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

Abstract

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.

Fig. 1.

Effects of aging and exercise training on vasoconstrictor responses to the cumulative addition of angiotensin II of soleus (A) and gastrocnemius (B) muscle arterioles from young sedentary (YS), old sedentary (OS), young exercise-trained (YT), and old exercise-trained (OT) rats. Values are means ± SE; n = number of animals studied per group. *Difference between groups (P < 0.05).

Fig. 2.

Effects of aging and exercise training on vasoconstrictor responses of soleus (A) and gastrocnemius (B) muscle arterioles to the single dose of angiotensin II (10⁻⁸ M). Values are means ± SE; n = number of animals studied per group. *Mean arteriolar response from OS animals different from that of all other groups (P < 0.05).

Fig. 3.

Effects of endothelium removal on vasoconstrictor responses to the cumulative addition of angiotensin II in YS, endothelium-removed YS (YS-E), old sedentary (OS), and endothelium-removed OS (OS-E) arterioles from the soleus (A) and gastrocnemius (B) muscles. Vasoconstrictor responses of YS and OS with intact endothelium are the same as those in Fig. 1, A and B. Values are means ± SE; n = number of animals studied per group. *Difference between groups (P < 0.05).

Fig. 4.

Effects of nitric oxide synthase (NOS) inhibition with N^G-nitro-l-arginine methyl ester (l-NAME) on vasoconstrictor responses to the cumulative addition of angiotensin II in YS, YS with l-NAME (YS+l-NAME), OS, and OS with l-NAME (OS+l-NAME) arterioles from the soleus (A) and gastrocnemius (B) muscles. Vasoconstrictor responses of YS and OS without NOS inhibition are the same as those in Fig. 1, A and B. Values are means ± SE; n = number of animals studied per group. *Difference between groups (P < 0.05).

Fig. 5.

Effects of endothelium removal on vasoconstrictor responses to the cumulative addition of angiotensin II in OS, OT, OS-E, and endothelium-removed OT (OT-E) arterioles from the soleus (A) and gastrocnemius (B) muscles. Vasoconstrictor responses of OS and OT with intact endothelium are the same as those in Fig. 1, A and B. Values are means ± SE; n = number of animals studied per group. *Difference between groups (P < 0.05).

Fig. 6.

Effects of NOS inhibition with l-NAME on vasoconstrictor response to the cumulative addition of angiotensin II in OS, OT, OS+l-NAME, and OT with l-NAME (OT+l-NAME) arterioles from the soleus (A) and gastrocnemius (B) muscles. Vasoconstrictor responses of OS and OT without NOS inhibition are the same as those in Fig. 1, A and B. Values are means ± SE; n = number of animals studied per group. *Difference between groups (P < 0.05).

Fig. 7.

Effects of endothelium removal and l-NAME on vasoconstrictor response to the cumulative addition of angiotensin II in YS and OS arterioles from the soleus (A) and gastrocnemius (B) muscles. Vasoconstrictor responses of YS-E and OS-E, and YS+l-NAME and OS+l-NAME, are the same as those in Figs. 3, A and B, and 4, A and B, respectively. Values are means ± SE; n = number of animals studied per group.

Fig. 8.

Effects of chronic TNF type 1 receptor inhibition on vasoconstrictor response to the cumulative addition of angiotensin II in gastrocnemius muscle arterioles from YS, OS, YS with the TNF-α inhibitor (YS-TNFα), and OS with TNF-α inhibitor (OS-TNFα). Values are means ± SE; n = number of animals studied per group. *Difference between groups (P < 0.05).