Effects of aging, TNF-α, and exercise training on angiotensin II-induced vasoconstriction of rat skeletal muscle arterioles

Skeletal muscle vascular resistance during physical exertion is higher with old age. The purpose of this study was to determine whether 1) aging enhances angiotensin II (ANG II)-induced vasoconstriction; 2) the proinflammatory cytokine tumor necrosis factor (TNF)-α contributes to alterations in ANG II-mediated vasoconstriction with aging; 3) exercise training attenuates putative age-associated increases in ANG II-mediated vasoconstriction; and 4) the mechanism(s) through which aging and exercise training alters ANG II-induced vasoconstriction in skeletal muscle arterioles. Male Fischer 344 rats were assigned to four groups: young sedentary (4 mo), old sedentary (24 mo), young trained, and old trained. In a separate group of young sedentary and old sedentary animals, a TNF type 1 receptor inhibitor was administered subcutaneously for 10 wk. First-order arterioles were isolated from soleus and gastrocnemius muscles for in vitro experimentation. Old age augmented ANG II-induced vasoconstriction in both soleus (young: 27 ± 3%; old: 38 ± 4%) and gastrocnemius (young: 42 ± 6%; old: 64 ± 9%) muscle arterioles; this augmented vasoconstriction was abolished with the removal of the endothelium, N(G)-nitro-l-arginine methyl ester, and chronic inhibition of TNF-α. In addition, exercise training ameliorated the age-induced increase in ANG II vasoconstriction. These findings demonstrate that old age enhances and exercise training diminishes ANG II-induced vasoconstrictor responses in skeletal muscle arterioles through an endothelium-dependent nitric oxide synthase signaling pathway. In addition, the enhancement of ANG II vasoconstriction with old age appears to be related to a proinflammatory state.