Degree Type

Dissertation

Date of Award

1998

Degree Name

Doctor of Philosophy

Department

Theses & dissertations (Interdisciplinary)

Major

Neuroscience

First Advisor

Lloyd L. Anderson

Abstract

This dissertation describes the central regulation of growth hormone (GH) secretion and mechanism of action of a substituted benzolactam GH secretagogue, L-692,585 (585), in young (40-45 kg) castrate male Yorkshire pigs;The first study describes the central regulation of GH secretion by 585 with intracerebroventricular (icv) stainless steel cannulas placed by stereotaxic coordinates. Dose-dependent increases in GH secretion by 585 occurred following icv injections of saline vehicle, 3, 10, 30 [mu]g/kg BW by a once daily increment. A switchback study of iv and icv 585 treatment determined central and peripheral regulation of GH secretion by the GH secretagogue;The second study investigated the possible involvement of neuropeptides administered icv on GH secretion. We injected somatostatin (SRIH), neuropeptide Y (NPY) and galanin (GAL) with or without 585. The results suggest that endogenous GH secretion was affected by SRIH and GAL but not by NPY, and 585-stimulated GH response appeared to be modulated by all three neuropeptides;The third study describes the effect of urocortin on GH release. Urocortin (0.01, 0.03, 0.01 mg/ kg BW) and saline vehicle were administered via icv cannula. A modest increase in GH release resulted from central administration of urocortin;The fourth study details the effect of 585 on hypothalamus-pituitary-adrenal axis by comparing the effects of hypophysectomy (HYPOX) and sham operation control (SOC). Intravenous administration of 585 (0.01, 0.1 mg/kg BW) significantly increased cortisol in the SOC but not in the HYPOX group. As expected, 585 increased GH in the SOC, but not in the HYPOX group. Compared with respective saline controls, ACTH caused increases in cortisol levels in the SOC and HYPOX groups. Results of this study indicate that 585 requires an intact pituitary to increase cortisol secretion suggesting that GH-secretagogue has no direct stimulatory effect on adrenal cortisol secretion in HYPOX or SOC pigs;The results of these studies investigating the central effect of L-692,585 in pigs support the idea that novel nonpeptidyl growth hormone secretagogues may mimic an unidentified endogenous hormone that amplifies and is capable of regulating pulsatile GH secretion in concert with GHRH, somatostatin, and neuropeptides.

DOI

https://doi.org/10.31274/rtd-180813-4957

Publisher

Digital Repository @ Iowa State University, http://lib.dr.iastate.edu/

Copyright Owner

Sang-Joon Cho

Language

en

Proquest ID

AAI9826522

File Format

application/pdf

File Size

215 pages

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