Direct Activation of Angiotensin II Type 2 Receptors Enhances Muscle Microvascular Perfusion, Oxygenation, and Insulin Delivery in Male Rats

Abstract

Angiotensin II receptors regulate muscle microvascular recruitment and the delivery of nutrients, oxygen, and insulin to muscle. Although angiotensin type 1 receptor antagonism increases muscle microvascular perfusion and insulin action, angiotensin type 2 receptor blockade markedly restricts muscle microvascular blood volume and decreases muscle delivery of insulin. To examine the effects of direct type 2 receptor stimulation using Compound 21 (C21) on microvascular perfusion, insulin delivery and action, and tissue oxygenation in muscle, overnight-fasted adult male rats were infused with C21 systemically. C21 potently increased microvascular blood volume without altering microvascular flow velocity or blood pressure, resulting in a net increase in microvascular blood flow in muscle. This was associated with a substantial increase in muscle interstitial oxygen saturation and insulin delivery into the skeletal and cardiac muscle. These effects were neutralized by coinfusion of the type 2 receptor antagonist or nitric oxide synthase inhibitor. Superimposing C21 infusion on insulin infusion increased insulin-mediated whole body glucose disposal by 50%. C21 significantly relaxed the preconstricted distal saphenous artery ex vivo. We have concluded that direct type 2 receptor stimulation markedly increases muscle microvascular perfusion through nitric oxide biosynthesis and enhances insulin delivery and action in muscle. These findings provide a physiologic mechanistic insight into type 2 receptor modulation of insulin action and suggest that type 2 receptor agonists might have therapeutic potential in the management of diabetes and its associated complications.

Chronic administration of the angiotensin type 2 receptor agonist C21 improves insulin sensitivity in C57BL/6 mice.

“…In this aspect, our studies do not agree with a recent report performed in rats, showing that a short‐term C21 infusion enhances insulin delivery and action in muscle (Yan et al. ). This could be ascribed to the several factors, including differences in the duration of the experimental protocol as well as the dose employed.…”

“…Administration of C21 has recently been shown to enhance insulin delivery and metabolic action in skeletal muscle (Yan et al. ). Remarkably, unlike results obtained from AT2R stimulation or antagonism, information obtained from AT2R‐KO mice has not been consistent so far (Shiuchi et al.…”

Muscle Insulin Resistance and the Inflamed Microvasculature: Fire from Within

“…Thus, insulin’s microvascular and metabolic actions appear to be closely coupled and the metabolic actions of insulin on skeletal muscle depend on the effects of insulin on the skeletal muscle microvasculature as well as the skeletal muscle fibers. The importance of muscle microcirculation in the regulation of insulin’s metabolic actions is further strengthened by many observations in both humans and laboratory animals that multiple factors with proven evidence to affect muscle insulin action and glucose metabolism are able to induce muscle microvasculature recruitment, including exercise [43,44], mixed meals [45,46], resveratrol [47], ranolazine [48], angiotensin II type 1 receptor blockers [49,50,51], angiotensin 1-7 [52], adiponectin [53,54], glucagon-like peptide-1 [55,56], and angiotensin II type 2 receptor agonist [57].…”

Ubiquitin Ligases at the Heart of Skeletal Muscle Atrophy Control

“…Angiotensin (Ang) is a peptide hormone that upon enzymatic processing [ 118 ] renders different variants like Ang-II and Ang-(1–7) ( Figure 1 ) that can either be linked to catabolic conditions (Ang-II) [ 118 , 119 , 120 , 121 , 122 , 123 ] or counteract muscle atrophy (Ang-(1–7)) [ 124 , 125 , 126 , 127 , 128 ]. However, Ang-II can also exhibit anticatabolic properties, but only in some circumstances [ 127 , 129 ]). High levels of Ang-II have been associated with skeletal muscle atrophy in CHF, CKD, and SARS-CoV-2 pathologies [ 120 , 130 ].…”