ABSTRACT
The aim of the present study was to evaluate the possible mechanisms of testicular toxicity of GR40370X, a follow-up 5-hydroxytryptamine (5-HT) receptor agonist. Administration to adult male rats of a single (toxic) dose of 750 mg/kg GR40370X induced marked distension of seminiferous tubules and an associated increase in testis weight at 12-24 h with a gradual recovery to normal by 96 h. Seminiferous tubule distension was due to expansion of the lumen, which occurred at all stages of the spermatogenic cycle and was accompanied by vacuolation of the cytoplasm of elongating spermatids. Seminiferous tubule distension was preceded/accompanied by distension of the efferent ducts and rete testis with maximal changes evident at 24-48 h. These changes could not be explained by increases in seminiferous tubule fluid or interstitial fluid production, as both were reduced (15-20%), rather than increased, by treatment. Examination of the vasculature after treatment with 750 mg/kg GR40370X revealed significant changes that were maximal at 4 h and thus preceded rete/testicular changes. Veins of the mediastinal venous plexus, which overlies the rete, were constricted and arteriovenous anastomoses in the spermatic cord were shut/constricted, as determined (indirectly) by measurement of the dilution of outflowing testicular venous blood by incoming arterial blood. The latter effect of GR40370X could be blocked by co-administration of minoxidil, a vasodilator. Vascular effects of GR40370X had normalised by 24-48 h. It was also noted that administration of a toxic dose of GR40370X significantly lowered blood levels of LH and testosterone, though these changes were considered to be incidental and not involved in the other changes described above. None of the above changes were induced by a pharmacologically active dose (1 mg/kg) of GR40370X. It is concluded that the mechanism of testicular toxicity induced by 750 mg/kg GR40370X results from primary effects on the vasculature of the testis/neighbouring region, which in turn lead to impaired fluid resorption from the efferent ducts and rete and thence to accumulation of seminiferous tubule fluid in the rete and testis.
