Phentolamine is a reversible competitive α-adrenergic antagonist with similar affinities for α1 and α2 receptors. It has a long history of safe clinical use, and was developed as a potential therapy for male erectile dysfunction because of its capacity to increase the arteriolar blood flow to the corpora cavernosa. Phentolamine mesylate was administered to rats by oral gavage at daily doses of 10, 50, and 150 mg/kg for 24 months. A dose-related increase in mortality, ascribed to an exaggerated pharmacologic effect, was seen at high doses. Systemic exposure as measured by plasma drug concentration increased with dose and duration of dosing and slight drug accumulation occurred, particularly in high-dose males. In the treated groups, 10 males and 1 female were diagnosed with hibernomas, neoplasms of brown adipose tissue, which appeared in the thoracic cavity or retroperitoneal area as circumscribed, tan to reddish-brown lobulated masses. Histologically, the masses were well circumscribed with variably sized lobules defined by a rich capillary network and consisted of closely apposed oval to polygonal cells with large amounts of cytoplasm and a centrally located nucleus. The cytoplasm's appearance varied from multivacuolated to univacuolated to granular eosinophilic. In a few cases, neoplastic emboli were observed in capsular vessels. Ultrastructurally, the neoplastic cells contained numerous mitochondria with transverse parallel cristae that occupied over 60% of the cytoplasm and lipid droplets. This study documents the previously unreported development of hibernomas in rats treated with phentolamine mesylate.
Al Zubaidy, A.J., and Finn, J.P. (1983). Brown fat tumours (hibernomas) in rats: histopathological and ultrastructural study. Lab Animals17, 13—7.
2.
Blanset, D. (1996). A 4-week toxicity study of phentolamine in the rat via oral gavage administration. Study Report No. 96-2453. Huntingdon Life Sciences, East Millstone, NJ.
3.
Blanset, D. (1997a). Phentolamine mesylate: a subchronic (3-month) toxicity study in the rat via oral gavage administration. Study Report No. 97-2510. Huntingdon Life Sciences, East Millstone, NJ.
4.
Blanset, D. (1997b). A chronic (6-month) toxicity study of phentolamine mesylate in the dog via oral gavage administration. Study Report No. 96-3323 . Huntingdon Life Sciences, East Millstone, NJ.
5.
Blanset, D. (1998). A chronic (6-month) toxicity study of phentolamine mesylate in the rat via oral gavage administration. Study Report No. 96-2482 . Huntingdon Life Sciences, East Millstone, NJ.
6.
Breider, M.A., Gough, A.W., Haskins, J.R., Sobocinski, G., and de la Iglesia, F.A. (1999). Troglitazone-induced heart and adipose tissue cell proliferation in mice. Toxicol Pathol27, 545—52.
7.
Chitoku, S., Kawai, S., Watabe, Y., Nishitani, M., Fujimoto, K., Otsuka, H., Fushimi, H., Kotoh, K., and Fuji, T. (1998). Intradural spinal hibernoma: case report. Surg Neurol49, 509—13.
8.
Coleman, G.L. (1980). Four intrathoracic hibernomas in rats. Vet Pathol17, 634—7.
9.
Cousin, B., Cinti, S., Morroni, M., Raimbault, S., Ricquier, D., Penicaud, L., and Casteilla, L. (1992). Occurrence of brown adipocytes in rat white adipose tissue: molecular and morphological characterization. J Cell Sci103, 931—42.
10.
Fox, N., Crooke, R., Hwang, L.-H. S., Schibler, U., Knowles, B.B., and Solter, D. (1989). Metastatic hibernomas in transgenic mice expressing an alpha-amylase-SV40 T antigen hybrid gene. Science244, 460—3.
11.
Gaffney, E.F., Hargreaves, H.K., Semple, E., and Vellios, F. (1983). Hibernoma: distinctive light and electron microscopic features and relationship to brown adipose tissue. Hum Pathol14, 677—87.
12.
Geloen, A., Collet, A.J., Guay, G., and Bukowiecki, L.J. (1988). Beta-adrenergic stimulation of brown adipocyte proliferation. Am J Physiol254, C175—82.
13.
Ghadially, F.N. (1988). Ultrastructural Pathology of the Cell and Matrix: A Text and Atlas of Physiological and Pathological Alterations in the Fine Structure of Cellular and Extracellular Components, 3rd ed. Butterworths, London.
14.
Herman, J.R., Dethloff, L.A., McGuire, E.J., Parker, R.F., Walsh, K.M., Gough, A.W., Masuda, H., and de la Iglesia, F.A. (2002). Rodent carcinogenicity with the thiazolidinedione antidiabetic agent troglitazone. Toxicol Sci68, 226—36.
15.
Himms-Hagen, J. (1985). Brown adipose tissue metabolism and thermogenesis . Ann Rev Nutr5, 69—94.
16.
Huttunen, P., Hirvonen, J., and Kinnula, V. (1981). The occurrence of brown adipose tissue in outdoor workers. Eur J Appl Physiol46, 339—45.
17.
Iatropoulos, M., Williams, G., and Seng, J. (2003). Phentolamine-induced responses in brown adipose tissue: a very important endocrine tissue. Society of Toxicologic Pathology 22nd Annual Meeting, Savannah, GA.
18.
Klaus, S., Muzzin, P., Revelli, J.-P., Cawthorne, M.A., Giacobino, J.-P., and Ricquier, D. (1995). Control of beta 3-adrenergic receptor gene expression in brown adipocytes in culture. Mol Cell Endocrinol109, 189—95.
19.
Lele, S.M., Chundru, S., Chaljub, G., Adegboyega, P., and Haque, A.K. (2002). Hibernoma. A report of 2 unusual cases with a review of the literature. Arch Pathol Lab Med126, 975—8.
20.
Mertens, F., Rydholm, A., Brosjo, O., Willen, H., Mitelman, F., and Mandahl, N. (1994). Hibernomas are characterized by rearrangements of chromosome bands 11q13-21. Int J Cancer58, 503—5.
21.
Mitchell, A.D. (1997). In vivo mouse bone marrow micronucleus test preceded by dose-range finding of phentolamine mesylate. Study Report No. 96067. Genesys Research, Inc., Research Triangle Park, NC .
22.
Murphy, C.J., Bellhorn, R.W., and Buyukmihci, N.C. (1986). Subconjunctival hibernoma in a goose. J Am Vet Med Assoc189, 1109—10.
23.
Nagase, I., Sasaki, N., Tsukazaki, K., Yoshida, T., Morimatsu, M., and Saito, M. (1994). Hyperplasia of brown adipose tissue after chronic stimulation of beta 3-adrenergic receptor in rats. Jpn J Vet Res42, 137—45.
24.
Ochoa, R. (1972). Hibernoma in a dog. Report of a case. Cornell Vet62, 138—44.
25.
Perling, L.H., Laurent, J.P., and Cheek, W.R. (1988). Epidural hibernoma as a complication of corticosteroid treatment. J Neurosurg69, 613—6.
26.
Putnam, D.L. (1988). Chromosome aberrations in Chinese hamster ovary (CHO) cells. Study Report No. T8199.337. Microbiological Associates, Inc., Rockville, MD.
27.
Ricquier, D., Nechad, M., and Mory, G. (1982). Ultrastructural and biochemical characterization of human brown adipose tissue in pheochromocytoma. J Clin Endocrinol Metab54, 803—7.
28.
Stefanski, S.A., Elwell, M.R., and Yoshitomi, K. (1987). Malignant hibernoma in a Fischer 344 rat. Lab Anim Sci37, 347—9.
29.
Teplitz, C., and Chan Lim, Y. (1974). The diagnostic significance of diffuse brown adipose tissue (BAT) transformation of adult human periadrenal fat: a morphologic indicator of severe chronic hypoxemia. Lab Invest30, 390.
30.
Teplitz, C., Farrugia, R., and Glicksman, A.S. (1980). Malignant hibernoma does exist. Lab Invest42, 154—5.
31.
Tsukazaki, K., Nikami, H., Shimizu, Y., Kawada, T., Yoshida, T., and Saito, M. (1995). Chronic administration of beta-adrenergic agonists can mimic the stimulative effect of cold exposure on protein synthesis in rat brown adipose tissue. J Biochem117, 96—100.
32.
Valerio, M., Landon, J.C., and Innes, J.R.M. (1968). Neoplastic diseases in simians. J Nat Cancer Inst40, 751—6.
33.
Wagner III, V.O., and Klug, M.L. (1999). Bacterial reverse mutation assay. Study Report No. G97AJ10.502. MA BioServices, Inc., Rockville, MD.
34.
Watkins, R.W., and Young, S. (1999). Effects of SCH 4515 in conscious rats. Schering-PloughResearch Institute, Kenilworth, NJ.
35.
Wenk, M.L. (1998). Twenty-six week oral gavage toxicity/carcinogenicity study in male and female p53+/- mice. Study report No. M97AJ10.7G82. MA Bioservices, Inc., Rockville, MD.
36.
Yamashita, H., Kizaki, T., Ookawara, T., Sato, Y., Yamamoto, M., Ohira, Y., and Ohno, H. (1994a). Is insulin-like growth factor I involved in brown adipose tissue enlargement?Life Sci55, 141—8.
37.
Yamashita, H., Sato, Y., Kizaki, T., Oh-ishi, S., Nagasawa, J.-I., and Ohno, H. (1994b). Basic fibroblast growth factor (bFGF) contributes to the enlargement of brown adipose tissue during cold acclimation. Pflugers Arch428, 352—6.
38.
Zennaro, M.C., Le Menuet, D., Viengchareun, S., Walker, F., Ricquier, D., and Lombes, M. (1998). Hibernoma development in transgenic mice identifies brown adipose tissue as a novel target of aldosterone action. J Clin Invest101, 1254—60.
39.
Zorgniotti, A.W. (1994). Experience with buccal phentolamine mesylate for impotence. Int J Impotence Res6, 37—41.
