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Congestive Heart Failure (Greenwich,... 2003Evidence from large, randomized, controlled clinical trials supports the use of angiotensin-converting enzyme (ACE) inhibitors, beta blockers, and spironolactone to... (Review)
Review
Evidence from large, randomized, controlled clinical trials supports the use of angiotensin-converting enzyme (ACE) inhibitors, beta blockers, and spironolactone to reduce mortality and morbidity. Despite these effective therapies, event rates related to heart failure remain high. Although ACE inhibitors reduce angiotensin II production, they do not fully suppress the increased angiotensin II production in heart failure. Angiotensin II receptor blockers (ARBs) directly block the effect of angiotensin II, derived from any source, at the receptor level and have the potential to be as effective or even more effective than ACE inhibitors. The results of a number of clinical studies have demonstrated ARBs are effective and well tolerated. However, no studies have demonstrated a convincing decrease in mortality with ARB use, although a decrease has been observed for heart failure hospitalization. The results from further studies are awaited to clarify the role of ARBs in the treatment of heart failure.
Topics: Adrenergic beta-Antagonists; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Clinical Trials as Topic; Drug Evaluation; Evidence-Based Medicine; Heart Failure; Humans; Receptors, Angiotensin; Treatment Outcome
PubMed: 12556675
DOI: 10.1111/j.1751-7133.2003.tb00019.x -
Kidney International Jun 1996Several new non-peptide, orally active, angiotensin II receptor antagonists have recently been developed which enable to block the renin-angiotensin system at the AT1... (Review)
Review
Several new non-peptide, orally active, angiotensin II receptor antagonists have recently been developed which enable to block the renin-angiotensin system at the AT1 receptor site. In contrast to angiotensin converting enzyme (ACE) inhibitors, these antagonists do not interfere with the metabolism of kinins. The effect of these agents on renal function may thus potentially differ from those of ACE inhibitors. Therefore, the renal pharmacology of various angiotensin II receptor antagonists has been examined in normotensive subjects. In normotensive subjects, losartan and irbesartan have been shown to have no effect on glomerular filtration rate and to induce either no change or a modest increase in renal blood flow. These results were confirmed thereafter in hypertensive patients where losartan produced a renal vasodilation with no change in glomerular filtration. In healthy subjects, both losartan and irbesartan induce an acute increase in urinary sodium excretion. The natriuretic response to losartan is proportionally more important during salt-depletion. In contrast to other angiotensin II receptor antagonists, losartan has a unique property to increase uric acid excretion. In this paper we show that this property is due to the potent inhibitory effect of the parent compound of losartan on the urate/anion transport in the human renal proximal tubule.
Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Enzyme Inhibitors; Humans; Kidney; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin
PubMed: 8743498
DOI: 10.1038/ki.1996.268 -
Congestive Heart Failure (Greenwich,... 2002Heart failure treatment centers on antagonism of the renin-angiotensin-aldosterone system and adrenergic nervous system. Angiotensin-converting enzyme (ACE) inhibitors... (Review)
Review
Heart failure treatment centers on antagonism of the renin-angiotensin-aldosterone system and adrenergic nervous system. Angiotensin-converting enzyme (ACE) inhibitors have been shown to benefit patients with left ventricular systolic dysfunction irrespective of symptoms. Despite ACE inhibitor use, left ventricular dysfunction continues to progress in most patients. In addition, ACE inhibitors are substantially underused in patients who would benefit, in large part due to physician concern over potential adverse effects. Angiotensin receptor blockers (ARBs) have been proposed as either potential substitutes for ACE inhibitors or as additive therapy for heart failure patients. The authors will review the importance of the renin-angiotensin-aldosterone system in the progression of heart failure, as well as the mechanisms by which ACE inhibitors and ARBs counteract this effect. The clinical evidence to date supporting the use of ARBs in heart failure also will be reviewed. Based on current trials, ARBs are suitable substitutes for ACE inhibitors in patients who have true ACE inhibitor intolerance, but ACE inhibitors should still be considered first-line therapy in the treatment of left ventricular systolic dysfunction and heart failure. ARBs are a reasonable additive therapy in patients on maximal ACE inhibitor therapy who remain symptomatic, especially in patients unable to tolerate beta blockade.
Topics: Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Drug Therapy, Combination; Heart Failure; Humans; Receptor, Angiotensin, Type 1; Receptors, Angiotensin; Renin-Angiotensin System; Ventricular Dysfunction, Left
PubMed: 12368586
DOI: 10.1111/j.1527-5299.2000.01156.x -
Traffic (Copenhagen, Denmark) Feb 2019Anterograde cell surface transport of nascent G protein-coupled receptors (GPCRs) en route from the endoplasmic reticulum (ER) through the Golgi apparatus represents a... (Review)
Review
Anterograde cell surface transport of nascent G protein-coupled receptors (GPCRs) en route from the endoplasmic reticulum (ER) through the Golgi apparatus represents a crucial checkpoint to control the amount of the receptors at the functional destination and the strength of receptor activation-elicited cellular responses. However, as compared with extensively studied internalization and recycling processes, the molecular mechanisms of cell surface trafficking of GPCRs are relatively less defined. Here, we will review the current advances in understanding the ER-Golgi-cell surface transport of GPCRs and use angiotensin II type 1 receptor as a representative GPCR to discuss emerging roles of receptor-interacting proteins and specific motifs embedded within the receptors in controlling the forward traffic of GPCRs along the biosynthetic pathway.
Topics: Animals; Humans; Protein Sorting Signals; Protein Transport; Receptor, Angiotensin, Type 1
PubMed: 30426616
DOI: 10.1111/tra.12624 -
Hypertension (Dallas, Tex. : 1979) Dec 2016
Topics: Angiotensin I; Angiotensin II; Humans; Peptide Fragments; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin
PubMed: 27698064
DOI: 10.1161/HYPERTENSIONAHA.116.08215 -
American Journal of Physiology.... Mar 2015The involvement of the nonclassical renin-angiotensin system (RAS) in the adrenomedullary response to stress is unclear. Therefore, we examined basal and immobilization...
The involvement of the nonclassical renin-angiotensin system (RAS) in the adrenomedullary response to stress is unclear. Therefore, we examined basal and immobilization stress (IMO)-triggered changes in gene expression of the classical and nonclassical RAS receptors in the rat adrenal medulla, specifically the angiotensin II type 2 (AT2) and type 4 (AT4) receptors, (pro)renin receptor [(P)RR], and Mas receptor (MasR). All RAS receptors were identified, with AT2 receptor mRNA levels being the most abundant, followed by the (P)RR, AT1A receptor, AT4 receptor, and MasR. Following a single IMO, AT2 and AT4 receptor mRNA levels decreased by 90 and 50%, respectively. Their mRNA levels were also transiently decreased by repeated IMO. MasR mRNA levels displayed a 75% transient decrease as well. Conversely, (P)RR mRNA levels were increased by 50% following single or repeated IMO. Because of its abundance, the function of the (P)RR was explored in PC-12 cells. Prorenin activation of the (P)RR increased phosphorylation of extracellular signal-regulated kinase 1/2 and tyrosine hydroxylase at Ser(31), likely increasing its enzymatic activity and catecholamine biosynthesis. Together, the broad and dynamic changes in gene expression of the nonclassical RAS receptors implicate their role in the intricate response of the adrenomedullary catecholaminergic system to stress.
Topics: Adrenal Medulla; Animals; Catecholamines; Disease Models, Animal; Gene Expression Regulation; Immobilization; Male; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; PC12 Cells; Phosphorylation; Proto-Oncogene Mas; Proto-Oncogene Proteins; Proton-Translocating ATPases; RNA, Messenger; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; Receptors, Cell Surface; Receptors, G-Protein-Coupled; Renin-Angiotensin System; Serine; Stress, Psychological; Time Factors; Tyrosine 3-Monooxygenase; Vacuolar Proton-Translocating ATPases
PubMed: 25589013
DOI: 10.1152/ajpregu.00130.2014 -
The Journal of Biological Chemistry Oct 2001An analysis of the functional role of a diacidic motif (Asp236-Asp237) in the third intracellular loop of the AT1A angiotensin II (Ang II) receptor (AT1-R) revealed that...
An analysis of the functional role of a diacidic motif (Asp236-Asp237) in the third intracellular loop of the AT1A angiotensin II (Ang II) receptor (AT1-R) revealed that substitution of both amino acids with alanine (DD-AA) or asparagine (DD-NN) residues diminished Ang II-induced receptor phosphorylation in COS-7 cells. However, Ang II-stimulated inositol phosphate production, mitogen-activated protein kinase, and AT1 receptor desensitization and internalization were not significantly impaired. Overexpression of dominant negative G protein-coupled receptor kinase 2 (GRK2)K220M decreased agonist-induced receptor phosphorylation by approximately 40%, but did not further reduce the impaired phosphorylation of DD-AA and DD-NN receptors. Inhibition of protein kinase C by bisindolylmaleimide reduced the phosphorylation of both the wild-type and the DD mutant receptors by approximately 30%. The inhibitory effects of GRK2K220M expression and protein kinase C inhibition by bisindolylmaleimide on agonist-induced phosphorylation were additive for the wild-type AT1-R, but not for the DD mutant receptor. Agonist-induced internalization of the wild-type and DD mutant receptors was similar and was unaltered by coexpression of GRK2K220M. These findings demonstrate that an acidic motif at position 236/237 in the third intracellular loop of the AT1-R is required for optimal Ang II-induced phosphorylation of its carboxyl-terminal tail by GRKs. Furthermore, the properties of the DD mutant receptor suggest that not only Ang II-induced signaling, but also receptor desensitization and internalization, are independent of agonist-induced GRK-mediated phosphorylation of the AT1 receptor.
Topics: Amino Acid Motifs; Amino Acid Sequence; Angiotensin I; Animals; COS Cells; Cell Line; Endocytosis; Humans; Indoles; Inositol Phosphates; Maleimides; Mutagenesis, Site-Directed; Phosphorylation; Rats; Receptors, Angiotensin; Signal Transduction
PubMed: 11495923
DOI: 10.1074/jbc.M106368200 -
Regulatory Peptides Oct 2007The brain renin-angiotensin system continues to be enigmatic more than 40 years after the brain was first recognized to be a site of action of angiotensin II. This... (Review)
Review
The brain renin-angiotensin system continues to be enigmatic more than 40 years after the brain was first recognized to be a site of action of angiotensin II. This review focuses on the enzymatic pathways for the formation and degradation of the growing number of active angiotensins in the brain. A brief description and nomenclature of the peptidases involved in the processing of angiotensin peptides in the brain is given. Of primary interest is the array of enzymes that degrade radiolabeled angiotensins in receptor binding assays. This poses major challenges to studies of brain angiotensin receptors and it is debatable whether an accurate determination of brain angiotensin receptor binding kinetics has yet been made. The quandary facing the investigator of brain angiotensin receptors is the need to protect the radioligand from metabolic alteration while maintaining the characteristics of the receptors in situ. It is the tenet of this review that we have yet to fully understand the binding characteristics of brain angiotensin receptors and the extent of their distribution in the brain because of our inability to fully protect the angiotensins from metabolic alteration until equilibrium binding conditions can be attained.
Topics: Angiotensins; Animals; Brain; Endopeptidases; Humans; Models, Biological; Peptide Hydrolases; Receptors, Angiotensin; Renin; Signal Transduction
PubMed: 17493693
DOI: 10.1016/j.regpep.2007.03.006 -
Endocrine Journal Feb 2006Insulin-resistant states are often associated with hypertension, and the accumulated data indicate that ARB decrease new-onset of diabetes with vasoprotective effects.... (Review)
Review
Insulin-resistant states are often associated with hypertension, and the accumulated data indicate that ARB decrease new-onset of diabetes with vasoprotective effects. Recent evidence suggests that activation of Ang II receptor subtypes could regulate insulin sensitivity at multiple sites of insulin signaling in various diabetic animal models and regulate vascular remodeling in concert with insulin in potentially distinct fashions. Moreover, the roles of Ang II receptor subtypes have been highlighted in insulin resistance in obesity, which is one of the major risk factors for the development of hypertension. More detailed analysis of the crosstalk of Ang II and insulin-mediated signaling in various tissues would provide further information to understand the clinical relevance of the effect of ARB on insulin resistance, thereby preventing cardiovascular events associated with insulin resistance.
Topics: Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Animals; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucose; Humans; Hypertension; Insulin; Insulin Resistance; Mice; Models, Animal; Rats; Receptor Cross-Talk; Receptors, Angiotensin; Risk Factors; Signal Transduction
PubMed: 16543666
DOI: 10.1507/endocrj.53.1 -
Hypertension Research : Official... Jul 1999Angiotensin (Ang) II plays an important role in regulating cardiovascular hemodynamics as well as cardiovascular structure. At least two distinct receptor subtypes of... (Review)
Review
Angiotensin (Ang) II plays an important role in regulating cardiovascular hemodynamics as well as cardiovascular structure. At least two distinct receptor subtypes of Ang II have been defined on the basis of their differential pharmacological and biochemical properties, and designated as Ang II type 1 (AT1) receptor and type 2 (AT2) receptor. Most of the known effects of Ang II in adult tissues are attributable to the AT1 receptor. Recent cloning of the AT2 receptor has revealed a variety of new physiological effects of Ang II. AT1 and AT2 receptors belong to the seven-transmembrane receptor family. However, the function and signaling mechanism of these receptor subtypes are quite different. These receptors seem to exert opposite effects in terms of cardiovascular hemodynamics and cell growth. Growth inhibitory effects of AT2 receptors are unique in that this receptor activates a variety of phosphatases and cross talks with the signaling of other seven-transmembrane, G protein-coupled receptors, as well as other classes of growth factor receptors. We will review recent concepts of the molecular and cellular mechanisms of AT2 receptor action in this article.
Topics: Angiotensin II; Animals; Cell Communication; Cell Division; Humans; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; Signal Transduction
PubMed: 10487321
DOI: 10.1291/hypres.22.67