Angiotensin II: a major regulator of subcutaneous adipose tissue blood flow in humans

Abstract

We investigated the functional roles of circulating and locally produced angiotensin II (Ang II) in fasting and postprandial adipose tissue blood flow (ATBF) regulation and examined the interaction between Ang II and nitric oxide (NO) in ATBF regulation. Local effects of the pharmacological agents (or contralateral saline) on ATBF, measured with 133Xe wash-out, were assessed using the recently developed microinfusion technique. Fasting and postprandial (75 g glucose challenge) ATBF regulation was investigated in nine lean healthy subjects (age, 29 +/- 3 years; BMI, 23.4 +/- 0.7 kg m(-2)) using local Ang II stimulation, Ang II type 1 (AT1) receptor blockade, and angiotensin-converting enzyme (ACE) inhibition. Furthermore, NO synthase (NOS) blockade alone and in combination with AT1 receptor blockade was used to examine the interaction between Ang II and NO. Ang II induced a dose-dependent decrease in ATBF (10(-9)m: -16%, P = 0.04; 10(-7)m: -33%, P < 0.01; 10(-5)m: -53%P < 0.01). Fasting ATBF was not affected by ACE inhibition, but was increased by approximately 55% (P < 0.01) by AT(1) receptor blockade. NOS blockade induced a approximately 30% (P = 0.001) decrease in fasting ATBF. Combined AT1 receptor and NOS blockade increased ATBF by approximately 40% (P = 0.003). ACE inhibition and AT1 receptor blockade did not affect the postprandial increase in ATBF. We therefore conclude that circulating Ang II is a major regulator of fasting ATBF, and a major proportion of the Ang II-induced decrease in ATBF is NO independent. Locally produced Ang II does not appear to regulate ATBF. Ang II appears to have no major effect on the postprandial enhancement of ATBF.

Figure 1. Time line diagrams of the different experiments

Ang II dose–response experiments were performed to assess the effect of local Ang II stimulation on adipose tissue blood flow (ATBF) (A). In addition, the functional ATBF response to the ACE inhibitor enalaprilate (inhibition of local Ang II production) and the AT₁ receptor blocker losartan (complete blockade of Ang II action) (B) was investigated under fasting and postprandial (after 75 g oral glucose at 60 min (t60)) conditions. To assess the contribution of NO action to the Ang II-induced effect on ATBF, the ATBF response to the NOS inhibitor l-NMMA (inhibition of local NO production) in combination with AT₁ receptor blockade was compared to the ATBF response to NOS blockade alone (C). Thick arrows represent blood samples and blood pressure time points.

Figure 2. ATBF in response to local stimulation with Ang II

Ang II was applied at three concentrations: 10⁻⁹m, 10⁻⁷m and 10⁻⁵m (•) (n = 4). ○, microinfusion of saline (control). Values are means ±s.e.m.

Figure 3. ATBF in response to local ACE inhibition

•, pharmacological inhibition of Ang II production by the ACE inhibitor enalaprilate (10⁻³m) (n = 6). ○, contralateral saline control. Oral glucose is given at t60 to stimulate ATBF. Values are means ±s.e.m.

Figure 4. ATBF in response to local AT₁ receptor blockade

•, pharmacological blockade of the AT₁ receptor by losartan (10⁻³m) (n = 6). ○, contralateral saline control. Oral glucose is given at t60 to stimulate ATBF. Values are means ±s.e.m.

Figure 5. ATBF in response to local AT₁ receptor blockade alone and in combination with NOS blockade

ATBF in response to local AT₁ receptor blockade by losartan (10⁻³m) (•), contralateral saline control for AT₁ receptor blockade (○), local NOS blockade by l-NMMA (10⁻³m) alone and in combination with AT₁ receptor blockade (10⁻³m) (▾), and local NOS blockade (10⁻³m) (control for AT₁ receptor blockade in combination with NOS blockade) (▿) (n = 5). Values are means ±s.e.m.