Endothelin-A-Mediated Vasoconstriction During Exercise With Advancing Age

Healthy aging is associated with an elevation in vascular tone (1,2), contributing to the attenuated resting skeletal muscle blood flow observed in the elderly (3–8). These age-related changes in vascular tone and the associated decline in skeletal muscle blood flow persist during exercise (4,8–10). Because adequate muscle perfusion is vital to meet the metabolic demand of the tissue and maintain normal muscle function at rest and during exercise, a better understanding of the mechanisms that contribute to the regulation of vascular tone in the elderly is essential. The functional consequence of these adaptations are substantial; indeed, impairment in perfusion of the exercising muscle may limit the capacity for physical activity, ultimately leading to immobility and an increased risk of cardiovascular disease in the elderly (11). The underlying mechanisms contributing to this age-related increase in vascular tone, and the apparent disparity in hemodynamic regulation between resting and exercising states, has long been a topic of investigation. Although there are a host of pathways that collectively contribute to increased vascular tone in the elderly, changes in the endothelin-1 (ET-1) pathway may be particularly relevant to this age-related adaptation. Indeed, there is evidence from both animal and human studies for an increase in the activity of the ET-1 pathway with advancing age (12–14), which has been linked to the age-associated reduction in resting skeletal muscle blood flow (15,16) via the endothelin subtype A (ETA) receptor pathway (16,17). Despite clear evidence implicating ET-1 as an important contributor to elevated resting vascular tone in the elderly, no studies to date have sought to examine the role of the ETA pathway in the regulation of exercising skeletal muscle blood flow with advancing age. Thus, this study evaluated the cardiovascular responses to knee-extensor exercise before and after inhibition of the ETA receptor via intra-arterial administration of BQ-123 in the exercising limb. We hypothesized that (a) ETA receptor blockade would enhance resting skeletal muscle blood flow in old, but not in young; (b) ETA receptor blockade during exercise would enhance skeletal muscle blood flow and reduce arterial blood pressure to a greater extent in old individuals, compared with their younger counterparts.