Pancreastatin: a novel peptide inhibitor of parietal cell secretion

Pancreastatin is a recently identified 49-amino-acid peptide found in gastrointestinal tract and gastric mucosa. Its biologic effects on gastric function are unknown. The aim of this study was to determine the effects of pancreastatin [33-49] (the synthetic C-terminal fragment) on acid secretion and somatostatin release in vitro. Isolated rabbit gastric glands were prepared by means of collagenase digestion. Acid secretion was assessed indirectly with use of 14C-aminopyrine (AP) uptake by glands, and somatostatin release from D cells was measured with radioimmunoassay. Pancreastatin alone (10(-10) to 10(-6) mol/L) had no effect on 14C-AP uptake compared with unstimulated glands. In contrast, pancreastatin inhibited with histamine-(10(-6), 10(-5) mol/L; p less than 0.005) and carbachol-(10(-5), 10(-4) mol/L; p less than 0.001) stimulated 14C-AP uptake in a dose-dependent manner. Neither forskolin-(10(-6), 10(-4) mol/L; p greater than 0.50) or 8-Br-cAMP-(10(-5), 10(-4) mol/L; p greater than 0.30) stimulated 14C-AP uptake were influenced by pancreastatin. Pancreastatin had no effect on somatostatin release from glands. These data suggest that pancreastatin probably acts at receptor or membrane level, inhibiting both histamine- and carbachol-stimulated 14C-AP uptake. These effects are not mediated by D cell somatostatin release. It is possible that pancreastatin acts as a paracrine or endocrine inhibitory regulator of parietal cell secretion.     

Evidence for nongastrin-mediated somatostatin inhibition of parietal cell function

Somatostatin (SRIF), a tetradecapeptide, has been reported to suppress gastrin release and hence inhibit acid secretion in vivo. This study was performed to determine whether SRIF has any direct effect on parietal cell (PC). Isolated gastric cells were prepared by collagenase digestion and calcium chelation of rabbit fundic mucosa. PC enrichment (75% +/- 5%) was accomplished by velocity sedimentation with an elutriator rotor. Acid, as assessed by the accumulation of 14C-aminopyrine (AP) and macromolecular (intrinsic factor [IF]) secretion were used as markers of PC function. Cells were stimulated with histamine (H) (10(-6) mol/L). SRIF (10(-10) to 10(-6) mol/L) significantly inhibited H-stimulated 14C-AP accumulation (p less than 0.05). Inhibition of H-stimulated IF release was less sensitive, occurring at 10(-8) and 10(-7) mol/L (p less than 0.05), and loss of inhibition was observed at 10(-6) mol/L (p less than 0.05). These results demonstrate a direct inhibitory action of SRIF on PC secretion. The difference in inhibitory effect on IF and proton secretion is consistent with the postulation that SRIF may function at more than one site within the PC.     

Inhibition of parietal cell H+ secretion by transforming growth factor alpha: a possible autocrine regulatory mechanism

Transforming growth factor-alpha (TGF alpha) and TGF alpha/epidermal growth factor receptor messenger ribonucleic acid have recently been demonstrated in isolated parietal cells. The aim of this study was to investigate the effects of TGF alpha on basal and stimulated secretion in vitro with the isolated rabbit parietal cell model. Acid secretion was assessed indirectly with cell uptake of carbon 14-labeled aminopyrine [( 14C]AP). TGF alpha (10(-11) to 10(-7) mol/L) had no effect on unstimulated [14C]AP uptake. TGF alpha dose dependently inhibited histamine (10(-5) to 10(-6) mol/L)-stimulated but not forskolin (10(-5) to 10(-7) mol/L)-stimulated [14C]AP uptake. This effect on histamine-stimulated activation was reversed by pertussis toxin (200 ng/ml) before incubation. TGF alpha had no effect on carbachol (10(-5) to 10(-6) mol/L)-stimulated [14C]AP uptake. Specific HCO3-buffer studies demonstrated that these observations were independent of extracellular buffer and possible TGF alpha effects on intracellular pH. Our data indicate that TGF alpha inhibits acid secretion by specifically uncoupling histamine/cyclic adenosine monophosphate transduction at the guanosine triphosphate-binding protein. TGF alpha, unlike epidermal growth factor, has no effect on carbachol stimulation, which suggests a qualitative difference between the biologic actions of TGF alpha and epidermal growth factor. Possible autocrine-paracrine modulation of histamine stimulation by TGF alpha invokes a novel regulatory mechanism of parietal cell secretion.     

Somatostatin analogue inhibition of isolated parietal cell secretion

Somatostatin, somatotropin release-inhibiting factor (SRIF), is a regulatory peptide that has proved to directly inhibit parietal cell acid secretion. However, the therapeutic usefulness of SRIF has been limited by a brief plasma half-life. Several analogues of SRIF that are effective in suppressing acid secretion in vivo have been developed. This study was undertaken to compare the effects of SRIF and two analogues, SMS 201-995 and L-363,568, on in vitro acid secretion. We used isolated rabbit parietal cells prepared by collagenase digestion and counterflow elutriation. Acid secretion was assessed by the accumulation of 14C-aminopyrine within the cells. Two types of secretagogues were utilized: histamine (10(-6) mol/L), a membrane receptor agonist which acts by means of adenylate cyclase and cyclic AMP, and forskolin (10(-6) mol/L), a direct activator of adenylate cyclase. SRIF, SMS 201-995, and L-363,568 (10(-11) to 10(-7) mol/L) all significantly inhibited histamine-stimulated 14C-AP uptake (p less than 0.001). On a molar basis, SMS 201-995 was 10 times more potent and L-363,568 was 40 times more potent than SRIF. SRIF, SMS 201-995, and L-363,568 significantly inhibited forskolin-stimulated 14C-AP uptake (p less than 0.005). The inhibitory effects of SRIF and both analogues on forskolin-stimulated acid secretion was, however, significantly less than that observed with histamine (p less than 0.05). These results demonstrate increased in vitro potency of SRIF analogues compared with the native peptide. The data are consistent with the hypothesis that SRIF and its analogues function at more than one site within the parietal cell.     

Bovine parathyroid tissue: a model to compare the biosynthesis and secretion of parathyroid hormone and parathyroid hormone-related peptide

Bovine parathyroid tissue was evaluated as a model to compare parathyroid hormone-related peptide (PTH-rP) and parathyroid hormone (PTH) secretion. Tissue was incubated in variable calcium levels (n = 5). A parathyroid cell digest was prepared from collagenase-treated glands. PTH-rP and PTH levels were determined by radioimmunoassay. PTH-rP bioactivity was determined by 3H-cAMP production in a UMR 106 cell bioassay. PTH-rP levels in the incubation medium were 2.0 ng/mg protein (0.25 mmol Ca++), 2.2 ng/mg protein (1.25 mmol Ca++), and 1.9 ng/mg protein (2.5 mmol/L Ca++). PTH levels were 321 ng/mg protein (0.25 mmol/L Ca++) and 200 ng/mg protein (2.5 mmol Ca++). Therefore, calcium significantly inhibited PTH but not PTH-rP secretion (p = 0.03). Addition of incubation medium to the bioassay resulted in 3H-cAMP levels that were 8 to 10 times greater than basal levels. Greater than 50% of the activity persisted after addition of PTH antibody, demonstrating that a significant amount of the activity was caused by PTH-rP. Tissue PTH-rP was 5.1 ng/mg protein, compared with 2080 ng/mg protein for PTH. We conclude that (1) bovine parathyroid tissue contains bioactive PTH-rP and is a useful model to compare the biosynthesis and secretion of PTH-rP and PTH in normal tissue and (2) unlike PTH, PTH-rP secretion is not regulated by calcium.     

cAMP- and calcium-mediated modulation of intrinsic factor secretion in isolated rabbit gastric glands

We have studied the role of cAMP-mediated and calcium-mediated secretagogues in stimulating secretion of intrinsic factor (IF) from parietal cells in isolated rabbit gastric glands. The magnitudes of IF release caused by maximally stimulating doses of the following agents were compared: histamine (5 x 10(-5) M), forskolin (10(-5) M), 8-bromo-cAMP (10(-3) M), pentagastrin (10(-7) M), carbachol (10(-5) M), and the calcium ionophore A23187 (10(-3) M). Each agent was tested simultaneously in gastric glands prepared from the same animal so as to minimize the effects of variations between preparations. Gastric glands were incubated 30 min alone (unstimulated) or with each of the secretagogues. IF release into the culture medium was measured using an assay based on the binding of IF to 57Co-cyanocobalamin. Results were expressed as percentages IF release above unstimulated levels. Three cAMP-mediated agents significantly (P less than 0.05) stimulated IF secretion above unstimulated levels: histamine (439 +/- 33%), forskolin (769 +/- 385%), and 8-bromo-cAMP (1483 +/- 362%). Two agents thought to act through calcium-dependent mechanisms significantly (P less than 0.05) stimulated IF release: carbachol (79 +/- 25%) and pentagastrin (16 +/- 6%). A23187 did not increase IF release above unstimulated levels (P greater than 0.05). In this study, cAMP-mediated secretagogues stimulated significantly (P less than 0.05) more IF release than carbachol or pentagastrin. This study supports the hypothesis that both cAMP- and calcium-mediated mechanisms participate in regulating IF release.     

生理浓度钙透析液对伴低甲状旁腺素水平血液透析患者矿物质及骨代谢的影响

目的观察生理浓度钙透析液对伴低甲状旁腺素水平血液透析患者矿物质及骨代谢的影响。方法将48例血清iPTH(65～150pg/ml)伴校正钙水平≥2.37mmol/L患者按使用透析液钙浓度不同随机分为:透析液钙浓度1.50mmol/L(DCa-1.50)与1.25mmol/L(DCa-1.25)两组;两组内按是否口服骨化三醇随机分为两亚组:口服骨化三醇(+Calcitriol)与非口服骨化三醇(-Calcitriol)组;治疗6个月。每3个月检测透前血清Ca,P,iPTH,ALP及BGP指标。结果观察结束时,DCa-1.5-Calcitriol,DCa-1.25+Calcitriol及DCa-1.25-Calcitriol组血清iPTH及BGP水平升高(P<0.05);DCa-1.25+Calcitriol及DCa-1.25-Calcitriol组血清Ca水平降低(P<0.05),Ca×P水平降低(P<0.05);DCa-1.5+Calcitriol组血清较同期DCa-1.25-Calcitriol组水平Ca水平增高(P<0.05);透前血清iPTH与BGP水平呈正相关(r=0.181,P<0.05)。结论生理浓度钙透析液能够减轻高钙负荷,持续有效刺激甲状旁腺素分泌及改善受抑制的骨代谢。联合骨化三醇及定期监测上述指标,可以安全有效的维持甲状旁腺素在适当水平不引发骨质疏松。     

Lithium effects on dispersed bovine parathyroid cells grown in tissue culture.

It is not clear whether hypercalcemia and hyperparathyroidism associated with lithium therapy are the result of an unmasking of preexisting disease or a direct effect of lithium on the parathyroid glands. To investigate this phenomenon, parathyroid hormone (PTH) secretion and cytosolic calcium concentrations [( Ca]i) were measured in normal and lithium-treated dispersed bovine parathyroid cells grown in tissue culture and incubated with varying concentrations of extracellular calcium [( Ca]e) (0.5 to 2.5 mmol/L). Results indicate that lithium has two effects on parathyroid secretory response: (1) a decrease in low calcium-stimulated PTH release and (2) a potentiation of PTH release at physiologic concentrations of extracellular calcium. [Ca]i was assessed by use of fura-2, a calcium-sensitive fluorescent indicator. Resting [Ca]i levels were unaffected by lithium (103 +/- 13 nmol/L in controls vs 101 +/- 5 nmol/l in lithium-treated cells, mean +/- SE). Subsequent increases in [Ca]i in response to increases in [Ca]e were significantly less in lithium-treated cells, with no difference at maximal [Ca]e. Increases in [Ca]i in response to a submaximal concentration of extracellular magnesium were also blunted in cells pretreated with lithium. In conclusion, our data suggest that, at physiologic calcium concentrations, lithium decreases parathyroid cell sensitivity to changes in [Ca]e, reducing [Ca]i levels and increasing PTH secretory response.     

Patients with Elevated Serum Parathyroid Hormone Levels after Parathyroidectomy: Showing Signs of Decreased Peripheral Parathyroid Hormone Sensitivity

We have previously shown that patients with elevated levels of parathyroid hormone (PTH) after surgery for parathyroid adenoma have normal parathyroid and renal function but demonstrate signs of remineralization of cortical bone, decreased calcium absorption, and low levels of vitamin D. We hypothesized that decreased peripheral PTH sensitivity could also be of importance for this condition. Thirteen patients operated on for a solitary parathyroid adenoma, with a mean +/- SD preoperative serum level of calcium of 2.72 +/- 0.12 mmol/L, were investigated 6 weeks after surgery with a standardized PTH (1-34) infusion test for 6 hours. The eight patients with elevated PTH levels had less increase in serum levels of ionized calcium (0.02 +/- 0.03 mmol/L) than did the five patients with normal PTH levels (0.06 +/- 0.02 mmol/L) (p < 0.05). Patients with elevated PTH also showed less decrease in serum phosphate levels (p < 0.05) and a trend to a larger decrease in the excretion of urinary calcium (p = 0.08). The increase in 1,25-dihydroxyvitamin D(3) did not differ between the two groups of patients. Thus patients operated on for parathyroid adenoma with postoperatively elevated serum PTH levels showed decreased peripheral sensitivity to PTH.     

Parathyroid hormone modulates the release of atrial natriuretic peptide during acute volume expansion.

In this study we investigated the effect of volume expansion on plasma and atrial concentrations of atrial natriuretic peptide (ANP) in the presence and absence of the parathyroid gland and under normocalcemic and hypocalcemic conditions. After volume expansion ANP concentration in plasma was significantly (p < 0.001) higher in intact (702 +/- 86 pg/ml) than in hypocalcemic parathyroidectomized (PTX) (271 +/- 38 pg/ml) rats. Plasma ANP of PTX rats rendered normocalcemic with oral calcium supplementation increased to 402 +/- 85 pg/ml after volume expansion. Results from this study suggest that parathyroid hormone (PTH) is required for augmented ANP secretion in response to acute volume loading and alterations of extracellular calcium may modulate volume-induced ANP release in PTX rats. We would discuss that a parathyroid gland-cardiac atria interaction exists and that changes in serum level of PTH may play a role in the regulation of fluid homeostasis via ANP secretion.     

Does routine blood bone biochemistry predict vitamin D insufficiency in elderly patients with low-velocity fractures?

PURPOSE: Vitamin D deficiency impairs bone mineralisation and can predispose individuals to fractures. This study aimed at testing whether measurement of plasma calcium, alkaline phosphatase, and phosphate levels could detect vitamin D insufficiency. METHODS: During a 10-week winter period from December 2000 to February 2001, all elderly patients presenting to a general hospital in Brighton--British seaside town--with a fracture of the proximal femur and without known bone mineralisation problems were invited to participate in the study. RESULTS: 23 (63.9%) of the 36 eligible patients had insufficient levels of vitamin D, with a plasma concentration of less than 30 nmol/L. The mean parathyroid hormone level was 56 pg/mL (range, 12-193 pg/mL). 11 of the 36 patients had an elevated level of parathyroid hormone were insufficient in vitamin D. The mean plasma concentration of calcium was 2.30 mmol/L (range, 2.05-2.98 mmol/L). The mean phosphate level was 0.98 mmol/L (range, 0.40-1.79 mmol/L), and the mean alkaline phosphatase level was 91 IU/L (range, 46-127 IU/L). There was poor correlation between vitamin D insufficiency and plasma calcium, alkaline phosphatase, or phosphate levels. CONCLUSION: Plasma calcium, alkaline phosphatase, and phosphate testing cannot detect vitamin D insufficiency. We recommend that vitamin D and calcium supplementation be considered for patients with low-energy hip fractures.     

Influence of sevelamer hydrochloride on serum concentration of whole (1-84) and N-terminally truncated (7-84) parathyroid hormone fragments in hemodialysis uremic patients

Phosphate retention stimulates parathyroid hormone (PTH) secretion in uremic patients. Sevelamer hydrochloride is an aluminium- and calcium-free phosphate binder used in the treatment of secondary hyperparathyroidism in uremic patients. The influence of the phosphate lowering effect on serum levels of whole PTH-1-84 and N-terminally truncated PTH-7-84 has not been studied. Seventeen hemodialysis (HD) patients (nine male, eight female) with chronic renal failure and serum phosphorus concentrations, despite calcium carbonate treatment, >2.0 mmol/L were enrolled in this study. Patients did not receive aluminium containing binders. Blood samples for serum concentration assessments of calcium, phosphorus, PTH-1-84 and N-terminally truncated PTH-7-84, carboxyterminal cross-linked collagen fragments (Ctx), total (AP) and bone specific alkaline phosphatase activity (BAP) were drawn twice: before and after 5-week sevelamer administration (in addition to calcium carbonate). Sevelamer treatment was followed by a significant reduction in serum phosphorus level (from 2.46 +/- 0.09 to 2.07 +/- 0.10 mmol/L; p=0.009), PTH-1-84 level (from 396 +/- 75 to 298 +/- 64 pg/mL; p=0.03) and PTH-1-84/PTH-7-84 ratio (from 1.78 +/- 0.18 to 1.55 +/- 0.19; p=0.01), while serum PTH-7-84 levels declined only slightly (from 220 +/- 35 to 183 +/- 25 pg/mL; p=0.11). Serum calcium, Ctx concentrations, AP and BAP activity did not change markedly. There was a significant positive correlation between changes of phosphorus and PTH-1-84 (tau=0.48; p=0.007) or PTH-7-84 concentration (tau=0.43; p=0.02). A 5-week sevelamer treatment suppressed both PTH-1-84 (change statistically significant) and PTH-7-84 (change statistically non-significant) serum concentration in HD uremic patients seemingly related to changes in phosphatemia.     

Surgery for hyperparathyroidism: does morphology or function matter most?

BACKGROUND: With minimally invasive parathyroidectomy (MIP) not all enlarged parathyroid glands are necessarily removed, and intraoperative measurement of parathyroid hormone levels (IO-PTH) does not necessarily predict multiple enlarged glands. The aim of this study was to compare morphology with function, using Ca(2+)-regulated PTH secretion. METHODS: PTH secretion was determined by perifusion: (1) cells from 12 normal parathyroids were compared with 14 parathyroid adenomas; (2) functional characteristics (PTH secretion, sestamibi uptake, IO-PTH decrease) were correlated with morphologic characteristics; (3) PTH secretion as a predictor of IO-PTH decrease was determined in 7 patients with 2 enlarged parathyroids. RESULTS: (1) There were significant differences between normal and pathological parathyroid cells consistent with reduced sensitivity to Ca(2+). Maximum secretion rates for normal and adenomatous cells were, respectively, 3.9 +/- 0.4 fg min(-1) cell(-1) and 2.0 +/- 0.4 fg min(-1) cell(-1) (P = .002) and minimum secretion rates, 0.7 +/- 0.1 fg min(-1) cell(-1) and 0.4 +/- 0.1 fg min(-1) cell(-1) (P = .008). However, the IC(50) value for Ca(2+) was elevated in adenomatous cells indicating an apparent loss of extracellular Ca(2+) sensitivity being 1.1 +/- 0.02 mmol/L for normal and 1.2 +/- 0.02 mmol/L for adenomatous cells (P = .02). (2) There was no overall correlation between PTH secretion and gland morphology. (3) In 5 of 7 cases, PTH secretion correctly predicted the decrease in IO-PTH. CONCLUSION: Parathyroid adenomas generally exhibit abnormal PTH secretory function; however, enlarged parathyroid glands that do not contribute to the biochemical changes of hyperparathyroidism do exist, and, in these cases, cellular secretory function is a useful predictor of IO-PTH dynamics.     

Disturbance of basal and stimulated serum levels of intact parathyroid hormone in primary hyperparathyroidism

In patients with primary hyperparathyroidism, measurements were made of basal and stimulated levels of intact parathyroid hormone (PTH). The basal PTH values were elevated in all but six of 89 patients and provided clear separation towards normal individuals (n = 75) and patients with hypercalcemia of other origin (n = 34). The PTH value correlated with the serum calcium concentration in hyperparathyroidism and with the weight of excised parathyroid adenomas but not with that of chief cell hyperplasias. A constant ethylenediaminetetraacetic acid infusion during 60 minutes of induced essentially linear reductions of plasma-ionized calcium concentrations, averaging 0.02 mmol/L/10 minutes, which were associated with swift, curvilinear, elevations of PTH levels that reached a plateau after 10 to 20 minutes. The increment in serum PTH level correlated with the basal PTH value both in patients with hyperparathyroidism and controls. However, in proportion to the much greater glandular mass in the patients with hyperparathyroidism, the secretion of PTH was relatively reduced. The findings support the value of the intact PTH assay in the differential diagnosis of hypercalcemia and show that PTH secretion in vivo is extremely sensitive to hypocalcemic stimulation, that the pathological parathyroid tissue in hyperparathyroidism is characterized by a reduction of hormone release per unit weight, and that the hormone secretion in hyperparathyroidism operates closer to its maximal capacity than under normal circumstances.     

Suramin and the human adrenocortex: results of experimental and clinical studies.

Suramin, a sulfonated drug, has been used successfully in the treatment of inoperable adrenocortical cancer. This study was undertaken to investigate the effects of suramin on the basal and the adrenocorticotropin-stimulated cortisol and pregnenolone secretion and on the proliferation of primary monolayer cultures of normal human adrenocortical cells. Suramin decreases basal and adrenocorticotropin-stimulated cortisol secretion in a dose-dependent manner (p less than 0.05 from 0.3 mmol/L upward). At a suramin concentration of 3 mmol/L cortisol, secretion was inhibited by 70% +/- 4% in adrenocorticotropin-stimulated cells and by 42% +/- 6% in unstimulated cells. The proliferation of adrenocortical cells in response to fetal calf serum was inhibited by suramin at concentrations from 0.3 mmol/L upward, maximal suppression (71% +/- 6%; p less than 0.05) being observed at a concentration of 10 mmol/L. Neither down-regulation of cortisol secretion nor inhibition of adrenocortical cell proliferation was caused by toxicity of the compound, as could be shown by adrenocorticotropin-restimulating cortisol secretion in suramin-treated cells. The results indicate that suramin exerts an inhibitory influence on the cortisol secretion and the proliferation of normal human adrenocortical cells and may be useful in treating adrenocortical cancer.     

The effects of cholecystokinin on parietal cell secretion in isolated gastric glands

Cholecystokinin (CCK), a peptide hormone found in both gut and brain, shares amino acid homologies with gastrin and has previously been shown to stimulate gastric acid secretion in whole animal experiments. To investigate possible direct effects of CCK apart from extrinsic neural and hormonal influences, we have investigated the effects of the sulfated octapeptide of CCK (CCK-8) in rabbit isolated gastric glands using 14C-aminopyrine accumulation and intrinsic factor (IF) secretion as markers of parietal cell function. CCK-8 stimulated a significant increase (p less than 0.05) in IF secretion and 14C-aminopyrine accumulation. IF secretion was dose dependent for CCK concentrations from 10(-10)M to 10(-6)M. The combination of CCK (10(-6)M) and histamine (5 X 10(-5)M) elicited IF secretion greater than that of either agent alone. These results are similar to those observed for pentagastrin (10(-7)M), suggesting that the effects of CCK on parietal cell secretion may be due at least in part to a direct receptor-mediated parietal cell response to this agent.     

Inhibition by 1,25 dihydroxycholecalciferol of hormonal secretion of rat parathyroid gland in organ culture

The effect of vitamin D metabolites on parathyroid hormone secretion was studied using rat parathyroid gland cultured in basal medium Eagle containing 5% serum obtained from thyroparathyroidectomized rat, 1 mM magnesium, and calcium concentration varying from 0.75-2.25 mM, and radioimmunoassay for rat parathyroid hormone (rPTH). 1.25 dihydroxycholecalciferol (1,25(OH)2D3), 5 X 10(-10)-2.5 X 10(-8) M, consistently decreased rPTH secretion in dose-related manner; the effect reached steady state after 24 h in vitro addition of 1,25(OH)2D3 and was also observed at different medium calcium concentrations (0.75, 1.25, 1.75 mM). Comparison of dose-responses for inhibitory activity of some vitamin D metabolites on rPTH secretion showed: 1,25(OH)2D3 = 1,24,25(OH)3D3 greater than 1 alpha OHD3 greater than 25 OHD3. Cholecalciferol (10(-5) M), 24,25-dihydroxy-cholecalciferol (10(-8)-10(-6) M) and 25,26-dihydroxy-cholecalciferol (5 X 10(-9)-5 X 10(-7) M) did not inhibit rPTH secretion. Analysis of structural activity relation of vitamin D metabolites studied indicated that 1 alpha or pseudo-1 alpha hydroxylated metabolites or analogs were active in inhibiting rPTH secretion, while, non-1 alpha hydroxylated metabolites were without or were weakly inhibitory only at very high concentrations. This study provides further evidence for a direct role of 1,25(OH)2D3 on a negative feedback loop for regulation of parathyroid gland function.     

In Vitro Parathyroid Hormone Release in Patients with Secondary Hyperparathyroidism

Background: The purpose of this study was to determine the precise endocrim. characteristics of parathyroid function in secondary hyperparathyroidism (sHPT).
Methods: We examined the effects of extracellular ionized calcium (Ca²⁺) varying from 0.5 to 2.0 mM on parathyroid hormone (PTH) release in parathyroid cell suspensions using a mid-regional PTH assay. Cells were obtained from 26 patients with sHPT who were divided into two groups according to the type of hyperplasia they exhibited, either nodular (n=16) or diffuse [n= 10). For compdrison, we also analyzed data from nine patients with primary hyperparathyroidism (pHPT; adenomas).
Results: Significant in vitro suppression of PTH release by Ca²⁺ was observed in the majority of subjects, regardless of the histologic abnormality. The pHPT group exhibited no significant relationship between clinical and in vitro data. In contrast, in the sHPT group (taken as a whole), suppression of PTH release by Ca²⁺ exhibited a plateau at a total serum calcium concentration of 2.5 mmol/L, and a parathyroid gland weight of 2 g.
Conclusions: These findings suggest that there is a curvilinear relationship in sHPT, but not pHPT, between the in vitro calcium sensitivity of parathyroid cells and total serum calcium, as well as gland weight. The in vitro calcium sensitivity in sHPT remains constant when the total serum calcium concentration exceeds 2.5 mmol/L, or when the gland weight exceeds 2 g.