CAPTOPRIL AND ANGIOTENSIN VASCULAR EFFECTS IN SENESCENCE

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Impaired homeostatic control of the circulatory system contributes to the high incidence of morbid and fatal cardiovascular episodes afflicting the elderly. Chronobiologic changes in the renin-angiotensin system (RAS), therefore, may represent important pathophysiologic modifications during the aging process. A number of studies have documented age-associated reductions in plasma renin activity (PRA) and plasma aldosterone concentration. Based on these data, many investigators have considered RAS activity to diminish during aging and predicted that angiotensin converting enzyme (ACE) inhibitors would not be efficacious in treating hypertension in the geriatric population. The conclusions regarding RAS activity, however, are inferences as few studies in elderly humans have measured angiotensin II (All), biologically the most important component of the RAS. Perhaps due to limitations in the assays employed to measure All, discordant and paradoxical results have been noted regarding the relationship between PRA and All concentration. Furthermore, All's vascular effect for a particular level of PRA has not been well characterized. Thus, it has not been shown that PRA remains a reliable index of RAS activity in senescence. Importantly, the accrued results from several lines of investigation, including data demonstrating a continued efficacy of ACE inhibitors in the elderly, suggest that the RAS continues to play an important role in the homeostatic control of blood pressure throughout all of life. This proposal will explore this issue in elderly humans by elucidating captopril's mechanism of action and characterizing the vascular activity of the RAS. Captopril's kinetic-dynamic relationship will be determined employing sensitive and specific assays for the drug and various response parameters. In addition to this manipulation of the RAS, other physiologic and pharmacologic maneuvers designed to alter the system will be used in order to study the relationships between PRA, All concentration and vascular reactivity. PRA will be measured by conventional methods and the true All concentration will be determined after chromatographic separation from interfering metabolites. To evaluate the vascular effect of All that corresponds to a particular state of RAS activity, the localized vascular response to All infused into the brachial artery will be measured by venous occlusion plethysmography. For comparison, young control subjects will also be studied. Results from this proposal should provide further insights into the functional significance of the age-associated affects on the RAS which, in turn, may influence treatment strategies for diseases such as hypertension in the elderly.