Abstract P174: Dynamics of the Renin-Angiotensin-Aldosterone System: Implications of Angiotensin-Peptide Fingerprinting on the Clinical Use and Development of Antihypertensive Drugs

Abstract

BACKGROUND: The Renin-Angiotensin-Aldosterone-System (RAAS) is an extensively studied peptide hormone system which is critically involved in the regulation of blood pressure and other important physiologic functions. Angiotensin-(1-10) which is liberated from angiotensinogen by kidney secreted Renin, is sequentially metabolized to different N- and C-terminal truncated fragments with partially described biologic activities. Beside Angiotensin II (Ang-(1-8)), various other angiotensin peptides including Ang-(1-7), Ang-(1-9), Ang-(2-8) and Ang-(3-8) are known to possess physiologic activity while Ang-(1-7) and more recently Ang-(1-9) were described to antagonize pathologic effects of Ang-(1-8) via vasodilation and antifibrotic action respectively. The role of Ang-(1-8) in hypertension converts enzymes participating in Ang-(1-8) generation to favorable targets for antihypertensive drugs. METHODS: Human blood was collected from healthy volunteers followed by ex-vivo incubation at 37°C in the presence of different inhibitors of angiotensin metabolism. Angiotensin concentrations were determined employing a novel sensitive LC-MS/MS based method, which allows the simultaneous quantification of a broad panel of angiotensin peptides in human plasma. RESULTS: The investigation of different angiotensin metabolism modifiers revealed agent specific patterns of angiotensin peptide levels reflecting the specificity of these inhibitors. Spiking experiments allowed the determination of turnover rates for distinct angiotensin conversion reactions surrounded by their physiological matrix. CONCLUSION: The measurement of blood concentrations of angiotensin peptides provides important information about the substrate specificities and activities of enzymes involved in their metabolism. This allows the identification of potential causes for pathologic conditions, facilitating a patient specific therapeutic modulation of the RAAS. The overall assessment of angiotensin peptide concentrations (Angiotensin-Peptide-Fingerprinting) represents a powerful tool to gain a more detailed understanding of blood pressure regulation, enabling the pharmacologic characterization of RAAS modifying agents in use and development.