Recent advances in understanding the epidemiology, genetics, diagnosis, clinical presentations, skeletal involvement, and therapeutic approaches to hypoparathyroidism led to the First International Workshop on Hypoparathyroidism that was held in 2009. At this conference, a group of experts convened to discuss these issues with a view towards a future research agenda for this disease. This review, which focuses primarily on hypoparathyroidism in the adult, provides a comprehensive summary of the latest information on this disease. © 2011 American Society for Bone and Mineral Research
Calcimimetic compounds, which activate the parathyroid cell Ca 2ϩ receptor (CaR) and inhibit parathyroid hormone (PTH) secretion, are under experimental study as a treatment for hyperparathyroidism. This report describes the salient pharmacodynamic properties, using several test systems, of a new calcimimetic compound, cinacalcet HCl. Cinacalcet HCl increased the concentration of cytoplasmic Ca 2ϩ ([Ca 2ϩ ] i ) in human embryonic kidney 293 cells expressing the human parathyroid CaR. Cinacalcet HCl (EC 50 ϭ 51 nM) in the presence of 0.5 mM extracellular Ca 2ϩ elicited increases in [Ca 2ϩ ] i in a dose-and calcium-dependent manner. Similarly, in the presence of 0.5 mM extracellular Ca 2ϩ , cinacalcet HCl (IC 50 ϭ 28 nM) produced a concentration-dependent decrease in PTH secretion from cultured bovine parathyroid cells. Using rat medullary thyroid carcinoma 6-23 cells expressing the CaR, cinacalcet HCl (EC 50 ϭ 34 nM) produced a concentrationdependent increase in calcitonin secretion. In vivo studies in rats demonstrated cinacalcet HCl is orally bioavailable and displays approximately linear pharmacokinetics over the dose range of 1 to 36 mg/kg. Furthermore, this compound suppressed serum PTH and blood-ionized Ca 2ϩ levels and increased serum calcitonin levels in a dose-dependent manner. Cinacalcet was about 30-fold more potent at lowering serum levels of PTH than it was at increasing serum calcitonin levels. The S-enantiomer of cinacalcet (S-AMG 073) was at least 75-fold less active in these assay systems. The present findings provide compelling evidence that cinacalcet HCl is a potent and stereoselective activator of the parathyroid CaR and, as such, might be beneficial in the treatment of hyperparathyroidism.
It is now established that all of the components necessary for the local formation of angiotensin II (ANG II) coexist in the kidney and can alter local ANG II production rate. However, data on ANG II concentrations in different compartments within the kidney are limited. Recently, proximal tubule fluid ANG II concentrations in the nanomolar range were reported. Using an ANG II radioimmunoassay procedure with enhanced sensitivity, we performed experiments to explore proximal tubular fluid ANG II levels further and to determine the source of the ANG II. Total free-flow proximal tubular fluid samples (n = 11) had an average ANG II concentration of 13 +/- 2 nM. These concentrations were similar (10 +/- 2 nM) in samples collected into pipettes containing the inhibitors enalaprilat and EDTA (n = 17). Fluid collected from blocked proximal tubules that were perfused with artificial tubular fluid showed similar ANG II concentrations both in the presence (22 +/- 3 nM) and absence (22 +/- 4 nM) of the angiotensin-converting-enzyme inhibitor, enalaprilat, in the perfusate. Plasma ANG II concentrations were much lower and averaged 155 +/- 26 pM. Isotonic saline expansion lowered plasma ANG II levels to 30 +/- 5 pM (P < 0.01) but did not significantly decrease intraluminal ANG II (8 +/- 1 nM). These data provide further evidence that intratubular ANG II concentrations are in the nanomolar range and are regulated independently of the plasma ANG II levels. The data obtained from perfused tubules indicate that the proximal tubule adds substantial amounts of ANG II or a precursor into the tubular lumen.
This study was designed to improve and validate methods for the accurate and consistent quantitation of angiotensin (ANG) I and II levels in rat kidney and to determine the effects on renal ANG I and II of changes in dietary sodium intake and ANG-converting enzyme (ACE) inhibition. Kidneys from pentobarbital-anesthetized rats were rapidly removed and homogenized in methanol before extraction and purification of ANG peptides by solid-phase extraction and high-performance liquid chromatography (HPLC). Recoveries of 125I-ANG I and II were greater than 80%. Reversed-phase HPLC of the partially purified methanol extract showed that greater than 75% of the ANG I- and greater than 82% of the ANG II-like immunoreactivity coeluted with ANG I and II, respectively. Dietary sodium deprivation (0.003 meq/g) and excess (1.34 meq/g) for 7 days significantly (P less than 0.01) increased and decreased renal ANG I (296 +/- 30 and 82.6 +/- 15.8 vs. 161 +/- 18 fmol/g) and ANG II (216 +/- 16 and 45.6 +/- 11.8 vs. 98 +/- 16 fmol/g) contents, respectively. Plasma ANG I and II levels showed similar changes. ACE activity was significantly upregulated by sodium deprivation in both kidney (44% increase) and plasma (30% increase). In rats fed normal chow, infusion of enalaprilat for 1 h abolished plasma ACE activity but decreased renal ACE activity by only 58%. ACE inhibition increased renal and plasma ANG I levels 2.8- and 12-fold, respectively, and decreased renal and plasma ANG II levels 75-78%.(ABSTRACT TRUNCATED AT 250 WORDS)
Renal tissue angiotensin I (Ang I) and II (Ang II) content and angiotensin converting enzyme activity were assessed in both kidneys during initial (7 days) and maintenance (25 days) phases of two-kidney, one clip hypertension in rats. At 7 and 25 days, systolic arterial pressure was 146±2 and 170±7 mm Hg, respectively. After 7 days, Ang I content of clipped kidneys was 64% and 70% higher (p< 0.001) than in nonclipped and sham-operated kidneys, respectively, when compared with levels in kidneys from sham-operated rats. In kidneys harvested 25 days after clipping one renal artery, Ang I and Ang II contents in clipped kidneys were increased 102% and 24% (p<0.01), respectively. Ang II content was also 32% higher in nonclipped kidneys. Angiotensin converting enzyme activity in nonclipped kidneys was greater (/?<0.05) than that in either clipped (46% higher) or sham-operated kidneys (57% higher). Plasma Ang I and Ang II levels were elevated at 7 days bat were not different at 25 days in clipped rats. These results demonstrate a dissociation between intrarenal and circulating levels of Ang I and Ang II and suggest that qualitatively different mechanisms may be responsible for the elevated intrarenal Ang II levels during the initial and maintenance phases of renal hypertension. (Hypertension 1992^0:763-767) KEY WORDS • renin-angjotensin system • hypertension, renal • hypertension, renovascnlar • angiotensin I • angiotensin II • kininase II T here is now considerable evidence demonstrating a close relation between the renin-angiotensin system (RAS) and the development of hypertension in the two-kidney, one clip (2K1C) Goldblatt hypertensive rat model.
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