Species: Rat Strain/breeder: Crl:CD (SD)IGS BR; Charles River France Sex: Male Age: 9 weeks Study type: 2 week continuous intravenous infusion toxicity study Treatment: EndothelinA-selective Receptor Antagonist; 500 mg/kg Animal status: Scheduled sacrifice at end of study Clinical findings: None Organ(s): Testis Macroscopic finding(s): None; slight organ weight increase Staining: H&E

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Abstract

A. ROMEIKE

Pfizer Global R & D, Amboise Laboratories, BP 109, 37401 Amboise Cedex, France

Key words: endothelin antagonist, endothelin-1, testicular changes, tubular dilatation, testicular fluid imbalance, peritubular myoid cells, SD rat

After 2-week continuous intravenous infusion of an endothelinA receptor antagonist (ETA) in rats, generalised dilatation of testicular tubules was observed in all dose groups. This was characterized by an increase in diameter of the tubular lumen, lined with a microscopically intact seminiferous epithelium and surrounded by a loosely arranged interstitium. The testicular weight was slightly elevated.

This change is considered to be a pharmacological effect of the compound (inhibition of endothelin receptors). Endothelin-1, a potent stimulator of smooth muscle contractility, has been shown to be produced in the testis, as well as to bind to specific receptors on peritubular myoid cells that stimulate tubular contraction. Seminiferous tubule contractility is fundamental for sperm progression towards the rete testis and for testicular fluid balance. Peritubular myoid cells are also involved in the control and maintenance of Sertoli cell function. The latter are responsible for the production of seminiferous tubule fluid. Such changes have been seen with a number of ETAs and the severity is both dose and time dependent. It therefore appears to be a pharmacological class effect.