Use this URL to cite or link to this record in EThOS:
Title: The novel testicular toxicity of a 5HT-1 receptor agonist
Author: Piner, J. A.
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 1998
Availability of Full Text:
Full text unavailable from EThOS.
Please contact the current institution’s library for further details.
The aims of the work presented in this Thesis were to establish the nature and mechanism of the testicular and epididymal toxicity in Charles River Wistar rats, at least 10 weeks of age, after administration of high dosages of GR403370D, a 5HT-1 receptor agonist that was under development by Glaxo Wellcome for the potential relief of migrainous headaches. Initial investigations used a detailed morphological examination of perfusion-fixed tissues which were confirmed and/or further characterised using image analysis. The testicular vasculature was implicated as the initial target, since a reduction in the cross-sectional area of the veins of the mediastinal venous plexus (MVP) was the earliest change found. Subsequent experiments found that arterial-venous anastomoses (AVAs) of the spermatic cord to be constricted or shut. These findings are consistent with the general pharmacological action of 5HT-1 receptor agonists, developed to act on the vasculature, specifically the AVAs of the carotid arterial bed. Changes in the testis and epididymis were considered to have occurred as a consequence of the effect on the testicular vasculature. Effects were evident at 12 to 48 hours post-dose and included increased testicular weight, an increase in the diameter of the seminferious tubules, distension of the rete testis, and an increase in vaculation of the cytoplasm of elongating spermatids. Furthermore, interstitial fluid volume and seminiferous tubular fluid production were reduced. Changes were seen later in the epididymis at 24 to 48 hours, and included an increase in the size of the lumen of the duct in the initial segment and caput regions with oedema of the interstitial space and a concurrent increase in weight of the epididymis. Testicular and epididymal changes were found to be fully reversible after sufficient time (up to 168 hours) was allowed. Further studies demonstrated that repeat administration of a toxic dosage resulted in more severe consequences.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available