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Treatment of humoral hypercalcemia of malignancy in rats with inhibitors of carbonic anhydrase
Author(s) -
Brown Gregory M.,
Morris Carol A.,
Mitnick Mary Ann,
Insogna Karl L.
Publication year - 1990
Publication title -
journal of bone and mineral research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.882
H-Index - 241
eISSN - 1523-4681
pISSN - 0884-0431
DOI - 10.1002/jbmr.5650051007
Subject(s) - acetazolamide , bone resorption , endocrinology , medicine , chemistry , carbonic anhydrase , carbonic anhydrase inhibitor , calcium , resorption , parathyroid hormone , enzyme , biochemistry
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 −9 M 36 Tyr(1–36)‐PTHrP‐amide (PTHrP, parathyroid hormone‐related protein). Acetazolamide also inhibited the resorption induced by 10 −8 M (1–141)‐PTHrP and 2.5 × 10 −9 M (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.