-
Molecular Pharmacology Dec 2010β-Adrenergic and angiotensin II type 1A receptors are therapeutic targets for the treatment of a number of common human diseases. Pharmacological agents designed as... (Review)
Review
β-Adrenergic and angiotensin II type 1A receptors are therapeutic targets for the treatment of a number of common human diseases. Pharmacological agents designed as antagonists for these receptors have positively affected the morbidity and mortality of patients with hypertension, heart failure, and renal disease. Antagonism of these receptors, however, may only partially explain the therapeutic benefits of β-blockers and angiotensin receptor blockers given the emerging concept of functional selectivity or biased agonism. This new pharmacological paradigm suggests that multiple signaling pathways can be differentially modified by a single ligand-receptor interaction. This review examines the functional selectivity of β-adrenergic and angiotensin II type 1A receptors with respect to their ability to signal via both G protein-dependent and G protein-independent mechanisms, with a focus on the multifunctional protein β-arrestin. Also highlighted are the concept of "biased signaling" through β-arrestin mediated pathways, the affect of ligand/receptor modification on such biased agonism, and the implications of functional selectivity for the development of the next generation of β-blockers and angiotensin receptor blockers.
Topics: Adrenergic Agents; Angiotensins; Animals; Arrestins; GTP-Binding Proteins; Humans; Receptors, Adrenergic; Receptors, Angiotensin; Receptors, G-Protein-Coupled; Signal Transduction; beta-Arrestins
PubMed: 20855464
DOI: 10.1124/mol.110.067066 -
Biology of Sex Differences Jul 2019Obesity is a global epidemic that greatly increases risk for developing cardiovascular disease and type II diabetes. Sex differences in the obese phenotype are well... (Review)
Review
Obesity is a global epidemic that greatly increases risk for developing cardiovascular disease and type II diabetes. Sex differences in the obese phenotype are well established in experimental animal models and clinical populations. While having higher adiposity and obesity prevalence, females are generally protected from obesity-related metabolic and cardiovascular complications. This protection is, at least in part, attributed to sex differences in metabolic effects of hormonal mediators such as the renin-angiotensin system (RAS). Previous literature has predominantly focused on the vasoconstrictor arm of the RAS and shown that, in contrast to male rodent models of obesity and diabetes, females are protected from metabolic and cardiovascular derangements produced by angiotensinogen, renin, and angiotensin II. A vasodilator arm of the RAS has more recently emerged which includes angiotensin-(1-7), angiotensin-converting enzyme 2 (ACE2), mas receptors, and alamandine. While accumulating evidence suggests that activation of components of this counter-regulatory axis produces positive effects on glucose homeostasis, lipid metabolism, and energy balance in male animal models, female comparison studies and clinical data related to metabolic outcomes are lacking. This review will summarize current knowledge of sex differences in metabolic effects of the RAS, focusing on interactions with gonadal hormones and potential clinical implications.
Topics: Angiotensins; Animals; Female; Gonadal Steroid Hormones; Humans; Male; Receptors, Angiotensin; Renin; Renin-Angiotensin System; Sex Characteristics
PubMed: 31262355
DOI: 10.1186/s13293-019-0247-5 -
Comprehensive Physiology Oct 2012The renin-angiotensin system (RAS) constitutes one of the most important hormonal systems in the physiological regulation of blood pressure through renal and nonrenal... (Review)
Review
The renin-angiotensin system (RAS) constitutes one of the most important hormonal systems in the physiological regulation of blood pressure through renal and nonrenal mechanisms. Indeed, dysregulation of the RAS is considered a major factor in the development of cardiovascular pathologies, including kidney injury, and blockade of this system by the inhibition of angiotensin converting enzyme (ACE) or blockade of the angiotensin type 1 receptor (AT1R) by selective antagonists constitutes an effective therapeutic regimen. It is now apparent with the identification of multiple components of the RAS within the kidney and other tissues that the system is actually composed of different angiotensin peptides with diverse biological actions mediated by distinct receptor subtypes. The classic RAS can be defined as the ACE-Ang II-AT1R axis that promotes vasoconstriction, water intake, sodium retention, and other mechanisms to maintain blood pressure, as well as increase oxidative stress, fibrosis, cellular growth, and inflammation in pathological conditions. In contrast, the nonclassical RAS composed primarily of the AngII/Ang III-AT2R pathway and the ACE2-Ang-(1-7)-AT7R axis generally opposes the actions of a stimulated Ang II-AT1R axis through an increase in nitric oxide and prostaglandins and mediates vasodilation, natriuresis, diuresis, and reduced oxidative stress. Moreover, increasing evidence suggests that these non-classical RAS components contribute to the therapeutic blockade of the classical system to reduce blood pressure and attenuate various indices of renal injury, as well as contribute to normal renal function.
Topics: Aminopeptidases; Angiotensins; Blood Pressure; Endopeptidases; Humans; Kidney; Peptidyl-Dipeptidase A; Renin; Renin-Angiotensin System; Signal Transduction
PubMed: 23720263
DOI: 10.1002/cphy.c120002 -
Peptides Dec 2012The renin-angiotensin system (RAS) is now regarded as an integral component in not only the development of hypertension, but also in physiologic and pathophysiologic... (Review)
Review
The renin-angiotensin system (RAS) is now regarded as an integral component in not only the development of hypertension, but also in physiologic and pathophysiologic mechanisms in multiple tissues and chronic disease states. While many of the endocrine (circulating), paracrine (cell-to-different cell) and autacrine (cell-to-same cell) effects of the RAS are believed to be mediated through the canonical extracellular RAS, a complete, independent and differentially regulated intracellular RAS (iRAS) has also been proposed. Angiotensinogen, the enzymes renin and angiotensin-converting enzyme (ACE) and the angiotensin peptides can all be synthesized and retained intracellularly. Angiotensin receptors (types I and 2) are also abundant intracellularly mainly at the nuclear and mitochondrial levels. The aim of this review is to focus on the most recent information concerning the subcellular localization, distribution and functions of the iRAS and to discuss the potential consequences of activation of the subcellular RAS on different organ systems.
Topics: Angiotensins; Animals; Humans; Renin; Renin-Angiotensin System
PubMed: 23032352
DOI: 10.1016/j.peptides.2012.09.016 -
Current Hypertension Reviews 2015Salt sensitive hypertension is characterized by increases in blood pressure in response to increases in dietary salt intake and is associated with an enhanced risk of... (Review)
Review
Salt sensitive hypertension is characterized by increases in blood pressure in response to increases in dietary salt intake and is associated with an enhanced risk of cardiovascular and renal morbidity. Although researchers have sought for decades to understand how salt sensitivity develops in humans, the mechanisms responsible for the increases in blood pressure in response to high salt intake are complex and only partially understood. Until now, scientists have been unable to explain why some individuals are salt sensitive and others are salt resistant. Although a central role for the kidneys in the development of salt sensitivity and hypertension has been generally accepted, it is also recognized that hypertension is of multifactorial origin and a variety of factors can induce, or prevent, blood pressure responsiveness to the manipulation of salt intake. Excess salt intake in susceptible persons may also induce inappropriate central and sympathetic nervous system responses and increase the production of intrarenal angiotensin II, catecholamines and other factors such as oxidative stress and inflammatory cytokines. One key factor is the concomitant inappropriate or paradoxical activation of the intrarenal renin-angiotensin system, by high salt intake. This is reflected by the increases in urinary angiotensinogen during high salt intake in salt sensitive models. A complex interaction between neuroendocrine factors and the kidney may underlie the propensity for some individuals to retain salt and develop salt-dependent hypertension. In this review, we focus mainly on the renal contributions that provide the mechanistic links between chronic salt intake and the development of hypertension.
Topics: Angiotensin II; Angiotensins; Animals; Blood Pressure; Humans; Hypertension; Kidney; Kidney Tubules, Proximal; Models, Biological; Oxidative Stress; Renin-Angiotensin System; Sodium, Dietary
PubMed: 26028244
DOI: 10.2174/1573402111666150530203858 -
Journal of Molecular and Cellular... Jan 2020Chronically elevated angiotensin II is a widely-established contributor to hypertension and heart failure via its action on the kidneys and vasculature. It also augments...
Chronically elevated angiotensin II is a widely-established contributor to hypertension and heart failure via its action on the kidneys and vasculature. It also augments the activity of peripheral sympathetic nerves through activation of presynaptic angiotensin II receptors, thus contributing to sympathetic over-activity. Although some cells can synthesise angiotensin II locally, it is not known if this machinery is present in neurons closely coupled to the heart. Using a combination of RNA sequencing and quantitative real-time polymerase chain reaction, we demonstrate evidence for a renin-angiotensin synthesis pathway within human and rat sympathetic stellate ganglia, where significant alterations were observed in the spontaneously hypertensive rat stellate ganglia compared with Wistar stellates. We also used Förster Resonance Energy Transfer to demonstrate that administration of angiotensin II and angiotensin 1-7 peptides significantly elevate cyclic guanosine monophosphate in the rat stellate ganglia. Whether the release of angiotensin peptides from the sympathetic stellate ganglia alters neurotransmission and/or exacerbates cardiac dysfunction in states associated with sympathetic over activity remains to be established.
Topics: Adult; Aged; Angiotensins; Animals; Cyclic GMP; Female; Gene Expression Regulation; Humans; Male; Middle Aged; Models, Biological; Nucleotides, Cyclic; Principal Component Analysis; RNA, Messenger; Rats, Inbred SHR; Rats, Wistar; Renin; Stellate Ganglion; Sympathetic Nervous System; Transcriptome; Young Adult
PubMed: 31836539
DOI: 10.1016/j.yjmcc.2019.11.157 -
Critical Care (London, England) Mar 2018This article is one of ten reviews selected from the Annual Update in Intensive Care and Emergency Medicine 2018. Other selected articles can be found online at... (Review)
Review
This article is one of ten reviews selected from the Annual Update in Intensive Care and Emergency Medicine 2018. Other selected articles can be found online at https://www.biomedcentral.com/collections/annualupdate2018 . Further information about the Annual Update in Intensive Care and Emergency Medicine is available from http://www.springer.com/series/8901 .
Topics: Angiotensin II; Angiotensins; Critical Care; Humans; Hypotension; Shock, Septic; Vasoconstrictor Agents
PubMed: 29558991
DOI: 10.1186/s13054-018-1995-z -
Journal of Molecular Medicine (Berlin,... Jun 2008For many years, prorenin has been considered to be nothing more than the inactive precursor of renin. Yet, its elevated levels in diabetic subjects with microvascular... (Review)
Review
For many years, prorenin has been considered to be nothing more than the inactive precursor of renin. Yet, its elevated levels in diabetic subjects with microvascular complications and its extrarenal production at various sites in the body suggest otherwise. This review discusses the origin, regulation, and enzymatic activity of prorenin, its role during renin inhibition, and the angiotensin-dependent and angiotensin-independent consequences of its binding to the recently discovered (pro)renin receptor. The review ends with the concept that prorenin rather than renin determines tissue angiotensin generation.
Topics: Angiotensins; Animals; Humans; Receptors, Cell Surface; Renin; Prorenin Receptor
PubMed: 18322669
DOI: 10.1007/s00109-008-0318-2 -
Hypertension Research : Official... May 2003Angiotensin II and sodium balance affect the status of each other and both--either separately or together--can lead to an increase in blood pressure. They also can cause... (Review)
Review
Angiotensin II and sodium balance affect the status of each other and both--either separately or together--can lead to an increase in blood pressure. They also can cause vascular and cardiac damage due to direct effects and effects mediated by the blood pressure increase. This paper reviews the important interactions among these three variables. Acute blood pressure elevation during sleeping but not during waking hours causes cardiac hypertrophy in rats. Similarly, lowering of blood pressure with an angiotension converting enzyme (ACE) inhibitor during sleep but not when awake causes regression of cardiac hypertrophy in rats with 2kidney (K)-1clip (C) Goldblatt hypertension. If angiotensin is given to rats on a low (0.4%) NaCl diet, blood pressure rises but there is less cardiac hypertrophy. Cardiac hypertrophy is greatest after angiotensin administration in rats on a high (4%) NaCl diet. In both the 2K-1C and 1K-1C Goldblatt models, a high salt intake reduces the blood pressure lowering effect of captopril and losartan and prevents regression of cardiac hypertrophy. Combined administration of an ACE inhibitor and an angiotensin type 1 (AT1) receptor blocker to rats on a low (0.2%) NaCl diet produces a syndrome that leads to death with cardiac involution. All features of the syndrome are reversed or prevented by 4% NaCl intake. It is hypothesised that the interaction between angiotensin II and sodium intake can be explained by differences in the way protons produced by contracting cells are neutralized. The sodium hydrogen exchanger and the sodium 2 bicarbonate cotransporter are stimulated by the AT1 and angiotensin type 2 (AT2) receptor, respectively. If the ratio of receptors is altered in favour of the AT2 receptor, then less cardiac hypertrophy will result from the same workload. Review of the clinical literature reveals that many of these results in rats have correlations in clinical medicine. Thus high night time blood pressure is associated with a greater morbidity and high salt intake causes cardiac hypertrophy and vascular stiffness independent of blood pressure levels. When deciding on treatment in human hypertension these results have important clinical implications.
Topics: Angiotensins; Animals; Humans; Hypertension; Renin; Sodium
PubMed: 12887125
DOI: 10.1291/hypres.26.349 -
Clinical Science (London, England :... Apr 2014Lessons learned from the characterization of the biological roles of Ang-(1-7) [angiotensin-(1-7)] in opposing the vasoconstrictor, proliferative and prothrombotic... (Review)
Review
Lessons learned from the characterization of the biological roles of Ang-(1-7) [angiotensin-(1-7)] in opposing the vasoconstrictor, proliferative and prothrombotic actions of AngII (angiotensin II) created an underpinning for a more comprehensive exploration of the multiple pathways by which the RAS (renin-angiotensin system) of blood and tissues regulates homoeostasis and its altered state in disease processes. The present review summarizes the progress that has been made in the novel exploration of intermediate shorter forms of angiotensinogen through the characterization of the expression and functions of the dodecapeptide Ang-(1-12) [angiotensin-(1-12)] in the cardiac production of AngII. The studies reveal significant differences in humans compared with rodents regarding the enzymatic pathway by which Ang-(1-12) undergoes metabolism. Highlights of the research include the demonstration of chymase-directed formation of AngII from Ang-(1-12) in human left atrial myocytes and left ventricular tissue, the presence of robust expression of Ang-(1-12) and chymase in the atrial appendage of subjects with resistant atrial fibrillation, and the preliminary observation of significantly higher Ang-(1-12) expression in human left atrial appendages.
Topics: Amino Acid Sequence; Angiotensin II; Angiotensinogen; Animals; Humans; Molecular Sequence Data; Rodentia
PubMed: 24329563
DOI: 10.1042/CS20130400