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Activation of the Calcium Receptor by a Calcimimetic Compound Halts the Progression of Secondary Hyperparathyroidism in Uremic Rats

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Activation of the Calcium Receptor by a Calcimimetic Compound Halts the Progression of Secondary Hyperparathyroidism in Uremic Rats J Am Soc Nephrol 11: 903–911, 2000 Activation of the Calcium Receptor by a Calcimimetic Compound Halts the Progression of Secondary Hyperparathyroidism in Uremic Rats JI CHIN,* SCOTT C. MILLER,* MICHIHITO WADA,† NOBUO NAGANO,† EDWARD F. NEMETH,* and JOHN FOX* *NPS Pharmaceuticals, Inc., Salt Lake City, Utah; and †Pharmaceutical Development Laboratory, Kirin Brewery Co., Ltd., Takasaki-shi, Gunma, Japan. Abstract. The secondary hyperparathyroidism that develops in infused NPS R-568 completely prevented further hyperplasia rats with chronic renal insufficiency (CRI) can be totally pre- but did not reduce total parathyroid cell number below that vented by activation of the parathyroid Ca2ϩ receptor with a present at the initiation of treatment. This prevention of cellular calcimimetic compound, when treatment is initiated before proliferation occurred despite increases in plasma phosphate parathyroid cell hyperplasia and increased circulating parathy- and decreases in Ca2ϩ and 1,25-dihydroxyvitamin D levels, roid hormone levels develop. In clinical practice, however, and supports the view that the Ca2ϩ receptor is the dominant secondary hyperparathyroidism is usually manifest by the time regulator of parathyroid cell hyperplasia in addition to para- CRI is diagnosed. This study examined the effects of daily oral thyroid hormone secretion. The clinical implications of these gavage or continuous subcutaneous infusion for 8 wk of the findings suggest that controlling Ca2ϩ receptor activity with calcimimetic NPS R-568 on the progression of established calcimimetic compounds could be sufficient to manage sec- mild or moderate-to-severe secondary hyperparathyroidism in ondary hyperparathyroidism in CRI. rats with CRI induced by 5/6 nephrectomy. Both oral and Secondary hyperparathyroidism (2°HPT), characterized by en- has been postulated to play a dominant role in the pathogenesis largement of the parathyroid glands and increased levels of of 2°HPT. This controversy results largely from the difficulty plasma parathyroid hormone (PTH), is a nearly invariant com- in manipulating the target mechanisms of these factors inde- plication of end-stage renal disease. Parathyroid gland enlarge- pendently of the others. Thus, the mechanism by which phos- ment results mostly from cellular hyperplasia in all four para- phate regulates parathyroid cell proliferation is unknown, and thyroid glands and is positively correlated with the magnitude changing 1,25(OH)2D3 receptor activity is difficult to achieve of circulating levels of PTH (1–5). Increased levels of plasma in the absence of corresponding changes in plasma levels of PTH are often detected long before the start of dialysis when phosphate and/or Ca2ϩ. At present, the Ca2ϩ receptor is the GFR has fallen to only half of normal. Because of this, it is only target mechanism that can be regulated independently of likely that parathyroid cell hyperplasia also occurs early in the 2ϩ plasma levels of Ca , 1,25(OH)2D3, or phosphate. This is course of renal failure. Indeed, studies of chronic renal insuf- possible because potent and selective pharmacologic activators ficiency (CRI) in rodents reveal increased proliferation of (calcimimetics) of this receptor have been identified. parathyroid cells within days of a partial nephrectomy (6,7). The use of calcimimetic compounds in rodent models of There is general agreement that lowered plasma levels of 2°HPT has provided evidence demonstrating an important role 2ϩ 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), hypocalcemia, and of the Ca receptor in regulating not only secretion of PTH hyperphosphatemia, as well as decreased expression in the but additionally parathyroid cell proliferation. Thus, the very 2ϩ parathyroid gland of the Ca and 1,25(OH)2D3 receptors, all rapid proliferative response of parathyroid cells to a partial contribute to parathyroid cell hyperplasia (7–17). However, the nephrectomy is prevented by the calcimimetic compound NPS relative role of these systemic factors is controversial, and each R-568 when administered from the time of the renal insult (6). In long-term studies, daily dosing with NPS R-568 completely prevented the development of 2°HPT as indexed by parathy- Received May 6, 1999. Accepted September 24, 1999. This work was presented in part at the 29th Annual Meeting of the American roid cell hyperplasia and circulating levels of PTH (18). Al- Society of Nephrology, New Orleans, LA, November 3 to 6, 1996, and has though these studies have contributed to the growing preclin- been published in abstract form (J Am Soc Nephrol 7: 1812, 1996). ical and clinical literature supporting the feasibility of this Correspondence to Dr. John Fox, NPS Pharmaceuticals, Inc., 420 Chipeta approach to treating hyperparathyroidism, they do not mimic Way, Salt Lake City, UT 84108. Phone: 801-583-4939; Fax: 801-583-4961; E-mail: [email protected] the situation faced by the clinician. Thus, by the time the 1046-6673/1105-0903 patient is diagnosed with CRI, which may lead to end-stage Journal of the American Society of Nephrology renal disease, 2°HPT is typically already present to some Copyright © 2000 by the American Society of Nephrology degree (5). In the foreseeable future, the treatment of 2°HPT 904 Journal of the American Society of Nephrology J Am Soc Nephrol 11: 903–911, 2000 will reflect managing an existing disease and should focus on anesthetized with isoflurane and a blood sample was collected from ϩ treatments that will prevent it from progressing to more severe the tail for determination of the plasma levels of urea nitrogen, Ca2 , forms. It is this clinical reality that underlies the present ex- phosphate, and PTH. Acute Effects of NPS R-568 on Plasma Levels of PTH and periments, which examined whether chronic treatment with 2؉ NPS R-568, administered either by daily oral gavage or by Ca . 5/6 Nx animals with moderate 2°HPT were catheterized and, 3 to 5 d later, the time course of the changes in the plasma levels of continuous subcutaneous infusion, could reverse the hyperpla- ϩ PTH and Ca2 following a single oral administration (1 ml/200 g sia and parathyroid gland enlargement in rats with CRI and body wt) of NPS R-568 (10 or 30 ␮mol/kg) or vehicle (10% cyclo- established 2°HPT. dextrin in water) was assessed. Blood samples (0.6 ml) were collected immediately before, and at 15, 30, 60, 90, 120, 180, and 240 min after Materials and Methods dosing. To prevent excessive blood loss, after removal of the plasma Animals, Diets, and Surgery sample, the red cell pellet was resuspended in an equal volume of normal rat plasma and reinjected. Normal male Sprague Dawley rats (Harlan Sprague Dawley, Indi- Effects of Chronic Treatment with NPS R-568. The sham- anapolis, IN), 7- to 8-wk-old and weighing 225 to 250 g upon receipt, operated rats were divided into two groups (groups 1 and 3) and the were used in these studies. They were provided with unlimited access remaining 5/6 Nx animals into five groups (groups 2, 4, 5, 6, and 7) to commercial rodent chow (Purina no. 5001), containing 1% Ca and matched by body weight and by the measured plasma parameters. 0.7% P, and tap water. After an acclimatization period of 6 to 8 d, Groups 1 and 2 were euthanized as untreated baseline controls at 11 each rat was anesthetized with ketamine (90 mg/kg) and xylazine (7 wk after surgery. Groups 3 and 4 received vehicle (10% cyclodextrin) mg/kg) injected intramuscularly and subjected to a one-stage 5/6 by oral gavage once daily for 8 wk in a volume of 1 ml/200 g body nephrectomy (Nx) in which both poles of one kidney were ligated and wt. Groups 5 and 6 received NPS R-568 orally (10 or 30 ␮mol/kg, excised and the contralateral kidney was removed. Control rats were respectively). Group 7 rats received NPS R-568 by subcutaneous subjected to a sham operation, which involved exposure of both infusion in a manner identical to that described above in Experiment kidneys via two separate flank incisions and subsequent closure of the 1. As before, the rats were anesthetized with isoflurane and the incisions. All procedures were reviewed and approved by the Institu- osmotic minipump was replaced at 4 wk. The animals were weighed tional Animal Care and Use Committee of NPS Pharmaceuticals, Inc. weekly throughout the study and were euthanized for tissue collection (Salt Lake City, UT). as described above. Experimental Protocols Parathyroid Gland Analysis Experiment 1 (Mild 2°HPT). The rats were fed normal rodent The parathyroid glands were fixed overnight in cold (4°C), neutral, chow throughout this study. Four weeks after surgery, the sham- phosphate-buffered formalin and dehydrated in ethanol. The glands operated and 5/6 Nx rats were divided into two and three weight- were embedded in Epon (Tedpella, Tustin, CA) in Experiment 1, and matched groups, respectively. One group of sham and one group of in JB-4 resin (Electron Microscopy Sciences, Fort Washington, PA) in 5/6 Nx rats were euthanized as baseline controls. The remaining group Experiment 2 to facilitate more rapid sectioning. Semithin (3 ␮m) of sham-operated rats and the two groups of 5/6 Nx rats were anes- sections of both glands of each rat were prepared and stained with thetized with isoflurane, and a model 2ML4 osmotic mini-pump basic fuschin and methylene blue and were examined by light micros- (Alza, Palo Alto, CA) was implanted subcutaneously between the copy using oil immersion and phase contrast techniques. shoulder blades. The sham-operated rats and one group of 5/6 Nx rats Total gland volume, average cell volume, and total cell number were infused with the vehicle, a 45% aqueous solution of 2-hy- were determined using stereologic techniques (12,19,20). The volume droxypropyl-␤-cyclodextrin (Research Biochemicals International, of each gland (V ) was estimated from parallel sections separated by Natick, MA); the remaining group of 5/6 Nx rats was infused with G a known distance t.
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