Treatment of humoral hypercalcemia of malignancy in rats with inhibitors of carbonic anhydrase.
Treatment of humoral hypercalcemia of malignancy in rats with inhibitors of carbonic anhydrase.
复制标题
用碳酸酐酶抑制剂治疗大鼠恶性肿瘤体液高钙血症。
DOI：
10.1002/jbmr.5650051007
复制
发表时间：
1990
期刊：
影响因子：
--
通讯作者：
Insogna,KL
中科院分区：
文献类型：
--
作者：
Brown,GM;Morris,CA;Mitnick,MA;Insogna,KL
碳酸酐酶已被认为是破骨细胞介导的骨吸收的关键参与者。在恶性体液高钙血症(HHM)中，强烈的破骨细胞性骨移植是观察到的高钙血症的主要原因。因此，我们致力于研究碳酸酐酶抑制剂乙酰唑胺对H500间质细胞瘤诱导的Fisher大鼠高钙血症的影响。乙酰唑胺以10 mg/h的速度处理10h后，5只用药动物的血钙水平显著下降(14.2±0.9至11.5±0.1 mg/dl，p<；0.05)。相反，单独输注赋形剂的6只动物的血清钙显著升高(12.5±0.5至13.8±0.1 mg/dl，p<；0.05)。在输液结束时，接受乙酰唑胺治疗的动物的平均血钙显著低于仅接受赋形剂治疗的动物(11.5±0.1比13.8±0.1，p<；0.05)。两组患者的血磷、尿钙、尿磷及肾源性环磷酸腺苷排泄量均无明显变化。乙酰唑胺和5-(3-羟基苯甲酰基)-2-硫代苯磺酰胺(HTS9M36Tyr(1-36)-−9M36Tyr(1-36)-PTHrP，甲状旁腺激素相关蛋白)在体外均能显著抑制甲状旁腺激素相关蛋白诱导的骨吸收。乙酰唑胺对10−8M(1-14 1)-PTHrP和2.5×10−9M(1-74)-PTHrP的吸收也有抑制作用。结论：乙酰唑胺能有效降低恶性肿瘤体液高钙血症动物的血钙水平。这些数据与这一效应的作用机制是直接抑制破骨细胞介导的骨吸收的假设是一致的。
The enzyme carbonic anhydrase has been suggested as a critical participant in osteoclast‐mediated bone resorption. In humoral hypercalcemia of malignancy (HHM) intense osteoclastic bone resoprtion is principally responsible for the observed hypercalcemia. We therefore undertook to examine the effect of the carbonic anhydrase inhibitor acetazolamide on the hypercalcemia induced by the H500 Leydig cell tumor in Fisher rats, a well‐described model of HHM. Acetazolamide treatment for 10 h at 10 mg/h resulted in a significant fall in serum calcium in the five drug‐treated animals (14.2 ± 0.9 to 11.5 ± 0.1 mg/dl,p< 0.05). Conversely, the six animals infused with vehicle alone showed a significant rise in serum calcium (12.5 ± 0.5 to 13.8 ± 0.1 mg/dl,p< 0.05). At the end of the infusion, the acetazolamide‐treated animals had a significantly lower mean serum calcium than those receiving vehicle alone (11.5 ± 0.1 versus 13.8 ± 0.1,p< 0.05). There was no significant change in serum phosphorus, urine calcium, urine phosphorus, or nephrogenous cyclic AMP excretion between the two groups. Acetazaolamide and HTS 5‐(3‐hydroxybenzoyl)‐2‐thiophenesulfonamide, another carbonic anhydrase inhibitor, both significantly inhibited in vitro bone resorption induced by 5 × 10−9M36Tyr(1–36)‐PTHrP‐amide (PTHrP, parathyroid hormone‐related protein). Acetazolamide also inhibited the resorption induced by 10−8M (1–141)‐PTHrP and 2.5 × 10−9M (1–74)‐PTHrP. We conclude that acetazolamide is effective in lowering the serum calcium in animals with humoral hypercalcemia of malignancy. The data are consistent with the hypothesis that the mechanism of action for this effect is direct inhibition of osteoclast‐mediated bone resorption.