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Title: Studies on the renal formation and actions of 5-hydroxytryptamine using its prodrugs in man
Author: Li Kam Wa, Tin Chien
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 1996
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In this thesis, I have employed the γ-glutamyl prodrug approach to targeting drugs to the kidney to explore the renal formation and actions of 5-HT in healthy human subjects. I compared the effects of intravenous infusions of 5-hydroxy-L-tryptophan (L-5-HTP), the immediate precursor of 5-HT, and γ-L-glutamyl-5-hydroxy-L-tryptophan (glu-5-HTP), the glutamyl derivative of L-5-HTP. There were marked increases in the urinary excretion of 5-HT, without changes in circulating 5-HT levels measured in platelet-rich plasma, consistent with intrarenal synthesis of 5-HT. Both compounds reduced urinary sodium excretion in the absence of significant alterations in renal haemodynamics suggesting a predominantly tubular effect on sodium reabsorption. The urinary metabolite data and reduced extrarenal effects of glu-5-HTP, as evidenced by changes in growth hormone and aldosterone release, blood pressure and incidence of adverse effects, suggested that the glutamyl prodrug was relatively more selective for the kidney than L-5-HTP. Carbidopa produced a 99% reduction in urinary excretion of 5-HT after glu-5-HTP and abolished its antinatriuretic effect. These observations indicated that glu-5-HTP, or its intermediate metabolite L-5-HTP, had no effect per se and required conversion to 5-HT to exert an effect on sodium excretion. I compared the relative effectiveness of γ-L-glutamyl-L -tryptophan (glu-TRP), the glutamyl derivative of L-tryptophan, and glu-5-HTP as substrates for 5-HT synthesis in the kidney. Glu-TRP, unlike glu-5-HTP, failed to increase the urinary excretion of 5-HTP or 5-HT and to reduce sodium excretion suggesting an absence of effective renal synthesis of 5-HT following glu-TRP infusion. Glu-5-HTP could be a valuable experimental tool for manipulating renal 5-HT production and exploring the renal formation and effects of 5-HT in man in health and disease.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available