Eight weeks of treatment with mineralocorticoid receptor blockade does not alter vascular function in individuals with and without type 2 diabetes.

Aldosterone has been suggested to be involved in the microvascular complications observed in type 2 diabetes. We aimed to investigate the effect of mineralocorticoid receptor (MR) blockade on endothelial function in individuals with type 2 diabetes compared to healthy controls. We included 12 participants with type 2 diabetes and 14 controls. We measured leg hemodynamics at baseline and during femoral arterial infusion of acetylcholine and sodium nitroprusside before and 8 weeks into treatment with MR blockade (eplerenone). Acetylcholine infusion was repeated with concomitant n-acetylcysteine (antioxidant) infusion. No difference in leg blood flow or vascular conductance was detected before or after the treatment with MR blockade in both groups and there was no difference between groups. Infusion of n-acetylcysteine increased baseline blood flow and vascular conductance, but did not change the vascular response to acetylcholine before or after treatment with MR blockade. Skeletal muscle eNOS content was unaltered by MR blockade and no difference between groups was detected. In conclusion, we found no effect of MR blockade endothelial function in individuals with and without type 2 diabetes. As the individuals with type 2 diabetes did not have vascular dysfunction, these results might not apply to individuals with vascular dysfunction.

The role of T-type calcium channels in elderly human vascular function: A pilot randomized controlled trial.

Endothelial dysfunction develops with age and may precede cardiovascular disease. Animal data suggest that T-type calcium channels play an important role in endothelial function, but data from humans are lacking. This study included 15 healthy, sedentary, elderly males for a double blinded, randomized controlled trial. For 8 weeks, they were given 40 mg/day of either efonidipine (L- and T-type calcium channel blocker (CCB)) or nifedipine (L-type CCB). Vascular function was evaluated by graded femoral arterial infusions of acetylcholine (ACh; endothelium-dependent vasodilator) and sodium nitroprusside (endothelium-independent vasodilator) both with and without co-infusion of N-acetylcysteine (NAC; antioxidant). We measured leg blood flow and mean arterial pressure and calculated leg vascular conductance to evaluate the leg vascular responses. Despite no significant change in blood pressure in either group, we observed higher leg blood flow responses (Δ 0.43 ± 0.45 l/min, P = 0.006) and leg vascular conductance (Δ 5.38 ± 5.67 ml/min/mmHg, P = 0.005) to intra-arterial ACh after efonidipine, whereas there was no change in the nifedipine group, and no differences between groups. We found no upregulation of endothelial nitric oxide synthase in vastus lateralis muscle biopsies within or between groups. Smooth muscle cell responsiveness was unaltered by efonidipine or nifedipine. Intravenous co-infusion of NAC did not affect endothelium-dependent vasodilatation in either of the CCB groups. These results suggest that 8 weeks' inhibition of T- and L-type calcium channels augments endothelium-dependent vasodilatory function in healthy elderly males. Further studies are required to elucidate if T-type calcium channel inhibition can counteract endothelial dysfunction.

Role of Endothelin-1 Receptors in Limiting Leg Blood Flow and Glucose Uptake During Hyperinsulinemia in Type 2 Diabetes.

Skeletal muscle insulin resistance is a hallmark of individuals with type 2 diabetes mellitus (T2D). In healthy individuals insulin stimulates vasodilation, which is markedly blunted in T2D; however, the mechanism(s) remain incompletely understood. Investigations in rodents indicate augmented endothelin-1 (ET-1) action as a major contributor. Human studies have been limited to young obese participants and focused exclusively on the ET-1 A (ETA) receptor. Herein, we have hypothesized that ETA receptor antagonism would improve insulin-stimulated vasodilation and glucose uptake in T2D, with further improvements observed during concurrent ETA + ET-1 B (ETB) antagonism. Arterial pressure (arterial line), leg blood flow (LBF; Doppler), and leg glucose uptake (LGU) were measured at rest, during hyperinsulinemia alone, and hyperinsulinemia with (1) femoral artery infusion of BQ-123, the selective ETA receptor antagonist (n = 10 control, n = 9 T2D) and then (2) addition of BQ-788 (selective ETB antagonist) for blockade of ETA and ETB receptors (n = 7 each). The LBF responses to hyperinsulinemia alone tended to be lower in T2D (controls: ∆161 ±â€…160 mL/minute; T2D: ∆58 ±â€…43 mL/minute, P = .08). BQ-123 during hyperinsulinemia augmented LBF to a greater extent in T2D (% change: controls: 14 ±â€…23%; T2D: 38 ±â€…21%, P = .029). LGU following BQ-123 increased similarly between groups (P = .85). Concurrent ETA + ETB antagonism did not further increase LBF or LGU in either group. Collectively, these findings suggest that during hyperinsulinemia ETA receptor activation restrains vasodilation more in T2D than controls while limiting glucose uptake similarly in both groups, with no further effect of ETB receptors (NCT04907838).

Eight weeks of mineralocorticoid blockade does not improve insulin sensitivity in type 2 diabetes.

Individuals with type 2 diabetes have an increased risk of cardiovascular disease. A correlation between plasma aldosterone and hyperinsulinemia has been demonstrated in vivo, and hyperinsulinemia and insulin resistance are independently associated with the development of cardiovascular complications. We investigated if mineralocorticoid blockade (Eplerenone) improves insulin sensitivity in individuals with type 2 diabetes compared to healthy controls. We included 13 participants with type 2 diabetes (<5 years; male/female, Caucasians) and 10 healthy control participants (male/female, Caucasians). On 2 experimental days, before and at the end of the 8 weeks of treatment with mineralocorticoid blockade, a two-stage hyperinsulinemic-isoglycemic clamp (20 and 50 mU∙m-2 min-1 ) was performed for the determination of insulin sensitivity. No change in insulin sensitivity was detected at the end of the mineralocorticoid blockade in the individuals with type 2 diabetes or the healthy controls. Both before and at the end of the treatment with mineralocorticoid blockade, the individuals with type 2 diabetes had a lower insulin sensitivity compared to healthy controls. In conclusion, mineralocorticoid receptor blockade does not appear to improve insulin sensitivity in individuals with type 2 diabetes. CLINICAL TRIAL REGISTRATION: NCT03017703. https://clinicaltrials.gov/ct2/show/NCT03017703.

Deficiency of T-type Ca2+ channels Cav3.1 and Cav3.2 has no effect on angiotensin II-induced hypertension but differential effect on plasma aldosterone in mice.

T-type Ca2+ channel Cav3.1 promotes microvessel contraction ex vivo. It was hypothesized that in vivo, functional deletion of Cav3.1, but not Cav3.2, protects mice against angiotensin II (ANG II)-induced hypertension. Mean arterial blood pressure (MAP) and heart rate were measured continuously with chronically indwelling catheters during infusion of ANG II (30 ng·kg-1·min-1, 7 days) in wild-type (WT), Cav3.1-/-, and Cav3.2-/- mice. Plasma aldosterone and renin concentrations were measured by radioimmunoassays. In a separate series, WT mice were infused with ANG II (100 ng·kg-1·min-1) with and without the mineralocorticoid receptor blocker canrenoate. Cav3.1-/- and Cav3.2-/- mice exhibited no baseline difference in MAP compared with WT mice, but day-night variation was blunted in both Cav3.1 and Cav3.2-/- mice. ANG II increased significantly MAP in WT, Cav3.1-/-, and Cav3.2-/- mice with no differences between genotypes. Heart rate was significantly lower in Cav3.1-/- and Cav3.2-/- mice compared with control mice. After ANG II infusion, plasma aldosterone concentration was significantly lower in Cav3.1-/- compared with Cav3.2-/- mice. In response to ANG II, fibrosis was observed in heart sections from both WT and Cav3.1-/- mice and while cardiac atrial natriuretic peptide mRNA was similar, the brain natriuretic peptide mRNA increase was mitigated in Cav3.1-/- mice ANG II at 100 ng/kg yielded elevated pressure and an increased heart weight-to-body weight ratio in WT mice. Cardiac hypertrophy, but not hypertension, was prevented by the mineralocorticoid receptor blocker canrenoate. In conclusion, T-type channels Cav3.1and Cav3.2 do not contribute to baseline blood pressure levels and ANG II-induced hypertension. Cav3.1, but not Cav3.2, contributes to aldosterone secretion. Aldosterone promotes cardiac hypertrophy during hypertension.

Reduced skeletal-muscle perfusion and impaired ATP release during hypoxia and exercise in individuals with type 2 diabetes.

AIMS/HYPOTHESIS: Plasma ATP is a potent vasodilator and is thought to play a role in the local regulation of blood flow. Type 2 diabetes is associated with reduced tissue perfusion. We aimed to examine whether individuals with type 2 diabetes have reduced plasma ATP concentrations compared with healthy control participants (case-control design). METHODS: We measured femoral arterial and venous plasma ATP levels with the intravascular microdialysis technique during normoxia, hypoxia and one-legged knee-extensor exercise (10 W and 30 W) in nine participants with type 2 diabetes and eight control participants. In addition, we infused acetylcholine (ACh), sodium nitroprusside (SNP) and ATP into the femoral artery to assess vascular function and ATP signalling. RESULTS: Individuals with type 2 diabetes had a lower leg blood flow (LBF; 2.9 ± 0.1 l/min) compared with the control participants (3.2 ± 0.1 l/min) during exercise (p < 0.05), in parallel with lower venous plasma ATP concentration (205 ± 35 vs 431 ± 72 nmol/l; p < 0.05). During systemic hypoxia, LBF increased from 0.35 ± 0.04 to 0.54 ± 0.06 l/min in control individuals, whereas it did not increase (0.25 ± 0.04 vs 0.31 ± 0.03 l/min) in the those with type 2 diabetes and was lower than in the control individuals (p < 0.05). Hypoxia increased venous plasma ATP levels in both groups (p < 0.05), but the increase was higher in control individuals (90 ± 26 nmol/l) compared to those with type 2 diabetes (18 ± 5 nmol/l). LBF and vascular conductance were lower during ATP (0.15 and 0.4 µmol min-1 [kg leg mass]-1) and ACh (100 µg min-1 [kg leg mass]-1) infusion in individuals with type 2 diabetes compared with the control participants (p < 0.05), whereas there was no difference during SNP infusion. CONCLUSIONS/INTERPRETATION: These findings demonstrate that individuals with type 2 diabetes have lower plasma ATP concentrations during exercise and hypoxia compared with control individuals, and this occurs in parallel with lower blood flow. Moreover, individuals with type 2 diabetes have a reduced vasodilatory response to infused ATP. These impairments in the ATP system are both likely to contribute to the reduced tissue perfusion associated with type 2 diabetes. TRIAL REGISTRATION: ClinicalTrials.gov NCT02001766.