Circulatory Renin-angiotensin System Research Articles

The mechanism underlying fluoride-induced low-renin hypertension is related to an imbalance in the circulatory and local renin-angiotensin systems

The renin-angiotensin system (RAS) is an important fluid regulation system in the body, and excessive activation of the circulatory or local RAS can increase blood pressure (BP). Excess fluoride can increase BP, although the underlying mechanism related to activation of the RAS remains unclear. Thus, the aim of this study was to elucidate the role of the RAS in fluoride-induced hypertension. Markers of the circulating and local RASs related to pathological changes to the kidneys, myocardium, and aorta were measured. Fluoride reduced serum levels of renin, angiotensin II (Ang II), and angiotensin (1−7) [Ang (1−7)], and dysregulated plasma levels of aldosterone and potassium levels. Excess fluoride can damage the kidneys, myocardium, and aorta, overactivate the renal angiotensin converting enzyme (ACE)-Ang II-angiotensin type 1 receptor axis, and inhibit activation of the ACE2-Ang (1−7)-Mas axis, leading to dysregulation of alpha epithelial sodium channels and significantly increased expression of Ang II in the myocardium and aorta. Hence, excess fluoride can cause low-renin hypertension via an imbalance between the circulatory and local RASs.

Circulating human sPRR increased blood pressure in female mice fed a low‐fat diet

Essential hypertension and obesity‐hypertension have been associated with elevated plasma soluble prorenin receptor (sPRR) in men. Additionally, our laboratory previously found that the infusion of mouse sPRR elevates systolic blood pressure (SBP) in high‐fat (HF) fed male mice through activation of the sympathetic nervous system but did not elevate SBP in HF‐fed female mice. Interestingly, the infusion of mouse sPRR increased renal and hepatic angiotensinogen (AGT) and plasma renin concentration in female mice fed a standard diet. However, the mechanistic role of sPRR on the renin angiotensin system (RAS) to regulate blood pressure in lean female mice remains to be investigated. Moreover, there is critical gap concerning the functional role of human sPRR on blood pressure in women. Therefore, in the present study, we aim to determine whether human sPRR participates to blood pressure control in lean female mice.A transgenic mouse model expressing the human form of the soluble prorenin receptor (HsPRR‐Myc‐tag) was developed. Human sPRR‐transgenic female mice were bred with male mice expressing Alb/Cre recombinase to generate mice selectively expressing human sPRR (Alb‐HsPRR) in the liver and control littermates (CTL). Control and Alb‐HsPRR female mice were fed a LF‐diet for 8 months (n=11/groups). Body weight was assessed weekly and body composition was examined monthly. Blood pressure was assessed by radiotelemetry. Human sPRR‐Myc‐tag was detected in the liver of Alb‐HsPRR female mice and plasma sPRR levels increased by 50‐fold (CTL: 3.6±0.5 ng/ml, Alb‐HsPRR: 190.5±24.4 ng/ml; P<0.05), which validated the humanized mouse model.Elevated circulating human sPRR did not change body weight (CTL: 22.2±0.4g, Alb‐HsPRR: 23.0±0.3g) or fat mass (CTL: 2.5±0.2, Alb‐HsPRR:3.1±0.2g). Liver‐derived human sPRR significantly elevated SBP in Alb‐HsPRR compared to control female mice (Night SBP: CTL, 130.5±1.2 mmHg; Alb‐HsPRR, 135.9±2 mmHg; P<0.05) and acute injection of Angiotensin II exacerbated the SBP elevation. Interestingly, the decrease in blood pressure mediated by Losartan was not different between Alb‐HsPRR and control female mice (Night □SBP: CTL, ‐13.1±2.2 mmHg; Alb‐HsPRR, ‐14.8±2.7 mmHg; P>0.05). Plasma AGT and renin activity were similar between Alb‐HsPRR and control littermate female mice suggesting that the elevation of SBP was not mediated by the circulating renin angiotensin system. Therefore, whether the sympathetic nervous system is involved in human sPRR‐mediated increase of SBP remains to be examined. Altogether, these results support an important role of circulating human sPRR in blood pressure control in women.

Sympathetic modulation by antihypertensive drugs.

Sympathetic modulation by antihypertensive drugs.

(Pro)renin receptor: Involvement in diabetic retinopathy and development of molecular targeted therapy.

The renin–angiotensin system (RAS), a crucial regulator of systemic blood pressure (circulatory RAS), plays distinct roles in pathological angiogenesis and inflammation in various organs (tissue RAS), such as diabetic microvascular complications. Using ocular clinical samples and animal disease models, we elucidated molecular mechanisms in which tissue RAS excites the expression of vascular endothelial growth factor (VEGF)‐A responsible for retinal inflammation and angiogenesis, the two major pathological events in diabetic retinopathy (DR). Furthermore, we showed the involvement of (pro)renin receptor [(P)RR] in retinal RAS activation and its concurrent intracellular signal transduction (e.g., extracellular signal‐regulated kinase); namely, the (P)RR‐induced dual pathogenic bioactivity referred to as the receptor‐associated prorenin system. Indeed, neovascular endothelial cells in the fibrovascular tissue collected from eyes with proliferative DR were immunoreactive for the receptor‐associated prorenin system components including prorenin, (P)RR, phosphorylated extracellular signal‐regulated kinase and VEGF‐A. Protein levels of soluble (P)RR increased with its positive correlations with prorenin, renin enzymatic activity and VEGF in the vitreous of proliferative DR eyes, suggesting a close link between (P)RR and VEGF‐A‐driven angiogenic activity. Furthermore, we revealed an unsuspected, PAPS‐independent role of (P)RR in glucose‐induced oxidative stress. Recently, we developed an innovative single‐strand ribonucleic acid interference molecule selectively targeting human and mouse (P)RR, and confirmed its efficacy in suppressing diabetes‐induced retinal inflammation in mice. Our data using clinical samples and animal models suggested the significant implication of (P)RR in the pathogenesis of DR, and the potential usefulness of the ribonucleic acid interference molecule as a therapeutic agent to attenuate ocular inflammation and angiogenesis.

Unsuccessfully Treated Hypertension: A Major Public Health Problem With a Potential Solution.

About one-half of all hypertensive adults do not have their blood pressure controlled. They are often prescribed medications that conform to national guidelines but they continue to have elevated blood pressure. This public health problem might be improved by applying plasma renin guided therapy. A contributor to the public health problem of unsuccessfully treated hypertension is that the circulating renin-angiotensin system (RAS) is not recognized in treatment guidelines as clinically relevant for the treatment of hypertension or as important as the body salt status for determining blood pressure levels. Another contributor to the problem is the lack of specificity in the package inserts for antihypertensive drugs. They do not specifically state under the heading "Indications" that RAS blockers are primarily most effective in hypertensive subjects with medium and high plasma renin levels; by contrast, natriuretic drugs are most effective in those with low plasma renin levels. Literature review. To address the problem of unsuccessfully treated hypertension, we recommend that the "Indications" section of package inserts for antihypertensive drugs be more specific. The primary indication for RAS blockers ought to be hypertension with medium and high plasma renin levels, and natriuretic agents for those with low plasma renin levels. Similar language ought to be added to treatment guidelines. Additionally, 3 other reasons for lack of blood pressure control also need to be addressed-failure to prescribe antihypertensive drugs to hypertensive subjects, failure of patients to fill prescriptions, and low drug adherence.

Novel Cardiac Intracrine Mechanisms Based on Ang-(1-12)/Chymase Axis Require a Revision of Therapeutic Approaches in Human Heart Disease.

Drugs targeting the renin-angiotensin system (RAS), namely angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers, are the most commonly prescribed drugs for patients with or at risk for cardiovascular events. However, new treatment strategies aimed at mitigating the rise of the heart failure pandemic are warranted because clinical trials show that RAS blockers have limited benefits in halting disease progression. The main goal of this review is to put forward the concept of an intracrine RAS signaling through the novel angiotensin-(1-12)/chymase axis as the main source of deleterious angiotensin II (Ang II) in cardiac maladaptive remodeling leading to heart failure (HF). Expanding traditional knowledge, Ang II can be produced in tissues independently from the circulatory renin-angiotensin system. In the heart, angiotensin-(1-12) [Ang-(1-12)], a recently discovered derivative of angiotensinogen, is a precursor of Ang II, and chymase rather than ACE is the main enzyme contributing to the direct production of Ang II from Ang-(1-12). The Ang-(1-12)/chymase axis is an independent intracrine pathway accounting for the trophic, contractile, and pro-arrhythmic Ang II actions in the human heart. Ang-(1-12) expression and chymase activity have been found elevated in the left atrial appendage of heart disease subjects, suggesting a pivotal role of this axis in the progression of HF. Recent meta-analysis of large clinical trials on the use of ACE inhibitors and angiotensin receptor blockers in cardiovascular disease has demonstrated an imbalance between patients that significantly benefit from these therapeutic agents and those that remain at risk for heart disease progression. Looking to find an explanation, detailed investigation on the RAS has unveiled a previously unrecognized complexity of substrates and enzymes in tissues ultimately associated with the production of Ang II that may explain the shortcomings of ACE inhibition and angiotensin receptor blockade. Discovery of the Ang-(1-12)/chymase axis in human hearts, capable of producing Ang II independently from the circulatory RAS, has led to the notion that a tissue-delimited RAS signaling in an intracrine fashion may account for the deleterious effects of Ang II in the heart, contributing to the transition from maladaptive cardiac remodeling to heart failure. Targeting intracellular RAS signaling may improve current therapies aimed at reducing the burden of heart failure.

Persistent and selective upregulation of renin-angiotensin system in circulating T lymphocytes in unstable angina.

Introduction:Unstable angina is associated with an acute systemic inflammatory reaction and circulating T lymphocytes are activated. We investigated whether in unstable angina with marked immune system activation a selective upregulation of the circulating T-cell renin–angiotensin system, modulated by angiotensin II, could occur.Methods:We studied 13 unstable angina patients, 10 patients with stable angina and 10 healthy subjects. After T-lymphocyte isolation, mRNAs for angiotensin-converting enzyme (ACE) and angiotensin type 1 receptor (AT1-R) were quantified at baseline and after angiotensin II stimulation. ACE activity in cell pellet and supernatant and angiotensin II cell content were measured.Results:Plasma renin activity was similar in controls, stable and unstable angina patients. At baseline ACE and AT1-R mRNA levels were higher (P<0.05) in T cells from unstable angina patients than in T cells from stable angina patients and controls, and further increased after angiotensin II addition to cultured T cells. ACE activity of unstable angina T cells was significantly higher than that of T cells from controls and stable angina patients. Only in T cells from unstable angina patients did angiotensin II stimulation cause the almost complete release of ACE activity in the supernatant.Conclusions:The circulating T-cell-based renin–angiotensin system from unstable angina patients was selectively upregulated. In vivo unstable angina T cells could locally increase angiotensin II concentration in tissues where they migrate independently of the circulating renin–angiotensin system.

The influence of angiotensin-converting enzyme gene ID polymorphism on human physical fitness performance in European and other populations

Angiotensin-converting enzyme (ACE) is a component of the circulating renin–angiotensin system, which influences circulatory homeostasis through the degradation of vasodilator kinins and the generation of vasopressor angiotensin II. Various phenotypic characteristics such as diseases and human performances could be associated with genetic polymorphisms within the ACE gene. To date, one of the most well-studied genetic polymorphisms that has been shown to be associated with athletic performance is that of the ACE gene. Previous studies investigating the influences of polymorphisms and various phenotypic characteristics have produced inconsistent findings due to inter-ethnic variations in the distribution of the different ACE alleles. For example, some studies showed that the I allele was associated with fatigue resistance in skeletal muscle and endurance performance while the D allele had been associated with power or sprint performance. Nevertheless, controversy still exists regarding the above conclusion as related studies reported that the I allele was associated with a better power or sprint performance rather than with athletic endurance abilities. This article discusses the inter-ethnic variations of the distribution of the different ACE alleles in several ethnic groups such as in European, African, American, and Asian populations. Additionally, the influences of the ACE ID polymorphism on human physical fitness performances in European and other populations are discussed.

Angiotensin-converting enzyme 2 amplification limited to the circulation does not protect mice from development of diabetic nephropathy

Blockers of the renin-angiotensin system are effective inthe treatment of experimental and clinical diabetic nephropathy. An approach different from blocking the formation or action of angiotensin II (1-8) that could also be effective involves fostering its degradation. Angiotensin-converting enzyme 2 (ACE2) is a monocarboxypeptidase that cleaves angiotensin II (1-8) to form angiotensin (1-7). Therefore, we examined the renal effects of murine recombinant ACE2 in mice with streptozotocin-induced diabetic nephropathy as well as that of amplification of circulating ACE2 using minicircle DNA delivery prior to induction of experimental diabetes. This delivery resulted in a long-term sustained and profound increase in serum ACE2 activity and enhanced ability to metabolize an acute angiotensin II (1-8) load. In mice with streptozotocin-induced diabetes pretreated with minicircle ACE2, ACE2 protein in plasma increased markedly and this was associated with a more than 100-fold increase in serum ACE2 activity. However, minicircle ACE2 did not result in changes in urinary ACE2 activity as compared to untreated diabetic mice. In both diabetic groups, glomerular filtration rate increased significantly and to the same extent ascompared to non-diabetic controls. Albuminuria, glomerular mesangial expansion, glomerular cellularity, and glomerular size were all increased to a similar extent in minicircle ACE2-treated and untreated diabetic mice, as compared to non-diabetic controls. Recombinant mouse ACE2 given for 4 weeks by intraperitoneal daily injections in mice with streptozotocin-induced diabetic nephropathy also failed to improve albuminuria or kidney pathology. Thus, a profound augmentation of ACE2 confined to the circulation failed to ameliorate the glomerular lesions and hyperfiltration characteristic of early diabetic nephropathy. These findings emphasize the importance of targeting thekidney rather than the circulatory renin angiotensin system to combat diabetic nephropathy.

Urinary angiotensinogen excretion is associated with blood pressure independent of the circulating renin-angiotensin system in a group of african ancestry.

Although the circulating renin-angiotensin system (RAS) is suppressed in salt-sensitive populations, the role of the intrarenal RAS in blood pressure (BP) control in these groups independent of the circulating RAS is uncertain. We evaluated the relationship between 24-hour urinary angiotensinogen excretion and either office (mean of 5 measurements; n=425) or 24-hour ambulatory (n=340) BP independent of the circulating RAS in a community-based sample of African descent that had never received antihypertensive drug therapy. Circulating RAS activity was determined from plasma renin and angiotensinogen and serum aldosterone concentrations. Urinary angiotensinogen to creatinine ratio (angiotensinogen/creat) was correlated with plasma angiotensinogen concentrations (P<0.0005) but not with indexes of salt intake. However, urinary angiotensinogen/creat was independently associated with office systolic BP (partial r=0.16; P<0.001), whereas plasma angiotensinogen (partial r=0.07; P=0.14) was not independently associated with office systolic BP. Urinary angiotensinogen/creat was also associated with 24-hour systolic BP (partial r=0.11; P<0.05). The relationships between urinary angiotensinogen/creat and BP survived further adjustments for plasma angiotensinogen and serum aldosterone concentrations, plasma renin concentrations, estimated glomerular filtration rate, urinary Na(+)/K(+), or 24-hour urinary Na(+) excretion rates (P<0.005 for all). Participants with the highest compared with the lowest quartile of urinary angiotensinogen/creat showed an 8.2-mm Hg higher office (P<0.005) and 4.6-mm Hg higher 24-hour (P=0.01) systolic BP. In conclusion, independent of the systemic RAS, including plasma angiotensinogen concentrations, urinary angiotensinogen excretion is associated with BP in a salt-sensitive, low-renin group of African descent. These data lend further support for a role of the RAS in BP control in salt-sensitive groups of African ancestry.

The role of the renin–angiotensin system in the pathogenesis of preeclampsia – New insights into the renin–angiotensin system in preeclampsia

The renin–angiotensin system (RAS) plays an important role in the pathogenesis of hypertension. However, the role of RAS in preeclampsia is largely unknown, because the plasma concentration of renin and angiotensin (AII) is lower in preeclampsia than in normal pregnancy, whereas its cardinal sign is hypertension. A pressor response to AII infusions can predict the onset of preeclampsia, resulting in involvement of RAS in the pathogenesis of preeclampsia. It has been reported that patients with preeclampsia exhibit angiotensin type I receptor agonistic autoantibody (AT1-AA), suggesting the involvement of RAS in the pathogenesis of this condition. The physiological action of AT1-AA can explain the various clinical symptoms of preeclampsia. However, the significance of circulatory RAS, including AT1-AA, in the pathogenesis of preeclampsia remains obscure. Since many reports state that circulating RAS is thought to be suppressed in preeclampsia it is difficult to explain the onset of hypertension in preeclampsia by circulating RAS. Therefore, I propose new insights into the role of RAS in preeclampsia to resolve the contradiction as above-mentioned. The recent discovery of tissue RAS, on which prorenin and its receptor act, suggests a promising new direction in understanding the role of RAS in the pathogenesis of preeclampsia.

The effect of sex on endothelial function responses to clamped hyperglycemia in type 1 diabetes

Although the female sex is associated with renal protection in non-diabetic nephropathy, men and women with type 1 diabetes mellitus (T1D) have a similar risk of developing nephropathy. As hyperglycemia is associated with exaggerated effects on blood pressure and renal hyperfiltration in women versus men with T1D, we examined the influence of clamped hyperglycemia on flow mediated vasodilatation (FMD) to determine if this parameter contributes to sex-related differences in the vascular function. After a controlled diet for seven days, blood pressure, ultrasound derived FMD and circulating renin angiotensin system mediators were measured in men (n=30) and women (n=28) with T1D during clamped euglycemia and hyperglycemia. Men and women were similar in pre-study dietary parameters, age, diabetes duration, body mass index, HbA1c, renal function and proteinuria. The systolic blood pressure (SBP) was higher in men during clamped euglycemia (121±2 vs. 108±2 mm Hg, P<0.0001) and hyperglycemia (121±2 vs. 111±2 mm Hg, P<0.0001), as were the circulating levels of angiotensin II (P<0.05). SBP increased in response to hyperglycemia in women but not in men. Consistently with differences in blood pressure during clamped euglycemia, FMD was higher in women than in men (8.06±0.55 vs. 4.15±0.52%, P<0.0001). In contrast, between-group differences in FMD during clamped hyperglycemia did not reach significance owing to a decline in FMD in women, versus men, in response to clamped hyperglycemia (P=0.040 for between-group change in FMD). Clamped hyperglycemia suppresses FMD in women, but not in men, with uncomplicated T1D, which may contribute to the relative loss of protection against renal disease progression in women with T1D.

Abstract 548: Reduced Urinary Angiotensinogen Excretion in Preeclampsia

Objective: Preeclampsia (preE) is a hypertensive disorder of pregnancy. We reported the suppression of circulatory renin-angiotensin system (RAS) in a rat model of preE. Urinary angiotensinogen has been considered as an indicator of intrarenal angiotensin status in hypertension. Little is known about the urinary angiotensinogen in preE. This study evaluates the level of urinary excretion of angiotensinogen in preE to assess the RAS status. Methods: Normal pregnant (n=57) and preE (n=32) patients were recruited from Scott &amp; White Hospital and had their blood drawn between 21 to 40 weeks of pregnancy. Criteria for diagnosis of preE included blood pressure &gt;140/90 mm Hg and proteinuria &gt;300 mg of protein/24h. Two groups of rats were used: normal pregnant (n=10) and preE rats (n=10) which were given weekly injections of desoxycorticosterone acetate and 0.9% saline to drink. Urinary angiotensinogen levels and the plasma AngII levels were assayed by ELISA. The kidney expression of (pro)renin receptor, AT 1 receptor, AT 2 receptor, and renin for the two groups of rats was measured by western blot. Results are expressed as means with SD and comparisons made using Student’s t test with p&lt;0.05 considered significant. Results: In preE patients, the mean urinary excretion of angiotensinogen (2.0 ± 1.1 ng/mg creatinine) differed (p&lt;0.05) from that in patients with normal pregnancy (2.7 ± 1.5 ng/mg creatinine). The urinary excretion of angiotensinogen (PreE: 1.5 ± 0.3, NP: 2. 3 ± 0.4 nmol/day) also differed (p&lt;0.05) in preE rats compared to NP. The plasma concentration of Ang II for preE rats (25 ± 3 fmol/ml) differed (p&lt;0.05) compared to NP rats (39 ± 5 fmol/ml). The kidney expression of (pro)renin receptor was downregulated (p=0.008), while the AT 1 receptor was upregulated (p=0.01) in preE rats compared to NP. However, the kidney expression of AT 2 receptor (1.0 vs 1.1) and renin (1.0 vs 1.4) were similar in NP and PDS rats (p=0.63 and p=0.12, respectively). Conclusions: We demonstrated that urinary excretion of angiotensinogen is reduced in both patients with preE and in a rat model of preE. The kidney expression of RAS components was either downregulated or remained unchanged in preE rats. This finding indicates that preE is an Ang-II independent form of systemic hypertension.

Effect of Renal Denervation on Neurohumoral Activation Triggering Atrial Fibrillation in Obstructive Sleep Apnea

Obstructive sleep apnea is characterized by repetitive collapses of the upper airway, negative thoracic pressure periods, and intermittent hypoxia, stimulating the autonomic nervous system. The increased sympathetic drive during obstructive sleep apnea results in postapneic blood pressure rises and neurohumoral activation potentially involved in the initiation and progression to permanent atrial fibrillation (AF). In a pig model mimicking obstructive sleep apnea, we studied the effects of repetitive obstructive respiratory events for 4 hours on the occurrence of spontaneous AF episodes, postapneic blood pressure rises, and neurohumoral activation. In addition, renal sympathetic denervation was performed to investigate the impact of the sympathetic nervous system. Repetitive obstructive respiratory events caused pronounced postapneic blood pressure rises, prolonged duration of spontaneous AF episodes triggered by spontaneous atrial beats, and increased plasma renin activity and aldosterone concentrations. This was associated with increased nicotinamide adenine dinucleotide phosphate-oxidase activity, reduced antioxidative capacity, and elevated expression of connective tissue growth factor, a redox-sensitive mediator of fibrosis. Renal sympathetic denervation inhibited postapneic blood pressure rises and decreased plasma renin activity and aldosterone concentrations. The occurrence and duration of spontaneous AF were reduced comparable with a combined pharmacological blockade of angiotensin receptor and β-adrenoceptor. Increased atrial oxidative stress, together with the activation of profibrotic pathways and intermittent hypoxia, was not attenuated after renal sympathetic denervation. Repetitive obstructive respiratory events triggered spontaneous AF, increased atrial oxidative stress, and activated profibrotic pathways in the atrium. Renal sympathetic denervation reduced spontaneous AF and postapneic blood pressure rises by combined reduction of sympathetic drive and components of the circulating renin-angiotensin system. However, the generation of atrial oxidative stress was not modulated.

Fetal sex and the circulating renin–angiotensin system during early gestation in women who later develop preeclampsia or gestational hypertension

There are fetal sex-specific differences in the balance between angiotensin (Ang) II and Ang-(1-7) in the maternal circulation during pregnancy. To determine whether at 15 weeks' gestation plasma levels of Ang II and Ang-(1-7), as well as levels of prorenin and Ang-converting enzyme (ACE), predicted the development of gestational hypertension (GH) or preeclampsia (PreE) and were associated with estimates of fetal and maternal health, women who later developed GH (n=50) or PreE (n=50) were compared with body mass index-matched controls (n=100). Women who subsequently developed PreE or GH had increased Ang-(1-7) levels at 15 weeks' gestation compared with women with normal pregnancies. When separated by fetal sex, this difference was seen only in women carrying a female fetus. Prorenin and ACE concentrations were not useful biomarkers for the prediction of either PreE or GH at 15 weeks' gestation. Women with a male fetus who developed PreE and women who subsequently developed GH had increased blood pressures at 15 weeks' gestation compared with women with normal pregnancies, suggesting that these women were on an early trajectory for the development of hypertension. We propose that measurement of Ang-(1-7) during early gestation could be useful in predicting, those women who will go on to develop new-onset hypertension in pregnancy.

ASSA13-16-6 The Increased Circulatory RAS Activity Can Be Inhibited by Statins

ObjectiveTo investigate the profile of circulatory renin-angiotensin system (RAS) activity in hypercholesterolemia (HC) patients treated with statins.MethodsThis study included 18 primary HC patients and 18 sex-and age-matched healthy adults. Total...

Increased circulatory RAS activity can be inhibited by statins in patients with hypercholesterolemia

The objective of this paper is to investigate a profile on circulatory renin-angiotensin system (RAS) activity in hypercholesterolemic (HC) patients treated with statins. Eighteen primary HC patients and 18 sex- and age-matched healthy adults were included in this study as controls. Total cholesterol (TC), triglyceride (TG), LDL-C, blood glucose, angiotensin-converting enzyme (ACE) activity, and angiotensin II (Ang II) levels were measured before and four and eight weeks after beginning statin treatment in the HC group. Similar measurements were taken in the control group at baseline. At baseline, TC, TG and LDL-C levels, as well as ACE activity and Ang II concentrations, were significantly higher in the HC group than in the control group. Based on the baseline data collection of 36 participants, there were significant positive correlations between ACE activity and TC (r = 0.54) or LDL-C (r = 0.51), and between Ang II level and TC (r = 0.34) or LDL-C (r = 0.27). TC, LDL-C, Ang II (35.46 ± 14.49 vs 71.10 ± 20.47 pg/ml, p < 0.05) levels and ACE activity (108.9 ± 51.9 vs 180.1 ± 71.3 U/L, p < 0.05) were decreased in HC patients eight weeks after starting statin treatment. In HC patients, RAS activity correlated positively with TC and LDL-C levels before and after treatment. In HC patients, lowering serum cholesterol with statins is associated with decreased circulatory RAS activity.

Renin-angiotensin system in pre-eclampsia: everything old is new again.

This review presents an update of the role of the renin-angiotensin system in normal pregnancy and pre-eclampsia. We have known for years that the circulatory renin-angiotensin system in pre-eclampsia is suppressed. We now know that the circulating renin-angiotensin system does not only have a vasoconstrictor arm, but also a vasodilator arm, which is upregulated in normal pregnancy; this balance is probably disturbed in pre-eclampsia. Recent studies show the importance of the local renin-angiotensin system in the uteroplacental unit for early placentation and regulation of placental blood flow. We discuss the possible role of autoantibodies against the AT1-receptor in pre-eclampsia and the suggestion that activation of the AT1-receptor in the placenta may lead to placental dysfunction and the clinical syndrome of pre-eclampsia.

Abstract 240: Interruption of Ivabradine Treatment in Middle-Aged Post-MI Rats May Lead to Heart Failure

Background: We have previously demonstrated that heart rate reduction (HRR) with the selective cardiac pacemaker I f current inhibitor ivabradine (IVA) improved LV function and coronary perfusion reserve in post-MI middle-aged rats. The beneficial effects of IVA treatment were associated with attenuated collagen accumulation in the surviving LV myocardium and inhibition of the circulatory renin-angiotensin system. However, sustainability of these positive changes after a period of IVA treatment interruption remains to be determined. Methods: MI was induced in 12-month-old male Sprague-Dawley rats by left coronary artery ligation. Twenty four hours later, the rats with a confirmed large transmural MI were randomly assigned in two experimental groups. In a first group, rats were treated with IVA i.p. via osmotic pumps in a dose of 10.5 mg/kg/d for 4 weeks followed by a 4-week period without treatment (MI+IVA). In a second group, rats received placebo for 4 weeks (MI). Sham-operated rats served as a control. Eight weeks after MI, the various LV parameters were examined. Results: During 4 weeks of treatment, heart rate in MI+IVA rats was consistently reduced compared to untreated MI rats (mean of HRR was 27%). After IVA withdrawal, heart rate increased to the levels of the placebo group. Eight weeks after MI, the IVA treated group demonstrated smaller LV free wall infarct size (57.5 ± 2.7% vs. 72.5 ± 2.5%, p&lt;0.01) and greater LV weight/body weight ratio (2.54 ± 0.06 vs. 2.26 ± 0.11 mg/g, p&lt;0.05), indicating greater myocardial compensatory hypertrophy. Furthermore, the interstitial collagen content was significantly lower in the remote LV myocardium of MI+IVA rats compared to MI rats (7.5 ± 0.7% vs. 13.3 ± 1.0% in free wall and 7.3 ± 0.8% vs. 11.2 ± 0.9% in septum, p &lt; 0.01). However, compared to non-infarcted controls, rats of both MI groups had markedly lower LV ejection fraction and coronary perfusion reserve. Conclusions: Our data demonstrate that although beneficial structural changes induced by IVA in post-MI myocardium can be sustainable for a long period of time they cannot prevent deterioration of LV function after withdrawal of treatment. Therefore, we believe that continuous treatment with IVA may be essential for attenuation of heart failure after a large MI.

Markers of cardiovascular disease risk after hypertension in pregnancy

Women with a history of preeclampsia or gestational hypertension have an increased risk of cardiovascular disease. Underlying cardiovascular risk factors, persistent endothelial dysfunction or sympathetic overactivity may contribute to this risk. We studied markers of cardiovascular disease risk in nonpregnant women with a history of hypertension in pregnancy. Women with a history of preeclampsia (n = 39), gestational hypertension (n = 27) and normal pregnancies (n = 35) were studied 2-12 years after delivery. Laboratory measures included plasma fasting lipids, glucose, insulin, creatinine and urinary albumin-to-creatinine ratio. Blood pressure was measured by 24-h ambulatory blood pressure monitoring, endothelial function by flow-mediated dilatation and sympathetic activity by both head-up tilt test and cold pressor test, including the response of the circulating renin-angiotensin system to tilt testing. Compared with women who had previous normal pregnancies, women with a history of preeclampsia or gestational hypertension have higher ambulatory blood pressure, BMI and relative insulin resistance. Glomerular filtration rate, albumin-to-creatinine ratio, endothelial function and sympathetic activity was similar among the three groups. Women with a history of preeclampsia or gestational hypertension have features of the metabolic syndrome which are presumably present already before pregnancy, predisposing them to hypertensive disorders of pregnancy and later cardiovascular risk. In this study, we found no evidence for early renal damage, endothelial dysfunction or sympathetic overactivity in the postpartum state.