Angiotensin II is known to act primarily on the angiotensin AT(1) receptors to mediate its physiological and pathological actions. Des-aspartate-angiotensin I (DAA-I) is a bioactive angiotensin peptide and have been shown to have contrasting vascular actions to angiotensin II. Previous work in this laboratory has demonstrated an overwhelming vasodepressor modulation on angiotensin II-induced vasoconstriction by DAA-I. The present study investigated the involvement of the AT(1) receptor in the actions of DAA-I on angiotensin II-induced vascular actions in the renal vasculature of normotensive Wistar-Kyoto rats (WKY), spontaneously hypertensive rats (SHR) and streptozotocin (STZ)-induced diabetic rats. The findings revealed that the angiotensin receptor in rat kidney homogenate was mainly of the AT(1) subtype. The AT(1) receptor density was significantly higher in the kidney of the SHR. The increase in AT(1) receptor density was also confirmed by RT-PCR and Western blot analysis. In contrast, AT(1) receptor density was significantly reduced in the kidney of the streptozotocin-induced diabetic rat. Perfusion with 10(-9)M DAA-I reduced the AT(1) receptor density in the kidneys of WKY and SHR rats suggesting that the previously observed vasodepressor modulation of the nonapeptide could be due to down-regulation or internalization of AT(1) receptors. RT-PCR and Western blot analysis showed no significant changes in the content of AT(1) receptor mRNA and protein. This supports the suggestion that DAA-I causes internalization of AT(1) receptors. In the streptozotocin-induced diabetic rat, no significant changes in renal AT(1) receptor density and expression were seen when its kidneys were similarly perfused with DAA-I.
Matched MeSH terms: Angiotensin II/genetics; Angiotensin II/metabolism; Angiotensin II/chemistry; Angiotensin II Type 1 Receptor Blockers/metabolism
Low vitamin D (vitD) levels have been reported to be a risk factor for diabetes-related cardiovascular complications. This study examined the effects of vitD deficiency on oxidative stress (OS), inflammation, and levels of the vasoconstrictor angiotensin II (Ang II) in the microvascular tissue of type 2 diabetic patients. Patients were categorized into (i) vitD non-deficient diabetics (DNP, n = 10) and (ii) vitD-deficient diabetics (DDP, n = 10), based on their serum 25(OH)D levels. Subcutaneous fat tissues with intact blood vessels were collected during lower limb surgical procedures. The blood vessel were isolated; measurements of the antioxidant enzyme superoxide dismutase (SOD) activity, OS marker malondialdehyde (MDA), Ang II, and the inflammatory marker, TNF-α of the microvascular tissues were determined. Elevated MDA levels and reduced SOD activity, with higher levels of TNF-α and Ang II were observed in the microvascular tissues of DDP compared to DNP. VitD deficiency did not associate with glycemic parameters (fasting blood glucose and glycated hemoglobin) levels. In conclusion, vitD deficiency was correlated with higher microvascular tissue OS, inflammation, and Ang II levels in type 2 diabetic patients. This may contribute to early vasculopathy that occurs in diabetic patients, thus, may contribute to the planning of therapeutic strategies to delay or prevent cardiovascular complications.
The renin-angiotensin system (RAS) plays an important role in the pathophysiology of cardiovascular disorders. Pharmacologic interventions targeting the RAS cascade have led to the discovery of renin inhibitors, angiotensin-converting enzyme inhibitors, and AT(1) receptor blockers (ARBs) to treat hypertension and some cardiovascular and renal disorders. Mutagenesis and modeling studies have revealed that differential functional outcomes are the results of multiple active states conformed by the AT(1) receptor upon interaction with angiotensin II (Ang II). The binding of agonist is dependent on both extracellular and intramembrane regions of the receptor molecule, and as a consequence occupies more extensive area of the receptor than a non-peptide antagonist. Both agonist and antagonist bind to the same intramembrane regions to interfere with each other's binding to exhibit competitive, surmountable interaction. The nature of interactions with the amino acids in the receptor is different for each of the ARBs given the small differences in the molecular structure between drugs. AT(1) receptors attain different conformation states after binding various Ang II analogues, resulting in variable responses through activation of multiple signaling pathways. These include both classical and non-classical pathways mediated through growth factor receptor transactivations, and provide cross-communication between downstream signaling molecules. The structural requirements for AT(1) receptors to activate extracellular signal-regulated kinases 1 and 2 through G proteins, or G protein-independently through β-arrestin, are different. We review the structural and functional characteristics of Ang II and its analogs and antagonists, and their interaction with amino acid residues in the AT(1) receptor.
Matched MeSH terms: Angiotensin II/metabolism; Angiotensin II Type 1 Receptor Blockers/pharmacology
Effect of losartan was assessed on systemic haemodynamic responses to angiotensin II (Ang II) and adrenergic agonists in the model of high-fructose-fed rat. Twenty-four Sprague-Dawley (SD) rats were fed for 8 weeks either 20% fructose solution (FFR) or tap water (C) ad libitum. FFR or C group received losartan (10mg/kg/day p.o.) for 1 week at the end of feeding period (FFR-L and L) respectively, then the vasopressor responses to Ang II, noradrenaline (NA), phenylephrine (PE) and methoxamine (ME) were determined. The responses (%) to NA, PE, ME and Ang II in FFR were lower (P<0.05) than C (FFR vs. C; 22±2 vs. 32±2, 30±3 vs. 40±3, 9±1 vs. 13±1, 10±1 vs. 17±1) respectively. L group had blunted (P<0.05) responses to NA, PE, ME and Ang II compared to C (L vs. C; 26±2 vs. 32±2, 30±3 vs. 40±3, 7±0.7 vs. 13±1, 5±0.4 vs. 17±1) respectively. FFR-L group had aggravated (P<0.05) response to NA and ME, but blunted response to Ang II compared to FFR (FFR-L vs. FFR; 39±3 vs. 22±2, 11±1 vs. 9±1, 3±0.4 vs. 10±1) respectively. Fructose intake for 8 weeks results in smaller vasopressor response to adrenergic agonists and Ang II. Data also demonstrated an important role played by Ang II in the control of systemic haemodynamics in FFR and point to its interaction with adrenergic neurotransmission.
PURPOSE: This article seeks to objectively review the clinical trial evidence to determine whether angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin-receptor blockers (ARBs) have special cardiovascular protective effects.
METHODS: An objective review of the clinical trial evidence.
RESULTS: Clinical trials in hypertensive patients comparing ACEI and ARB with other drugs generally showed no difference in the primary cardiovascular outcome (United Kingdom Prospective Diabetes Study Group, Captopril Prevention Project, Swedish Trial in Old Patients with Hypertension 2, Japan Multicenter Investigation for Cardiovascular Diseases-B Randomized Trial, Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial, Second Australian National Blood Pressure Study Group, Valsartan Antihypertensive Long-Term Use Evaluation). Where the primary, or major secondary, cardiovascular end-point favors one of the treatment arms, it was always the arm with the lower achieved blood pressure that saw the better clinical result as in Losartan Intervention For Endpoint Reduction in Hypertension Study, Captopril Prevention Project, Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial, and Valsartan Antihypertensive Long-Term Use Evaluation. Trials comparing ACEI or ARB against placebo in patients at high risk of cardiovascular events have not showed a consistent result; cardiovascular outcomes were reduced in Heart Outcomes Prevention Evaluation, European Trial on Reduction of Cardiac Events with Perindopril in Stable Coronary Artery Disease, and the Jikei Heart Study, but were not significantly reduced in Perindopril Protection Against Recurrent Stroke Study, Comparison of Arnlodipine vs Enalapril to Limit Occurrences of Thrombosis Trial, Prevention of Events with ACEIs Trial, Telmisartan Randomized Assessment Study in ACE-Intolerant Subjects with Cardiovascular Disease Trial, and Prevention Regimen for Effectively Avoiding Second Strokes Trial. In the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial, combining ACEIs with ARBs in high-risk patients did not reduce cardiovascular or renal outcomes compared with ACEI monotherapy alone. This absence of a reduction in cardiovascular outcome from the ACEI and ARB combination arm is further evidence suggesting that these drugs do not have any special cardiovascular protective effect. This objective review thus shows that the rennin-angiotensin antagonists do not have special cardiovascular protective properties.
CONCLUSION: The key to reducing cardiovascular outcome is to appropriately control blood pressure as well as to treat all other coronary risk factors.
Matched MeSH terms: Angiotensin II Type 1 Receptor Blockers/therapeutic use*
SARS-CoV-2, the agent of COVID-19, shares a lineage with SARS-CoV-1, and a common fatal pulmonary profile but with striking differences in presentation, clinical course, and response to treatment. In contrast to SARS-CoV-1 (SARS), COVID-19 has presented as an often bi-phasic, multi-organ pathology, with a proclivity for severe disease in the elderly and those with hypertension, diabetes and cardiovascular disease. Whilst death is usually related to respiratory collapse, autopsy reveals multi-organ pathology. Chronic pulmonary disease is underrepresented in the group with severe COVID-19. A commonality of aberrant renin angiotensin system (RAS) is suggested in the at-risk group. The identification of angiotensin-converting-enzyme 2 (ACE2) as the receptor allowing viral entry to cells precipitated our interest in the role of ACE2 in COVID-19 pathogenesis. We propose that COVID-19 is a viral multisystem disease, with dominant vascular pathology, mediated by global reduction in ACE2 function, pronounced in disease conditions with RAS bias toward angiotensin-converting-enzyme (ACE) over ACE2. It is further complicated by organ specific pathology related to loss of ACE2 expressing cells particularly affecting the endothelium, alveolus, glomerulus and cardiac microvasculature. The possible upregulation in ACE2 receptor expression may predispose individuals with aberrant RAS status to higher viral load on infection and relatively more cell loss. Relative ACE2 deficiency leads to enhanced and protracted tissue, and vessel exposure to angiotensin II, characterised by vasoconstriction, enhanced thrombosis, cell proliferation and recruitment, increased tissue permeability, and cytokine production (including IL-6) resulting in inflammation. Additionally, there is a profound loss of the "protective" angiotensin (1-7), a vasodilator with anti-inflammatory, anti-thrombotic, antiproliferative, antifibrotic, anti-arrhythmic, and antioxidant activity. Our model predicts global vascular insult related to direct endothelial cell damage, vasoconstriction and thrombosis with a disease specific cytokine profile related to angiotensin II rather than "cytokine storm". Our proposed mechanism of lung injury provides an explanation for early hypoxia without reduction in lung compliance and suggests a need for revision of treatment protocols to address vasoconstriction, thromboprophylaxis, and to minimize additional small airways and alveolar trauma via ventilation choice. Our model predicts long term sequelae of scarring/fibrosis in vessels, lungs, renal and cardiac tissue with protracted illness in at-risk individuals. It is hoped that our model stimulates review of current diagnostic and therapeutic intervention protocols, particularly with respect to early anticoagulation, vasodilatation and revision of ventilatory support choices.
Oxidative stress induced by hyperuricemia is closely associated with the renin-angiotensin system, as well as the onset and progression of cardiovascular disease (CVD) and chronic kidney disease (CKD). It is therefore important to reduce oxidative stress to treat hyperuricemia. We previously found that benzbromarone, a uricosuric agent, has a direct free radical scavenging effect in vitro. The antioxidant effects of benzbromarone were evaluated in vivo via oral administration of benzbromarone for 4 weeks to model rats with angiotensin II- and salt-induced hypertension. Benzbromarone did not alter plasma uric acid levels or blood pressure but significantly reduced the levels of advanced oxidation protein products, which are oxidative stress markers. Furthermore, dihydroethidium staining of the kidney revealed a reduction in oxidative stress after benzbromarone administration. These results suggest that benzbromarone has a direct antioxidant effect in vivo and great potential to prevent CVD and CKD.
Epigallocatechin gallate (EGCG) has been shown to have antihypertensive activity. However, the role of epigallocatechin gallate (EGCG) in improving vascular function via modulation of endothelial nitric oxide synthase (eNOS) in hypertensive subjects is not well researched. Angiotensin II-infused hypertensive mice (8-10 weeks old) received EGCG (50 mg/kg/day) for 14 days via oral gavage. The arterial systolic blood pressure (SBP) was measured using the tail-cuff method every three days. At the end of the treatment, the vascular reactivity of the isolated aortae was studied using wire myographs. The level of nitric oxide (NO), cyclic guanosine monophosphate (cGMP) and tetrahydrobiopterine (BH4) were determined using assay kits while the presence of proteins (NOS, p-eNOS and NOx-2) were determined using by Western blotting. In vivo treatment with EGCG for 14 days significantly attenuated the increase in SBP, alleviated the vascular dysfunction, increased the vascular cGMP and BH4 level as well as the expression of p-eNOS and decreased elevated ROS level and NOx-2 protein in angiotensin II-infused hypertensive mice. Collectively, treatment with EGCG in hypertensive mice exerts a blood pressure lowering effect which is partly attributed to the improvement in the vascular function due to its ability to reduce vascular oxidative stress in the aortic tissue leading to a decrease in eNOS uncoupling thus increasing NO bioavailability.
The aim of the study was to ascertain if there was any difference in the levels of prorenin and active renin between pre-eclamptic and normotensive feto-placental tissues.
A wealth of information concerning the essential role of renal sympathetic nerve activity (RSNA) in the regulation of renal function and mean arterial blood pressure homeostasis has been established. However, many important parameters with which RSNA interacts are yet to be explicitly characterized. Therefore, the present study aimed to investigate the impact of acute renal denervation (ARD) on sodium and water excretory responses to intravenous (iv) infusions of either norepinephrine (NE) or angiotensin II (Ang II) in anaesthetized spontaneously hypertensive rats (SHR).
In addition to being recognised for involvement in cardiovascular control and hydromineral balance, the renin-angiotensin system (RAS) has also been associated with the neuroendocrine control of energy balance. One of the main brain sites for angiotensin II (ANG II)/type 1 receptor (AT1 R) signalling is the subfornical organ (SFO), a circumventricular organ related to the control of autonomic functions, motivated behaviours and energy metabolism. Thus, we hypothesised that circulating ANG II may act on the SFO AT1 R receptors to integrate metabolic and hydromineral balance. We evaluated whether food deprivation can modulate systemic RAS activity and Agrt1a brain expression, and if ANG II/AT1 R signalling influences the hypothalamic expression of mRNAs encoding neuropeptides and food and water ingestion in fed and fasted Wistar rats. We found a significant increase in both ANG I and ANG II plasma levels after 24 and 48 h of fasting. Expression of Agrt1a mRNA in the SFO and paraventricular nucleus (PVN) also increased after food deprivation for 48 h. Treatment of fasted rats with low doses of losartan in drinking water attenuated the decrease in glycemia and meal-associated water intake without changing the expression in PVN or arcuate nucleus of mRNAs encoding selected neuropeptides related to energy homeostasis control. These findings point to a possible role of peripheral ANG II/SFO-AT1 R signalling in the control of refeeding-induced thirst. On the other hand, intracerebroventricular losartan treatment decreased food and water intake over dark time in fed but not in fasted rats.
Hypoadiponectinemia is associated with renal dysfunctions. Irbesartan and pioglitazone activate Peroxisome proliferator-activated gamma receptor (PPAR-γ) as partial and full agonists. We investigated a crosstalk interaction and synergistic action between adiponectin receptors, PPAR-γ agonists in attenuating renal hemodynamics to adrenergic agonists in diabetic Wistar Kyoto rats (WKY). Streptozotocin (40 mg/kg) was used to induce diabetes, whereas, pioglitazone (10 mg/kg/day), irbesartan (30 mg/kg/day) administered orally for 28 days and adiponectin intraperitoneally (2.5 μg/kg/day) for last 7 days. Metabolic and plasma samples were analyzed on days 0, 8, 21, and 28. During the acute study (day 29), renal vasoconstrictor actions to adrenergic agonists and angiotensin-II were determined. Diabetic WKYs had lower plasma adiponectin, higher creatinine clearance, urinary and fractional sodium excretion but were normalized to a greater extent in pioglitazone and adiponectin combined treatment. Responses to intra-renal administration of adrenergic agonists including noradrenaline (NA), phenylephrine (PE), methoxamine (ME), and angiotensin-II (ANG-II) were larger in diabetic WKY, but significantly blunted with adiponectin treatment in diabetic WKYs to 35-40%, and further reduced by 65-70% in combination with pioglitazone. Attenuation to ANG-II responses in adiponectin and combination with irbesartan was 30-35% and 75-80%, respectively (P
1 Interaction between renin-angiotensin (RAS) and sympathetic nervous systems (SNS) was investigated by examining the effect of cumulative blockade of angiotensin II (Ang II) and adrenergic receptors in normal Sprague Dawley rats. 2 Rats were treated with losartan (10 mg/kg), carvedilol (5 mg/kg), or losartan plus carvedilol (10+5 mg/kg) orally for 7 days. On day 8, the animals were anaesthetized with pentobarbitone and prepared for systemic haemodynamic study. Dose-response relationships for the elevation of mean arterial pressure or change in heart rate (HR) in response to intravenous injections of noradrenaline (NA), phenylephrine (PE), methoxamine (ME) and Ang II were determined. 3 Losartan or the combination of losartan with carvedilol blunted vasopressor responses to ME and Ang II. Dose-response relationships for agonist action on HR were significantly inhibited by all treatments except for the combination of losartan and carvedilol on the decrease in HR induced by PE. Carvedilol decreased vasopressor responses to NA, PE and Ang II, and HR responses to NA, ME and Ang II. Combination treatment produced similar effects to losartan on the vasopressor and HR responses but had a greater effect on vasopressor responses to ME and Ang II, and on HR responses to NA and Ang II than carvedilol alone. 4 It is concluded that peripheral vasoconstriction induced by Ang II is partly mediated by adrenergic action and that the vasopressor responses to adrenergic agonists depend on an intact RAS. These observations suggest an interactive relationship between RAS and SNS in determining systemic haemodynamic responses in 'normal' rats.
Matched MeSH terms: Angiotensin II/pharmacology; Angiotensin II/physiology*; Angiotensin II Type 1 Receptor Blockers/pharmacology*
Angiotensin II is one of the key regulatory peptides implicated in the pathogenesis of liver disease. The mechanisms underlying the salubrious role of α-tocopherol and β-carotene on liver pathology have not been comprehensively assessed. Here, we investigated the mechanisms underlying the role of Angiotensin II on hepatic damage and if α-tocopherol and β-carotene supplementation attenuates hepatic damage. Hepatic damage was induced in Apoe(-/-)mice by infusion of Angiotensin II followed by oral administration with α-tocopherol and β-carotene-enriched diet for 60 days. Investigations showed fibrosis, kupffer cell hyperplasia, hepatocyte degeneration and hepatic cell apoptosis; sinusoidal dilatation along with haemorrhages; evidence of fluid accumulation; increased ROS level and increased AST and ALT activities. In addition, tPA and uPA were down-regulated due to 42-fold up-regulation of PAI-1. MMP-2, MMP-9, MMP-12, and M-CSF were down-regulated in Angiotensin II-treated animals. Notably, α-tocopherol and β-carotene treatment controlled ROS, fibrosis, hepatocyte degeneration, kupffer cell hyperplasia, hepatocyte apoptosis, sinusoidal dilatation and fluid accumulation in the liver sinusoids, and liver enzyme levels. In addition, PAI-1, tPA and uPA expressions were markedly controlled by β-carotene treatment. Thus, Angiotensin II markedly influenced hepatic damage possibly by restraining fibrinolytic system. We concluded that α-tocopherol and β-carotene treatment has salubrious role in repairing hepatic pathology.
NEW FINDINGS: What is the topic of this review? We describe roles of crucial signalling molecules in the paraventricular nucleus of the hypothalamus and highlight recent data suggesting sex-specific changes in the expression of crucial signalling molecules and their receptors, which may underlie sex differences in both cardiovascular and metabolic function. What advances does it highlight? This review highlights the integrative capacity of the paraventricular nucleus in mediating cardiovascular and metabolic effects by integrating information from multiple signalling molecules. It also proposes that these signalling molecules have sex-specific differential gene expression, indicating the importance of considering these differences in our ongoing search to understand the female-male differences in the regulation of crucial autonomic systems. Many traditional cardiovascular hormones have been implicated in metabolic function. Conversely, many hormones traditionally involved in metabolic regulation have an effect on cardiovascular function. Many of these signalling molecules exert such effects through specific actions in the paraventricular nucleus, an integrative autonomic control centre located in the hypothalamus. Here, we focus on four cardiovascular/metabolic peptide hormones that signal within the paraventricular nucleus, namely angiotensin II, orexin, adiponectin and nesfatin-1. Each of these hormones has specific electrophysiological effects on paraventricular nucleus neurons that can be related to its physiological actions. In addition, we introduce preliminary transcriptomic data indicating that the genes for some of these hormones and their receptors have sex-specific differential expression.
This study investigated the influence of angiotensin II (Ang II) receptor and adrenergic blockade on the renal vasoconstrictions caused by Ang II and adrenergic agonists in spontaneously hypertensive rats (SHR).
Matched MeSH terms: Angiotensin II/pharmacology; Angiotensin II Type 1 Receptor Blockers/pharmacology
This study investigated the effects of combined minimal concentrations of quercetin and pioglitazone on angiotensin II-induced contraction of the aorta from fructose-streptozotocin (F-STZ)-induced type 2 diabetic rats and the possible role of superoxide anions (O2(-)) and nitric oxide (NO) in their potential therapeutic interaction. Contractile responses to Ang II of aortic rings from Sprague-Dawley (SD) and F-STZ rats were tested following pre-incubation of the tissues in the vehicle (DMSO; 0.05%), quercetin (Q, 0.1 μM), pioglitazone (P, 0.1 μM) or their combination (P + Q; 0.1 μM each). The amount of superoxide anion was evaluated by lucigenin-enhanced chemiluminescence and dihydroethidium fluorescence, and NO by assay of total nitrate/nitrite, and 4-Amino-5-Methylamino-2',7'-Difluorofluorescein (DAF-FM) diacetate. The synergistic reduction of Ang II-induced contraction of diabetic but not normal aorta with minimally effective concentrations of P + Q occurs through inhibiting O2(-) and increasing NO bioavailability. This finding opens the possibility of maximal vascular protective/antidiabetic effects with low dose pioglitazone combined with quercetin, thus minimizing the risk of adverse effects.
Obstructive sleep apnea is a chronic, sleep-related breathing disorder, which is an independent risk factor for cardiovascular disease. The renin-angiotensin-aldosterone system regulates salt and water homeostasis, blood pressure, and cardiovascular remodelling. Elevated aldosterone levels are associated with excess morbidity and mortality. We aimed to analyse the influence and implications of renin-angiotensin-aldosterone system derangement in individuals with and without obstructive sleep apnea. We pooled data from 20 relevant studies involving 2828 participants (1554 with obstructive sleep apnea, 1274 without obstructive sleep apnea). The study outcomes were the levels of renin-angiotensin-aldosterone system hormones, blood pressure and heart rate. Patients with obstructive sleep apnea had higher levels of plasma renin activity (pooled wmd+ 0.25 [95% confidence interval 0.04-0.46], p = 0.0219), plasma aldosterone (pooled wmd+ 30.79 [95% confidence interval 1.05-60.53], p = 0.0424), angiotensin II (pooled wmd+ 5.19 [95% confidence interval 3.11-7.27], p angiotensin II were significantly higher only among the Asian population with obstructive sleep apnea compared with those without obstructive sleep apnea. Body mass index accounted for less than 10% of the between-study variance in elevation of the renin-angiotensin-aldosterone system parameters. Patients with obstructive sleep apnea have higher levels of renin-angiotensin-aldosterone system hormones, blood pressure and heart rate compared with those without obstructive sleep apnea, which remains significant even among patients without resistant hypertension.