and after treatment: GRP I, 3 +/- 1 (+/- SEM) vs. 0 +/- 1 pmol/L (P less than 0.05); GRP II, 5 +/- 1 vs. -3 +/- 1 pmol/L; P less than 0.01)]. A further increase in plasma ACTH concentration occurred after cessation of GRP infusion (7 +/- 2 vs. 0 +/- 1 pmol/L; P less than 0.025). GRP caused a similar dose-dependent stimulation of cortisol secretion compared with the effect of saline [delta cortisol before and after treatment: GRP I, -19 +/- 21 vs. -68 +/- 14 nmol/L (P less than 0.05); GRP II, 38 +/- 33 vs. -86 +/- 15 nmol/L (P less than 0.005)]. The serum cortisol concentration increased further after cessation of the GRP infusion (72 +/- 31 vs. -124 +/- 33 nmol/L; P less than 0.0025). GRP dose-dependently stimulated beta-endorphin immunoreactivity compared with the effect of saline [delta beta-endorphin immunoreactivity before and after treatment: GRP I, 6 +/- 1 vs. -3 +/- 1 pmol/L (P less than 0.01); GRP II, 11 +/- 4 vs. -6 +/- 2 pg/mL (P less than 0.025)]. GRP had no effect on PRL or GH secretion. We suggest that GRP participates in the neuroendocrine regulation of the secretion of proopiomelanocortin-derived peptides.     

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.     

Significance of intracellular free calcium and magnesium and calcium-regulating hormones with sodium chloride loading in patients with essential hypertension.

This study was designed: (1) to test the hypothesis that the pressor response to sodium chloride loading in patients with essential hypertension is associated with disorder of divalent cations (calcium and magnesium); and (2) to clarify the relationship between intracellular free calcium concentration and serum levels of calcium-regulating factors and intracellular magnesium concentration. With sodium chloride loading, mean blood pressure, urinary calcium and magnesium excretions and platelet calcium concentration were increased, and serum total and ionized calcium, magnesium concentrations and erythrocyte magnesium concentration were decreased. Change in mean blood pressure was correlated with changes in parathyroid hormone (r = 0.49, P less than 0.05), serum total and ionized calcium (r = -0.50, P less than 0.05) and erythrocyte magnesium (r = -0.56, P less than 0.05) and platelet calcium concentrations (r = 0.46, P less than 0.05). In addition, change in platelet calcium concentration was related to changes in parathyroid hormone (r = 0.44, P = 0.05), serum total and ionized calcium (r = -0.66, P less than 0.01) and erythrocyte magnesium concentration (r = -0.49, P less than 0.05). It is concluded that the pressor effect of excessive sodium chloride intake on blood pressure in patients with essential hypertension is associated with a disorder of divalent cations and that alteration of the intracellular free calcium concentration with sodium chloride loading may occur through handling of serum total and ionized calcium, parathyroid hormone and/or intracellular magnesium concentration.     

Changes in lipoproteins induced by the remnant kidney tissue or binephrectomy in chronic uremic patients treated by hemodialysis

The role of the remmant kidney tissue in uremic patients undergoing hemodialysis treatment has rarely been considered to influence the changes in lipoprotein and lipid metabolism. Twenty hemodialyzed patients with remnant kidneys and 11 anephric patients were studied to examine whether the presence or the absence of remnant kidney leads to qualitative or quantitative changes of the lipids and lipoproteins. Anephric patients showed a significantly higher triglyceride level, 3.66 +/- 0.49 (SEM) mmol/L v 2.34 +/- 0.09 mmol/L in patients with remnant kidneys (P less than .01), higher very-low-density lipoprotein (VLDL) triglycerides, 1.24 +/- 0.30 mmol/L v 0.69 +/- 0.09 (P less than .04), and higher HDL-triglycerides, 1.22 +/- 0.29 mmol/L v 0.66 +/- 0.09 mmol/L (P less than .04). APO-AI was significantly decreased in anephric patients, 95.2 +/- 13.3 mg/dL v 129.7 +/- 6.02 mg/dL in patients with remnant kidneys (P less than .01). APO-B was similar in both groups. All APO-C and APO-E were significantly lower in anephric patients, APO-CI 6.13 +/- 0.87 mg/dL v 8.47 +/- 0.42 mg/dL in patients with remnant kidneys (P less than .01), APO CII 1.00 +/- 0.01 mg/dL v 10.0 +/- 0.01 mg/dL (P less than .0001), APO-CIII 10.12 +/- 1.43 mg/dL v 26.0 +/- 2.86 mg/dL (P less than .0005), and APO-E 8.0 +/- 0.02 mg/dL v 12.0 +/- 0.01 mg/dL (P less than .03). These results point out important differences between women and men. In women binephrectomy promotes a decreased concentration of all APO-C but has no influence on APO-AI concentration.(ABSTRACT TRUNCATED AT 250 WORDS)     

Nicardipine Infusion Improved Hepatic Function But Failed to Reduce Hepatic Venous Pressure Gradient in Patients with Cirrhosis

We investigated the effects of nicardipine on systemic and splanchnic hemodynamics and on liver function in 16 patients with cirrhosis and portal hypertension. Patients received a continuous infusion of 0.3 mg/min of nicardipine (n = 10) and a control infusion (n = 6). No significant changes were observed after a control infusion. In contrast, systemic vasodilatation, evidenced by a significant fall in mean arterial pressure (-14%, p less than 0.01) and systemic vascular resistance (-30%, p less than 0.01), increased heart rate (+8%, p less than 0.01) and cardiac output (+21%, p less than 0.01), and increased hepatic blood flow (+43%, p less than 0.01) were observed at 60 min after a continuous infusion of nicardipine. Although nicardipine improved hepatic function (intrinsic clearance from 0.29 +/- 0.13 to 0.33 +/- 0.15 L/min, p less than 0.05), portal pressure evaluated by hepatic venous pressure gradient was not reduced significantly (from 16.3 +/- 4.9 to 15.1 +/- 5.7 mm Hg; NS). We conclude that a continuous infusion of nicardipine improves liver function but has no beneficial effect on portal pressure in patients with cirrhosis.     

Intralymphocytic sodium and free calcium and plasma renin in essential hypertension

Intracellular sodium, potassium, and free calcium concentrations were investigated in lymphocytes of 30 patients with essential hypertension and 30 normotensive controls. All subjects were placed on a diet containing 8 to 10 g of sodium chloride per day. Lymphocyte sodium concentration was higher in hypertensive patients than in normotensive controls (19.8 +/- 1.8 vs 18.4 +/- 1.8 mmol/kg wet weight; p less than 0.01), whereas lymphocyte potassium concentration was similar in both groups. Lymphocyte free calcium concentration was also higher in hypertensive patients than in normotensive controls (134.6 +/- 13.2 vs 120.2 +/- 16.4 nmol/L; p less than 0.01). There was a positive correlation between lymphocyte sodium and free calcium concentrations in normotensive controls, in hypertensive patients, and in the subjects combined (r = 0.59, p less than 0.01; r = 0.71, p less than 0.001; and r = 0.70, p less than 0.001, respectively). Lymphocyte potassium concentration was not related to lymphocyte sodium or free calcium concentration in each group. In patients with essential hypertension, intracellular sodium and free calcium concentrations were negatively correlated with plasma renin activity (r = -0.66, p less than 0.001; r = -0.60, p less than 0.001, plasma norepinephrine concentration. These results suggest that a considerable relationship exists between intracellular sodium and free calcium in lymphocytes and that, in essential hypertension, the alteration in cellular metabolism of sodium and calcium may be linked to the renin system but not to blood pressure, age, or adrenergic activity.     

Inotropic effect of nicardipine in patients with heart failure: assessment by left ventricular end-systolic pressure-volume analysis

Nicardipine, a new dihydropyridine calcium channel blocker, has been investigated for the treatment of coronary artery disease and heart failure. To assess the inotropic effect of nicardipine in humans independent of its vasodilator effect, equihypotensive doses of intravenous nitroprusside (mean infusion rate 65 +/- 13 micrograms/min) and nicardipine (mean dose 5.2 +/- 0.4 mg) were administered to 15 patients with heart failure (New York Heart Association functional classes II to IV, radionuclide left ventricular ejection fraction 0.15 +/- 0.02). Left ventricular micromanometer pressure and simultaneous radionuclide left ventricular volume were obtained at baseline, during nitroprusside infusion, during a second baseline period and during nicardipine infusion. Heart rate did not change significantly with either nitroprusside or nicardipine. Mean systemic arterial pressure decreased by an average of 21 mm Hg with both drugs. A greater decrease in left ventricular end-diastolic pressure occurred with nitroprusside (27 +/- 2 to 14 +/- 2 mm Hg, p less than 0.01) than with nicardipine (27 +/- 2 to 23 +/- 3 mm Hg, p less than 0.05), and pulmonary capillary wedge pressure decreased significantly only with nitroprusside. Cardiac index increased from 1.8 +/- 0.1 to 2.1 +/- 0.1 liters/min per m2 (p less than 0.05) with nitroprusside and to a greater extent from 1.7 +/- 0.1 to 2.4 +/- 0.1 liters/min per m2 (p less than 0.01) with nicardipine. Left ventricular ejection fraction increased with nicardipine (0.15 +/- 0.01 to 0.19 +/- 0.01, p less than 0.01), but not with nitroprusside. Peak positive first derivative of left ventricular pressure (dP/dt) decreased by 9% with both agents.(ABSTRACT TRUNCATED AT 250 WORDS)     

Hysteresis in the relationship between serum ionized calcium and intact parathyroid hormone during recovery from induced hyper- and hypocalcemia in normal humans

We have used an immunoradiometric assay for intact PTH in conjunction with calcium and citrate infusions to study whether levels of intact PTH are responsive to reversal of the direction of change in ionized calcium in normal humans. Eleven normal subjects received graded infusions of citrate or calcium on separate days to produce linear rates of decrease or increase in calcium. After discontinuation of the infusions, the return of calcium toward baseline was followed. Six subjects were given an infusion of citrate after the calcium infusion to speed the recovery of calcium toward baseline. Citrate-induced hypocalcemia produced a rise in serum PTH levels from 28.1 +/- 3.6 to 69.4 +/- 4.8 ng/L as calcium fell from 1.26 +/- 0.01 to 1.06 +/- 0.02 mmol/L. As calcium returned toward baseline, PTH levels fell dramatically, reaching levels indistinguishable from baseline despite persistent hypocalcemia. Slopes of regression lines defining the PTH-calcium relationships during decreasing and increasing calcium levels were significantly different. Those subjects receiving a calcium infusion alone showed a prompt suppression of PTH levels. As calcium returned toward baseline after the infusion, a modest decline in calcium produced no significant change in the PTH-calcium relationship. When citrate was used to return calcium to baseline, PTH levels rose from 7.8 +/- 2.0 to 55.0 +/- 6.8 ng/L as calcium fell from 1.42 +/- 0.02 to 1.26 +/- 0.02 mmol/L and defined a regression relationship significantly different from the period of increasing calcium. Thus, a hysteretic relationship between ionized calcium and levels of intact PTH can be induced in normal humans by reversing the direction of change in calcium. Therefore, the role played by calcium concentration per se in controlling PTH secretion may be part of more complex and dynamic regulatory mechanisms.