Potential role of angiotensin-(1-7) in the improvement of vascular insulin sensitivity after a bout of exercise.

NEW FINDINGS: What is the central question of this study? What is the mechanism by which a bout of exercise increases subsequent insulin-stimulated vasodilatation? What is the main finding and its importance? Angiotensin-(1-7) through the Mas receptor participates in enhanced insulin-induced vasorelaxation after a bout of exercise in healthy rats. This new potential role of angiotensin-(1-7) could help in understanding how physical activity improves vascular insulin sensitivity in normal and insulin-resistant states. ABSTRACT: Exercise increases insulin-stimulated vasodilatation, but the mechanisms involved are unclear. This study was performed to investigate the possible involvement of angiotensin-(1-7) (Ang-(1-7)), a vasoactive peptide of the renin-angiotensin system (RAS), in enhanced vascular insulin sensitivity after a bout of exercise. Male Wistar rats were subjected to swimming for 2.5 h. After exercise, carbachol- or insulin-induced relaxation in aorta was assessed. Prior exercise improved insulin-stimulated vasorelaxation; however, this insulin-sensitizing effect was prevented by the selective Mas receptor (MasR; an Ang-(1-7) receptor) antagonist A779. Carbachol-mediated vascular relaxation was not modified by exercise. These results suggest that Ang-(1-7) acting through MasR participates in the enhancement of vascular insulin sensitivity after an exercise session. This new potential role of Ang-(1-7) could help in understanding how exercise improves vascular insulin sensitivity in normal and insulin-resistant states.

Participation of angiotensin-(1-7) in exercise-induced analgesia in rats with neuropathic pain.

Exercise reduces neuropathic pain in animals and humans. Recent studies indicate that training exercise favors the synthesis and action of angiotensin-(1-7) (Ang-(1-7)), a vasoactive peptide of the renin-angiotensin system (RAS), in various tissues. Interestingly, Ang-(1-7) also relieves neuropathic pain; however, it remains to be elucidated whether exercise mitigates this type of pain through Ang-(1-7). In this study, we investigated the role of Ang-(1-7) in exercise-induced analgesia in a neuropathic pain model. Male Wistar rats were ligated of lumbar spinal nerves (L5 and L6) or sham-operated. Then, they were subjected to acute (2-h) or chronic (4-week) exercise protocols. Tactile allodynia was evaluated before and after each exercise intervention. Microosmotic pumps were implanted subcutaneously for the release of Ang-(1-7) or A779 (selective Mas receptor (MasR; Ang-(1-7) receptor) antagonist). Plasma levels of Ang II and Ang-(1-7) were quantified by HPLC. Spinal nerve ligation (SNL) produced tactile allodynia. Both acute and chronic exercise reversed this neuropathic behavior. A779 treatment prevented the antiallodynic effect induced by each exercise protocol. SNL increased the plasma Ang II/Ang-(1-7) ratio; however, exercise did not modify it. Acute treatment with Ang-(1-7) via MasR mimicked exercise-mediated antinociception. Collectively, these results suggest that activation of the Ang-(1-7)/MasR axis of the RAS represents a potential novel mechanism by which exercise attenuates neuropathic pain in rats.

Angiotensin-(1-7) Participates in Enhanced Skeletal Muscle Insulin Sensitivity After a Bout of Exercise.

A single bout of exercise increases subsequent insulin-stimulated glucose uptake in skeletal muscle; however, it is unknown whether angiotensin-(1-7) (Ang-(1-7)), a vasoactive peptide of the renin-angiotensin system, participates in this process. The aim of this study was to investigate the possible involvement of Ang-(1-7) in enhanced skeletal muscle insulin sensitivity after an exercise session. Male Wistar rats were forced to swim for 2.5 hours. Two hours after exercise, insulin tolerance tests and 2-deoxyglucose uptake in isolated soleus muscle were assessed in the absence or presence of the selective Mas receptor (MasR, Ang-(1-7) receptor) antagonist A779. Ang II and Ang-(1-7) levels were quantified in plasma and soleus muscle by HPLC. The protein abundance of angiotensin-converting enzyme (ACE), ACE2, Ang II type 1 receptor (AT1R), and MasR was measured in soleus muscle by Western blot. Prior exercise enhanced insulin tolerance and insulin-mediated 2-deoxyglucose disposal in soleus muscle. Interestingly, these insulin-sensitizing effects were abolished by A779. After exercise, the Ang-(1-7)/Ang II ratio decreased in plasma, whereas it increased in muscle. In addition, exercise reduced ACE expression, but it did not change the protein abundance of AT1R, ACE2, and MasR. These results suggest that Ang-(1-7) acting through MasR participates in enhanced insulin sensitivity of skeletal muscle after a bout of exercise.

Angiotensin 1-7 improves insulin sensitivity by increasing skeletal muscle glucose uptake in vivo.

The renin-angiotensin system (RAS) regulates skeletal muscle insulin sensitivity through different mechanisms. The overactivation of the ACE (angiotensin-converting enzyme)/Ang (angiotensin) II/AT1R (Ang II type 1 receptor) axis has been associated with the development of insulin resistance, whereas the stimulation of the ACE2/Ang 1-7/MasR (Mas receptor) axis improves insulin sensitivity. The in vivo mechanisms by which this axis enhances skeletal muscle insulin sensitivity are scarcely known. In this work, we investigated whether rat soleus muscle expresses the ACE2/Ang 1-7/MasR axis and determined the effect of Ang 1-7 on rat skeletal muscle glucose uptake in vivo. Western blot analysis revealed the expression of ACE2 and MasR, while Ang 1-7 levels were detected in rat soleus muscle by capillary zone electrophoresis. The euglycemic clamp exhibited that Ang 1-7 by itself did not promote glucose transport, but it increased insulin-stimulated glucose disposal in the rat. In a similar manner, captopril (an ACE inhibitor) enhanced insulin-induced glucose uptake and this effect was blocked by the MasR antagonist A-779. Our results show for the first time that rat soleus muscle expresses the ACE2/Ang 1-7/MasR axis of the RAS, and Ang 1-7 improves insulin sensitivity by enhancing insulin-stimulated glucose uptake in rat skeletal muscle in vivo. Thus, endogenous (systemic and/or local) Ang 1-7 could regulate insulin-mediated glucose transport in vivo.