| Description |
The objective of this thesis was to determine the role of nonadrenergic vasoactive substances in the control of blood flow in the elderly. The first study aimed to determine the individual and potentiating effects of the renin-angiotensin-aldosterone (RAAS) and alpha-adrenergic systems on the regulation of blood flow in the young and old. We observed an enhanced maximal reduction in brachial artery blood flow in response to angiotensin-II (ANG-II) in the old compared to the young, which was abolished when the alpha-adrenergic component of the response was pharmacologically eliminated with phentolamine. These data suggest that with healthy aging, the increased ANG-IImediated vasoconstriction may be attributed, in part, to potentiation of alpha-adrenergic vasoconstriction, and indicates that the "cross-talk" between the RAAS and adrenergic systems could be an important therapeutic consideration for hypertension in the elderly. The second study of this project was focused on the role of endogenous endothelin-1 (ET-1) in the regulation of vascular tone at rest and during exercise, with a secondary emphasis on how this pathway is altered with advancing age. The first portion of the second study thus sought to characterize the role of ET-1 on blood flow, arterial blood pressure, and oxygen consumption (VO2) during knee extensor exercise in young, healthy adults. This study documented an increase in exercising limb blood flow following ET-1 receptor subtype A (ETA) antagonism (BQ-123), which was accompanied by a decrement in arterial blood pressure and an increase in VO2. Together, these findings have identified a significant role of the ET-1 pathway in the cardiovascular response to exercise, implicating vasoconstriction via the ETA receptor as an important mechanism for both restraint of blood flow in the exercising limb and support of arterial blood pressure in healthy, young adults. During the aging portion of the second study, at rest, blood flow was reduced by 30% in the elderly compared to the young. ETA antagonism did not change resting blood flow in the young, but restored blood flow in the old to a level similar to that of the young. During exercise, BQ-123 increased blood flow and VO2 to a similar degree in both the young and old. Likewise, the increase in arterial blood pressure during exercise was attenuated in a similar manner between groups after BQ-123 administration. Together these findings demonstrate differences in the regulatory role of the ET-1 pathway at rest and exercise with advancing age. Collectively, these studies have provided insight into the role of nonadrenergic vasoactive substances, specifically ANG-II and ET-1, in the regulation of vascular tone with age. Findings from these studies may provide new information concerning the prevention and treatment of ageassociated cardiovascular diseases. |
