Showing papers on "Angiotensin II published in 1995"
TL;DR: The results show that the growth modulating actions of ANG II depend on the type of angiotensin receptor present on a given cell, and in coronary endothelial cells, the antiproliferative actions of the AT2-receptor offset the growth promoting effects mediated by the AT1- receptor.
Abstract: Angiotensin II (ANG II) is known to be a potent growth promoting factor for vascular smooth muscle cells and fibroblasts but little is known about its influence on growth in endothelial cells. We studied the effects of ANG II on endothelial growth and the role of the angiotensin receptor subtypes involved. Proliferation of rat coronary endothelial cells (CEC) and rat vascular smooth muscle cells (VSMC) was determined by [3H]thymidine incorporation, the MTT-test and by directly counting cells in a coulter counter. Angiotensin AT1- and AT2-receptors were demonstrated by binding studies and by the presence of their respective mRNA through reverse transcription polymerase chain reaction (RT-PCR). In contrast to VSMC, which in culture only express the AT1-receptor, CEC express both, AT1- and AT2-receptors simultaneously up to the third passage. Whereas ANG II stimulated growth of quiescent VSMC, an effect abolished by pretreatment with the AT1-receptor antagonist, losartan, ANG II did not induce proliferation in quiescent CEC. However, after pretreatment of quiescent endothelial cells (< passage 4) with the AT2-receptor antagonist, PD 123177, ANG II induced proliferation. This effect was reversed by additional pretreatment with losartan. ANG II significantly inhibited the proliferation of bFGF-stimulated CEC in a dose-dependent manner by maximally 50%. This effect was prevented by PD 123177 while losartan was ineffective. The AT2-receptor agonist, CGP 42112, mimicked the antiproliferative actions of ANG II, confirming the specificity of the effect. Our results show that the growth modulating actions of ANG II depend on the type of angiotensin receptor present on a given cell. In coronary endothelial cells, the antiproliferative actions of the AT2-receptor offset the growth promoting effects mediated by the AT1-receptor.
917 citations
TL;DR: The results show that angiotensin II activates AT1 and AT2, which have mutually counteracting haemo-dynamic effects, and that AT2 regulates central nervous system functions, including behaviour.
Abstract: There are two major angiotensin II receptor isoforms, AT1 and AT2. AT1 mediates the well-known pressor and mitogenic effects of angiotensin II, but the signalling mechanism and physiological role of AT2 has not been established. Its abundant expression in fetal tissues and certain brain nuclei suggest possible roles in growth, development and neuronal functions. Here we report the unexpected finding that the targeted disruption of the mouse AT2 gene resulted in a significant increase in blood pressure and increased sensitivity to the pressor action of angiotensin II. Thus AT2 mediates a depressor effect and antagonizes the AT1-mediated pressor action of angiotensin II. In addition, disruption of the AT2 gene attenuated exploratory behaviour and lowered body temperature. Our results show that angiotensin II activates AT1 and AT2, which have mutually counteracting haemodynamic effects, and that AT2 regulates central nervous system functions, including behaviour.
863 citations
TL;DR: Elevated cardiac ACE activity in subjects who died of noncardiac disorders may result in increased cardiac angiotensin II levels, and this may be a mechanism underlying the reported association between the ACE deletion polymorphism and the increased risk for several cardiovascular disorders.
Abstract: Background An insertion (I)/deletion (D) polymorphism of the angiotensin-converting enzyme (ACE) gene has been associated with differences in the plasma levels of ACE as well as with myocardial infarction, cardiomyopathy, left ventricular hypertrophy, and coronary artery disease. Methods and Results We determined the cardiac ACE activity and the ACE genotype in 71 subjects who died of noncardiac disorders. Cardiac ACE activity was significantly higher (P<.01) in subjects with the ACE DD genotype (12.7±1.9 mU/g wet wt) compared with subjects with the ID (8.7±0.8 mU/g) and the II (9.1±1.0 mU/g) genotypes. This difference was independent of sex, age, and the time required for tissue collection. Conclusions Cardiac ACE activity is highest in subjects with the DD genotype. Elevated cardiac ACE activity in these subjects may result in increased cardiac angiotensin II levels, and this may be a mechanism underlying the reported association between the ACE deletion polymorphism and the increased risk for several c...
792 citations
TL;DR: Although the AT2 receptor is not required for embryonic development, it plays a role in the central nervous system and cardiovascular functions that are mediated by the renin-angiotensin system.
Abstract: ANGIOTENSIN II, a potent regulator of blood pressure and of water and electrolyte balance, binds to two different G-protein-coupled receptors. The type-1 receptor (AT1,) mediates the vasopressive and aldosterone-secreting effects of angiotensin II, but the function of the type-2 receptor (AT2; refs 1, 2) is unknown, although it is expressed in both adult3 and embryonic4 life. To address this question, we have generated mice lacking the gene encoding the AT2 receptor. Mutant mice develop normally, but have an impaired drinking response to water deprivation as well as a reduction in spontaneous movements. Their baseline blood pressure is normal, but they show an increased vasopressor response to injection of angiotensin II. Thus, although the AT2 receptor is not required for embryonic development, it plays a role in the central nervous system and cardiovascular functions that are mediated by the renin-angiotensin system.
753 citations
TL;DR: It is shown here that angiotensin II induces the rapid phosphorylation of tyrosine in the intracellular kinases Jak2 and Tyk2 in rat aortic smooth-muscle cells and that thisosphorylation is associated with increased activity of Jak2.
Abstract: The peptide angiotensin II is the effector molecule of the reninangiotensin system. All the haemodynamic effects of angiotensin II, including vasoconstriction and adrenal aldosterone release, are mediated through a single class of cell-surface receptors known as AT1 (refs 1, 2). These receptors contain the structural features of the G-protein-coupled receptor superfamily. We show here that angiotensin II induces the rapid phosphorylation of tyrosine in the intracellular kinases Jak2 and Tyk2 in rat aortic smooth-muscle cells and that this phosphorylation is associated with increased activity of Jak2. The Jak family substrates STAT1 and STAT2 (for signal transducers and activators of transcription) are rapidly tyrosine-phosphorylated in response to angiotensin II. We also find that Jak2 co-precipitates with the AT1 receptor, indicating that G-protein-coupled receptors may be able to signal through the intracellular phosphorylation pathways used by cytokine receptors.
747 citations
TL;DR: The role of the Ace gene is investigated using mice generated to carry an insertional mutation that is designed to inactivate both forms of ACE and the fertility of homozygous male mutants was greatly reduced.
Abstract: Angiotensin-converting enzyme (ACE) is a dipeptidyl carboxy-peptidase that generates the vasoconstricting peptide angiotensin II and inactivates the vasodilating peptide bradykinin. The gene encoding ACE is composed of two homologous regions and codes for both a somatic and testis isoenzyme. Experiments with hypertensive rats and some, but not other, studies of humans suggest that sequences at or linked to the gene influence blood pressure. The testis-specific form of ACE has its own promoter within intron 12 (ref. 14), is encoded by the 3' region of the gene, and is found only in postmeiotic spermatogenic cells and sperm. Its function is unknown. Here we investigate the role of the Ace gene in blood pressure control and reproduction using mice generated to carry an insertional mutation that is designed to inactivate both forms of ACE. All homozygous female mutants were found to be fertile, but the fertility of homozygous male mutants was greatly reduced. Heterozygous males but not females had blood pressures that were 15-20 mm Hg less than normal, although both male and female heterozygotes had reduced serum ACE activity.
649 citations
TL;DR: It is demonstrated that type 1A angiotensin II receptor function is required for vascular and hemodynamic responses to angiotENSin II and that altered expression of the Agtr1A gene has marked effects on blood pressures.
Abstract: The renin-angiotensin system plays a critical role in sodium and fluid homeostasis. Genetic or acquired alterations in the expression of components of this system are strongly implicated in the pathogenesis of hypertension. To specifically examine the physiological and genetic functions of the type 1A receptor for angiotensin II, we have disrupted the mouse gene encoding this receptor in embryonic stem cells by gene targeting. Agtr1A(-/-) mice were born in expected numbers, and the histomorphology of their kidneys, heart, and vasculature was normal. AT1 receptor-specific angiotensin II binding was not detected in the kidneys of homozygous Agtr1A(-/-) mutant animals, and Agtr1A(+/-) heterozygotes exhibited a reduction in renal AT1 receptor-specific binding to approximately 50% of wild-type [Agtr1A(+/+)] levels. Pressor responses to infused angiotensin II were virtually absent in Agtr1A(-/-) mice and were qualitatively altered in Agtr1A(+/-) heterozygotes. Compared with wild-type controls, systolic blood pressure measured by tail cuff sphygmomanometer was reduced by 12 mmHg (1 mmHg = 133 Pa) in Agtr1A(+/-) mice and by 24 mmHg in Agtr1A(-/-) mice. Similar differences in blood pressure between the groups were seen when intraarterial pressures were measured by carotid cannulation. These studies demonstrate that type 1A angiotensin II receptor function is required for vascular and hemodynamic responses to angiotensin II and that altered expression of the Agtr1A gene has marked effects on blood pressures.
609 citations
TL;DR: Data indicate that Ang II regulates the expression of PAI-1 in cultured endothelial cells and that this response is mediated via a pharmacologically distinct form of the angiotensin receptor.
Abstract: Plasminogen activator-inhibitor C-1 (PAI-1) plays a critical role in the regulation of fibrinolysis, serving as the primary inhibitor of tissue-type plasminogen activator. Elevated levels of PAI-1 are a risk factor for recurrent myocardial infarction, and locally increased PAI-1 expression has been described in atherosclerotic human arteries. Recent studies have shown that the administration of angiotensin converting enzyme inhibitors reduces the risk of recurrent myocardial infarction in selected patients. Since angiotensin II (Ang II) has been reported to induce PAI-1 production in cultured astrocytes, we have hypothesized that one mechanism that may contribute to the beneficial effect of angiotensin converting enzyme inhibitors is an effect on fibrinolytic balance. In the present study, we examined the interaction of Ang II with cultured bovine aortic endothelial cells (BAECs) and the effects of this peptide on the production of PAI-1. 125I-Ang II was found to bind to BAECs in a saturable and specific manner, with an apparent Kd of 1.4 nM and Bmax of 74 fmol per mg of protein. Exposure of BAECs to Ang II induced dose-dependent increases in PAI-1 antigen in the media and in PAI-1 mRNA levels. Induction of PAI-1 mRNA expression by Ang II was not inhibited by pretreating BAECs with either Dup 753 or [Sar1, Ile8]-Ang II, agents that are known to compete effectively for binding to the two major angiotensin receptor subtypes. These data indicate that Ang II regulates the expression of PAI-1 in cultured endothelial cells and that this response is mediated via a pharmacologically distinct form of the angiotensin receptor.
529 citations
TL;DR: It is demonstrated that myocardial infarction causes an increase in the gene transcription and protein expression of cardiac AT1a-R and AT2-R, whereas the AT1b-R gene is unaffected, and that therapy with an AT1-R antagonist, but not with an At2- R antagonist, is effective in reducing the increased expression of AngII receptor subtypes induced by myocardia infarct.
Abstract: Increasing evidence suggests that angiotensin II (AngII) acts as a modulator for ventricular remodeling after myocardial infarction. Using competitive reverse-transcriptase polymerase chain reaction, nuclear runoff, and binding assays, we examined the regulation of AngII type 1a and 1b (AT1a-R and AT1b-R) and type 2 receptor (AT2-R) expression in the infarcted rat heart as well as the effects of AngII receptor antagonists. AT1a-R mRNA levels were increased in the infarcted (4.2-fold) and noninfarcted portions (2.2-fold) of the myocardium 7 d after myocardial infarction as compared with those in sham-operated controls, whereas AT1b-R mRNA levels were unchanged. The amount of detectable AT2-R mRNA increased in infarcted (3.1-fold) and noninfarcted (1.9-fold) portions relative to that in the control. The transcription rates for AT1a-R and AT2-R genes, determined by means of a nuclear runoff assay, were significantly increased in the infarcted heart. The AngII receptor numbers were elevated (from 12 to 35 fmol/mg protein) in the infarcted myocardium in which the increases in AT1-R and AT2-R were 3.2- and 2.3-fold, respectively, while the receptor affinity was unchanged. Therapy with AT1-R antagonist for 7 d reduced the increase in AT1-R and AT2-R expressions in the infarcted heart together with a decrease in blood pressure, whereas therapy with an AT2-R antagonist did not affect mRNA levels and blood pressure. Neither AT1-R nor AT2-R antagonists affected the infarct sizes. These results demonstrated that myocardial infarction causes an increase in the gene transcription and protein expression of cardiac AT1a-R and AT2-R, whereas the AT1b-R gene is unaffected, and that therapy with an AT1-R antagonist, but not with an AT2-R antagonist, is effective in reducing the increased expression of AngII receptor subtypes induced by myocardial infarction.
446 citations
TL;DR: It is demonstrated that an AT1a-mediated signal transduction pathway is, at least in part, involved in the regulation of blood pressure and renin gene expression.
362 citations
TL;DR: An important requirement for angiotensin in achieving and maintaining the normal morphology of the kidney is demonstrated and the mechanism through which angiotENSin maintains the volume homeostasis in mammals includes promotion of the maturational growth of the papilla.
Abstract: Elevated levels of endogenous angiotensin can cause hypertensive nephrosclerosis as a result of the potent vasopressor action of the peptide. We have produced by gene targeting mice homozygous for a null mutation in the angiotensinogen gene (Atg-1-). Postnatally, Atg-1- animals show a modest delay in glomerular maturation. Although Atg-1- animals are hypotensive by 7 wk of age, they develop, by 3 wk of age, pronounced lesions in the renal cortex, similar to those of hypertensive nephrosclerosis. In addition, the papillae of homozygous mutant kidneys are reduced in size. These lesions are accompanied by local up-regulation of PDGF-B and TGF-beta1 mRNA in the cortex and down-regulation of PDGF-A mRNA in the papilla. The study demonstrates an important requirement for angiotensin in achieving and maintaining the normal morphology of the kidney. The mechanism through which angiotensin maintains the volume homeostasis in mammals includes promotion of the maturational growth of the papilla.
TL;DR: The principal finding is that cardiac norepinephrine uptake as assessed by 123I-metaiodobenzylguanidine scintigraphy increased with spironolactone, which is a good result for patients with New York Heart Association II to III congestive heart failure.
Abstract: In chronic heart failure, a diuretic plus an angiotensin-converting enzyme (ACE) inhibitor only partially suppresses aldosterone despite the fact that aldosterone has many harmful effects independent of angiotensin II. These possible harmful effects of aldosterone are magnesium loss, increased cardiac sympathetic activity, and increased ventricular arrhythmias. We have therefore assessed whether adding the aldosterone antagonist, spironolactone, to a loop diuretic and ACE inhibitor reverses any of these potentially harmful effects of residual aldosterone. In a preliminary animal study, we found that exogenous aldosterone reduced myocardial norepinephrine uptake by 24% in anesthetized rats in vivo. In our main study, 42 patients with New York Heart Association II to III congestive heart failure were randomized to spironolactone (50 to 100 mg/day, titrated to blood pressure and plasma potassium) or placebo in a double-blind fashion. Our principal finding is that cardiac norepinephrine uptake as assessed by 123I-metaiodobenzylguanidine scintigraphy increased with spironolactone (p < 0.01). Spironolactone also elevated plasma magnesium (p < 0.05), reduced urinary magnesium excretion (p < 0.05), and caused a reduction in ventricular arrhythmias on 24-hour ambulatory electrocardiography (p < 0.05). Spironolactone increased plasma renin activity, plasma aldosterone (p < 0.01), 24-hour urinary sodium excretion (p < 0.05), and urinary sodium/potassium ratio (p < 0.01). Echocardiographic-determined measurements of left ventricular systolic and diastolic function were unaltered by spironolactone.(ABSTRACT TRUNCATED AT 250 WORDS)
TL;DR: Findings indicate that NO inhibits AII-induced migration of vascular SMCs; the antimigratory effect of NO is mediated in part via a cGMP-dependent mechanism; and (c) AII stimulates SMC migration via an AT1 receptor.
Abstract: Nitric oxide (NO) and angiotensin II (AII) can effect vascular smooth muscle cell (SMC) proliferation. However, the effects of such agents on SMC migration, an equally important phenomenon with regard to vascular pathophysiology, have received little attention. The objectives of the present study were: (a) to determine whether NO inhibits AII-induced migration of vascular SMCs; (b) to investigate the mechanism of the interaction of NO and AII on SMC migration; and (c) to evaluate the AII receptor subtype that mediates AII-induced SMC migration. Migration of rat SMCs was evaluated using a modified Boydens Chamber (transwell inserts with gelatin-coated polycarbonate membranes, 8 microns pore size). AII stimulated SMC migration in a concentration-dependent manner, and this effect was inhibited by sodium nitroprusside (SNP) and S-nitroso-N-acetylpenicillamine (SNAP). In the presence of L-arginine, but not D-arginine, IL-1 beta, an inducer of inducible NO synthase, also inhibited AII-induced SMC migration, and this effect was prevented by the NO-synthase inhibitor, N-nitro-L-arginine methyl ester. The effects of NO donors on AII-induced SMC migration were mimicked by 8-bromo-cGMP. Also, the antimigratory effects of SNAP were partially inhibited by LY83583 (an inhibitor of soluble guanylyl cyclase) and by KT5823 (an inhibitor of cGMP-dependent protein kinase). Although 8-bromo-cAMP (cAMP) also mimicked the antimigratory effects of NO donors, the antimigratory effects of SNAP were not altered by 2',5'-dideoxyadenosine (an inhibitor of adenyl cyclase) or by (R)-p-adenosine-3',5'-cyclic phosphorothioate (an inhibitor of the cAMP-dependent protein kinase). Low concentrations of the subtype AT1-receptor antagonist CGP 48933, but not the subtype AT2-receptor antagonist CGP 42112, blocked AII-induced SMC migration. These findings indicate that (a) NO inhibits AII-induced migration of vascular SMCs; (b) the antimigratory effect of NO is mediated in part via a cGMP-dependent mechanism; and (c) AII stimulates SMC migration via an AT1 receptor.
TL;DR: The results suggest that Ang II plays an important role in mechanical stress-induced cardiac hypertrophy and that there are also other (possibly nonsecretory) factors to induce hypertrophic responses.
Abstract: We have previously shown that mechanical stress induces activation of protein kinases and increases in specific gene expression and protein synthesis in cardiac myocytes, all of which are similar to those evoked by humoral factors such as growth factors and hormones. Many lines of evidence have suggested that angiotensin II (Ang II) plays a vital role in cardiac hypertrophy, and it has been reported that secretion of Ang II from cultured cardiac myocytes was induced by mechanical stretch. To examine the role of Ang II in mechanical stress-induced cardiac hypertrophy, we stretched neonatal rat cardiac myocytes in the absence or presence of the Ang II receptor antagonists saralasin (an antagonist of both type 1 and type 2 receptors), CV-11974 (a type 1 receptor-specific antagonist), and PD123319 (a type 2 receptor-specific antagonist). Stretching cardiac myocytes by 20% using deformable silicone dishes rapidly increased the activities of mitogen-activated protein (MAP) kinase kinase activators and MAP kinases. Both saralasin and CV-11974 partially inhibited the stretch-induced increases in the activities of both kinases, whereas PD123319 showed no inhibitory effects. Stretching cardiac myocytes increased amino acid incorporation, which was also inhibited by approximately 70% with the pretreatment by saralasin or CV-11974. When the culture medium conditioned by stretching cardiocytes was transferred to nonstretched cardiac myocytes, the increase in MAP kinase activity was observed, and this increase was completely suppressed by saralasin or CV-11974. These results suggest that Ang II plays an important role in mechanical stress-induced cardiac hypertrophy and that there are also other (possibly nonsecretory) factors to induce hypertrophic responses.
TL;DR: It is indicated that the renin-angiotensin system has a major role in the pathogenesis of the tubulointerstitial fibrosis of obstructive nephropathy.
TL;DR: Results indicate that the hexapeptide Ang IV is the form of angiotensin that stimulates endothelial expression of PAI-1 and appears to be mediated via the stimulation of an endothelial receptor that is specific for Ang IV.
Abstract: Recent studies from this laboratory have demonstrated that angiotensin II (Ang II) stimulates the expression of plasminogen activator inhibitor 1 (PAI-1) in cultured endothelial cells. This response does not appear to be mediated via an interaction with either the AT1 or the AT2 receptor subtype. Since a novel angiotensin receptor has been identified in a variety of tissues that specifically binds the hexapeptide Ang IV (Ang II, [3-8]), we therefore examined the effects of Ang IV on the expression of PAI-1 mRNA in bovine aortic endothelial cells. Ang IV stimulated dose- and time-dependent increases in the expression of PAI-1 mRNA. The effect of Ang IV (10 nM) was not inhibited by Dup 753 (1.0 microM), a highly specific antagonist of the AT1 receptor, or by PD123177 (1.0 microM), a highly specific antagonist of the AT2 receptor. In contrast, the AT4 receptor antagonist, WSU1291 (1.0 microM), effectively prevented PAI-1 expression. Although larger forms of angiotensin (i.e., Ang I, Ang II, and Ang III) are capable of inducing PAI-1 expression, this property is lost in the presence of converting enzyme or aminopeptidase inhibitors. These results indicate that the hexapeptide Ang IV is the form of angiotensin that stimulates endothelial expression of PAI-1. This effect appears to be mediated via the stimulation of an endothelial receptor that is specific for Ang IV.
TL;DR: The tissue distribution and the substrate specificity of peptidyl-dipeptidase A/angiotensin I-converting enzyme is discussed, which belongs to the gluzincin family of metalloproteases of which thermolysin is the prototype.
Abstract: Publisher Summary This chapter discusses the tissue distribution and the substrate specificity of peptidyl-dipeptidase A/angiotensin I-converting enzyme. Angiotensin I-Converting Enzyme (ACE) is a zinc metallopeptidase that belongs to the gluzincin family (clan MA) of metalloproteases of which thermolysin is the prototype. ACE cleaves the C-terminal dipeptide from angiotensin I to produce the potent vasopressor octapeptide angiotensin II and inactivates bradykinin by the sequential removal of two C-terminal dipeptides. In addition to these two main physiological substrates, which are involved in blood pressure regulation and water and salt metabolism, ACE cleaves C-terminal dipeptides from various oligopeptides with a free C-terminus. ACE is also able to cleave a C-terminal dipeptide-amide. The maximum expression of ACE occurs during the acrosome phase in murine species. ACE is exclusively produced in haploid germ cells and belongs to the group of proteins whose expression during definite maturation steps of spermiogenesis appears to be correlated with the unique process of germ cell differentiation. The inactivation of the ACE gene by homologous recombination leads to homozygous male mice with markedly reduced blood pressure, severe renal abnormalities and severely reduced fertility.
TL;DR: A new action of Ang II on human vascular smooth muscle is described, notably the induction of vascular permeability factor mRNA expression, suggesting a novel mechanism whereby Ang II could locally and directly influence the permeability, growth, and function of the vascular endothelium independent of changes in hemodynamics.
Abstract: Angiotensin II (Ang II) has been implicated in the pathogenesis of the vascular injury associated with hypertension and diabetes mellitus. Increased vascular permeability is an important early manifestation of endothelial dysfunction and the pathogenesis of atherosclerosis. How Ang II contributes to endothelial dysfunction and promotes an increase in vascular permeability is unknown but is classically attributed to its pressor actions. We demonstrate that human vascular smooth muscle cells express abundant mRNA for vascular permeability/endothelial growth factor. Vascular permeability factor is a 34- to 42-kD glycoprotein that markedly increases vascular endothelial permeability and is a potent endothelial mitogen. Ang II potently induced a concentration-dependent (maximal, 10(-7) mol/L) and time-dependent increase in vascular permeability factor mRNA expression by human vascular smooth muscle cells that was maximal after 3 hours and diminished by 24 hours. Ang II-induced vascular permeability factor mRNA expression by human vascular smooth muscle cells was inhibited by the specific Ang II receptor antagonist losartan (DuP 753), confirming that this is an Ang II receptor subtype 1-mediated event. These results describe a new action of Ang II on human vascular smooth muscle, notably the induction of vascular permeability factor mRNA expression. The wide spectrum and potent activity of vascular permeability factor suggest a novel mechanism whereby Ang II could locally and directly influence the permeability, growth, and function of the vascular endothelium independent of changes in hemodynamics.
TL;DR: It is demonstrated that angiotensin II converges with platelet-derived growth factor (PDGF) β-receptor signaling cascades, independent of PDGF, and a novel model for cross-talk between the G-protein-linked angiotENSin II receptor and the PDGF receptor tyrosine kinase in vascular smooth muscle cells is supported.
TL;DR: Restoration or replacement of endothelium-derived factors such as nitric oxide and prostacyclin, which impede the progression of vascular disease, or preventing the action of mediators such as vasoconstrictor eicosanoids, angiotensin II, or endothelin, which accelerate the progression in vascular disease have become a useful paradigm in the treatment and prevention of vascular Disease.
Journal Article•
TL;DR: The results show that no appreciable increase of macromolecular uptake should occur either by an acute or by a chronic increase of blood pressure, and the effectiveness of a vasoconstrictor such as angiotensin II to increase macromolescular delivery should be significantly enhanced by periodic rather than bolus or continuous administration of the vasoactive agent.
Abstract: Elevated interstitial fluid pressure (IFP) may constitute a significant physiological barrier to drug delivery in solid tumors. Strategies for overcoming this barrier have not been developed to date. To identify and characterize various mechanisms regulating IFP and to develop strategies for overcoming the IFP barrier, we modeled the tumor as a poroelastic solid. We used this model to simulate the effect of changes in microvascular pressure and tumor blood flow (TBF) on IFP. To test model predictions, the effects of changes in arterial pressure and TBF on IFP were measured using a tissue-isolated tumor preparation. IFP in the center of an isolated tumor was predicted to follow variation of the arterial pressure with a time delay of the order of magnitude of 10 s, and this delay was found to be 11 +/- 6 s experimentally. Following a cessation of TBF, the time constant of the drop in IFP was predicted to be of the order of 1000 s and was found to be 1500 +/- 900 s experimentally. The former time scale is characteristic of transcapillary fluid exchange, and the latter of percolation of fluid through the interstitial matrix. Relying on the good agreement between theoretical predictions and experimental data, we estimated the effect of blood pressure modulation on macromolecular uptake in solid tumors. Our results show that no appreciable increase of macromolecular uptake should occur either by an acute or by a chronic increase of blood pressure. On the other hand, higher uptake would result from periodic modulation of blood pressure. Therefore, the effectiveness of a vasoconstrictor such as angiotensin II to increase macromolecular delivery should be significantly enhanced by periodic rather than bolus or continuous administration of the vasoactive agent.
TL;DR: In this paper, a multicenter, placebo-controlled, oral, multidose (2.5, 10, 25, and 50 mg losartan once daily) double-blind comparison in patients with symptomatic heart failure and impaired left ventricular function (ejection fraction <40%).
Abstract: Background The aim of the present study was to assess the short- and long-term effects of multiple doses of the angiotensin II receptor antagonist losartan in heart failure. Methods and Results A multicenter, placebo-controlled, oral, multidose (2.5, 10, 25, and 50 mg losartan once daily) double-blind comparison in patients with symptomatic heart failure and impaired left ventricular function (ejection fraction <40%). Invasive 24-hour hemodynamic assessment was performed after the first dose and after 12 weeks of treatment. Clinical status and tolerability of treatment with losartan over the 12-week period were also evaluated. One hundred fifty-four patients were enrolled, of which 134 met the protocol criterion of baseline pulmonary capillary wedge pressure ≥13 mm Hg. During short-term administration, systemic vascular resistance (SVR) (largest reduction against placebo of 197 dyne · s−1 · cm−5 at 4 hours) and blood pressure fell significantly with 50 mg, lesser decreases were seen with 25 mg, and no dis...
TL;DR: The data suggest the possible role of endogenous ET-1 as an autocrine/paracrine growth factor for cardiac fibroblasts and its close interaction with natriuretic peptides in the regulation of cardiac fibrosis.
Abstract: The present study was aimed to test the role of endothelin-1 (ET-1) as a possible autocrine/paracrine growth factor for cardiac fibroblasts, and to examine its interaction with cardiac natriuretic hormones. Expression of preproET-1 (ppET-1) mRNA by cultured cardiac fibroblasts from neonatal rats was demonstrated by Northern blot analysis using cDNA for rat ppET-1 as a probe. Angiotensin II (ANG II) and ET-1 transiently (30 min) increased steady-state ppET-1 mRNA levels in cardiac fibroblasts. Both ET-1 and ANG II significantly stimulated [3H] thymidine incorporation into cardiac fibroblasts, whose effects were dose-dependently inhibited by an ETA receptor antagonist (BQ123), BQ123 also inhibited both ET-1- and ANG II-induced ppET-1 mRNA expression. Both atrial and brain natriuretic peptides (ANP, BNP), which activate particulate guanylate cyclase, inhibited ppET-1 mRNA expression and [3H]thymidine incorporation stimulated by ANG II and ET-1. Sodium nitroprusside, a soluble guanylate cyclase activator, and 8-bromocyclic GMP, a membrane-permeable cGMP derivative, similarly inhibited ppET-1 mRNA expression and [3H]-thymidine incorporation. BNP was more potent than ANP to inhibit ANG II- and ET-1-stimulated DNA synthesis, whereas BNP and ANP were almost equipotent in stimulating cGMP generation in cardiac fibroblasts. Our data demonstrated that ANG II and ET-1 upregulate ET-1 gene expression in rat cardiac fibroblasts partly via cyclic GMP-dependent mechanism, and that natriuretic peptides inhibit ANG II-stimulated proliferation of cardiac fibroblasts, possibly by inhibiting ET-1 gene expression. Our data suggest the possible role of endogenous ET-1 as an autocrine/paracrine growth factor for cardiac fibroblasts and its close interaction with natriuretic peptides in the regulation of cardiac fibrosis.
TL;DR: In this article, the effects of all angiotensins were blocked by N ω -nitro-larginine methyl ester (100 μmol/L), indicating that nitrite was a product of nitric oxide metabolism, and by Hoe 140 (10 μmol /L), a specific bradykinin B 2 receptor antagonist, indicating a potential role for local kinin formation.
Abstract: Our goal was to determine whether angiotensin II (Ang II) and its metabolic fragments release nitric oxide and the mechanisms by which this occurs in blood vessels from the canine heart. We incubated 20 mg of microvessels or large coronary arteries in phosphate-buffered saline for 20 minutes and measured nitrite release. Nitrite release increased from 27±2 up to 103±5, 145±17, 84±4, 107±16, and 54±4 pmol/mg ( P −5 mol/L of Ang I, II, III, IV, and Ang-(1-7), respectively. The effects of all angiotensins were blocked by N ω -nitro-l-arginine methyl ester (100 μmol/L), indicating that nitrite was a product of nitric oxide metabolism, and by Hoe 140 (10 μmol/L), a specific bradykinin B 2 receptor antagonist, indicating a potential role for local kinin formation. The protease inhibitors aprotinin (10 μmol/L) and soybean trypsin inhibitor, which block local kinin formation, inhibited nitrite release by all of the angiotensins. Angiotensin nonselective (saralasin), type 1–specific (losartan), and type 2–specific (PD 123319) receptor antagonists abolished the nitrite released in response to all the fragments. Angiotensin type 1 and type 2 and receptors mediate nitrite release after Ang I, II, III, and Ang-(1-7), whereas only type 2 receptors mediate nitrite release after Ang IV. Similar results were obtained in large coronary arteries. In summary, formation of nitrite from coronary microvessels and large arteries in the normal dog heart in response to angiotensin peptides is due to the activation of local kinin production in the coronary vessel wall.
TL;DR: In controlled clinical trials, losartan was better tolerated than other antihypertensive agents as determined by the incidence of patients reporting any drug-related adverse experiences, and demonstrated an excellent tolerability profile.
Abstract: This report presents data on the safety and tolerability of losartan potassium (losartan), a selective antagonist of the angiotensin II AT-1 receptor, in approximately 2,900 hypertensive patients treated in double-blind clinical trials. In these studies, headache (14.1%), upper respiratory infection (6.5%), dizziness (14.1%), asthenia/fatigue (3.8%), and cough (3.1%) were the clinical adverse experiences most often reported in patients treated with losartan. These adverse experiences were also frequently reported in patients receiving placebo: 17.2%, 5.6%, 2.4%, 3.9%, and 2.6%, respectively. Dry cough as an adverse event was reported in 8.8% of patients treated with angiotensin-converting enzyme inhibitors, and in 3.1% and 2.6% of patients treated with losartan or placebo, respectively. Only dizziness was considered "drug-related" more often in losartan-treated (2.4%) than placebo-treated (1.3%) patients. In controlled clinical trials, losartan was better tolerated than other antihypertensive agents as determined by the incidence of patients reporting any drug-related adverse experiences. Rates of discontinuation due to clinical adverse experiences in patients who received losartan monotherapy or losartan+hydrochlorothiazide were 2.3% and 2.8%, respectively, compared with placebo (3.7%). No laboratory adverse experiences were unexpected or of clinical importance. First-dose hypotension rarely occurred with losartan or with losartan plus hydrochlorothiazide, and withdrawal effects such as rebound hypertension were not observed in clinical trials. There were no clinically important differences in the clinical or laboratory safety profiles in the demographic subgroups for age, gender, or race. In controlled clinical trials, losartan demonstrated an excellent tolerability profile.
TL;DR: The physiology and pathophysiology of NO in the kidney will lead to the development of new therapeutic avenues and increased NO production may be involved in the early pathogenic hemodynamic changes in diabetes and in the physiologic hemodynamic responses to normal pregnancy.
TL;DR: Results indicate that angiotensin II regulates nephrovascular development, a role that is conserved across species.
Abstract: To test the hypothesis that angiotensin II (ANG II) is necessary for normal embryonic and postnatal kidney development, the effect of angiotensin receptor blockade or angiotensin converting enzyme inhibition on nephrovascular development was studied in newborn Sprague-Dawley rats and in Rana catesbeiana tadpoles undergoing prometamorphosis. Blockade of ANG II type 1 receptor (AT1) in newborn rats induced an arrest in nephrovascular maturation and renal growth, resulting in altered kidney architecture, characterized by fewer, thicker, and shorter afferent arterioles, reduced glomerular size and number, and tubular dilatation. Inhibition of ANG II generation in tadpoles induced even more marked developmental renal abnormalities. Blockade of ANG II type 2 receptor (AT2) in newborn rats did not alter renal growth or morphology. Results indicate that ANG II regulates nephrovascular development, a role that is conserved across species.
TL;DR: The pharmacokinetics of the angiotensin II receptor antagonist losartan potassium and its active carboxylic acid metabolite EXP3174 were characterized in 18 healthy male subjects after administration of intravenous and oralLosartan.
Abstract: The pharmacokinetics of the angiotensin II receptor antagonist losartan potassium and its active carboxylic acid metabolite EXP3174 were characterized in 18 healthy male subjects after administration of intravenous losartan, intravenous EXP3174, and oral losartan. In these subjects, the average plasma clearance of losartan was 610 ml/min, and the volume of distribution was 34 L. Renal clearance (70 ml/min) accounted for 12% of plasma clearance. Terminal half-life was 2.1 hours. In contrast, the average plasma clearance of EXP3174 was 47 ml/min, and its volume of distribution was 10 L. Renal clearance was 26 ml/min, which accounted for 55% of plasma clearance; terminal half-life was 6.3 hours. After oral administration of losartan, peak concentrations of losartan were reached in 1 hour. Peak concentrations of EXP3174 were reached in 3 1/2 hours. The area under the plasma concentration-time curve of EXP3174 was about four times that of losartan. The oral bioavailability of losartan tablets was 33%. The low bioavailability was mainly attributable to first-pass metabolism. After intravenous or oral administration of losartan the conversion of losartan to the metabolite EXP3174 was 14%.
TL;DR: Findings suggest that AII may regulate plasminogen activation in the vasculature by inducing both PAI-1 andPAI-2 expression.
Abstract: Angiotensin II (AII)- and Arg8-vasopressin (AVP)-regulated gene expression in vascular cells has been reported to contribute to vascular homeostasis and hypertrophy. In this report, AVP-induced expression of plasminogen activator inhibitor (PAI)-2 mRNA in rat microvessel endothelial (RME) cells was identified using differential mRNA display. Further characterization of vasoactive peptide effects on PAI expression revealed that AII stimulated a 44.8 +/- 25.2-fold and a 12.4 +/- 3.2-fold increase in PAI-2 mRNA in RME cells and rat aortic smooth muscle cells (RASMC), respectively. AII also stimulated a 10- and 48-fold increase in PAI-1 mRNA in RME cells and RASMC, respectively. These AII effects were inhibited by either Sar1, Ile8-angiotensin or the AT1 antagonist DuP 735, but were not significantly altered in the presence of the AT2 antagonist PD123319. AII stimulation of RASMC and RME cells also significantly increased both PAI-1 protein and PAI activity released to the culture medium. Inhibition of protein kinase C completely blocked PMA-stimulated induction of PAI-2 mRNA in both cell types and inhibited the AII-stimulated increase in RASMC by 98.6 +/- 2.8%. In contrast, protein kinase C inhibition only partially decreased the AII-stimulated PAI-2 expression in RME cells by 68.8 +/- 11.1%, suggesting that a protein kinase C-independent mechanism contributes to a 6.9 +/- 1.5-fold AII induction of PAI-2 expression in endothelial cells. AII and PMA also stimulated protein tyrosine phosphorylation in RME cells, and the tyrosine kinase inhibitor genistein partially blocked their induction of PAI-2 mRNA. These findings suggest that AII may regulate plasminogen activation in the vasculature by inducing both PAI-1 and PAI-2 expression.
TL;DR: It was concluded that angiotensin II contributes to the vasculopathy (hyalinosis) induced by CsA, and the interstitial fibrosis mediated byCsA can be partially prevented by both an angiotENSin II Type I receptor antagonist or by hydralazine and furosemide.
Abstract: Low-salt-diet, cyclosporine (CsA; 15 mg/kg per day)-treated rats develop striped interstitial fibrosis, arteriolar hyalinosis, and azotemia similar to the chronic nephropathy observed in humans. To examine the role of angiotensin II in this model, rats on a low-salt diet were given CsA, CsA and the angiotensin II receptor Type I antagonist Losartan (10 mg/kg per day), CsA and hydralazine/furosemide, or vehicle. At Day 35, CsA-treated rats had tubular injury, arteriolopathy of the afferent arteriole, increased expression of the monocyte-macrophage adhesive protein osteopontin, interstitial macrophage infiltration, increased interstitial transforming growth factor-beta expression, and interstitial fibrosis. This study provides new insight in both pathogenic and therapeutic aspects of CsA nephropathy. The pathogenesis of CsA nephropathy involves the expression of osteopontin by tubular epithelial cells, the level of which closely correlates with the degree of macrophage infiltration and interstitial fibrosis in all groups (r = 0.79 and 0.74, respectively; P < 0.001). Therapeutic conclusions can be drawn from the observation that both losartan and hydralazine/furosemide reduced osteopontin expression, macrophage infiltration, transforming growth factor-beta expression, and interstitial fibrosis, but did not prevent the decrease in GFR. Treatment with losartan, but not with hydralazine and furosemide, markedly reduced arteriolopathy. It was concluded that angiotensin II contributes to the vasculopathy (hyalinosis) induced by CsA. In contrast, the interstitial fibrosis mediated by CsA can be partially prevented by both an angiotensin II Type I receptor antagonist or by hydralazine and furosemide. This suggests that the interstitial fibrosis can be dissociated from the vascular effects of CsA. The beneficial effects of lowering blood pressure or vasodilation per se may be difficult to distinguish from the specific effects of angiotensin II receptor blockade.