Plasma Angiotensin II Research Articles

Blood pressure response to angiotensin II is enhanced in obese Zucker rats and is attributed to an aldosterone‐dependent mechanism

Plasma aldosterone levels correlate positively with obesity, suggesting a link between the hypertension associated with obesity and increased mineralocorticoid levels. We tested the hypothesis that aldosterone is involved in the BP response to angiotensin II (AngII) in obese rats. Lean (LZR) and obese (OZR) Zucker rats were treated with AngII (9 µg·h(-1) ; 4 weeks), and BP and plasma AngII and aldosterone were determined. Chronic AngII increased the BP in OZR markedly more so than in LZR. Plasma AngII levels in LZR and OZR were similar after AngII treatment. The AngII stimulated a rise in plasma aldosterone that was sixfold more in OZR than in LZR. The thickness of the zona glomerulosa of the adrenal glands was selectively increased by AngII in OZR. Adrenal mRNA levels of CYP11B2 aldosterone synthase and the AT(1B) receptor were selectively increased in AngII-treated OZR. The BP response to chronic AngII stimulation was diminished in OZR after adrenalectomy when plasma aldosterone was absent. Acute bolus injections of AngII did not increase the BP response or aldosterone release in OZR. The AngII-induced BP response is enhanced in obesity and this is associated with a specific increase in circulating aldosterone. Due to the AngII-induced growth of the zona glomerulosa in OZR, the AT(1B) receptors and aldosterone synthase may be selectively enhanced in obesity under concomitant AngII stimulation, increasing the adrenal synthesis of aldosterone. Our results confirm functionally that aldosterone plays a major role in obesity-related hypertension.

Capturing the dynamics of systemic Renin‐Angiotensin‐Aldosterone System (RAAS) peptides heightens the understanding of the effect of benazepril in dogs

In dogs, activation of the Renin-Angiotensin-Aldosterone System (RAAS) is an important feature of congestive heart failure (CHF). Long-term increases in angiotensin II (AII) and aldosterone (ALD) lead to the progression of heart failure to its end stage. Angiotensin-converting enzyme inhibitors (ACEIs) are the foremost therapeutic option in the management of CHF. Recent literature has challenged the efficacy of ACEIs, based on modest reduction in urinary aldosterone (UALD) excretion despite marked inhibition of ACE activity. This study was designed to heighten the understanding of the effect of benazepril, a potent ACEI, on the RAAS, using a low-sodium diet as an experimental model of RAAS activation. Time course profiles of RAAS peptides and related areas under the curve (AUC) were used for comparison between benazepril and placebo groups. Results indicated substantial changes in the dynamics of these biomarkers. At presumed benazeprilat steady state, significant differences in AUC of plasma renin activity (+90%), angiotensin I (+43%), and AII (-53%) were found between benazepril and placebo-treated dogs. ALD decreased by 73% in plasma but only by 5% in urine. In conclusion, despite modest reduction in UALD excretion, benazepril markedly influences RAAS dynamics in dogs.

The Role of Plasma Angiotensin II in Orthostatic Intolerance during Heat Stress Conditions

An increase in internal temperature renders individuals more susceptible to syncope during a simulated hemorrhage challenge relative to during normothermia but the extent of this susceptibility varies amongst individuals. The objective of this study was to investigate the role of plasma angiotensin II (AngII) in this interindividual variability. This study tested the hypothesis that individuals with the greatest reduction in orthostatic tolerance between normothermic and heat stress conditions would have the smallest heat‐stress induced increase in plasma AngII. On separate days, 10 individuals were subjected to a maximal simulated hemorrhage challenge via a lower body negative pressure (LBNP) protocol. One trial was conducted under normothermic conditions and the other under hyperthermic conditions, following a 1.5 °C increase in internal temperature. Tolerance was quantified as cumulative stress index (CSI); calculated by summing the product of the LBNP and the time at each level until the test was terminated (i.e., 10 mmHg × 3 min + 20 mmHg × 3 min + 30 mmHg × 3 min, etc.). There was no correlation between the difference in CSI and the increase in plasma AngII from normothermic to heat‐stress conditions (r=0.05, p>.05). These results indicate that plasma AngII does not play a role in the interindividual variability in the tolerance to a simulated hemorrhage challenge during heat stress.

Effect of inter-renal aortic coarctation-induced hypertension on function and expression of vascular α1A- and α1D-adrenoceptors

We investigated the effect of inter-renal aortic coarctation on the function and expression of vascular α(1A)- and α(1D)-adrenoceptors and plasma angiotensin II (ATII) in rats. Male Wistar rats, either sham operated (SO), or with aortic coarctation for 7 (AC7) and 14days (AC14) were used for agonist-induced pressor responses in vehicle (physiological saline)- and antagonist-treated anesthetized animals, immunoblot analysis (α(1A)- and α(1D)-adrenoceptor in aorta and caudal arteries), and immunoassay (plasma ATII). The α(1D)-adrenoceptor antagonist, BMY-7378 (BMY) blocked noradrenaline-induced responses in the order SO> AC7≫ AC14; in contrast, the α(1A)-adrenoceptor antagonist RS-100329 (RS), produced a marginal shift to the right of the dose-response curve to noradrenaline, along with a strong decrease of the maximum pressor effect in the order SO> AC7= AC14. The potency of the α(1A)-adrenoceptor agonist A-61603 increased in rats with AC14, and responses were inhibited by RS in the order AC14> AC7> SO. In aorta, α(1D)-adrenoceptor protein increased in AC7 and decreased in AC14; α(1A)-adrenoreceptor protein increased in the caudal artery of AC7 and returned to control values in AC14. Plasma ATII increased in AC7 and AC14, compared with SO rats. These results suggest an early and direct relationship between ATII and α(1D)-adrenoreceptors in the development of hypertension in this experimental model.

Angiotensin-converting enzyme insertion/deletion polymorphism is associated with severe hypoxemia in pediatric ARDS

The D allele of the insertion/deletion (I/D) polymorphism of a 287-bp sequence in the angiotensin-converting enzyme (ACE) gene has been associated with an increased activity of this enzyme. Its role in susceptibility to acute respiratory distress syndrome (ARDS) has not been well defined. We hypothesized that ACE I/D genotype in pediatrics is associated with ARDS and plasma levels of angiotensin II. Prospective case-control study in patients under 15 years of age from a mixed Chilean population. Sixty patients with ARDS and 60 controls were included. Association between ACE genotype and ARDS was evaluated as the primary outcome; mortality and severe hypoxemia were examined as secondary outcomes. Plasma angiotensin-II concentration was measured by immunoassay at admission. Frequency of ACE I/D genotype was similar in ARDS and control groups (p = 0.18). In the ARDS group, severe hypoxemia was less frequent in D allele carriers (p < 0.05). Plasma angiotensin-II levels were associated with genotype in the ARDS group, but not controls, being higher in D allele carriers (p = 0.016). These data do not support the association between ACE I/D genotype and ARDS, although severe hypoxemia was less frequent in D allele carriers. ACE I/D polymorphism modified angiotensin-II levels in pediatric ARDS, but its pathogenic role is not well understood and needs to be addressed in future studies.

ACE2-Mediated Reduction of Oxidative Stress in the Central Nervous System Is Associated with Improvement of Autonomic Function

Oxidative stress in the central nervous system mediates the increase in sympathetic tone that precedes the development of hypertension. We hypothesized that by transforming Angiotensin-II (AngII) into Ang-(1–7), ACE2 might reduce AngII-mediated oxidative stress in the brain and prevent autonomic dysfunction. To test this hypothesis, a relationship between ACE2 and oxidative stress was first confirmed in a mouse neuroblastoma cell line (Neuro2A cells) treated with AngII and infected with Ad-hACE2. ACE2 overexpression resulted in a reduction of reactive oxygen species (ROS) formation. In vivo, ACE2 knockout (ACE2−/y) mice and non-transgenic (NT) littermates were infused with AngII (10 days) and infected with Ad-hACE2 in the paraventricular nucleus (PVN). Baseline blood pressure (BP), AngII and brain ROS levels were not different between young mice (12 weeks). However, cardiac sympathetic tone, brain NADPH oxidase and SOD activities were significantly increased in ACE2−/y. Post infusion, plasma and brain AngII levels were also significantly higher in ACE2−/y, although BP was similarly increased in both genotypes. ROS formation in the PVN and RVLM was significantly higher in ACE2−/y mice following AngII infusion. Similar phenotypes, i.e. increased oxidative stress, exacerbated dysautonomia and hypertension, were also observed on baseline in mature ACE2−/y mice (48 weeks). ACE2 gene therapy to the PVN reduced AngII-mediated increase in NADPH oxidase activity and normalized cardiac dysautonomia in ACE2−/y mice. Altogether, these data indicate that ACE2 gene deletion promotes age-dependent oxidative stress, autonomic dysfunction and hypertension, while PVN-targeted ACE2 gene therapy decreases ROS formation via NADPH oxidase inhibition and improves autonomic function. Accordingly, ACE2 could represent a new target for the treatment of hypertension-associated dysautonomia and oxidative stress.

Antihypertensive effects of Ocimum basilicum L. (OBL) on blood pressure in renovascular hypertensive rats

Ocimum basilicum L. (OBL), sweet basil, is a medicinal herb used in traditional Chinese medicine to treat cardiovascular diseases including hypertension. The objective of the study was to investigate the possible antihypertensive effects of OBL extract in renovascular hypertensive rats. The two-kidney one-clip (2K1C) Goldblatt model of renovascular hypertension was used in Wistar rats. Rats were randomized into sham, untreated 2K1C, captopril- (30 mg kg(-1) per day orally) and OBL- (100, 200, 400 mg kg(-1) per day orally) (low (L)-, medium (M)-, high (H)-OBL) treated 2K1C groups (n=10-12 per group), followed up for 4 weeks. Blood pressure, heart weight/body weight, plasma angiotensin-II and endothelin (ET)-1 were studied. OBL reduced systolic and diastolic blood pressure by about 20 and 15 mm Hg, respectively, compared with 35 and 22 mm Hg for captopril, from the lowest dose tested with no dose dependency. Cardiac hypertrophy was reduced from 3.6+/-0.7 mg g(-1) for untreated 2K1C to 3.0+/-0.6, 2.9+/-0.6 and 2.4+/-0.4 mg g(-1) for L-, M- and H-OBL, respectively, compared with 2.6+/-0.5 for sham and 3.1+/-0.4 mg g(-1) for captopril (P<0.05). Renal function was improved with captopril. Angiotensin was reduced to a lesser extent than with captopril. ET was reduced to lower concentrations (78+/-15, 80+/-22, 82+/-15 pg ml(-1) for L-, M-, H-OBL, respectively) than in sham (116+/-31 pg ml(-1)), untreated 2K1C (174+/-72 pg ml(-1)) or captopril (117+/-72 pg ml(-1)) groups. The effects of OBL on blood pressure, cardiac hypertrophy and ET, are consistent with an effect on ET-converting enzyme, and warrant further exploration.

The effects of the selective mineralocorticoid receptor antagonist eplerenone on hepatic fibrosis induced by bile duct ligation in rat

The aim of this study was to examine the effects of eplerenone on hepatic fibrosis induced by bile duct ligation (BDL) in rat. Low- (1.0 mg/kg body weight, BW) and high- (4.0 mg/kg BW) dose eplerenone was administered orally for 21 days immediately following BDL. Fibrosis was assessed by measuring the fibrotic area after Sirius red staining. Immunostaining for alpha-smooth muscle actin (SMA), 4-hydroxy-2-nonenal (4-HNE) and 8-hydroxy-2-deoxyguanosine (8-OHdG) was also carried out. Gene expression levels of procollagen-I, transforming growth factor-beta1 (TGF-beta1), connective tissue growth factor (CTGF), tissue inhibitor of metalloproteinases-1 (TIMP-1) and matrix metalloproteinase-13 (MMP-13) in the liver were examined by real-time reverse transcriptase polymerase chain reaction. Plasma angiotensin II (ATII) concentration was measured via radioimmunoassay. The area of hepatic fibrosis and alpha-SMA positivity in the high-dose group was significantly decreased compared with that in the BDL group, but not in the low-dose group. 8-OHdG-positive cells in the low- and high-dose groups were significantly decreased compared with those in the BDL group. Immunostaining of 4-HNE in the high-dose group was significantly lower compared with that in the BDL group. Furthermore, TIMP-1 mRNA levels in the low- and high-dose groups were lower than that in the BDL group. The expression of TGF-beta1, CTGF, procollagen-1 and MMP-13 showed no differences. Plasma ATII concentration in the high-dose group was significantly decreased. Eplerenone attenuated the development of BDL-induced hepatic fibrosis by reducing oxidative stress, suppressing activated hepatic stellate cells and decreasing plasma ATII levels. Eplerenone may prove useful as an alternative treatment for antifibrosis therapy.

Natriuretic and renoprotective effect of chronic oral neutral endopeptidase inhibition in acute renal failure

Neutral endopeptidase (NEP: EC 3.4.24.11) is involved in the degradation of peptides such as atrial natriuretic peptide, angiotensin II (AngII), and endothelin-1 (ET-1). In this study we propose that NEP inhibition provides protection in glycerol-induced acute renal failure (ARF). Renal vascular responses were evaluated in ARF rats where ARF was induced by injecting 50% glycerol in candoxatril, a NEP inhibitor (30 mg/kg, orally; for 3 weeks) pretreated rats. AngII and U46619 (a TxA2 mimetic) vasoconstriction was increased (2- to 4-fold) in ARF while ET-1 vasoconstriction was surprisingly reduced (23 ± 3%; p < 0.05). In ARF, candoxatril paradoxically enhanced ET-1 response (60 ± 20%; p < 0.05) but reduced AngII vasoconstriction (51 ± 11%; p < 0.05) without affecting U46619 response. However, candoxatril treatment was without effect on plasma ET-1 and TxB2 levels in ARF. Candoxatril reduced plasma AngII by 34 ± 4% (p < 0.05) in ARF which was ∼3.5-fold higher compared to control. Candoxatril doubled the nitrite excretion in control but was without effect on proteinuria or nitrite excretion in ARF. Candoxatril enhanced Na+ and creatinine excretion in ARF by 73 ± 9% and 33 ± 2%, respectively. These results suggest that NEP inhibition may confer protection in glycerol-induced ARF by stimulating renal function but without a consistent effect on renal production and renal vascular responses to endogenous vasoconstrictors.

Pioglitazone Decreases Plasma Angiotensin II Concentration inType 2 Diabetes

Adipocytes express all components of the renin-angiotensin system (RAS), and adipocyte RAS regulates adipocyte differentiation and metabolism. Plasma angiotensin II (AII) is a putative marker of adipocyte RAS production. The aim of this study was to investigate the effect of pioglitazone on plasma AII in type 2 diabetes (T2D). Fifty Japanese subjects with T2D were randomly allocated to two groups. One group was administered pioglitazone 30 mg/day (pioglitazone group) and the other group was not given pioglitazone (control group) for 16 weeks. Lipoprotein lipase mass in preheparin serum (LPL mass) was measured as an adipocyte-derived factor and a marker of insulin sensitivity. In the pioglitazone group, the mean HbA1c decreased (p<0.0001), LPL mass increased (p<0.0001), and plasma AII decreased (p=0.0007), whereas these parameters were unchanged in the control group. The change in plasma AII correlated negatively with the change in LPL mass (r=-0.312) in the pioglitazone group. In the pioglitazone group, the decrease in plasma AII was higher (p=0.0002) and the increase in LPL mass tended to be higher (p=0.0941) in the subgroup with higher baseline plasma AII than that with lower plasma AII. The present study indicates that pioglitazone decreases plasma AII associated with an increase in LPL mass in T2D. The insulin-sensitizing effect of pioglitazone may be involved in suppressing adipocyte RAS.

Role of caveolin and heat shock protein 70 interaction in the antioxidative effects of an angiotensin II type 1 receptor blocker in spontaneously hypertensive rats proximal tubules

Role of caveolin and heat shock protein 70 interaction in the antioxidative effects of an angiotensin II type 1 receptor blocker in spontaneously hypertensive rats proximal tubules

Protective effects of vasonatrin peptide against hypobaric hypoxia‐induced pulmonary hypertension in rats

1. The aim of the present study was to investigate the in vivo effects of vasonatrin peptide (VNP) on hypoxia-induced pulmonary hypertension (HPH). 2. The HPH model was developed by subjecting rats to hypobaric hypoxia. The HPH rats were then treated with either VNP (50 microg/kg per day, i.p.) or saline (0.5 mL, i.p.) every day for 7 days. Haemodynamic indices, right ventricular hypertrophy (RVH) and remodelling of the pulmonary arteries were evaluated. In addition, plasma levels of atrial natriuretic peptide (ANP), endothelin (ET)-1 and angiotensin II (AngII) were determined, as was natriuretic peptide receptor-C (NPR-C) mRNA expression in the right ventricle. 3. Hypobaric hypoxia induced severe HPH compared with the normoxic control group. Treatment of HPH rats with VNP for 1 week significantly reduced mean pulmonary arterial pressure, pulmonary vascular resistance, RVH and muscularization of the pulmonary arteries, although pulmonary blood flow was increased in this group. In addition, significantly lower levels of plasma ET-1 and AngII and cardiac NPR-C mRNA expression were observed in VNP-treated compared with saline-treated HPH rats, whereas higher plasma concentrations of ANP were found in the former group. Acute intravenous administration of 50 microg/kg VNP significantly ameliorated pulmonary haemodynamics in HPH rats. 4. Taken together, the date indicate that VNP has certain preventative and therapeutic effects against HPH.

Independent and combined influence of AGTR1 variants and aerobic exercise on oxidative stress in hypertensives

Angiotensin II (AngII), via the AngII type 1 receptor (AT1R), contributes to oxidative stress. Aerobic exercise training (AEXT) reduces the risk of cardiovascular (CV) disease, presumably by reducing the grade of oxidative stress. We investigated the independent and combined influence of the AGTR1 A1166C and -825 T/A polymorphisms on oxidative stress and plasma AngII responses to AEXT in pre- and stage 1 hypertensives. Urinary 8-iso-PGF2α significantly increased with AEXT (p=0.002); however, there were no significant changes in superoxide dismutase activity or AngII levels. There was a significant difference in the change in AngII levels with AEXT between A1166C genotype groups (p=0.04) resulting in a significant interactive effect of the A1166C polymorphism and AEXT on the change in AngII (p<0.05). Only the TT genotype group of the -825 T/A polymorphism had a significant reduction in plasma AngII (p=0.02). Risk allele analysis revealed a significant reduction in plasma AngII (p=0.04) and a significant increase in urinary 8-iso-PGF2α (p=0.01) with AEXT in individuals with two risk alleles only. Our findings suggest that variation in the AGTR1 gene is associated with differential changes in plasma AngII but not oxidative stress.

Intrarenal activation of renin angiotensin system in the development of cyclosporine A induced chronic nephrotoxicity

The relationship between cyclosporine-induced chronic nephrotoxicity (CAN) and renin-angiotensin II in humans is still contradictory. This study was conducted to detect the levels of renin and angiotensin II (ANGII) both in renal tissue and plasma from kidney transplantation patients suffering from CAN. Twenty-six patients with allograft biopsy-proven CsA-related chronic nephrotoxicity (CAN group) and chronic rejection (control group) were enrolled in this study. Renal tissues were subjected to immunohistochemical staining with renin and ANGII antibodies. Renin and ANGII plasma levels were measured when the biopsy was performed. The relationship between expression of renin or ANGII and clinicopathological manifestations were also investigated. The cyclosporine plasma level was obtained 2 hours after morning dose (C2). In vitro, human umbilical vein endothelial cells (HUVEC) and rat mesangial cells (MC) were incubated with different concentrations of CsA (0, 250, 500, 1000 microg/L) for 24 hours. Secretion and expression of renin and ANGII was measured by radioimmunoassay or immunohistochemical staining. Renal pathological scores for renin and ANGII expression were significantly higher in specimens of CAN than in controls (P < 0.05). The plasma levels of renin, ANGII and C(2) in the CAN group were higher than the control group, but no significant difference was found ((0.37 +/- 0.12) ng x ml(-1)x h(-1) vs (0.20 +/- 0.10) ng x ml(-1) x h(-1), P = 0.076; (122.69 +/- 26.73) pg/ml vs (121.88 +/- 36.35) pg/ml, P = 0.977; (719.04 +/- 55.89) ng/ml vs (658.80 +/- 90.78) ng/ml, P = 0.196, respectively). In vitro, renin as well as ANGII expression increased significantly in both HUVEC and MC after the cells were incubated with CsA for 24 hours (P < 0.05). CsA also stimulated the secretion of ANGII in HUVEC and MC in a dose-dependent manner. Renal allograft biopsy is important to differentiate chronic CsA-related nephropathy from chronic rejection. The intrarenal renin angiotensin system plays an important role in CsA-related chronic nephropathy. The histological lesions of CsA nephrotoxicity fail to correspond spontaneously to either the change of C2 level or the change of renin and ANGII plasma level. CsA stimulates the secretion of ANGII and the expression of renin and ANGII in HUVEC and MC. Blockage of RAS may be helpful for therapeutic intervention in the progression of CsA-related chronic nephropathy.

Influence Of AGTR1 Gene Variants And Aerobic Exercise Training On Angiotensin II And Oxidative Stress

Oxidative stress is implicated in the pathogenesis of cardiovascular disease (CVD) and angiotensin II (AngII), via the AngII type 1 receptor (AGTR1), is a major contributor to oxidative stress. Aerobic exercise training (AEXT) is a non-pharmacological intervention that reduces the risk of CVD, presumably by reducing the grade of oxidative stress. PURPOSE: To investigate the independent and combined influence of the AGTR1 A1166C and -825 T/A polymorphisms on oxidative stress and AngII responses to AEXT in hypertensives. METHODS: Sedentary men and women (58.4±0.5 yrs), BMI <37kg/m2, were recruited for the study. Blood samples were drawn after >12hr fast. Casual BP was measured on three separate occasions and averaged. Plasma AngII and superoxide dismutase (SOD), and urinary 8-iso-PGF2α levels were determined by colorimetric assays, and radioimmunoassay respectively. Genotyping was done by standard PCR methods and TaqMan assay. The interaction between the two variants was determined using risk allele combinations. ANCOVA was performed with adjustments for age, AGTM235T and ACEI/D polymorphisms. RESULTS: Overall, there was a significant increase in urinary 8-iso-PGF2α, a major F2-isoprostane and reliable in vivo marker of oxidative stress, with AEXT (0.32±0.01 Vs 0.42±0.03 nmol/mmol creatinine, p = 0.002); however, there were no significant changes in SOD activity or AngII levels. There was a significant difference in the change in AngII levels with AEXT between A1166C genotype groups (AA, −0.48±0.18 Vs AC+CC, 0.24±0.24 pg/ml; p = 0.04) resulting in a significant interactive effect of the A1166C polymorphism and AEXT on the change in AngII (p < 0.05). Only the TT genotype group of the −825 T/A polymorphism had a significant reduction in plasma AngII (p = 0.02). Risk allele analysis revealed a significant reduction in plasma AngII (p = 0.04) and a significant increase in urinary 8-iso-PGF2α (p = 0.01) with AEXT in individuals with 2 risk alleles. CONCLUSIONS: Our findings suggest that variation in the AGTR1gene is associated with differential changes in plasma AngII but not with oxidative stress. Furthermore, our results may have clinical implications for the prescription of AEXT in a population at risk for CVD. Supported by NIH/NIA grant # KO1AG19640, #AG15384, #AG17474, #AG00268, #AG022791, and AHA Grant #0415444U.

The plasma angiotensin II level increases in very low-birth weight infants with neonatal chronic lung disease

Background Angiotensin II (AII) has been reported to play an important role in organ fibrosis, and a local renin–angiotensin-system (RAS) has been demonstrated in the lungs. However, the relationship of the RAS to chronic lung disease of the newborn (CLD) remains obscure. Objective To investigate the plasma AII levels throughout the neonatal period in very low-birth weight (VLBW) infants and examine the possible factors that might affect the AII levels. Study design The study includes 20 VLBW infants. Blood samples were collected on days 0, 7, 21 and 35 and plasma AII levels were assayed using an enzyme immunoassay. The data were analyzed by a multiple linear regression analysis with the plasma AII level as the dependent variable and significant factors determined based on a univariate analysis as independent variables. Results The geometric mean of the plasma AII concentrations on days 0, 7, 21 and 35 was 51 pg/mL, 86 pg/mL, 132 pg/mL, and 50 pg/mL, respectively. On day 21, only CLD ( p < 0.01) had a highly significant association with the plasma AII level. On day 35, birth weight ( p < 0.05) and CLD ( p < 0.01) had a highly significant association with the plasma AII level. This analysis confirmed CLD to be the most significant factor associated with plasma AII level on days 21 and 35. Conclusion These findings suggest that higher levels of plasma AII in VLBW infants appear to be related to the development of CLD.

Angiotensin II Type 1 Receptor Blockade Corrects Cutaneous Nitric Oxide Deficit in Postural Tachycardia Syndrome

Low flow postural tachycardia syndrome (POTS), is associated with increased plasma angiotensin-II (Ang-II) and reduced neuronal nitric oxide (NO) which decreases NO-dependent vasodilation. We tested whether the angiotensin-II type 1 Receptor antagonist losartan would improve NO-dependent vasodilation in these POTS patients. Further if the action of Ang-II is dependent on NO, then the NOS inhibitor nitro-L-arginine (NLA) would reverse this improvement. We used local heating of the skin of the left calf to 41°C and laser Doppler Flowmetry to assess NO-dependent conductance (%CVCmax) in 12 low flow POTS patients aged 22.5±8 years and in 15 control subjects aged 22.0±1.3 years. After measuring the baseline local heating response at 3 separate sites, we perfused individual intradermal microdialysis catheters at those sites with losartan 2μg/L, or NLA 10mM, or losartan + NLA. The pre-drug heat response was reduced in POTS, particularly the plateau phase reflecting NO-dependent vasodilation. Losartan increased baseline flow in both control and POTS subjects. The baseline increase was blunted by NLA. Losartan increased the POTS heat response to equal the control response (Figure). NLA decreased both control and POTS heat responses to similar conductances. The addition of NLA to losartan reduced control and POTS conductances compared to losartan alone. The data suggest that the reduction in cutaneous nitric oxide dependent vasodilation in low flow POTS is related to angiotensin-II.

Secondary Pulmonary Hypertension

Experimental data have demonstrated controversial results regarding loop diuretics and their influence on the pulmonary vasculature. The aim of this pilot study was to compare the effect of torasemide versus furosemide on systemic and pulmonary haemodynamics in patients with secondary pulmonary hypertension. Twenty-one patients were enrolled in this double-blind, randomized trial: the furosemide group (n = 11) received 40 mg intravenously (IV) and 80 mg orally whereas the torasemide group (n = 10) received 20 mg IV and 20 mg orally. Haemodynamic variables were documented and endothelin-1 and arterial angiotensin-II plasma levels were simultaneously analysed at baseline (T0), 5 minutes after IV administration (T1), at baseline prior to oral administration (T2), and 60 minutes after oral administration (T3). Cardiac output (relative treatment effect over time between groups; p = 0.03) increased significantly in the torasemide group compared with the furosemide group. In the furosemide group, a significant increase in arterial angiotensin-II (AT-II) plasma levels was observed compared with the torasemide group (relative treatment effect over time between groups; p = 0.031). Torasemide increased cardiac output (relative treatment effect over the time), whereas treatment with furosemide significantly increased arterial AT-II plasma levels. A possible explanation for these findings might be activation of the renin-angiotensin system by furosemide. However, the underlying pathomechanism remains to be established and evidence from an adequately powered trial is needed to determine if furosemide aggravates cardiac function by increasing AT-II plasma levels.

Reduced body mass index is associated with increased angiotensin II in young women with postural tachycardia syndrome

Altered peripheral haemodynamics, decreased cardiac output, decreased blood volume and increased AngII (angiotensin II) have been reported in POTS (postural tachycardia syndrome). Recent findings indicate that BMI (body mass index) may be reduced. In the present study, we investigated the hypothesis that reduced BMI is associated with haemodynamic abnormalities in POTS and that this is related to AngII. We studied 52 patients with POTS, aged 14-29 years, compared with 36 control subjects, aged 14-27 years. BMI was not significantly reduced on average in the POTS patients, but was reduced in patients with decreased peripheral blood flow. POTS patients were then subdivided on the basis of BMI, and supine haemodynamics were measured. There was no difference in blood volume or cardiac output once BMI or body mass were accounted for. When POTS patients with BMI <50th percentile were compared with controls, calf blood flow [1.63+/-0.31 compared with 3.58+/-0.67 ml(-1).min(-1).(100 ml of tissue)(-1)] and maximum venous capacity (3.87+/-0.32 compared with 4.98+/-0.36 ml/100 ml of tissue) were decreased, whereas arterial resistance [56+/-0.5 compared with 30+/-4 mmHg.ml(-1).min(-1).(100 ml of tissue)(-1)] and venous resistance [1.23+/-0.17 compared with 0.79+/-0.11 mmHg.ml(-1).min(-1).(100 ml of tissue)(-1)] were increased. Similar findings were also observed when POTS patients with BMI <50th percentile were compared with POTS patients with BMI >50th percentile. There was no relationship between blood flow, resistance or maximum venous capacity with BMI in control subjects. BMI was inversely related to plasma AngII concentrations in those POTS patients with decreased peripheral blood flow, consistent with cachectic properties of the octapeptide. Patients with low-flow POTS had decreased body mass, but decreased body mass alone cannot account for findings of peripheral vasoconstriction. In conclusion, the findings suggest that reduced body mass relates to increased plasma AngII.

Gradual reactivation of vascular angiotensin I to angiotensin II conversion during chronic ACE inhibitor therapy in patients with diabetes mellitus

In chronic heart failure there is gradual reactivation of vascular tissue angiotensin I (AI) to angiotensin II (AII) conversion over time in patients taking chronic ACE inhibitor therapy. However, it remains unknown whether the same overall phenomenon occurs in other patients taking chronic ACE inhibitor therapy, such as patients with type 2 diabetes mellitus. We studied 30 patients with type 2 diabetes mellitus (mean age 43.5 +/- 10.8 years), all of whom received lisinopril (20 mg/day) as part of their normal treatment. Over the course of the 18 month study, we made measurements at 0, 9 and 18 months. These measurements included plasma values for components of the renin-angiotensin-aldosterone system. In addition, we infused AI and AII into the brachial arteries of patients to assess vascular tissue AI to AII conversion. There were no significant changes in plasma renin activity, ACE, AI, AII or aldosterone during the study. In contrast, vascular AI to AII conversion was significantly (p = 0.01) greater at 18 months than at 0 months. There was no change over time in the response to infused AII. We have shown in vivo that vascular tissue AI to AII conversion gradually increases over time in patients with type 2 diabetes being treated with lisinopril. Further studies are required to determine whether this reactivation detracts from the cardioprotective effects of chronic ACE inhibitor therapy in diabetic patients, and if so, how best to overcome it.