The effects of aging and exercise training on endothelin-1 vasoconstrictor responses in rat skeletal muscle arterioles

Objectives: The incidence of cardiovascular disease increases with advancing age. Vascular dysfunction has been linked to cardiovascular disease and aging, although most research has focused on endothelium-dependent vasodilator dysfunction. Another possible mechanism for this vascular dysfunction with aging is enhanced vasoconstrictor responsiveness of the resistance vasculature, and in particular, reactivity of arterioles to endothelin-1 (ET-1). We hypothesized that vasoreactivity to ET-1 would be greater in skeletal muscle arterioles from old rats, and that endurance exercise training would abolish differences in ET-1 responsiveness between young and old animals. Methods: Young sedentary (YS; 4 months; n=18), old sedentary (OS; 24 months; n=17), young trained (YT; n=9) and old trained (OT; n=7) male Fischer 344 rats were used. Training modality was treadmill exercise at 15 m/min up a 15 degrees incline, 1 h/day, 5 days/week, for 12 weeks. Soleus and white gastrocnemius muscle first-order arterioles were isolated for in vitro experimentation. Intraluminal diameter was measured in response to increasing concentrations of ET-1 (10(-11) to 10(-8) M) or KCl (10-100 mM) in arterioles with an intact or denuded endothelium and with and without an ETA (BQ-123 [10(-6) M]) or ETB (BQ-788 [10(-8) M]) receptor antagonist present. Results: There was an age-associated increase in gastrocnemius vasoconstrictor responsiveness and sensitivity to ET-1 in arterioles with intact endothelium (ET-1 EC50: YS, 5.2 E-9 +/- 1.1 E-9 M; OS, 2.0 E-9 +/- 0.8 E-9 M); neither removal of the endothelium nor ETB blockade abolished this difference in arteriolar sensitivity to ET-1 between old and young rats. In contrast, ETA inhibition abolished the greater sensitivity (EC50) of arterioles from old animals (ET-1 EC50: YS, 10 E-9 +/- 0.7 E-9 M; OS, 10 E-9 +/- 1.5 E-9 M). Gastrocnemius muscle arterioles exhibited an age-related reduction in KCl-induced vasoconstriction which was abolished with the removal of the endothelium. Soleus muscle arteriolar responses to ET-l and KCl were unaffected by aging. Additionally, exercise training had no effect on ET-1 vasoconstriction of soleus or gastrocnemius muscle arterioles. Conclusions: Aging results in an augmented gastrocnemius muscle arteriolar vasoconstriction to ET-1 which is mediated through an enhanced ETA receptor signaling pathway and not through an ETB receptor mechanism associated with either the endothelium or vascular smooth muscle. These findings suggest that enhanced vascular ET-1 sensitivity in fast-twitch skeletal muscles may play a role in the vascular dysfunction that is often associated with old age. (c) 2004 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.