Angiotensin II type 2 receptor effect on microvascular hydraulic permeability

BACKGROUND: Angiotensin II (Ang II) is a potent vasoconstrictor that modulates microvascular permeability. Angiotensin II type 1 (AT1) and type 2 (AT2) receptors have been described with subsequent development of their respective antagonists. We hypothesized that the AT2 receptor modulates microvascular permeability. MATERIALS AND METHODS: Hydraulic permeability (L(p)) was measured in rat mesenteric venules using the Landis micro-occlusion technique. Following baseline L(p) measurements, paired measures of microvessel L(p) were obtained after perfusion with a test solution. The test solutions consisted of the AT2 receptor agonist CGP42112A at 10 microm (n = 6), 100 microm (n = 6), and 200 microm (n = 6), as well as the AT2 receptor antagonist PD-123319 at 3 microm (n = 6), 30 microm (n = 6), 300 microm (n = 6), and 600 microm (n = 6). RESULTS: From mean baseline L(p) of 0.99 +/- 0.03, 100 microm CGP42112A decreased L(p) to 0.76 +/- 0.02 (P = 0.005), and 200 microm CGP42112A decreased L(p) to 0.61 +/- 0.02 (P < 0.001). From mean baseline L(p) of 0.90 +/- 0.05, PD-123319 increased L(p) at 30 microm to 1.60 +/- 0.2 (P = 0.003), at 300 microm to 2.28 +/- 0.3 (P = 0.008), and at 600 microm to 4.30 +/- 0.9 (P = 0.03). Units for L(p) are mean +/- SEM x 10(-7) cm s(-1) cmH(2)O(-1). CONCLUSION: AT2 activation decreased L(p), while AT2 blockade increased L(p). These changes in L(p) may be explained by (1). a permeability-decreasing effect of the AT2 receptor that is induced by AT2 activation and inhibited by AT2 blockade; and/or (2). a permeability-increasing effect of the AT1 receptor observed during AT2 blockade and selective AT1 activation by endogenous locally released Ang II. These mechanisms would support the theories that the AT1 receptor increases microvascular permeability, while the AT2 receptor decreases microvascular permeability.     

Expression of AT1amRNA in rat hepatic stellate cells and its effects on cell growth collagen production

Activated hepatic stellate cells (HSCs) play important roles in hepatic fibrosis. Studies on HSCs activation in vitro have shown that this process is regulated by a wide variety of growth factors and cytokines。 Recent data indicate that Ang Ⅱ is responsible for the mechanisms of myocardial fibrosis and kidney fibrosis; but there are only few reports on hepatic fibrosis.     

AT1 antagonism by eprosartan lowers heart rate variability and baroreflex gain

INTRODUCTION: Blockade of the renin-angiotensin system (RAS) by ACE inhibitors has been demonstrated to reduce total mortality in cardiovascular diseases. This advantage was attributed in part to changes of autonomic cardiovascular control, exemplified by an increase of heart rate variability (HRV) and baroreflex gain (BRG). We sought to assess the effects of the angiotensin type 1 (AT1) receptor blocker eprosartan on HRV and BRG. MATERIALS AND METHODS: In a double-blind randomized cross-over design 25 young males took eprosartan (600 mg/day) and placebo each for a period of 7 days with a wash-out period of at least 4 weeks in between. At the end of the intake phases simultaneous recordings of arterial blood pressure (AP; Finapres) and electrocardiogram (ECG) were taken. Power spectra of HRV and arterial blood pressure variability (APV) were calculated by fast Fourier transform (FFT) and served to calculate BRG. Ang-II levels were measured by radioimmunoassay. RESULTS: Eprosartan tended to lower mean AP, it slightly increased heart rate (HR) (p<0.05), and markedly increased circulating Ang-II levels (p<0.01). Eprosartan diminished the total power of HRV (p<0.05) and the BRG (p<0.01). The low/high frequency (LF/HF) ratio of HRV and the APV were not altered. CONCLUSIONS: AT1 antagonism by eprosartan lowers heart rate variability and baroreflex gain. We speculate that these findings are due to the marked increase in circulating angiotensin II (Ang II). Further studies are needed to clarify whether angiotensin type 1 (AT1) blockers with potential actions inside the blood-brain barrier (BBB) may have different effects on HRV and BRG.     

Role of angiotensin AT1 and AT2 receptors in cardiac hypertrophy and cardiac remodelling

1. Left ventricular hypertrophy (LVH) is an independent cardiovascular risk factor. Angiotensin AT1 receptor antagonism has been considered as a specific approach to block the renin-angiotensin system and been demonstrated to be able to prevent or regress LVH by interfering with the remodelling process of the heart. 2. Angiotensin AT1 receptor blockade induces a marked increase in angiotensin (Ang) II, which may stimulate the AT2 receptors. Gene expression of AT1 and AT2 receptors increases in a time-dependent manner in cardiac remodelling following myocardial infarction. 3. Considerable efforts have been made to clarify the role of AT2 receptors in cardiac hypertrophy and remodelling since the mid-1990s, resulting in controversial reports: the AT2 receptor mediates actions either opposite to or in coordination with those of the AT1 receptor. Moreover, there are many reports of no significant effects mediated by AT2 receptors. 4. Based on the studies reviewed in the present article, we assume that the predominant effect of AngII in cardiac hypertrophy and cardiac remodelling is growth promoting and that this effect is mediated mainly via AT1 receptors. The AT2 receptors may affect the hypertrophic process by interacting with other cardiac membrane proteins, enzymes and autacoids. Before coming to a conclusion as to whether AT2 receptor stimulation or antagonism is beneficial to the heart, more studies should be performed in different LVH models, especially long-term treatment protocols in vivo.     

Unchanged cardiac angiotensin II levels accompany losartan-sensitive cardiac injury due to nitric oxide synthase inhibition

Chronic nitric oxide synthase (NOS) inhibition results in hypertension and myocardial injury. In a rapid and severe model of chronic NOS inhibition, we determined the role of angiotensin II in these effects by using angiotensin II receptor blockade and by measuring cardiac angiotensin II concentrations before and during development of cardiac damage. Rats received either no treatment, the NOS inhibitor Nomega-nitro-L-arginine (L-NNA; 500 mg/l), the angiotensin AT(1) receptor antagonist losartan (400 mg/kg chow), or L-NNA plus losartan for 21 days. In the second protocol, five groups of rats received L-NNA (500 mg/l) for 0, 4, 7, 14 and 21 days, respectively. L-NNA increased systolic blood pressure (SBP) (227+/-8 versus 143+/-6 mm Hg; P<0.01), heart weight index (0.44+/-0.02 versus 0.32+/-0.01; P<0.01) and induced coronary vasculitis and myocardial necrosis. Co-treatment with losartan prevented all changes. L-NNA during 4 days decreased cardiac angiotensin II (23+/-4 versus 61+/-15 fmol/g; P<0.05). Although after 7 days, fresh infarcts and after 14 days organized infarcts were present, cardiac angiotensin II was only slightly increased after 21 days (100+/-10 fmol/g; P<0.05). In conclusion, losartan-sensitive cardiac damage due to chronic NOS inhibition is not associated with primary increase of cardiac angiotensin II, suggesting that chronic NOS inhibition increases cardiac sensitivity for angiotensin II.     

Renin–angiotensin systems and reproduction

Calcium and vitamin D supplementation have been shown to reduce secondary hyperparathyroidism and play a role in age-related osteoporosis. In order to define the optimal regimen of calcium and vitamin D supplementation to produce the maximal inhibition of parathyroid hormone secretion ,we compared the administration of a calcium-vitamin D supplement as a single morning dose with the administration of two divided doses at 6-hour intervals. Twelve healthy male volunteers were assigned to three investigational procedures ,which were alternated at weekly intervals. After a 'blank' control procedure ,when they were not exposed to any supplements ,they received one of two calcium-vitamin D supplement regimens: either two doses of Orocal^® D3 (500 mg calcium and 400 IU vitamin D3) with a 6-hour interval between doses ,or one water-soluble effervescent powder pack of Cacit^® vitamin D3 ,taken in the morning (1000 mg calcium and 880 IU vitamin D3). During the three procedures (control and the two calcium-vitamin D supplementation protocols) ,veinous blood was drawn every 60 minutes for up to 9 hours ,for serum calcium and parathyroid hormone measurements. The order of administration of the two calcium and vitamin D supplementation regimens was allocated by randomization. No significant changes in serum calcium were observed during the study. During the first 6 hours following calcium-vitamin D supplementation ,a statistically significant decrease in serum parathyroid hormone was observed with both regimens ,compared with baseline and the control procedure. During this first period ,no differences were observed between the two treatment regimens. However ,between the 6th and the 9th hour ,serum parathyroid hormone levels remained significantly decreased compared to baseline with the twice-daily Orocal D3 administration ,while they returned to baseline values with the once-daily Cacit D3 preparation. During this period ,the percentage decrease in serum parathyroid hormone relative to baseline was significantly greater with Orocal D3 than Cacit D3 (p = 0.0021). We therefore conclude that the twice-daily administration of 500 mg calcium and 400 IU vitamin D3 at 6-hour intervals provides a more prolonged decrease in serum parathyroid hormone levels than the administration of the same total amount of calcium and vitamin D ,as a single morning dose in young healthy volunteers. These results might have implications in terms of protection of the skeleton against secondary hyperparathyroidism and increased bone resorption and turnover in elderly subjects.     

Brain renin-angiotensin system modifies the blood pressure response to intracerebroventricular cadmium in rats

In order to elucidate the involvement of the brain renin-angiotensin system (RAS) in cadmium intracerebroventricular (ICV) hypertension, we evaluated the effects of a pretreatment with different drugs: clonidine, an α₂ adrenergic agonist, enalapril and captopril, both ACE inhibitors, and saralasin, a competitive nonselective AT₁ and AT₂ receptor antagonist. We used a rat strain with low levels of kallikrein (LKR) that was more sensitive to ICV cadmium hypertension, compared with normal kallikrein rats (NKRs), the control strain. The interplay between the kallikrein-kinin system and the RAS in the LKR strain caused various hemodynamic alterations, which we believe were the result of elevated RAS activity in these animals. Moreover, we suggest that the defective kallikrein-kinin system in LKR may also cause an alteration in the activation of brain RAS in these animals. The LKR displayed elevated concentrations of plasma AII, hypertrophy of the myocardium, and initial alterations in the renal glomerulotubular system. With the exception of clonidine, all of the other drugs showed greater antihypertensive effects of differing statistical significance in LKR, compared with NKR. Both ACE inhibitors were able to significantly reduce pressor response to cadmium ICV in LKR throughout the experiment, whereas in NKR, they were only able to reduce the hypertensive peak of cadmium. A significant protective effect was also observed in LKR pretreated with saralasin, while no effect was observed in NKR. These findings confirm the presence of brain RAS activation in LKR and its contribution to the central control of pressor response to cadmium ICV.     

Child and Adolescent Labor,Socioeconomic Status,and Reduced Adult Height

Abstract

This population-based cross-sectional study of 3262 individuals aged 18 to 65 years from Aracaju, Brazil investigates the effects of child/adolescent labor (CAL) experience on adult height, considering gender, socioeconomic status (SES), and skin color. We hypothesized that the younger children are at their first job, the greater the negative effects will be on their later growth as adults. Child/adolescent laborers reported having paid jobs before 14 years of age. Among males in the low and medium SES strata, CAL experience was negatively associated with adult height independent of skin color; among females, this inverse association was observed for those in the low and high SES strata. Among males in the low and medium SES strata, there was a linear inverse relation between age at first job and adult height. CAL could reduce height in adulthood, suggesting a need for programs that reduce the impact of CAL on future physical development.     

Renin–angiotensin gene polymorphisms in relation to severe chronic periodontitis

Aim: Evidence suggests that the ultimate product of the renin–angiotensin system (RAS), angiotensin II, exerts inflammatory actions. The present study aimed to evaluate the inter‐relation between gene polymorphisms of the RAS components; angiotensin converting enzyme (ACE), angiotensinogen (AGT) and angiotensin II type‐I receptor (AT1R), and severe chronic periodontitis (CP). Material and Methods: DNA was obtained from peripheral blood of 90 CP patients and 126 periodontally healthy subjects, and the clinical parameters were recorded. ACE I/D, AGT M235T and AT1R A1166C polymorphisms were genotyped by the PCR–RFLP method. Chi‐square, anova and logistic regression methods were used in statistical analyses. Results: The frequency of the ACE D allele was significantly lower in the CP group than the healthy group (p_corr=0.015). CP subjects exhibited increased C allele carriage and C allele frequency of the AT1R gene (p_corr=0.03 and p_corr=0.03, respectively). All clinical parameters of CP patients were found to be similar in variant allele‐carrying and non‐carrying subjects (p>0.05). Conclusions: The present findings suggest that ACE I/D and AT1R polymorphisms might be associated with susceptibility to CP but not with disease severity. The D allele of ACE I/D might be associated with decreased, whereas the C variant of AT1R A1166C might be associated with an elevated risk for CP in Turkish population.