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Biomedical subjects

H Heath

Publications and source records attributed to H Heath.

At least 127 records · Page 7Linked to original sources
PubMed1984

Vitamin D metabolism in familial benign hypercalcemia (hypocalciuric hypercalcemia) differs from that in primary hyperparathyroidism.

We compared serum concentrations of immunoreactive PTH and plasma levels of vitamin D metabolites in 11 patients with adenomatous primary hyperparathyroidism and 32 individuals with the syndrome of familial benign hypercalcemia or familial hypocalciuric hypercalcemia (FHH). Serum immunoreactive PTH was elevated in the hyperparathyroid group but indistinguishable from control in FHH, despite comparable degrees of hypercalcemia. Plasma 25-hydroxyvitamin D concentrations were normal in both groups, but plasma 1,25-dihydroxyvitamin D levels in FHH were significantly lower than control (P less than 0.0025) or hyperparathyroid (P less than 0.01) values. FHH is pathogenetically distinct from primary hyperparathyroidism and should not be thought of simply as a variant of that condition.

Adult↗
PubMed1984

Increased renal responses to exogenous parathyroid hormone in postsurgical hypoparathyroidism.

Prior exposure to excess PTH desensitizes the kidney to subsequent doses of the hormone. We tested the hypothesis that prior deficiency of PTH would increase renal responsiveness to the agent. Ten normal subjects and nine patients with treated chronic postsurgical hypoparathyroidism received infusions of synthetic human PTH fragment 1-34 [hPTH-(1-34), Armour], 200 U over 10 min. All subjects responded to hPTH-(1-34) infusion with marked increases in plasma and urinary cAMP and phosphaturia. Mean (and median) urinary cAMP responses in the hypoparathyroid subjects were 62% (and 91%) above the responses in normal subjects, while mean (and median) nephrogenous cAMP responses were 65% (and 88%) higher than those in normal subjects. Mean (and median) phosphaturic responses to hPTH-(1-34) in hypoparathyroidism were 49% (and 52%) above normal subjects' responses. All of these differences were statistically significant. These data and others from the literature suggest that chronic hypoparathyroidism enhances renal responses to PTH, consistent with the concept of hormonal regulation of tissue sensitivity to the hormone.

Adult↗
PubMed1984

"Nonspecific" increases in plasma immunoreactive calcitonin in healthy individuals: discrimination from medullary thyroid carcinoma by a new extraction technique.

Occasional seemingly healthy individuals have above-normal concentrations of calcitonin-like immunoreactivity in their plasma, which can lead to mistaken diagnosis of thyroidal or other cancer. We measured immunoreactive calcitonin (CT) before and after extracting the plasma on columns of silica (to improve sensitivity and specificity of the assay for monomeric calcitonin) in five "healthy high-CT" men (I), five patients with known medullary thyroid carcinoma (II), and 30 normal controls (III). Median (and range) values (pg/mL = ng/L) for whole-plasma immunoreactive CT in these groups were, respectively, 379 (157-526), 429 (174-563), and 33 (less than 25-92). Dose-dilution curves for plasma samples from group I did not parallel the standard curve, in contrast to samples from the other two groups. Values for extractable CT from plasma from groups I and III, however, were indistinguishable, but remained significantly increased in group II. Infusions of Ca, 2 mg/kg body wt. in 5 min, produced the expected (normal) increases in extractable CT in group I. The occasional factor (or factors) in plasma of healthy persons that interferes in assays for CT is eliminated by the silica extraction method, and in this way such cases can be distinguished from cases of medullary thyroid carcinoma.

Adult↗
PubMed1984

Radioimmunoassay of calcitonin in normal human plasma: problems, perspectives and prospects.

Radioimmunoassay of calcitonin in normal human plasma is hindered by immunochemical heterogeneity in plasma, variable susceptibility of antisera to non-specific factors, limited assay sensitivity, and other problems. Many controversial points in the literature arise from these difficulties. Measurement of calcitonin after various extraction procedures yields greater consistency of results. Recent advances in calcitonin assay technology offer the promise of measuring calcitonin monomer with sufficient sensitivity to permit studies of normal calcitonin physiology and of the hormone's role in human disease.

Animals↗
PubMed1983

Inhibition of aldose reductase in five tissues of the streptozotocin-diabetic rat.

For 22 days, streptozotocin-diabetic and normal rats were intubated once daily with ICI 105552 (1-(3,4-dichlorobenzyl)-3-methyl-1,2-dihydro-2-oxoquinol-4-ylacetic acid, sodium salt: 50 mg/kg body weight) an inhibitor of aldose reductase (EC 1.1.1.21), the first enzyme of the sorbitol pathway. Treatment with ICI 105552 affected neither glycaemia nor tissue glucose nor inositol concentrations yet reduced significantly the abnormal accumulations in diabetes of sorbitol in the lens (70% reduction), sciatic nerve (86%) and seminal vesicles with coagulating glands (S.V.C.G., 55%). ICI 105552 had no effect upon sorbitol accumulated in the diabetic kidney but it reduced the level in controls by 43%. The compound reduced the accumulation of sorbitol in diabetic retina by 58% although variation was too great for the decrease to be significant statistically. Treatment with ICI 105552 produced small (less than or equal to 11%) yet statistically significant increases in the weights of the kidneys, and both liver and kidney weight/100 g residual body weight but did not affect the weights of the body, lens, retina or S.V.C.G. The importance of these findings for the development of potentially chemotherapeutic aldose reductase inhibitors is discussed.

Aldehyde Reductase↗
PubMed1983

Lack of influence of isoproterenol, propranolol, and dopamine on immunoreactive parathyroid hormone and calcitonin in normal man.

Available evidence in vitro and in vivo suggests that pharmacologic doses of isoproterenol stimulate the secretion of parathyroid hormone (PTH) and calcitonin (CT) and propranolol inhibits secretion. However, the findings in man are either quite modest or inconsistent. In view of this controversy, we examined the effects of isoproterenol, 0.15 micrograms intradermally (i.d.), dopamine, 5 micrograms/kg body weight over 60 min intravenously (i.v.), and propranolol, 1 mg over 5 min followed by 60 micrograms per min for 2 i.v. in normal human subjects. It was found that these agents did not alter serum calcium, serum immunoreactive PTH, or plasma immunoreactive CT. The findings do not support a physiologic role for biogenic amines in the control and regulation of PTH or CT secretion in normal man.

Adult↗
PubMed1983

The effects of long-term treatment of streptozotocin-diabetic rats with an aldose reductase inhibitor.

To test the possible involvement of the sorbitol pathway in the pathogenesis of retinopathy in long-term experimentally-diabetic rats, streptozotocin-diabetic and normal rats were dosed orally (50 mg/kg body weight daily) for up to 373 days with an aldose reductase inhibitor (ICI 105552) or a placebo. Long-term treatment with ICI 105552 (1,(3,4-dichlorobenzyl)-3-methyl-1,2-dihydro-2-oxoquinol-4-ylaceti c acid; sodium salt) markedly reduced the normal accumulations of sorbitol and fructose in the sciatic nerves (86 and 69% reductions) and seminal vesicles with coagulating glands (75 and 49% reductions). Thus, by these criteria, the inhibitor was as effective after several months of dosing as after three weeks. There was no evidence that treatment with this aldose reductase inhibitor had any protective effect against the development of pathological changes in the retina and kidney of these rats.

Aldehyde Reductase↗
PubMed1983

The effects of an aldose reductase inhibitor upon the sorbitol pathway, fructose-1-phosphate and lactate in the retina and nerve of streptozotocin-diabetic rats.

UNLABELLED: To investigate the aetiology of complications secondary to experimental diabetes in the rat, the concentrations of glucose, sorbitol, fructose, fructose-1-phosphate, lactate and inositol were measured in the retina and sciatic nerve of streptozotocin-diabetic and normal rats treated for 22 days with ICI 105552 (1-(3,4-dichlorobenzyl)-3-methyl-1,2-dihydro-2-oxoquinol-4-ylacetic acid, sodium salt; 50 mg/kg body wt daily), an inhibitor of aldose reductase (E.C. 1.1.1.21) the first enzyme of the sorbitol pathway. In the diabetic nerve, where accumulation of sorbitol may be pathogenic, treatment with ICI 105552 reduced the accumulations of sorbitol (70%), fructose (47%) and lactate (34%) without affecting glucose, fructose-1-phosphate or inositol. In the nerves of controls, the inhibitor reduced both sorbitol (23%) and fructose (20%) levels without other effects. In the diabetic retina where accumulation of sorbitol or lactate might be pathogenic, treatment with ICI 105552 had no statistically significant effect upon the concentrations of glucose, sorbitol, fructose, fructose-1-phosphate or inositol. However, the inhibitor reduced the concentration of lactate to below the non-diabetic level. In the retinas of controls, dosage with ICI 105552 reduced the concentration of sorbitol by 36% without other effects. THE RESULTS: (1) demonstrated that ICI 105552 was a potent inhibitor of aldose reductase in sciatic nerve and suggested that a proportion of nerve lactate in diabetes could result from sorbitol pathway activity; (2) implied that flux through the sorbitol pathway, eventually to form lactate, increases in diabetic retina; and (3) indicated, by the drug's reduction of retinal lactate concentration, that inhibitors of aldose reductase might be of potential use in diabetic retinopathy.

Aldehyde Reductase↗
PubMed1983

Do tissues other than the kidney produce 1,25-dihydroxyvitamin D3 in vivo? A reexamination.

Recent experiments have shown that 1,25-dihydroxyvitamin D3-like material is produced in cultured nonrenal cells and may be present in the sera of anephric patients. We reexamined the question of whether 1,25-dihydroxyvitamin D3 can be synthesized extrarenally in the rat in vivo. To intact, sham-operated, ureter-ligated, or acutely nephrectomized vitamin D-deficient rats raised on a diet normal in calcium and phosphorus, we gave a physiologic dose of high-specific-activity 25-hydroxy-[3H]vitamin D3 (3.6-3.8 microCi; approximately equal to 25 pmol per rat). Twenty-four hours later we examined their tissues and plasma for the presence of radiolabeled 1,25-dihydroxyvitamin D3. Large amounts of radioactivity that behaved chromatographically as identical with authentic 1,25-dihydroxyvitamin D3 were present in the plasma, bone, and intestine of the intact, sham-operated, or ureter-ligated rats. However, no radioactivity eluting in a manner similar to 1,25-dihydroxyvitamin D3 was found in plasma, bone, or intestine of acutely nephrectomized rats. We conclude that, in the acutely nephrectomized living rat, 1,25-dihydroxyvitamin D3 is not present in plasma, bone, or intestine in quantities detectable by the sensitive techniques we have used. No conversion of 25-hydroxyvitamin D3 to 1,25-dihydroxyvitamin D3 was observed during a 24-hr period after nephrectomy of vitamin D-deprived rats. This fact casts doubt upon the significance of the in vitro production of 1,25-dihydroxyvitamin D3 by nonrenal cells as an in vivo phenomenon.

Animals↗
PubMed1983

Epinephrine is a hypophosphatemic hormone in man. Physiological effects of circulating epinephrine on plasma calcium, magnesium, phosphorus, parathyroid hormone, and calcitonin.

The physiologic effects of epinephrine on mineral metabolism are not known. In six healthy men, insulin-induced hypoglycemia, a potent stimulus to endogenous epinephrine secretion, resulted in a decrement of 0.9+/-0.1 mg/dl (mean+/-SE, P < 0.001) in serum inorganic phosphorus and smaller increments in magnesium and total and ionized calcium. Plasma immunoreactive parathyroid hormone (iPTH) decreased and plasma immunoreactive calcitonin (iCT) increased appropriately with the increments in calcium and magnesium. We wished to determine to what extent these changes in mineral metabolism might be attributable to epinephrine. Therefore, in the same protocol, we infused the hormone over 60 min in these six men, in doses that resulted in steady-state plasma epinephrine concentrations ranging from 52 to 945 pg/ml (levels that span the physiologic range), for a total of 25 studies. Serum ionized calcium, iPTH, and iCT concentrations were unaltered by these physiologic elevations of plasma epinephrine. However, epinephrine resulted in dose-dependent decrements in serum inorganic phosphorus of 0.6+/-0.1 mg/dl (P < 0.005) for the highest epinephrine infusion rate. The plasma epinephrine concentration threshold for this hypophosphatemic effect was approximately 50-100 pg/ml. Thus, the sensitivity of the hypophosphatemic response to epinephrine is comparable to that of the cardiac chronotropic, systolic pressor, and lipolytic responses to epinephrine, and considerably greater than that of the diastolic depressor, glycogenolytic, glycolytic, and ketogenic responses to the hormone in human beings. In view of its rapidity, the hypophosphatemic effect of epinephrine is probably the result of a net shift of phosphate from the extracellular compartment to intracellular compartments. We suggest that it is a direct effect of epinephrine, in that it is not mediated by changes in availability of the primary regulatory hormones PTH and CT, although indirect effects mediated by changes in other hormones, such as insulin, cannot be excluded. The hypophosphatemic response is also not attributable to increments in plasma calcium. These data indicate that epinephrine in physiologic concentrations is a hypophosphatemic hormone in man.

Adult↗
PubMed1983

Rapid development of renal resistance to low doses of synthetic bovine parathyroid hormone fragment 1-34. Dissociation of urinary cyclic adenosine monophosphate, phosphaturic, and calciuric responses.

The designing of parathyroid hormone (PTH)-renal dose-response studies in human beings is complicated by the possibility of rapid homologous receptor down-regulation, a phenomenon that is clearly shown to occur in vitro. Large amounts of PTH given to human subjects as serial injections or prolonged infusions cause decreased urinary 3',5'-cyclic adenosine monophosphate (cAMP) responses to subsequent PTH doses, but it is uncertain whether lower doses given over shorter periods similarly cause renal tachyphylaxis to PTH action. Thus, in seven water-loaded adults, we infused in ascending order 10, 30, 75, 150, and 300 U of synthetic bovine PTH fragment 1-34 (bPTH 1-34) per 70 kg body wt over 15 min on widely separated days ("separate day administration"). On another day, each subject received all five 15-min doses in ascending order at 75-min intervals ("single day administration"). Urine collection intervals were control, 0-30 min (including the PTH infusion), and 30-60 min. Peak nephrogenous cAMP (NcAMP, nmol/100 ml glomerular filtrate) response was linearly related to the dose of PTH (separate day study, r = 0.94, P less than 0.001; single day study, r = 0.88, P less than 0.001). However, the slope of NcAMP responses plotted against PTH dose for the single day study was only 36% of that derived from separate day administration of the same PTH doses (P less than 0.001). After only 40 U (10 + 30) of bPTH 1-34/70 kg, the NcAMP response to 75 U was reduced 44%, and the effect of 300 U/70 kg, when given as the last of the sequential single day infusions, was 64% less than the response to 300 U of bPTH 1-34 given alone (P less than 0.001). The phosphaturic response (fractional excretion of phosphorus, FEP [percent]) was also linearly related to bPTH 1-34 dose, but combined administration of the PTH infusions on one day increased FEP at each dose identically with the effects of separate day administration. A transient, dose-related, early hypercalciuric response to bPTH 1-34 also occurred, and was of equal magnitude in both protocols. These studies demonstrate that significant blunting of the NcAMP response to bPTH 1-34 occurs rapidly and follows brief exposure to relatively low doses of hormone. In contrast, there is no effect of recent PTH administration on the phosphaturic and early hypercalciuric actions of bPTH 1-34. This seeming dissociation of PTH effects makes unclear the physiologic importance of PTH-induced cAMP tachyphylaxis in the regulation of final PTH actions. In any case, studies of NcAMP responses in which the occurrence of tachyphylaxis would be undesirable should be designed to avoid prolonged or closely spaced administrations of the hormone.

Adult↗
PubMed1983

Hyperphosphatemic tumoral calcinosis: effects of phosphate depletion on vitamin D metabolism, and of acute hypocalcemia on parathyroid hormone secretion and action.

In hyperphosphatemic tumoral calcinosis, plasma 1,25-dihydroxyvitamin D [1,25(OH)2D] levels are inappropriately elevated, suggesting an abnormality in vitamin D metabolism. To define this abnormality further, we measured vitamin D metabolites in two patients and four controls before and after phosphate depletion. The patients showed elevated plasma levels of 1,25(OH)2D in the basal state. Phosphate depletion reduced serum phosphate in patients from a mean of 6.1 to 2.6 mg/dl; this was accompanied by a rise in plasma 25-hydroxyvitamin D from 33.6 to 41.9 ng/dl, and in 1,25(OH)2D from 67.7 to 93.2 pg/ml. The absolute rise in 1,25(OH)2D was similar to that of controls. EDTA infusion produced a normal increase of serum immunoreactive PTH levels and urinary cAMP excretion. In this form of tumoral calcinosis, 1,25(OH)2D levels are elevated despite hyperphosphatemia, normal immunoreactive PTH, and normal serum calcium concentrations, suggesting an abnormality in the regulation of 1,25(OH)2D synthesis or metabolism, or alternatively, another undefined stimulus for 1,25(OH)2D synthesis. These patients appear to have concurrent abnormalities of renal tubular phosphate transport and vitamin D metabolism.

Calcinosis↗
PubMed1983

Preparation of synthetic bovine parathyroid hormone fragment 1-34 for parenteral use in human studies.

There is growing interest in use of synthetic parathyroid hormone peptides such as the aminoterminal 1-34 fragment (PTH 1-34) in human studies, since bovine parathyroid extract is no longer commercially available. We found no data concerning how to sterilize and dilute the synthetic bovine PTH 1-34 (bPTH 1-34) to minimize adsorptive losses and maximize conservation of bioactivity. Therefore, we examined adsorptive losses of electrolytically-labelled, biologically-active bPTH 1-34 onto sterile filtration devices (Millex GV, Millipore Corp.) in solutions of 0.1 M acetic acid containing varying human serum albumin (HSA) concentrations (0.1-5.0%, w/v) and varying hormone concentrations (1-50 micrograms bPTH 1-34/ml). We also assessed preservation of bPTH 1-34 bioactivity (canine renal cortical plasma membranes) in diluted, sterile-filtered solutions refrigerated for 4 days. Adsorptive losses were inversely related to bPTH 1-34 concentrations, being least with 50 micrograms bPTH 1-34/ml, at all concentrations of HSA. Losses during filtration were essentially indistinguishable at HSA concentrations of 0.1 - 1.0%, but were, surprisingly, increased by 2.5 and 5.0% HSA. There were no important differences in adsorptive losses among five different lots of Millex-GV filters. Full bioactivity was preserved over 4 days of refrigeration at a bPTH 1-34 concentration of 20 micrograms/ml. The data suggest that bPTH 1-34 should be sterile-filtered at a concentration of greater than or equal to 20 micrograms/ml in 0.1M acetic acid containing 0.1 - 1.0% HSA. Such sterile solutions are stable at 4 degrees C for at least 4 days.

Dosage Forms↗
PubMed1983

Estimates of circulating monomeric calcitonin: physiological studies in normal and thyroidectomized man.

To avoid the limitations of present human calcitonin (hCT) assays, we have developed a silica extraction and concentration method for plasma hCT that lowers the detection limit of the assay 40-fold (to 0.5-1.0 pg/ml), and markedly improves specificity of the assay for the CT monomer (hCT-M). Extraction recoveries of radioiodinated and unlabeled synthetic hCT-M added to 20 ml plasma were, respectively, 90 +/- 1% and 99 +/- 4% (mean +/- SE). Gel filtration chromatography of plasma from patients with medullary thyroid carcinoma demonstrated that the extract was markedly enriched in hCT-M. Basal plasma immunoreactive hCT was measured before (iCT) and after extraction (exCT) in 60 normal individuals; basal exCT levels were higher in young men than in young women [8.0 +/- 0.8 (+/- SE) vs. 4.6 +/- 0.5 pg/ml; P less than 0.001] and higher in elderly men than in elderly women (9.4 +/- 0.8 vs. 4.7 +/- 0.6 pg/ml; P less than 0.05), but not different with age. Calcium infusions (2 mg Ca/kg over 5 min) in 36 subjects showed a significantly greater secretory capacity for exCT in men than in women, but showed no decline of exCT response with age. There was no correlation between basal iCT and exCT concentrations, but there was a good correlation between peak Ca-stimulated iCT and peak Ca-stimulated exCT levels (r = 0.94; P less than 0.001), suggesting that hCT-M was the main form released by acute stimulation. The mean extractable CT level in 6 totally thyroidectomized individuals was 2.7 +/- 0.3 pg/ml and did not increase after Ca challenge. We found no significant differences in basal or Ca-stimulated exCT levels measured in 5 women on 3 different occasions over the span of 1 menstrual cycle. After a meal, exCT levels did not change in women, but there was a consistent increase in the men (28 +/- 7% over baseline at 3 h; P less than 0.01). In summary, plasma concentrations of exCT and, most likely, hCT-M were very low (less than 10 pg/ml in most healthy adults) and always increased after calcium infusion. The measurement of plasma exCT is a useful technique that provides new sensitivity and specificity for the study of hCT physiology.

Adolescent↗
PubMed1983

Effect of plasma calcium concentration on the metabolic clearance rate of parathyroid hormone in the dog.

Low perfusate calcium concentrations reportedly enhance the degradation of intact bPTH in isolated rat liver and dog kidney. Depending on the magnitude of such effects, they might affect the metabolic clearance of intact PTH in vivo. Therefore we have investigated the effect of acute and chronic hypocalcemia and hypercalcemia on the MCR of intact PTH in vivo in dogs. The t 1/2 of endogenous PTH was unchanged after 5, 30, and 480 min of hypocalcemia and ranged from 1.2 to 2.8 min. The MCR of bPTH infused to constant plasma levels in TPTX dogs also did not change with short- or long-term changes in the plasma calcium concentration by approximately 7 mg/dl. The MCR averaged 13 ml/min per kilogram for fully biologically active bPTH and 6 ml/min per kilogram for oxidized bPTH. Thus neither acute nor chronic hypocalcemia or hypercalcemia at extremes observed in disease states significantly altered the MCR of PTH. We conclude that changes in plasma intact PTH concentrations during changes in plasma calcium accurately reflect PTH secretion rate.

Animals↗