Aldosterone blockade confers substantial cardiovascular and renal protection. The effects of aldosterone on mineralocorticoid receptors (MR) expressed in endothelial cells (EC) within the renal vasculature have not been delineated. We hypothesized that lack of MR in EC may be protective in renal vasculature and examined this by ablating the Nr3c2 gene in endothelial cells (EC-MR) in mice. Blood pressure, heart rate and PAH clearance were measured using indwelling catheters in conscious mice. The role of the MR in EC on contraction and relaxation was investigated in the renal artery and in perfused afferent arterioles. Urinary sodium excretion was determined by use of metabolic cages. EC-MR transgenics had markedly decreased MR expression in isolated aortic endothelial cells as compared to littermates (WT). Blood pressure and effective renal plasma flow at baseline and following AngII infusion was similar between groups. No differences in contraction and relaxation were observed between WT and EC-MR KO in isolated renal arteries during baseline or following 2 or 4 weeks of AngII infusion. The constriction or dilatations of afferent arterioles between genotypes were not different. No changes were found between the groups with respect to urinary excretion of sodium after 4 weeks of AngII infusion, or in urinary albumin excretion and kidney morphology. In conclusion, deletion of the EC-MR does not confer protection towards the development of hypertension, endothelial dysfunction of renal arteries or renal function following prolonged AngII-infusion.

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.

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.

Context Individuals with type 2 diabetes have an increased risk of endothelial dysfunction and vascular disease. Plasma aldosterone could contribute by reactive oxygen species dependent mechanisms by inducing a shift in the balance between a vasoconstrictor and vasodilator response to aldosterone. Objective We aimed to investigate the acute vascular effects of aldosterone in individuals with type 2 diabetes compared to healthy controls and if infusion of an antioxidant (n-acetylcysteine) would alter the vascular response. Design, settings and participants In a case-control design 12 participants with type 2 diabetes and 14 healthy controls, recruited from the general community, were studied. Interventions and main outcome measurements Leg hemodynamics were measured before and during aldosterone infusion (0.2 and 5 ng min -1 [L leg volume] -1) for 10 minutes into the femoral artery with and without co-infusion of n-acetylcysteine (125 mg·kg -1 hour -1 followed by 25 mg·kg -1 hour -1). Leg blood flow and arterial blood pressure was measured, and femoral arterial and venous blood samples were collected. Results Compared to the control group, leg blood flow and vascular conductance decreased during infusion of aldosterone at the high dose in the individuals with type 2 diabetes, whereas co-infusion of NAC attenuated this response. Plasma aldosterone increased in both groups during aldosterone infusion and there was no difference between groups at baseline or during the infusions. Conclusion These results suggests that type 2 diabetes is associated with a vasoconstrictor response to physiological levels of infused aldosterone and that the antioxidant NAC diminishes this response.

Rationale & Objective Left ventricular (LV) mass (LVM) is a predictor of cardiovascular morbidity and mortality and commonly calculated using 1-dimensional (1D) echocardiographic methods. These methods are vulnerable to small measurement errors and LVM may wrongly change according to changes in LV volume (LVV). Less commonly used 2-dimensional (2D) methods can accommodate to the changes in LVV and may be a better alternative among patients receiving hemodialysis (HD) with large fluid fluctuations. Study Design Observational study. Setting & Participants Patients with end-stage kidney disease receiving HD. Exposure One HD session. Analytical Approach Transthoracic echocardiography was performed right before and after HD. LVM was calculated using 1D (Devereux, Penn, and Teichholz) and 2D methods (truncated ellipsoid and area-length). Outcomes Significant differences in LVM after HD. Results We compared dimensions, LVV and LVM, in 53 patients (mean age, 63 ± 15 years; 66% men). For each 1-L increase in ultrafiltration volume (UFV), LV internal diameter decreased 1.1 mm (95% CI, 0.5-1.7 mm; P = 0.001). Patients were divided into 2 groups by the median UFV of 1.6 L. Patients with UFV > 1.6 L had significant smaller LVV and LV internal diameter after HD. LVM calculated using 1D methods decreased according to changes in LVV. Conversely, LVM calculated using 2D methods was not significantly different after HD. No significant change in differences between diastolic − systolic myocardial thickness or LVM as assessed using 1D and 2D methods was observed before and after HD, indicating that LVM remained constant despite HD. Limitations We did not use contrast enhancement, 3-dimensional methods, or cardiac magnetic resonance. Conclusions LVM calculated using 2D methods, truncated ellipsoid and area-length, is less affected by fluctuations in fluid and LVV, in contrast to 1D methods. Complementary LVM calculation using 2D methods is encouraged, especially in patients with large fluid fluctuations in which increased LVM using a 1D method has been detected.