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Angiotensin-converting enzyme inhibitors (ACEI) such as benazepril are commonly prescribed in both humans and dogs with heart disease to mitigate the renin–angiotensin–aldosterone system (RAAS); however, the dose-dependent effects of benazepril on comprehensive RAAS components remain unknown. In this study, nine purpose-bred healthy dogs received three different dosages of oral benazepril (0.125 mg/kg, 0.25 mg/kg, or 0.5 mg/kg) in a randomized crossover design following induction of RAAS activation by consuming a low-sodium diet. Blood samples were collected at serial time intervals after benazepril dosing to measure plasma benazeprilat (active metabolite of benazepril) and serum RAAS biomarkers. Blood pressure and echocardiogram were performed at baseline and after each benazepril administration. Time-weighted averages for RAAS biomarkers for 12 h post-dose and hemodynamic variables were compared between dosing groups using Wilcoxon rank-sum testing. Compared to the lowest dosage of benazepril (0.125 mg/kg), the highest dosage (0.5 mg/kg) resulted in lower time-weighted average values of angiotensin (Ang) II (− 38%, P = 0.004), Ang1-5 (− 53%, P = 0.001), ACE-S (surrogate for ACE activity; − 59%, P = 0.0002), and ALT-S (surrogate for alternative RAAS activity; − 22%, P = 0.004), and higher values of AngI (+ 78%, P = 0.014) and PRA-S (surrogate for plasma renin activity; + 58%, P = 0.040). There were no relevant differences between dosing groups for blood pressure or echocardiographic variables. Knowledge of dose-dependent alterations in biomarkers of the classical and alternative RAAS pathways could help inform clinical trials for dosage optimization in both dogs and humans. [ABSTRACT FROM AUTHOR]

Leptin is a hormone related to metabolism. It also influences blood pressure, but the mechanisms triggered in this process are not yet elucidated. Angiotensin-I converting enzyme (ACE) regulates cardiovascular functions and recently has been associated with metabolism control and obesity. Here, we used ob/ob mice, a model lacking leptin, to answer the question whether ACE and leptin could interact to influence blood pressure, thereby linking the renin-angiotensin system and obesity. These mice are obese and diabetic but have normal 24 h mean arterial pressure. Our results show that plasma and lung ACE activities as well as ACE mRNA expression were significantly decreased in ob/ob mice. In agreement with these findings, the hypotensive effect produced by enalapril administration was attenuated in the obese mice. Plasma renin, angiotensinogen, angiotensin I, bradykinin, and angiotensin 1–7 were increased, whereas plasma angiotensin II concentration was unchanged in obese mice. Chronic infusion of leptin increased renin activity and angiotensin II concentration in both groups and increased ACE activity in ob/ob mice. Acute leptin infusion restored ACE activity in leptin-deficient mice. Moreover, the effect of an ACE inhibitor on blood pressure was not changed in ob/+ mice during leptin treatment but increased four times in obese mice. In summary, our findings show that the renin–angiotensin system is altered in ob/ob mice, with markedly reduced ACE activity, which suggests a possible connection between the renin–angiotensin system and leptin. These results point to an important interplay between the angiotensinergic and the leptinergic systems, which may play a role in the pathogenesis of obesity, hypertension, and metabolic syndrome. [ABSTRACT FROM AUTHOR]

The renin-angiotensin system (RAS) is a critical regulator of blood pressure and fluid homeostasis. Angiotensin II, the primary bioactive peptide of the RAS, is generated from angiotensin I by angiotensin-converting enzyme (ACE). A homologue of ACE, ACE2, is able to convert angiotensin II to a peptide with opposing effects, angiotensin-(1-7). It is proposed that disturbance of the balance of ACE and ACE2 expression and/or function is important in pathologies in which angiotensin II plays a role. These include cardiovascular and renal disease, lung injury and liver fibrosis. The critical roles of ACE and ACE2 in regulating angiotensin II levels have traditionally focussed attention on their activities as angiotensinases. Recent discoveries, however, have illuminated the roles of these enzymes and of the ACE2 homologue, collectrin, in intracellular trafficking and signalling. This paper reviews the key literature regarding both the catalytic and non-catalytic roles of the angiotensin-converting enzyme gene family. [ABSTRACT FROM AUTHOR]

The article reports that monotherapy with renin-angiotensin system blocker may not be suitable for patients with low-renin hypertension. It states that pretreatment plasma renin activity levels with ambulatory blood pressure responses to angiotension receptor blockers in essential hypertension. It adds that the effectiveness of antihypertensive medications is based from the blood pressure-lowering effect rather than the characteristic actions of hypertensive drugs.

A salmon protein hydrolysate (SPH) was developed containing several angiotensin I-converting enzyme (ACE) inhibitory tripeptides the most abundant of which were Val-Leu-Trp, Val-Phe-Tyr, and Leu-Ala-Phe. Simulated digestion experiments showed that active constituents of SPH would survive in the digestive tract and be available for absorption into the bloodstream. In fact, ACE inhibitory activity was improved following simulated digestion suggesting that there were larger peptides in SPH that might contribute to bioactivity in vivo. A single oral dose (1,500 mg/kg body mass) of SPH significantly lowered blood pressure in spontaneously hypertensive rats (SHR). The treatment of SHR with either SPH fraction (<3,000 Da) or SPH fraction (>3,000 Da) reduced blood pressure. We conclude that the ability of SPH to lower blood pressure is due to a combination of ACE inhibitory tripeptides as identified, as well as additional unknown, peptide species that are generated during digestion of SPH in the gastrointestinal tract. [ABSTRACT FROM AUTHOR]

High levels of activity of the renin–angiotensin system (RAS) and sympathetic nervous system (SNS) are related to left ventricular hypertrophy (LVH). A percentage of subjects with hyperactivity to treadmill stress test show LVH to echocardiogram. This paper aims at evaluating neurohumoral influence over these subjects by comparing drugs that block both the RAS and the SNS. In a 1-year open protocol, 195 normotensive subjects, with hyperactivity to treadmill stress test and LVH, were randomly assigned to supervised physical exercise, rilmenidine 1 mg day−1, atenolol 50 mg day−1, enalapril 10 mg day−1 or losartan 50 mg day−1. Changes in left ventricular mass index (LVMI), measured by means of echocardiogram, were the primary end point. Changes in systolic blood pressure (SBP) at rest and peak effort were also evaluated. Enalapril significantly brought LVMI down in relation to the basal value (28.2%; n=36) similarly to losartan (26.9%; n=42); P>0.05. However, both were more efficient than physical exercise (2.9%; n=39), rilmenidine (5.1%; n=38) and atenolol (7.2%; n=40); P<0.001. There was no significant difference in SBP reduction at rest and peak effort in groups assigned to atenolol, enalapril and losartan; P>0.05. In such groups, reduction was greater than in groups assigned to physical exercise and rimenidine; P<0.001. In conclusion, drugs that block RAS were more efficient in reducing LVH than physical exercise and drugs that block SNS, and such reduction took place regardless of SBP level reduction at rest and peak effort.Journal of Human Hypertension (2009) 23, 259–266; doi:10.1038/jhh.2008.127; published online 23 October 2008 [ABSTRACT FROM AUTHOR]

The acute effects of the renin-angiotensin system (RAS) blockers may be important in some clinical settings. To assess the acute impact of such drugs on arterial function, we studied the effects of captopril 25 mg, quinapril 20 mg and telmisartan 80 mg on 100 hypertensive patients, according to a randomized, double-blind, placebo-controlled study. Central (aortic) blood pressure (BP) and augmentation index (AIx, a measure of wave reflections), as well as flow-mediated dilatation (FMD) of the brachial artery and forearm blood flow (FBF) (measures of conduit and resistance artery endothelial function, respectively), were evaluated before and 2 h after oral drug administration. Compared to placebo, captopril and quinapril decreased central systolic (by 7.5 mm Hg, P<0.05 and by 12.3 mm Hg, P<0.001) and diastolic BP (by 4.9 mm Hg, P<0.01 and by 8.4 mm Hg, P<0.001), whereas telmisartan had no significant effect (P=NS). Additionally, AIx was reduced after quinapril (absolute decrease of 7.2%, P<0.01) and marginally after captopril (decrease of 4.7%, P=0.07). Only quinapril led to a beneficial change of FMD (absolute increase of 2.7%, P<0.001). No treatment was related to significant changes of peak hyperaemic or 3-min hyperaemic FBF. In adjusted analyses, all the favourable alterations induced by quinapril were independent of potential confounding haemodynamic factors. Our data show that acute RAS inhibition with quinapril (20 mg) may be more beneficial in terms of arterial function and central haemodynamics compared to captopril (25 mg) or telmisartan (80 mg). Further studies are needed to investigate whether these acute arterial effects of quinapril are clinically significant.Journal of Human Hypertension (2007) 21, 654–663; doi:10.1038/sj.jhh.1002211; published online 26 April 2007 [ABSTRACT FROM AUTHOR]

The incidence of end-stage renal disease (ESRD) is rising worldwide, accompanied by corresponding increases in the risk of morbidity and mortality. Underlying this trend are increasing rates of hypertension and diabetes mellitus, the two most common causes of ESRD. In addition to the adverse haemodynamic effects of hypertension on the kidney, elevated blood pressure (BP) can activate components of the renin–angiotensin–aldosterone system (RAAS), which, in turn, activate mediators of inflammation, oxidative stress, cell growth, and matrix accumulation. Lowering BP reduces the risk of cardiovascular events and renal damage. Accumulating evidence from clinical and laboratory studies suggests that interrupting the RAAS with therapies such as angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, and aldosterone receptor blockers can interfere with the mechanisms that promote diabetic and non-diabetic renal damage. Moreover, clinical trials of RAAS blockade have demonstrated reductions in microalbuminuria, a predictor of increased cardiorenal risk and overt nephropathy in patients with and without diabetes and/or hypertension. In this way, agents that block the RAAS should be considered the drugs of first choice as they provide enhanced renoprotection compared with other classes of antihypertensive agents such as calcium channel blockers and β-blockers.Journal of Human Hypertension (2006) 20, 239–253. doi:10.1038/sj.jhh.1001982; published online 2 February 2006 [ABSTRACT FROM AUTHOR]

Screening for primary hyperaldosteronism (PHA) is often indicated in individuals with resistant hypertension or hypokalaemia. However, in the far larger subset of the hypertensive population who do not fit into these criteria, the evidence for screening is conflicting and dependent on the disease prevalence. The purpose of this study was to examine the prevalence of PHA in a large population with mild to moderate hypertension and without hypokalaemia using a carefully controlled study protocol including a normotensive control population. Hypertensive subjects underwent medication washout and both hypertensive and normotensive subjects placed on a high-sodium diet prior to biochemical and haemodynamic testing. Study specific cutoff values were based on results from the normotensive population studied under identical conditions. A screening test (serum aldosterone/PRA ratio [ARR]>25 with a serum aldosterone level >8 ng/dl) was followed by a confirmatory test (urine aldosterone excretion rate [AER] >17 μg/24 h) to demonstrate evidence of PHA. An elevated ARR with a concomitant elevated serum aldosterone was present in 26 (7.5%) individuals. Of these, 11 (3.2%) had an elevated AER, consistent with evidence of PHA. Individuals with PHA had higher blood pressure and lower serum potassium levels while on a high-sodium diet. Sodium restriction neutralized these differences between PHA and essential hypertensives. The prevalence of PHA in this mild to moderate hypertensive population without hypokalaemia is at most 3.2%, a rate that might lead to excessive false positives with random screening in comparable populations. Hyperaldosteronism, when present, is responsive to sodium restriction.Journal of Human Hypertension (2006) 20, 129–136. doi:10.1038/sj.jhh.1001948; published online 17 November 2005 [ABSTRACT FROM AUTHOR]

Drugs that inhibit the renin–angiotensin system (RAS), namely angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin receptor antagonists (ARA) are gaining increasing popularity as initial medications for the management of hypertensive patients. In the year 2002, ACE-I were the most commonly prescribed drugs for the treatment of hypertension in USA. Although their antihypertensive efficacy as monotherapy is similar to other antihypertensive agents, they have the advantage of better tolerability, limited side effects and a favorable metabolic profile. When compared to other antihypertensive agents (diuretics, beta-adrenergic blockers and calcium antagonists) in large clinical trials, ACE-I and ARA provided no additional advantages regarding improvement in cardiovascular and total mortality. With the exception of the superiority of ARA in prevention of stroke, RAS inhibitors have no advantage over other agents in prevention of other cardiovascular morbid events, namely, heart failure (though ACE-I are superior to calcium antagonists), coronary heart disease and total cardiovascular events. However, there is the possibility that these agents have other benefits beyond blood pressure lowering. At equal degrees of blood pressure reduction, RAS inhibitors prevent or delay the development of diabetes mellitus and provide better end-organ protection, kidneys, blood vessels and the heart when compared with other antihypertensive agents. The combined use of ACE-I and ARA is particularly useful in organ protection. RAS inhibitors are specifically indicated in the treatment of hypertension in patients with impaired left ventricular systolic function, diabetes, proteinuria, impaired kidney function, myocardial infarction, multiple cardiovascular risk factors and possibly elderly patients. The main limitation of the ACE-I is cough and rarely angioedema. Elderly patients or those who are volume depleted or receiving large doses of diuretics or in heart failure are liable to develop hypotensive reaction and/or deterioration in kidney function.Journal of Human Hypertension (2006) 20, 101–108. doi:10.1038/sj.jhh.1001960; published online 5 January 2006 [ABSTRACT FROM AUTHOR]

We investigated the interplay of dietary sodium and renin-angiotensin-aldosterone system (RAAS) activity with the prevalence of left ventricular hypertrophy (LVH) in essential hypertension. Electrocardiograms (EKG) were reviewed for the presence of LVH in 160 hypertensive patients. We then compared the rate of LVH to levels of plasma renin activity (PRA) and serum aldosterone under high and low sodium diet conditions. On high sodium diet, serum aldosterone was significantly higher (7.7±0.93 vs 5.7±0.35?ng/dl, P=0.02) in participants with LVH. With low sodium diet and upright posture, PRA was significantly lower in subjects with LVH vs those without (5.6±1.1 vs 7.6±0.56?ng/ml/h, P=0.026). Aldosterone levels on low sodium diet were not different between those with and those without LVH. PRA was then dichotomized at the lowest quartile under low sodium/upright posture conditions to define a‘low renin’group. In a multivariate logistic regression containing renin status (low renin vs normal/high renin), aldosterone on a high sodium diet, age, body mass index, gender, race, duration of hypertension, systolic and diastolic blood pressure and salt-sensitivity only low-renin status on a low sodium diet (P=0.019) and serum aldosterone on a high sodium diet (P=0.04) were significant predictors of LVH. Thus, reduced modulation of renin activity in response to sodium restriction and an increased aldosterone on a high sodium diet appear to identify characteristics of hypertensive patients predisposed to abnormal cardiac remodelling.Journal of Human Hypertension (2005) 19, 133-138. doi:10.1038/sj.jhh.1001784 Published online 9 September 2004 [ABSTRACT FROM AUTHOR]

This study analyzed the relationship between four renin-angiotensin system (RAS) gene polymorphisms and the response to blood pressure lowering and development of microalbuminuria in 206 patients with essential hypertension treated once daily for 12 months with telmisartan 80?mg. Seated cuff blood pressure and urinary albumin excretion (UAE) were measured throughout the study. Patients were screened for the presence of the A-6G variant of the angiotensinogen gene, angiotensin-converting enzyme insertion/deletion polymorphism, and the A1166C and C573T polymorphisms of the angiotensin II type 1 receptor gene. No significant association was found between the presence of any gene polymorphism and the reduction of blood or UAE following telmisartan treatment. The results indicate that these RAS gene polymorphisms do not affect the antihypertensive activity and renoprotection in mild-to-moderate hypertensive patients treated with telmisartan.The Pharmacogenomics Journal (2005) 5, 14-20. doi:10.1038/sj.tpj.6500280 Published online 26 October 2004 [ABSTRACT FROM AUTHOR]

Systolic blood pressure is a major cardiovascular risk factor which is often associated with arterial stiffness. Markers of arterial stiffness, such as pulse pressure and carotid-femoral pulse wave velocity, have been proved independent predictors of cardiovascular risk. Recent evidence suggests that the renin-angiotensin system is involved in the pathogenesis of systolic hypertension and arterial stiffness. Outcome trials have shown impressive cardiovascular protection by reducing systolic blood pressure (BP) with drug treatment. However, in clinical practice systolic hypertension remains largely uncontrolled, first, because systolic BP goal is more difficult to be reached than diastolic and, second, because physicians are often reluctant to intensify treatment in patients with systolic BP close to 150?mmHg. Recent trials have focused on the effects of antihypertensive drugs not only on blood pressure, but also on pulse pressure and pulse-wave velocity. Blockade of the renin-angiotensin-aldosterone system, using angiotensin-converting enzyme inhibitors and more recently angiotensin receptor blockers, has been shown to provide beneficial effects on arterial stiffness that appear to be independent of their antihypertensive effects. Recent outcome trials have shown significant cardiovascular protection with angiotensin receptor blockers. These drugs have an excellent placebolike profile of adverse effects which is maintained when these drugs are combined with low-dose diuretics. Therefore, an angiotensin receptor blocker-based treatment strategy appears to be an attractive and evidence-based approach for the management of systolic hypertension, the reduction of arterial stiffness and the prevention of cardiovascular disease.Journal of Human Hypertension (2004) 18, 837-847. doi:10.1038/sj.jhh.1001762 Published online 19 August 2004 [ABSTRACT FROM AUTHOR]

Generation of angiotensin II (Ang II) contributes to the pathogenesis of cardiovascular diseases. Owing to the existence of high levels of Ang II within the kidney, blockade of the intrarenal Ang II levels may be important since long term outcome seems not only to be related to blood pressure per se. This was a prospective, randomized, double-blind, placebo-controlled study, with crossover design. We examined in 13 patients with mild to moderate hypertension the specific systemic and renal blocking properties of two different Ang II receptor blockers during a wide range of Ang II concentrations, 24?h post dose. The effects were evaluated after 4 weeks treatment with candesartan cilexetil (16?mg OD), losartan (50?mg OD) and placebo using clearance techniques. Candesartan reduced the 24?h blood pressure better than losartan (138*/87±12/8 vs 145/89±12/7?mmHg,*P<0.05 vs losartan) and placebo. Despite the lower blood pressure, candesartan attenuated the Ang II-induced response on ERPF and RVR markedly better than losartan or placebo. The GFR decreased, as expected, with placebo, but remained stable with candesartan. The present study demonstrates that in hypertensive patients candesartan and to a lesser degree losartan are effective in blocking the systemic and renal effects of Ang II during a wide range of Ang II infusion rates. Interestingly, 24?h post dose, candesartan effectively diminished the change in ERPF as well as GFR. This sustained renal effect of candesartan may be of importance, especially in pathophysiological circumstances in which (high renal levels of) Ang II contributes to cardiovascular damage.Journal of Human Hypertension (2004) 18, 857-863. doi:10.1038/sj.jhh.1001769 Published online 9 September 2004 [ABSTRACT FROM AUTHOR]

Population blood pressure variation is most likely due to multiple genes. This is likely the reason why monogenic testing with the angiotensinogen (AGT) gene polymorphisms on chromosome 1 (1q42-43), especially M235T, has met with negative results, especially in those of African descent. The RH blood group system, also on chromosome 1 (1 p36.2-34), has likewise been associated with blood pressure variation in African-Americans and with the rise in blood pressure with age in whites. Using a random sample of the population, we investigated the combined effects of single and combined variation of the AGTN M235T and RH genotypes on blood pressure, lipids, and lipoprotein concentrations in Afro-Caribbeans aged 18-60 years from the island nation of Dominica. In monogenic analysis, AGT M235T was not associated with blood pressure. However, it was associated with HDL (MM 42±23, MT 44±12, TT 52±14 (P=0.002)). RH genotype was significantly associated with systolic blood pressure (P=0.006) and Apo-A (P=0.003). These effects remained after adjustment for age, gender, weight, and BMI. In the polygenetic analysis, AGT M235T and RH were significantly associated with systolic blood pressure (P=0.037; interaction effects, P=0.068). The association of the AGT M235T with blood pressure across RH blood group haplotypes was then tested. Of the five RH haplotypes available for analysis, the AGT M235T was significantly associated with blood pressure within the “D” haplotype (P=0.01). The RH blood group and gender were significantly associated with systolic blood pressure and Apo-A levels (P=0.005 and 0.012, respectively). All interactions were independent of age and weight. In conclusion, we demonstrate a significant association of AGT M235T with blood pressure and cholesterol metabolism in an Afro-Caribbean population in the “genetic context” of the RH blood group system. Further investigation of these interactions may help understand the effects of genetic factors on cardiovascular risk in African-derived and other populations.Journal of Human Hypertension (2004) 18, 351-363. doi:10.1038/sj.jhh.1001679 Published online 12 February 2004 [ABSTRACT FROM AUTHOR]

The purpose of the study was to evalute the impact of the renin-angiotensin-aldosterone (RAA) system on blood pressure (BP) response in patients with hypertensive emergencies and urgencies treated with intravenous enalaprilat. Thirty-five patients with a systolic BP (SBP) >210 mm Hg and/or diastolic BP (DBP) >110 mm Hg received 5 mg enalaprilat intravenously. The extent of systolic and DBP reduction was correlated with pretreatment concentrations of angiotensin II (ANG II) (SBP: r = -0.47; P = 0.006; DBP: r = -0.55; P = 0.001) and plasma renin activity (PRA) (SBP: r = -0.49; P = 0.003; DBP: r = 0.48; P = 0.007). Non-responders to enalaprilat exhibited significant lower pretreatment levels of PRA, angiotensin-converting enzyme (ACE) and ANG II compared to responders (PRA: 5.5 ± 3.7 vs 1.1 ± 2.2 ng/ml/h, P < 0.001; ACE: 12.8 ± 3.5 vs 8.2 ± 4.8 U/l, P = 0.003; ANG II:8.7 ± 6.2 vs 5.0 ± 3.8 pg/ml, P = 0.04). In patients with severe hypotension following application of enalaprilat ANG II concentrations were significantly higher compared to patients with mean arterial BP reduction <25% (12.3 ± 6.7 vs 5.6 ± 4.0 pg/ml, P = 0.013). These data indicate that PRA and ANG II are the major determinants for BP response to enalaprilat. This relation between BP response and RAA system activity have important clinical implications for the treatment of patients with severe hypertension. Primary therapeutic failure indicates that the RAA system contributes very little to the hypertensive status of the patient. Thus, repetitive application on an ACE inhibitor in primary responders is clinically unhelpful and may result in an unnecessary delay of an effective BP reduction. In contrast, high ANG II concentrations are associated with a considerable risk for severe hypotension after enolanalaprilat application. Therefore, the status of the RAA system determines the efficacy as well as the safety of ACE inhibitor treatment in... [ABSTRACT FROM AUTHOR]

Report that change in blood pressure predicts regression of cardiac hypertrophy in patients of African ancestry receiving agents influencing the renin angiotensin system. Extent of blood pressure changes; Reductions in left ventricular mass.

The author discusses the fibroblast growth factor (FGF)-21 hormone and its association with hypertension. The author mentions that levels of FGF-21 are regulated independently by renin-angiotensin system of systemic blood pressure lowering. The author notes that the inclusion of triglyceride levels as an explanatory variable weakened the association between hypertension and FGF-21 levels.

The article discusses the conformational changes of angiotensinogen peptide hormone mediated by oxidative stress in the area cleaved by renin which increases blood pressure. It states that reactive oxygen species produces a common thread binding to cellular receptors induced by diverse cellular process of angiotensin. Findings of the study by A. Zhou and colleagues indicate the influence of reactive oxygen species in rennin-angiotensin system and its pro-hypertensive impacts.

The author discusses the role of angiotensin II hormone in fighting heart disease or in killing a person. The authors explain that angiotensin AT1 receptor binding can raise blood pressure and damage of cells of the left ventricle of the heart while AT2 receptor expands the size of blood vessels and prevent heart damage. The authors cite that the mechanism in the renin-angiotensin system shows the complexity of molecular pathways of different receptors.