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 13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It has been recently shown that angiotensin II (Ang II) is not the only active peptide of the renin-angiotensin system. Several of its degradation products including Ang III (obtained by deletion of the N terminal amino acids), Ang IV (obtained by deletion of the two N terminal amino acids), and Ang II (1-7) (obtained by deletion of the C terminal amino acid), also possess biological functions. These peptides are formed via the activity of several enzymes: angiotensin--converting enzyme, aminopeptidases A and N, neutral endopeptidase and prolylendopeptidase. Ang III possesses most of the properties of Ang II and shares the same receptors AT1 and AT2. In addition this peptide is particularly important in brain physiology and plays a major role in the secretion of arginine vasopressine. Ang IV possesses its own receptors distinct from AT1 and AT2. Some of its effects (for example, stimulation of the synthesis of the type 1 inhibitor of plasminogen activator by endothelial cells) were previously attributed to Ang II. Others effects, like renal and cerebral vasodilatation, are opposed to Ang II effects. The role of Ang IV in renal physiology remains to be determined. Ang II (1-7) exhibits direct and indirect effects, the latter resulting from Ang II (1-7)-dependent formation of nitric oxide and vasodilatory prostaglandins. Ang II (1-7) potentiates the hypotensive effect of bradykinin and plays also a major role in the control of the hydroelectrolytic balance. It possesses its own receptor: AT1-7, recognizable by (sar1-thr8) Ang II or Sarthran. Finally Ang II (1-7) is converted into Ango II (1-5), by angiotensin-converting enzyme. This peptide is inactive. All of these enzymes, peptides and receptors are present in kidney. Thus the renin-angiotensin system appears to be much more complicated than thought a few years ago, setting the problem of new therapeutic tools for the treatment of hypertension and glomerulosclerosis.
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PMID:[Active metabolites derived from angiotensin II]. 985 79

Accumulating evidence suggests that angiotensin-(1-7) [Ang-(1-7)] is an important component of the renin-angiotensin system. As the most pleiotropic metabolite of angiotensin I (Ang I) it manifest actions which are most often the opposite of those described for angiotensin II (Ang II). Ang-(1-7) is produced from Ang I bypassing the prerequisite formation of Ang II. The generation of Ang-(1-7) is under the control of at least three enzymes, which include neprilysin, thimet oligopeptidase, and prolyl oligopeptidase depending on the tissue compartment. Both neprilysin and thimet oligopeptidase are also involved in the metabolism of bradykinin and the atrial natriuretic peptide. Moreover, recent studies suggest that in addition to Ang I and bradykinin, Ang-(1-7) is an endogenous substrate for angiotensin converting enzyme. This suggests that there is a complex relationship between the enzymatic pathways forming angiotensin II and other various vasodepressor peptides from either the renin-angiotensin system or other peptide systems. The antihypertensive actions of angiotensin-(1-7) are mediated by an angiotensin receptor that is distinct from the pharmacologically characterized AT1 or AT2 receptor subtypes. Ang-(1-7) mediates it antihypertensive effects by stimulating synthesis and release of vasodilator prostaglandins, and nitric oxide and potentiating the hypotensive effects of bradykinin.
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PMID:Angiotensin-(1-7): a bioactive fragment of the renin-angiotensin system. 987 42

This review examines the recent progress in the field of angiotensin receptors. Multiplicity of these receptors was demonstrated initially on the basis of pharmacologic differences and then confirmed by expression cloning. AT1 receptors are predominant in the adult. They are widely distributed and mediate all of the known biologic effects of angiotensin II (AngII) through a variety of signal transduction systems, including activation of phospholipases C and A2, inhibition of adenylate cyclase, opening of calcium channels, and activation of tyrosine kinases. AT2 receptors are predominant in the fetus, but also present in adult tissues such as the adrenals, ovaries, uterus, and brain. AngII via these receptors exerts effects often opposed to those mediated by the AT1 receptors. Signal transduction implicates protein tyrosine phosphatase stimulation. AT1 and AT2 receptor expressions are regulated differently, and regulation is also tissue-specific. AT1 and AT2 receptors have been demonstrated in endothelial cells. Activation of AT1 receptors results in production of vasodilatory agents, nitric oxide, and prostacyclin (PGI2), which counteract the direct vasoconstrictor effects of Ang II on the adjacent smooth muscle cells. AT1 receptors on mesangial cells, smooth muscle cells, and fibroblasts are involved in cell growth and fibrosis, the latter being due both to an increase in the synthesis and a decrease in the degradation of the main components of the extracellular matrix. These AT1 receptor-dependent effects are for the most part indirect and mediated by growth factors, cytokines, and other peptides, including endothelin, transforming growth factor-beta1, and platelet-derived growth factor. AngII is metabolized into active fragments by deletion of the terminal amino acids on both ends. AngIII and AngIV are formed by successive deletions of aspartic acid and arginine at the N terminus. AngII (1-7) is obtained by deletion of phenylalanine at the C terminus. AngIII shares the same receptors and exerts the same effects as AngII. AngIV and AngII (1-7) recognize the AT1 and AT2 receptors with a lesser affinity than AngII and, in addition, possess their own receptors that mediate effects often opposed to those of AngII.
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PMID:Angiotensin II receptors. 989 38

The renin-angiotensin system is activated during myocardial ischemia, and local angiotensin II formation occurs in ischemic hearts. At least two angiotensin II receptor subtypes, the AT1 and the AT2 receptor, have been identified. The cardiovascular effects of angiotensin II have been attributed largely to activation of AT1 receptors. In ventricular preparations from normal rat and pig hearts, the density of AT1 receptors is higher than that of AT2 receptors, whereas data on the AT receptor subtype density and its distribution in human hearts remain controversial. AT1 receptor blockade increases coronary blood flow during ischemia in dogs and during reperfusion in rats, reduces the incidence of ischemia-related arrhythmias in rats and guinea pigs, limits infarct size in pigs, improves functional and metabolic recovery after myocardial ischemia, and attenuates ventricular remodeling post-myocardial infarction in rats. The potential mechanisms responsible for the cardioprotection by AT1 receptor blockade remain to be elucidated in detail, but appear to involve AT2 receptor activation and the subsequent action of bradykinin, prostaglandins, and/or nitric oxide. Patients under treatment with AT1 receptor blockers for indications such as hypertension and ventricular dilation after myocardial infarction are likely to have improved prognosis when suffering an acute myocardial infarction.
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PMID:AT1 receptor blockade in experimental myocardial ischemia/reperfusion. 989 53

Inhibition of nitric oxide synthase by L-arginine analogues was shown to attenuate the antihypertensive effect of angiotensin II (AngII) type-1 receptor blockade, thus suggesting that nitric oxide might partly mediate the systemic effect of these agents. In the present experiment, the effects of an acute administration of candesartan on arterial pressure, renal blood flow (transit time method), and resistance were assessed in anesthetized normotensive rats infused or not with NG-nitro-L-arginine methyl ester (L-NAME) (20 microg/kg per min for 60 min). Candesartan was given at a dose of 0.5 mg/kg intravenous bolus in normotensive rats. Candesartan reduced arterial pressure by 15+/-2% and renal vascular resistance by 31+/-2% in nonpretreated rats. Pretreatment by L-NAME did not affect the BP lowering effect of candesartan but blunted by 60 to 100% the renal response to candesartan. Concomitant administration of L-arginine restored the renal vasodilatory action of candesartan. Plasma renin concentration was reduced by L-NAME from 122+/-23 to 69+/-14 ng AngI/ml per h and not further modified by L-arginine (71+/-16 ng AngI/ml per h). Neither the systemic and renal hemodynamic responses to AngII nor its blockade by candesartan were affected by L-NAME. The loss of renal vasodilatory effect of candesartan during L-NAME infusion suggests that AT1 receptor blockade is associated with an increase in nitric oxide-dependent tone, which participates in the full expression of the renal vasodilatory action of AngII type-1 receptor blockade in anesthetized normotensive rats.
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PMID:Nitric oxide participates in the renal vasodilatory effect of candesartan in anesthetized rats. 989 65

Nitric oxide (NO) is known to modulate the vascular effects of angiotensin II (AngII) in the kidney. To investigate the effect of AngII on NO release, a new technique was used that employs an NO-sensitive microelectrode to measure NO release from the vascular endothelium of perfused renal resistance arteries (tertiary branches of the renal artery or primary arcuate arteries) in vitro. The vessels were microdissected from isolated perfused rat kidneys, cannulated, and perfused at constant flow and pressure with Krebs-Ringer bicarbonate solution. The electrode was placed inside the glass collection cannula to measure vessel effluent NO concentration. Addition of AngII to the perfusate stimulated NO release in a dose-dependent manner; 0.1, 10, and 1000 nM AngII increased NO oxidation current by 85+/-18 pA (n=11), 148+/-22 pA (n=11), and 193+/-29 pA (n=11), respectively. These currents correspond to changes in effluent NO concentration of 3.4+/-0.5, 6.1+/-1.1, and 8.2+/-1.3 nM, respectively. The presence of 0.1 mM N(G)-nitro-L-arginine methyl ester in the perfusate significantly reduced the response to 10 nM AngII by 90.5+/-3.4% (n=5). Neither losartan (1 microM) nor candesartan (1 nM) significantly affected basal NO production, but both of these AT1-receptor blockers markedly blunted NO release in response to AngII (10 nM): 77+/-6% inhibition with losartan (n=8) and 63+/-9% with candesartan (n=8). These results demonstrate that AngII stimulates N(G)-nitro-L-arginine methyl ester-inhibitable NO release in isolated renal resistance arteries. Because the response was significantly blunted by AT1 receptor blockade, the findings suggest that endothelium-dependent modulation of AngII-induced vasoconstriction in renal resistance arteries is mediated, at least in part, by AT1 receptor-dependent NO release.
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PMID:AT1 receptor inhibition blunts angiotensin II-stimulated nitric oxide release in renal arteries. 989 67

In this study, a nitric oxide (NO) sensor was used to examine the ability of angiotensin II (AngII), AngIV, and bradykinin (Bk) to stimulate NO release from porcine pulmonary artery (PPAE) and porcine aortic endothelial (PAE) cells and to explore the mechanism of the AngII-stimulated NO release. Physiologic concentrations of AngII, but not Bk, caused release of NO from PPAE cells. In contrast, Bk, but not AngII, stimulated NO release from PAE cells. AngIII-stimulated NO release from PPAE cells required extracellular L-arginine and was inhibited by L-nitro-arginine methyl ester. AT1 and AT2 receptor inhibition had no affect on AngII-mediated NO release or activation of NO synthase (NOS). AngIV, an AngII metabolite with binding sites that are pharmacologically distinct from the classic AngII receptors, stimulated considerably greater NO release and greater endothelial-type constitutive NOS activity than the same amount of AngII. The AngIV receptor antagonist, divalinal AngIV, blocked both AngII- and AngIV-mediated NO release as well as NOS activation. The results demonstrate that AngIV and the AngIV receptor are responsible, at least in part, for AngII-stimulated NO release and the associated endothelium-dependent vasorelaxation. Furthermore, these results suggest that differences exist in both AngII- and Bk-mediated NO release between PPAE and PAE cells, which may reflect important differences in response to these hormones between vascular beds.
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PMID:Angiotensin II-stimulated nitric oxide release from porcine pulmonary endothelium is mediated by angiotensin IV. 1007 98

Chronic renal failure is associated with disturbances in nitric oxide (NO) production. This study was conducted to determine the effect of 5/6 nephrectomy (5/6 Nx) on expression of intrarenal neuronal nitric oxide synthase (nNOS) in the rat. In normal rat kidney, nNOS protein was detected in the macula densa and in the cytoplasm and nuclei of cells of the inner medullary collecting duct by both immunofluorescence and electron microscopy. Western blot analysis revealed that 2 wk after 5/6 Nx, there were significant decreases in nNOS protein expression in renal cortex (sham: 95.42+/-15.60 versus 5/6 Nx: 47.55+/-12.78 arbitrary units, P<0.05, n = 4) and inner medulla (sham: 147.70+/-26.96 versus 5/6 Nx: 36.95+/-17.24 arbitrary units, P<0.005, n = 8). Losartan treatment was used to determine the role of angiotensin II (AngII) AT1 receptors in the inhibition of nNOS expression in 5/6 Nx. Losartan had no effect on the decreased expression of nNOS in the inner medulla, but partially increased nNOS protein expression in the cortex of 5/6 Nx rats. In contrast, in sham rats losartan significantly inhibited nNOS protein expression in the cortex (0.66+/-0.04-fold of sham values, P<0.05, n = 6) and inner medulla (0.74+/-0.12-fold of sham values, P<0.05, n = 6). nNOS mRNA was significantly decreased in cortex and inner medulla from 5/6 Nx rats, and the effects of losartan on nNOS mRNA paralleled those observed on nNOS protein expression. These data indicate that 5/6 Nx downregulates intrarenal nNOS mRNA and protein expression. In normal rats, AngII AT1 receptors exert a tonic stimulatory effect on expression of intrarenal nNOS. These findings suggest that the reduction in intrarenal nNOS expression in 5/6 Nx may play a role in contributing to hypertension and altered tubular transport responses in chronic renal failure.
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PMID:Downregulation of neuronal nitric oxide synthase in the rat remnant kidney. 1020 53

The potential antithrombotic action of losartan, an AT1 receptor antagonist, administered to two-kidney, one-clip rats (2K1C) in an experimental model of venous thrombosis was evaluated. The involvement of nitric oxide (NO) in this effect was also studied. Venous stasis was induced by ligation of the vena cava. Losartan after single dose (10 mg/kg, p.o.) significantly reduced the venous thrombus growth. The antithrombotic action of losartan in 2K1C rats was abolished by N(G)-nitro-L-arginine methyl ester (L-NAME, 30 mg/kg s.c.) and restored by L-arginine (1000 mg/kg s.c.). Platelet adhesion to fibrillar collagen significantly decreased after administration of losartan. No changes in primary hemostasis and platelet aggregation were observed. Moreover, coagulation parameters such as activated partial thromboplastin time, prothrombin time and euglobulin clot lysis time were found unchanged after losartan administration either in systemic circulation or at the place of thrombus formation. Our results indicate that antithrombotic activity of losartan in 2K1C rats is NO--dependent; observed inhibition of platelet adhesion could also play a role in this phenomenon.
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PMID:Antithrombotic activity of losartan in two kidney, one clip hypertensive rats. A study on the mechanism of action. 1021 Jan 58

The receptors for angiotensin (Ang) II are classified into two subtypes (AT1-R and AT2-R) by the discovery of non-peptidic ligands and AT1-R mediates most of the cardiovascular actions of Ang II. AT2-R is expressed at very high levels in the developing fetus, whereas in the adult its expression in the cardiovascular system is very low. Cardiac myocyte- or vascular smooth muscle-specific overexpression mice of AT2-R display an inhibitory effect on Ang II-induced chronotropic or pressor actions, suggesting the role of AT2-R on the activity of cardiac pacemaker cells or maintenance of vascular resistance. AT2-R also activates the kinin/nitric oxide/cGMP system in the cardiovascular and renal system, resulting in the AT2-R-mediated cardioprotection, vasodilation and pressure natriuresis. These effects transmitted by AT2-R are mainly exerted by stimulation of protein tyrosine or serine/threonine phosphatases in Gi-protein dependent manner. The expression level of AT2-R is much higher in human hearts than in those of rodents, and the AT2-R-mediated actions are likely enhanced, especially by clinical application of AT1-R antagonists.
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PMID:[Angiotensin II receptor-mediated function unmasked by gene-engineered animals]. 1036 39


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