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Query: UMLS:C0004135 (ATM)
 13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Bovine fasciculata cells in culture (BAC) express both AT1 and AT2 angiotensin receptors. The role and signaling pathways of this latter receptor are still the subject of debate. We found that in BAC stimulation of cortisol (F) production by angiotensin II (A II) is accounted for by both receptor subtypes. We have investigated the potential AT2 signalling pathways involved in this response. As previously described in other cells, we found this receptor to mediate inhibition of ANP stimulated cGMP production through a phosphodiesterase independent pathway. This phenomenon does however not appear to be involved in cortisol production as this response was not affected by the addition of 8-Br-cGMP or ANP. It was however abolished after down-regulation of PKC by phorbol esters, but not by Gi inhibition with pertussis toxin. Moreover and as opposed to the AT1 mediated response, AT2 receptor stimulation potentiated K+ induced F production. In conclusion, these observations suggest that the AT2 pathway which mediates F production requires intact PKC and might involve a Gi independent stimulation of Ca++ or K+ channels.
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PMID:Stimulation of cortisol production through angiotensin AT2 receptors in bovine fasciculata cells. 758 79

In order to examine the effects and the interaction of angiotensin II (ANG II, 1 pM) and atrial natriuretic peptide (ANP, 1 microM) on the kinetics of bicarbonate reabsorption in the rat middle proximal tubule, we performed in vivo experiments using a stopped-flow microperfusion technique with the determination of lumen pH by Sb microelectrodes. These studies confirmed that ANG II added to the luminal or peritubular capillary perfusion fluid stimulates proximal bicarbonate reabsorption and showed that ANP alone does not affect this process, but impairs the stimulation caused by ANG II. We also studied the effects and the interaction of these hormones in cortical distal nephron acidification. Bicarbonate reabsorption was evaluated by the acidification kinetic technique in early (ED) and late (LD) distal tubules in rats during in vivo stopped-flow microperfusion experiments. The intratubular pH was measured with a double-barreled microelectrode with H(+)-sensitive resin. The results indicate that ANG II acted by stimulating Na+/H+ exchange in ED (81%) and LD (54%) segments via activation of AT1 receptors, as well as vacuolar H(+)-ATPase in LD segments (33%). ANP did not affect bicarbonate reabsorption in either segment and, as opposed to what was seen in the proximal tubule, did not impair the stimulation caused by ANG II. To investigate the mechanism of action of these hormones in more detail, we studied cell pH dependence on ANG II and ANP in MDCK cells using the fluorescent probe BCECF. We showed that the velocity of cell pH recovery was almost abolished in the absence of Na+, indicating that it is dependent on Na+/H+ exchange. ANP (1 microM) alone had no effect on this recovery but reversed both the acceleration of H+ extrusion at low ANG II levels (1 pM and 1 nM), and inhibition of H+ extrusion at higher ANG II levels (100 nM). To obtain more information on the mechanism of interaction of these hormones, we also studied their effects on the regulation of intracellular free calcium concentration, [Ca2+]i, monitored with the fluorescent probe Fura-2 in MDCK cells in suspension. The data indicate that the addition of increasing concentrations of ANG II (1 pM to 1 microM) to the cell suspension led to a progressive increase in [Ca2+]i to 2-3 times the basal level. In contrast, the addition of ANP (1 microM) to the cell suspension led to a very rapid 60% decrease in [Ca2+]i and reduced the increase elicited by ANG II, thus modulating the effect of ANG II on [Ca2+]i. These results may indicate a role of [Ca2+]i in the regulation of the H+ extrusion process mediated by Na+/H+ exchange and stimulated/impaired by ANG II. The data are compatible with stimulation of Na+/H+ exchange by increases of [Ca2+]i in the lower range, and inhibition at high [Ca2+]i levels.
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PMID:Interactions of ANP and ANG II in tubular nephron acidification. 925 67

The mechanism of acidification in the cortical distal tubule of mammalian kidney was analysed by "in vivo" microperfusion and using MDCK cells in culture, by electrophysiological and by cell pH microfluorescence techniques. An electrogenic effect of the vacuolar H(+)-ATPase, which has been localized to the intercalated cells of the cortical distal tubule (connecting segment and initial collecting duct) was only observed after blocking Cl- channels by NPPB. In MDCK cells, the recovery of cell pH after an acid pulse in Na(+)-free medium was also depressed by NPPB, indicating that Cl- ions have an important role in the function of H+ ATPase. The regulation by hormonal agents of distal H+ transport due to Na+/H+ exchange and to vacuolar H+ ATPase, was also studied by microperfusion and cell pH techniques. Angiotensin and vasopressin at picomolar concentrations stimulated both transport mechanisms in late distal tubule, and only Na+/H+ exchange in the early segment. In MDCK cells, cell pH recovery in the presence of Na+ was stimulated by picomolar concentrations of angiotensin and vasopressin, and inhibited by micromolar levels, both effects being reverted by micromolar ANP. Studies with specific antagonists suggest that the luminal effect of angiotensin is mediated by AT1 receptors, and of vasopressin by V1 receptors. There is evidence that cell Ca2+ may have an important regulatory role in the action of these hormones.
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PMID:Mechanisms and regulation of H+ transport in distal tubule epithelial cells. 926 82

The natriuretic peptide (NP) system is one of the most important systems regulating blood pressure and body-fluid homeostasis. The biological activities of the system are determined by the NPs and the receptors, which are comprised of three subtypes: NP-AR and NP-BR related to biological activities and NP-CR related to the clearance of NP. We focused our studies on the receptor subtypes. In hypertensive rats (SHR-SP/Izm, DOCA/salt), NP-AR was upregulated and NP-CR was downregulated. The ACE inhibitor derapril, but not the Ca2+ blocker manidipine, normalized the upregulated NP-AR, but the effect was completely abolished by the bradykinin beta 2-receptor antagonist, suggesting that bradykinin regulates the vascular NP-AR. The AT1 antagonist TCV-116, but not manidipine, reversed the downregulated NP-CR. Ang II decreased NP-CR in cultured aortic smooth muscle cells. These results suggest that upregulation of NP-AR and downregulation of NP-CR with the increased plasma NPs counteract hypertension by enhancing the action of NP. A beta-blocker (carvedilol) potentiated the hypotensive action of NPs by increasing plasma NPs and enhancing the vascular response to NPs via downregulation of the vascular and lung NP-CR. The newly found mode of actions could be related to its anti-heart failure effect. In genetically hyperglycemic Wistar fatty rats, vascular NP-BR and NP-AR were upregulated. Since plasma ANP and vascular CNP were significantly increased, the local CNP/NP-BR system as well as the systemic ANP/NP-AR system may play an important role in counteracting vascular remodeling in diabetes mellitus. All these observations provide in vivo evidence for the pathophysiological significance of the receptor subtype of the NPs.
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PMID:[Pathophysiological significance of the natriuretic peptide system: receptor subtype as another key factor]. 979 68

The object of this review is to describe the role of the renin-angiotensin system in control of aldosterone secretion. The review focuses on the roles of the circulating renin-angiotensin (RAS) system, the activity of which is determined predominantly by control of renin secretion from the kidney and on the role of the intra-adrenal RAS. Angiotensin can bind to two types of G protein coupled receptors, the AT1 and AT2 receptors. Both receptors are found on cells from the zona glomerulosa, the site of aldosterone synthesis. Angiotensin II acting via the AT1 receptor stimulates the synthesis of aldosterone at early and late steps in the pathway. Its effect on aldosterone is influenced by a number of other factors such as plasma potassium levels, sodium status, other peptides such as ANP and adrenomedullin and proadrenomedullin N-terminal peptide. All components of the RAS are found in the adrenal gland. The activity of this intra-adrenal RAS is unmasked and amplified in nephrectomised animals. Aldosterone controls sodium transport across epithelial cells, but recently novel effects on the heart have been described.
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PMID:Angiotensin and aldosterone. 1042 51

Previous studies have suggested that angiotensin II modulates ANP secretion and this action appears to be largely independent from its hemodynamic effects. In order to explore the contribution of angiotensin II AT1 (AT1r) and AT2 (AT2r) receptor subtypes in the regulation of cardiac ANP, we studied the effects of selective antagonists of these receptors on ANP mRNA levels in the cardiac chambers of salt-restricted rats. Thirty-one Sprague-Dawley rats (12 weeks-old) weighing 250-350 g were studied during a low salt regimen and randomly assigned to the following treatment groups: AT1r-blockade (losartan) (10 mg/kg/day) (n = 18), AT2r-blockade (PD123319) (50 microg/kg/min) (n = 6), Control (salt-restriction) (n = 7). Treatments were maintained for 7 days; subsequently, 12 rats from the AT1r-blockade group were subdivided in to two groups: AT1r/AT2r-blockade (losartan +PD123319) (n = 6) and AT1r-blockade/vehicle (losartan+vehible) (n = 6), and treated for 7 additional days. Systolic blood pressure was significantly reduced by AT1r-blockade (p < 0.001), while it was not affected by AT2r-blockade. Concomitant treatment with both antagonists (AT1r/AT2r-blockade) restored blood pressure values to baseline (p < 0.001 vs. AT1r-blockade, p = n.s. vs Control). Atrial ANP mRNA was reduced by AT1r-blockade (-42%, p < 0.05) and did not change during AT1r-blockade alone. On the contrary, concomitant treatment with both antagonists resulted in a further significant inhibition of ANP expression (-65% and -36% vs Control and AT1r-blockade, respectively, both p < 0.05). ANP expression in ventricles was not affected by any of these treatments. Our results demonstrate that angiotensin II tonically modulates cardiac ANP expression in our experimental model. In particular, angiotensin II receptor subtypes AT1r and AT2r regulate atrial ANP mRNA levels through a synergic action and independently from blood pressure changes.
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PMID:Role of angiotensin II AT1 and AT2 subtype receptors in the regulation of atrial natriuretic peptide expression in salt-restricted rats. 1075 47

Essential Hypertension (EH) is a multifactorial and polygenic syndrome with a high impact in public health. Recently, rare mendelian forms of hypertension such as glucocorticoid-remediable aldosteronism (GRA), apparent mineralocorticoid excess (AME) and Liddle Syndrome caused by single gene mutations have been identified in which the mechanism is an increased sodium retention. Therefore, it is tempting to speculate that the most common forms of EH may be due to diverse highly prevalent molecular variants of susceptibility genes with low penetrance that are involved in arterial blood pressure (ABP) and electrolytic balance. Although a number of candidate genes such as NO synthases, ANP, ion transporters, adducins, LDL receptor, etc. can participate, renin-angiotensin system components are the most extensively studied. Although not associated with EH, the ACE D allele seems to confer a high risk of CHD or LVH. Angiotensinogen 235T and 174M variants are more likely associated with EH and positively correlate with clinical or ambulatory ABP in adolescents or adults. Individuals who carry these angiotensinogen alleles would be at 1.4 higher risk of suffering EH than homozygotes for M235 or T174 alleles. Associations of AT1 receptor variants with EH remain to be definitively defined. In conclusion, the characterization of the genetic background, although difficult at the present time, may have clear benefits in terms of defining a more rational therapy and prevention in individuals at risk. Even though this aim seems difficult to achieve since more than 150 candidate genes have been postulated as the cause of EH, with 6 to 10 SNPs in each of them, new technologies such as DNA micro-arrays will provide us with the opportunity to analyse the total genetic risk in each subject.
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PMID:[Molecular genetics of essential hypertension. Susceptibility and resistance genes]. 1083 1

We have previously shown that treatment of A10 vascular smooth muscle cells (VSMCs) with angiotensin II (Ang II) enhanced the expression of inhibitory guanine nucleotide regulatory proteins (Gi alpha2 and Gi alpha3). In the present studies, we have investigated the role of type 1 angiotensin receptors (AT1) in the Ang-II-induced enhanced expression of Gi alpha proteins and their functions in A10 SMCs. Ang II enhanced the levels of Gi alpha2 and Gi alpha3 proteins and their mRNA, as determined by Western and Northern blot analysis, respectively; losartan treatment attenuated the enhanced expression of Gi alpha2 and Gi alpha3 proteins and their mRNA in a concentration-dependent manner. In addition, the inhibition of adenylyl cyclase induced by Ang II and des(Glu18,Ser19,Glu20,Leu21,Gly22)ANP(4-23)-NH2 (C-ANP(4-23)), which was attenuated by Ang-II treatment, was partially restored by losartan treatment. Similarly, losartan was also able to restore the Ang-II-induced stimulatory responses of isoproterenol and N-ethylcarboxamide adenosine (NECA) on adenylyl cyclase activity. These results suggest a role for AT1 receptors in Ang-II-evoked increases in Gi alpha protein expression and Gs-mediated stimulation in VSMCs.
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PMID:Angiotensin-II-induced enhanced expression of Gi proteins is attenuated by losartan in A10 vascular smooth muscle cells: role of AT1 receptors. 1271 May 29

Blockade of AngII (angiotensin II) and ET (endothelin)-1, established and potential therapeutic strategies respectively, for heart failure, may have an adverse effect on the cardiac secretion of the natriuretic peptides, hormones with actions beneficial in this disease. The present study investigates the roles of AngII and ET-1 in regulating the stretch-induced release of the natriuretic peptides during the development of heart failure. On seven separate days, eight sheep underwent incremental left ventricular pacing (155, 190 and 225 beats/min for 90 min each) with concurrent infusions of a vehicle control, AngII, ET-1, AngII+ET-1, losartan [AT1 (AngII type 1) receptor antagonist], bosentan (ET(A)/ET(B) receptor antagonist) or losartan+bosentan. Pacing-induced rises in LAP (left atrial pressure) were amplified by the simultaneous administration of separate AngII and ET-1, and attenuated following blockade of the peptides, with maximum effects observed during combined treatments. Although these changes in atrial pressure were paralleled by concomitant alterations in circulating levels of both ANP (atrial natriuretic peptide) and BNP (brain natriuretic peptide), the plasma natriuretic peptide/atrial pressure relationship tended to be augmented by AngII and ET-1 and diminished by their blockade. A significant difference was demonstrated between the enhanced plasma BNP response to increasing LAP during combined AngII+ET-1 administration and decreased response during losartan+bosentan treatment ( P <0.05). A similar, but non-significant, trend was evident for ANP. The present study indicates dual AngII/ET-1 blockade diminishes BNP (and to a lesser extent ANP) secretion in developing heart failure, suggesting that augmentation of the natriuretic peptide system during the combination of these therapies may be of benefit.
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PMID:Combined inhibition of angiotensin II and endothelin suppresses the brain natriuretic peptide response to developing heart failure. 1472 2

Cardiotrophin-1 (CT-1) produces longitudinal elongation of neonatal cardiomyocytes, but its effects in adult cardiomyocytes are not known. Recent observations indicate that CT-1 may be involved in pressure overload left ventricular hypertrophy (LVH). We investigated whether the hypertrophic effects of CT-1 are different in cardiomyocytes isolated from adult normotensive and spontaneously hypertensive rats (SHR). Hypertrophy was evaluated by planimetry and confocal microscopy, contractile proteins were quantified by Western blotting and real-time RT-PCR, and intracellular pathways were analyzed with specific chemical inhibitors. CT-1 increased c-fos and ANP expression (p<0.01) and cell area (p<0.01) in cardiomyocytes from both rat strains. In Wistar cells, CT-1 augmented cell length (p<0.01) but did not modify either the transverse diameter or cell depth. In SHR cells, CT-1 increased cell length (p<0.05), cell width (p<0.01) and cell depth, augmented the expression of myosin light chain-2v (MLC-2v) and skeletal alpha-actin (p<0.01) and enhanced MLC-2v phosphorylation (p<0.01). The blockade of gp130 or LIFR abolished CT-1-induced growth in the two cell types. All distinct effects observed in cardiomyocytes from SHR were mediated by STAT3. Baseline angiotensinogen expression was higher in SHR cells, and CT-1 induced a 1.7-fold and 3.2-fold increase of angiotensinogen mRNA in cardiomyocytes from Wistar rats and SHR respectively. In addition, AT1 blockade inhibited the specific effects of CT-1 in SHR cells. Finally, ex vivo determinations revealed that adult SHR exhibited enhanced myocardial CT-1 (mRNA and protein, p<0.01), increased cell width (p<0.01) and concentric LVH compared with pre-hypertensive SHR. These findings reveal a specific cell-broadening effect of CT-1 in cardiomyocytes from adult SHR and suggest that the hypertensive phenotype of these cells may influence the hypertrophic effects of CT-1, probably by means of an exaggerated induction of angiotensinogen expression. We suggest that CT-1 might facilitate LVH in genetic hypertension through a cross-talk with the renin-angiotensin system.
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PMID:Differential hypertrophic effects of cardiotrophin-1 on adult cardiomyocytes from normotensive and spontaneously hypertensive rats. 1701 64


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