Constant Infusion Technique Research Articles

Arginine vasopressin metabolism in dogs. I. Evidence for a receptor-mediated mechanism.

The plasma clearance rates (PCR) of arginine vasopressin (AVP), and iodinated AVP (125I-AVP) were determined after pulse injection in conscious water-loaded dogs. Both the PCR and the apparent initial volume of distribution were significantly greater for AVP than for the biologically inactive iodinated AVP 37.4 +/- 4.8 ml/kg per min vs. 6.7 +/- 0.8 ml/kg per min (P less than 0.001) and 12.7 +/- 0.9% body wt vs. 7.1 +/- 0.4% body wt (P less than 0.001). AVP clearance was then determined by the constant-infusion technique at doses that produced equilibrium AVP concentrations within and above the physiological range. AVP-PCR was 37.4 +/- 7.1 ml/kg per min at 34 microU/kg per min, which was comparable to that after pulse injection (P less than 0.9). AVP clearance fell progressively, and urine osmolality progressively increased with increasing AVP infusion rates to plateau values at 136 microU/kg per min; a strong negative correlation was observed between mean AVP-PCR and urine osmolality (r = -0.993). The data suggest a relationship between the biological activity of AVP and its clearance. It is proposed that plasma membrane receptors may mediate a portion of the metabolic clearance of AVP.

Kinetics of testosterone metabolism in normal postmenopausal women and women with breast cancer

The constant infusion and single injection techniques were utilized to study the kinetics of 3H-testosterone (T) metabolism in postmenopausal women with and without breast cancer. The metabolic clearance rates (mean ± SEM) for normal postmenopausal women were 578 ± 82 and 644 ±128 1 24 h as obtained by the constant infusion and single injection techniques, respectively. The corresponding results for the women with breast cancer (patients) are 644 ± 25 and 617 ± 106 1 24 h . The single injection technique yielded values for rate constants (units) and volumes of distribution (1); k 1 = 37.5 ± 1.6 for the normals and 34.5 ±1.9 for the patients. K 2 = 76.6 ± 5.1 for the normals and 71.1 ± 1.6 for the patients, V 1 = 7.9 ± 2.2 for the normals and 8.7 ± 1.4 for the patients and V 2 = 7.0 ± 1.5 for the normals and 6.4 ± 1.2 for the patients. The constant infusion technique yielded values for the conversion ratios for the transformation of T to several products; 4-androstene-3,17-dione/T of 0.02 ± 0.003 for normals and 0.03± 0.002 for patients, 5α-dihydrotestosterone/T of 0.02 ± 0.002 for normals and 0.03 ± 0.002 for patients, estrone/T of 0.04 ± 0.01 for normals and 0.04 ± 0.01 for patients, estradiol-17β/T of 0.02 ± 0.005 for normals and 0.03 ± 0.005 for patients and estrone sulfate/T of O.16 ± 0.02 for normals and 0.24 ± 0.06 for patients. The T plasma concentrations and production rates were similar for the two groups of subjects. Hence there were no significant differences between the normals and the patients for all the kinetic parameters. It was determined that all the estradiol being produced in postmenopausal women could be coming from circulating T.

Dehydroepiandrosterone: Kinetics of Metabolism in Normal Men and Women*

The single injection and constant infusion techniques were utilized to study the kinetics of dehydroepiandrosterone (DHEA) metabolism and its peripheral conversion to several other C19-steroids including C19-steroid sulfates. The MCRs (mean +/- SEM) for normal men and normal women were 1866 +/- 144 and 1901 +/- 87 liters/24 h, respectively. The single injection technique yielded values for rate constants (units) and volumes of distribution (1) as follows: K1, 42.6 +/- 7.7 for men and 37.1 +/- 5.0 for women; K2, 64.3 +/- 11.2 for men and 55.5 +/- 5.0 for women; K2, 64.3 +/- 11.2 for men and 55.5 +/- 5.0 for women; V1, 38.5 +/- 6.0 for men and 33.7 +/- 2.5 for women; V2, 30.4 +/- 7.3 for men and 27.5 +/- 9.9 for women. The constant infusion technique yielded values for the conversion ratios for the transformation of DHEA to several products: delta 5-androstene-3 beta, 17 beta-diol to DHEA of 0.10 +/- 0.01 for men and 0.16 +/- 0.03 for women, delta 4-androstenedione to DHEA of 0.04 +/- 0.01 for men and 0.07 +/- 0.02 for women, DHEA sulfate (DHEAS) to DHEA of 6.36 +/- 0.81 for men and 10.09 +/- 0.87 for women, delta 5-androstene-3 beta, 17 beta-diol sulfate to DHEA of 0.42 +/- 0.06 for men and 0.50 +/- 0.04 for women, and androsterone sulfate to DHEA of 1.11 +/- 0.13 for men and 2.06 +/- 0.18 for women. The ratios for the conversion to DHEA sulfate and androsterone sulfate were significantly higher for women than men. The plasma concentrations of DHEA were 8.50 +/- 0.95 and 8.75 +/- 1.01 ng/ml for men and women, respectively. The calculated production rates for DHEA were 16.34 +/- 2.66 and 16.19 +/- 1.78 mg/24 h for men and women, respectively. There was no sex difference in the binding of DHEA to plasma proteins and this is reflected in the lack of sex difference in the MCRs. Calculations indicate that DHEA is a major precursor of circulating delta 5-diol.

Estimation of rate of protein synthesis by constant infusion of labelled amino acids in pigs

1. The fractional synthetic rates of tissue proteins were studied in growing pigs using the constant-infusion technique of tracer-labelled amino acids ([14C]leucine and [14C]lysine) and the mathetmatical model for calculation, employed in rats by Garlick, Millward & James (1973). 2. During a 6 h infusion, samples were taken from blood and muscle and at the end of the infusion from liver, muscle, pancreas, heart, duodenum, jejunum, ileum, colon, and skin. The specific radioactivity of free and protein-bound leucine and lysine was estimated. 3. A quasi-steady-state in the specific radioactivity of free plasma leucine and lysine was reached within approximately 2 h, the rate-constants being 35 and 48/d respectively. 4. The specific radioactivity of free leucine and lysine in plasma was used to calculate the flux of these amino acids. It was found to be higher than the daily intake. 5. The average fractional rate of protein synthesis in muscle and heart 8.1% d, in small and large intestine the values were 50 and 33% d respectively and in liver and pancreas more than 100% d. 6. The calculation of protein synthetic rate in pig tissue using the constant-infusion method of labelled amino acids seems to be a suitable toof for study of this species.

Effect of Adrenocorticotropin on Production Rates and Metabolic Clearance Rates of Testosterone and Estradiol*

Using the constant infusion technique, [7-3H]testosterone and [4-l4C]estradiol were infused into six men and two women and [7-3H]androstenedione and [4-l4C]estrone were infused into two men before and after the administration of 60 U ACTH every 12 h for four doses. Measurements of the MCRs, plasma levels of endogenous hormones, and blood production rates (PBs) were performed before and after ACTH. The fraction of infused androgen converted to and measured as estrogen ([ρ]AND,ESTBB) was also determined before and after ACTH. In all six men, ACTH caused a significant rise in the mean value for the MCR of testosterone from 900 ± 80 to 1250 ± 80 (SE) liters/day, a significant decrease in the mean value for levels of testosterone from 5.2 ± 0.9 to 2.0 ± 0.6 ng/ml, and a significant decrease in the PB of testosterone from 4.5 ± 0.5 to 2.3 ± 0.6 mg/day. In both women, MCR of testosterone rose, the plasma levels remained essentially unchanged, and the PBS increased. In the men, ACTH administration resulted in a nonsignificant rise in the MCR of estradiol from 1760 ± 50 to 2010 ± 120 liters/day, and no change in the circulating level (30 ± 2 to 26 ± 2 pg/ml) or the PB (53 ± 4 to 54 ± 6 μg/day). The fractional conversion of testosterone to estradiol, [ρ]T,2BB, did not change (0.0032 ± 0.0006 to 0.0032 ± 0.0004). In both women, the MCR for estradiol rose, but the changes in levels and estradiol PB were divergent. In both men, although the MCRs for androstenedione and estrone did not change appreciably, the circulating levels and PBS rose. The mean level of LH in six men did not change under these conditions (51 ± 11 before and 57 ± 11 ng/ml after ACTH). We conclude that in men, ACTH increases the metabolism of testosterone and decreases its circulating level, synthesis, and production rate. During the course of the study, LH levels did not rise in response to the fall in testosterone. The circulating level and PB of estradiol remain unchanged because ACTH results in increased production of androstenedione and estrone, both of which are converted to estradiol. In women, the PB of testosterone does not fall after ACTH, presumably because of the increased PB of androstenedione.

Kinetics of human connecting peptide in normal and diabetic subjects.

The metabolic clearance rate (MCR) of synthetic human connecting peptide (C-peptide) was measured with a single-dose injection technique in six normal and seven diabetic subjects and with a constant infusion technique in one normal subject. The MCR of C-peptide did not differ in normal subjects (4.4 ml/min per kg; range, 3.7-4.9) and in diabetic subjects (4.7 ml/min per kg; range, 3.7-5.8). Employment of both techniques in one subject gave similar MCR. The average half-life of C-peptide in plasma calculated from the last 1-h period of the single-dose injection studies was longer in the insulin-dependent diabetics (42.5 min; range, 39.4-48.5) than in the normal subjects (33.5 min; range, 24.9-45.3). These results indicate that the beta-cell secretory capacity of normal and insulin-dependent diabetic subjects can be compared by measuring the C-peptide concentration in peripheral venous plasma. The difference in the half-life of C-peptide in plasma between diabetics and normals suggests an altered kinetics of the disappearance of the peptide, while the overall metabolism, as expressed by the MCR, is similar.

MALE PSEUDOHERMAPHRODITISM WITH GYNAECOMASTIA DUE TO TESTICULAR 17-KETOSTEROID REDUCTASE DEFICIENCY

SUMMARY A 28-year-old male pseudohermaphrodite with gynaecomastia was raised as a female until the age of 17 years, at which time he developed masculine features (deepening of the voice, development of facial hair, male distribution of body hair and male body habitus) and assumed a male gender role. He had a small phallus with perineal urethra, absence of labioscrotal fusion, presence of vaginal pouch and undescended testes. The testicular biopsy showed hyalinization of the tubular basement membrane, lack of spermatogenesis and hyperplastic Leydig cells. Baseline peripheral plasma studies showed androstenedione concentrations ten times normal, low testosterone, elevated oestrone and elevated gonadotrophins. The in vitro incubation of testicular tissue showed no significant conversion of androstenedione to testosterone. However, two types of peripheral tissues, skin fibroblasts and erythrocytes, had a normal conversion, as did the body overall as measured by the technique of androstenedione constant infusion. These studies demonstrate that the 17-keto-steroid reductase deficiency of the patient was limited to the testes.

3,3'-Diiodothyronine production, a major pathway of peripheral iodothyronine metabolism in man.

3,3'-Diiodothyronine (3,3'-T(2)) has been detected in human serum and in thyroglobulin. However, no quantitative assessment of its clearance rate (CR), production rate (PR), or of the importance of extrathyroidal sources of 3,3'-T(2) relative to direct thyroidal secretion is yet available. This study examines these parameters in seven euthyroid subjects, and in eight athyreotic subjects (H) eumetabolic due to thyroxine therapy (HT(4)) (n = 5) or triiodothyronine replacement (HT(3)) (n = 3). A highly specific radioimmunoassay for the measurement of 3,3'-T(2) in whole serum was developed. Serum 3,3'-T(2) concentrations were (mean +/- SD) 6.0+/-1.0 ng/100 ml in 13 normal subjects, 9.0+/-4.6 ng/100 ml in 25 hyperthyroid patients, and 2.7+/-1.1 ng/100 ml in 17 hypothyroid patients. The values in each of the latter two groups were significantly different from normal. 3,3'-T(2) was detected regularly in normal concentrations in 11 hypothyroid patients eumetabolic by treatment with synthetic T(4), in 10 eumetabolic patients suffering from nonthyroidal systemic illness, and in 2 subjects with elevated serum T(4)-binding globulin. The 3,3'-T(2) CR was assessed from data acquired from the (125)I-3,3'-T(2) constant infusion technique. The 3,3'-T(2) PR was calculated from CR and serum concentration of 3,3'-T(2) determined by radio-immunoassay. In the HT(4) subjects the 3,3'-T(2) CR averaged 840+/-377 liters/day and 3,3'-T(2) PR 33.9+/-12.5 mug/day. These results were not significantly different from those in the control group: 3,3'-T(2) CR 628+/-218 liters/day and 3,3'-T(2) PR 39.8+/-19.8 mug/day (all corrected to 70 kg body wt). In addition to 3,3'-T(2) PR, T(3), and reverse triiodothyronine (rT(3)) PR were determined in three of the HT(4) subjects. In each case studied, the 3,3'-T(2) PR was close to the combined triiodothyronine (T(3) + rT(3)) PR. The mean molar ratio of T(2) PR/(T(3) + rT(3)) PR was 1.08+/-0.10. The results obtained in the HT(4) subjects indicate that the production of 3,3'-T(2) is a major route of T(4) metabolism. The combined studies of 3,3'-T(2), T(3) and rT(3) PR in the HT(4) subjects indicate that both T(3) and rT(3) are major precursors of 3,3'-T(2). In the HT(3) subjects, the conversion of T(3) to 3,3'-T(2), determined as the molar ratio of 3,3'-T(2) PR to T(3) PR, ranged from 0.36 to 0.92, providing further evidence that T(3) is a precursor of 3,3'-T(2). From the close agreement between the mean values for 3,3'-T(2) PR in the euthyroid and HT(4) group it is concluded that most, if not all of the 3,3'-T(2) produced in normal humans is derived by extrathyroidal conversion from T(3) and rT(3).

Glucoregulatory Response to Insulin-Induced Hypoglycemia in Laennec’s Cirrhosis

The glucoregulatory response to hypoglycemia induced by the iv injection of 0.15 U/kg insulin was studied in eight normal subjects and 11 cirrhotic patients after an overnight fast. Glucose release by the liver (Ra) and tissue uptake (Rd) were determined by the primed constant infusion technique using [3–3H]– glucose. Under basal conditions, no significant differences in plasma glucose, Ra, and Rd between the two groups were observed, whereas hyperinsulinemia and hyperglucagonemia were present in cirrhotics. After insulin injection, the pattern of the hypoglycemic response was similar in the two groups. In normal subjects, Ra displayed a prompt fall soon after insulin and then rose to a peak 74% above the baseline at 60 min, whereas in cirrhotics, the initial fall in Ra was significantly greater and the recovery was slower and delayed. The enhancement of glucose uptake by insulin was less marked in cirrhotics than in controls; the reduced responsiveness to insulin effect was also evident if the tissue sen...

867 ESTIMATION OF GLUCOSE PRODUCTION IN THE HUMAN NEWBORN USING SIMULTANEOUS 13C-AND D-LABELLED GLUCOSE

In order to compare two methods of quantifying systemic glucose production (SGP), 5 newborn infants age 2 h-3 days were infused simultaneously with glucose-1-13C (G113C) and glucose-6-6-D2 (G6D2) tracers. The older infants were studied 6 h after a meal. G113C was infused at 6μg/Kg min according to the prime constant rate infusion technique and 13C enrichment of C-1 of glucose measured by enzymatic decarboxylation and mass spectrometry. G6D2 was infused at 60μg/Kg min and deuterium enrichment of glucose measured by gas chromatography-mass spectrometry. SGP was calculated from the tracer dilution assuming steady state kinetics, from 30 min for 13C and from 120 min for D. Although 13C was expected to randomize away from C-1, recycling occurred and was estimated from the difference in rate of SGP quantified by dilution of the two tracers (mean ± S.D.) SGP ranged from 3.5 to 5.1 mg/Kg min. Recycling of glucose C-1 was 11-15% of SGP and it did not change with the age of infant. Conclusion: 1) SGP is established in the human newborn by 2 hours of age. 2) The two stable tracers used give similar estimates of SGP.

Altered metabolism of androgens in elderly men with benign prostatic hyperplasia.

Kinetics of testosterone, dihydrotestosterone (DHT) and 5alpha-androstane-3alpha,17beta-diol (3alpha-diol) were studied in 7 elderly healthy men (ages 61 to 80 years) with benign prostatic hyperplasia (BPH). Clearance rates were determined by the constant infusion technique with labeled testosterone and DHT. Metabolic clearance rate (MCR), conversion ratio (CR), the transfer constants (rho) and production rates (PB) were calculated. Plasma androgens were measured by specific radioimmunoassay. Plasma testosterone was 516 +/- 314 (SD) ng/dl, plasma DHT was 74.6 +/- 19.6 (SD) ng/dl and plasma 3alpha-diol was 16.4 +/- 4.1 (SD) ng/dl. An elevated DHT level in elderly men with BPH wasconfirmed. MCRT was 620 +/- 65 (SD) liter/day and MCRDHT was 393 +/- 50 (SD) liter/day. Both MCRT and MCRDHT in elderly men were significantly lower than in young men. PBT was 3.2 +/- 2.1 (SD) mg/day and PBDHT was 291 +/- 87 (SD)migrogram/day. PBDHT was the same in elderly and young men. DHT production is maintained in elderly men despite reduction of testosterone production. From the data, it was claculated that in contrast to young men where greater than 80% of blood DHT is from secreted testosterone, over 50% in elderly men is derived from secretion or production of DHT by the testis or even more likely the prostate.

Does glucagon play a role in the insulin resistance of patients with adult non-ketotic diabetes?

Using a constant intravenous infusion technique we have measured in vivo insulin resistance in 17 normal subjects, five patients with chemical diabetes, and 13 non-ketotic diabetic patients with fasting hyperglycaemia (FBS greater than 120 mg/100 ml). All of the diabetic patients were non-obese. The results demonstrated that the diabetic patients were insulin resistant compared to normals and that the degree of insulin resistance was greater the more severe the diabetes. No differences in plasma glucagon levels were found among the different groups during the infusion studies. These results demonstrate that non-obese, non-ketotic diabetic patients are insulin resistant and that abnormalities in plasma glucagon concentrations do not account for this insulin resistance.

PROTEIN SYNTHESIS AND CATABOLISM IN HEALTHY CHILDREN, BEFORE AND AFTER ELECTIVE SURGERY

We measured whole body rates of protein synthesis(S) and catabolism(C) in seven healthy children, age 4 to 15 yrs., before reconstructive surgery and in six of them, 5 days post-operatively using a constant 15N infusion technique. Pre-op, S and C fell between reported infant and adult normal values (g prot/kg/d) but did not vary with age of our subjects. S decreased 15% (P<.05) post-op although body weight, intake of protein and calories, N balance, and C did not change. S did correlate with protein (r = +.75) and calorie (r = + .58) intake. Pre-op, mean S (g prot/d) expressed per unit BMR (0.11) or per g protein allowance (5.0) was the same as that previously estimated for infants or adults. Our studies show: 1 Minor surgery causes decreased protein synthetic rate in face of unchanged protein and calorie intake, N balance, and catabolic rate. 2. Energy expenditure relates closely to protein synthetic rates at all ages. 3. The efficiency of N utilization in healthy children is similar to that in infants and adults.

Depression of renal clearance of furosemide in man by azotemia.

The renal clearance of furosemide and tetraethylammonium (TEA) were compared in 10 patients with hypertensive nephropathy. BUN and creatinine ranges were 10 to 88 mg/dl and 0.9 to 3.8 mg/dl, respectively. Diuretics were discontinued 48 hr prior to the study, and 2 consecutive clearances (ml/min/1.73 m2BSA) of creatinine were performed. The patient then received a bolus followed by a constant infusion of furosemide-14C and tetraethylammonium-14C (analyzed by specific methodology for plasma and urine), both in subpharmacologic doses. After 40-min equilibration sequential 20-min clearance periods were obtained. Both the clearance of furosemide (range 17 to 133) and TEA (range 99 to 443) correlated negatively with BUN and serum creatinine and positively with creatinine and urea clearances. Thus, by using a constant-infusion technique we demonstrated that the renal clearance of furosemide is depressed by azotemia in man and that there was greater depression with furosemide than with TEA.

Delta5-androstenediol: kinetics of metabolism and binding to plasma proteins in normal men and women.

Using the constant fusion and single injection technique the metabolic clearance rates (mean +/- SEM) for delta5-androstene-3beta, 17beta-diol (delta5-idol) were measured for 19 normal men (1311 +/- 67 1/24 h) and 10 normal women (858 +/- 63 1/24 h). The constant infusion technique yielded values for the conversation ratios for the transformation of delta5-diol to several products: dehydroepiandrosterone (DHEA)/delta5-diol of 0.06+/-0.01 for men and 0.05 +/- 0.01 for women, of delta5-diol sulfate/delta5-diol of 0.45 +/- 0.04 for men and 0.52 +/- 0.03 for women and of DHEA sulfate/delta5-diol of 5.53 +/- 0.26 for men and 5.02 +/- 0.42 for women. The single injection technique yielded rate constants (units) and volumes of distribution (liters) for delta5-diol; Ki = 34.3 +/- 4.3 for men and 35.0 +/- 3.9 for women, K2 = 63.7 +/- 4.1 for men and 75.1 +/- 4.2 for women, V1 = 23.1 +/- 3.2 for men and 11.9 +/- 2.3 for women, V2 = 14.8 +/- 3.7 for men and 9.2 +/- 3.2 for women. The mean delta5-diol plasma concentration was 1.08 +/- 0.10 ng/ml for 12 men and 1.17 +/- 0.16 ng/ml for 9 women. (he calculated blood production rates for delta5-diol were 1357 +/- 117 mug/24 h for 12 men and 969 +/- 131 mug/24 h for 9 women. The per cent binding (equilibrium dialysis) was higher for women (94.9 +/- 0.3) than for men (93.0 +/- 0.2). Paper electrophoresis showed that significant fractions of 3H-delta5-diol migrated with both the beta-globulin and albumin fractions. Estrogen administration to two normal men increased the per cent binding of delta5-diol to plasma proteins and decreased the metabolic clearance rate towards the values found for normal women.

Biological properties of chemically modified insulins. I. Biological activity of proinsulin and insulin modified at A1-glycine and B29-lysine.

Beef insulin, pork proinsulin and four derivatives of beef insulin modified at the A1-B29 site on the molecular surface have been studied. Three derivatives had a synthetic crosslink between the A and B chains. Previous studies with these materials [2, 3 and 5] had demonstrated in vivo bioactivities which were much higher than those displayed in vitro. This paper reports experiments which explain this discrepancy. The analogues were administered at equimolar rates to anaesthetised greyhounds by a priming-dose constant infusion technique and the plasma concentrations achieved were estimated by radioimmunoassay. Proinsulin and the modified insulins were metabolised more slowly than insulin. Biopotency values, which related fall in plasma glucose concentration to the total administered dose of analogue, agreed broadly with published results of conventional in vivo bioassays. On the other hand, calculation of potency in relation to the serum concentration of analogue actually achieved, yielded results which agreed more closely with in vitro assay data. We conclude that for these analogues, reported discrepancies between in vitro and in vivo biopotencies can be largely explained by the different rates at which these materials are metabolised.

Estimation of tissue protein synthesis in rats fed diets labeled with (U-14C)tyrosine.

The rate of liver and muscle protein synthesis has been measured in 27 rats after feeding L-[U-14C]tyrosine in L-amino acid diets prepared as agar gels. Constant specific activity of the free tyrosine pool, as indicated by constant excretion of 14CO2, was reached within 2 h of feeding and was maintained for the remaining 6 h of the 8-h experiment. Muscle protein synthesis was decreased (P less than 0.05) in rats fed a 0.3% methionine diet compared with rats fed this diet supplemented with 0.51% cystine (fractional rate of synthesis, ks: 0.098 vs. 0.121). No effect (P greater than 0.05) of these diets on liver protein synthesis was observed (ks: 0.603 vs. 0.532). Protein synthetic rate was also determined by the constant-intravenous infusion technique in 17 rats fed unlabeled diets. The two techniques gave similar estimates. Restraint of the rats or the infusion of saline had no measurable effect on the rate of protein synthesis in rats fed labeled diets. This feeding technique is essentially equivalent to the constant-infusion technique and offers an easier, more physiological approach to achieving a steady state.

Inulin Clearance in the Newborn Infant: Relationship to Gestational and Postnatal Age

Thirty-eight healthy newborn infants with gestational ages ranging from 25 to 42 weeks were studied at 2 days to 9 weeks postnatal age to evaluate the rate of glomerular maturation after birth. Glomerular function was assessed by a constant infusion method for inulin clearance (Cin). Cin was nearly identical when measured by the traditional clearance method and by the constant infusion technique. The Cin of 22 infants 2-3 days old ranged from 0.6 to 17.9 ml/min and was directly related to gestational age (r = 0.81, P less than 0.001). For 26 infants studied at 1-9 weeks of age, Cin was directly proportional to conceptual (gestational and postnatal) age (r = 0.89, P less than 0.001), and approximated that of infants of similar gestational age studied at 2-3 days of age.

Aldosterone metabolic clearance is normal in low-renin essential hypertension.

The possibility that an abnormality of aldosterone metabolism plays a role in the pathogenesis of low-renin essential hypertension was investigated. Normal subjects and patients with low-renin or normal-renin essential hypertension were evaluated while in balance, ingesting a diet providing 120 mEq sodium and 70 mEq potassium. Aldosterone metabolic clearances were determined by a constant infusion technique using tritium-labeled aldosterone. Aldosterone secretion rates and plasma aldosterone concentrations were measured by radioimmunoassay. Aldosterone metabolic clearance in normal subjects was 1422 +/- 69 (mean +/- SE) liters/24 hours. In patients with low-renin essential hypertension, aldosterone metabolic clearance was 1351 +/- 61 liters/24 hours, and in patients with normal-renin essential hypertension, it was 1412 +/- 66 liters/24 hours. These values were not significantly different from those of normal subjects. Although aldosterone secretion rates in both groups of hypertensive patients were within the normal range, patients with low-renin essential hypertension, under the conditions of this study, had significantly higher secretion rates than patients with normal-renin essential hypertension. We have concluded that the maintenance of plasma aldosterone in low-renin essential hypertension reflects sustained aldosterone secretion despite suppression of plasma renin activity, rather than reduced aldosterone metabolism. The maintenance of normal aldosterone secretion in low-renin essential hypertension appears to be inappropriate and is not explained by alterations of known regulatory mechanisms.

Lactate metabolism in resting and exercising dogs.

The effect of treadmill run on the turnover rates of glucose ([2-3H]glucose) and lactate ([U-14C]lactate), on the rates of oxidation (ROX) of lactate, and its conversion to glucose (L LEADS TO G) were measured with the primed constant-infusion technique. Comparable lactate turnover rates were obtained at rest by infusing epinephrine, or Na-L(+)-lactate with or without norepinephrine. With increasing lactate levels (L) the rate of disappearance (RdL), ROX, and L leads to G increase in a linear manner. At the same lactate level, RdL, ROX, and L leads to G are significantly higher in the running dog. Exercise increased the metabolic clearance rate of lactate threefold. At rest ROX and L leads to G represented about 50% and 18-19% of RdL, respectively. The corresponding values in the running dogs were 55% and 25%, respectively. At rest about 9% of the hepatic glucose output arose from lactate while during exercise this varied from 7 to 26% depending on RdL. It is concluded that a) the working muscle produces and utilizes lactate at the same time, and b) "in vivo" the major factor which controls both ROX and gluconeogenesis is the substrate supply.