Development of Hibernomas in Rats Dosed with Phentolamine Mesylate During the 24-Month Carcinogenicity Study

Abstract

Phentolamine is a reversible competitive alpha-adrenergic antagonist with similar affinities for alphal and alpha2 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.

Spontaneous Hibernomas in Sprague-Dawley Rats

“…In addition to the Charles River compilations, Al Zubaidy and Finn (1983), Coleman (1980), and Stefanski (1987) reported small numbers of hibernomas as incidental findings in the thoracic cavity of Poulet et al (2004) and by Brees et al (2008). In Poulet's report, eleven hibernomas were observed in a population of 520 Sprague-Dawley [Crl:CD BR] rats (260/sex) assigned to a two-year carcinogenesis study of phentolamine mesylate (an a-adrenergic antagonist) administered at daily doses of 10, 50, and 150 mg/kg.…”

Clinical, Morphologic, and Immunohistochemical Features of Canine Orbital Hibernomas

“…The orbital hibernomas presented here consistently exhibited histologic, ultrastructural, and immunohistochemical features similar to those of hibernomas reported in a dog, rodents, and humans. 2,8,9,16,22,24,25 Potential differentials for the orbital neoplasms reported here include lipomatous neoplasms, rhabdomyomas, granular cell tumors, oncocytomas, and xanthogranulomas. Lipomas differ from hibernomas as they are less vascularized and resemble mature white adipose tissue with neoplastic cells having characteristic, large, cytoplasmic, lipid vacuoles that eccentrically displace the nucleus.…”

Pharmacological Effects of Nicotine on Norepinephrine Metabolism in Rat Brown Adipose Tissue: Relevance to Nicotinic Therapies for Smoking Cessation

“…In that study, male and female rats were given 10, 50, or 150 mg/kg phentolamine mesylate orally, which resulted in the occurrence of hibernomas (largely localized to mediastinal BAT), with a much higher frequency in male rats compared with female rats (10:1). Phentolamine is believed to cause hibernomas in rats via an increase in NE from a chronic adaptive sympathetic response to the effects of phentolamine on blood pressure (Poulet et al, 2004), but this drug has never been linked with the occurrence of hibernoma in humans.…”