Published online before print February 27, 2006, doi: 10.1161/01.HYP.0000208302.62399.68
(Hypertension. 2006;47:727.)
© 2006 American Heart Association, Inc.
Original Articles |
The Positive Inotropic Effect of Angiotensin II
Role of Endothelin-1 and Reactive Oxygen Species
From the Centro de Investigaciones Cardiovasculares (H.E.C., M.C.V.-A., M.C., A.N., I.L.E., C.G., M.V.C., M.C.C.d.H., E.A.A.), Facultad de Ciencias Médicas, Universidad Nacional de La Plata, La Plata; and Facultad de Ciencias Biomédicas (A.M.S., V.T.), Universidad Austral, Pilar, Buenos Aires, Argentina.
Correspondence to Horacio E. Cingolani, Centro de Investigaciones Cardiovasculares, Facultad de Ciencias Médicas, Universidad Nacional de La Plata, 60 y 120 (1900) La Plata, Argentina. E-mail cimes{at}infovia.com.ar
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Many effects believed to be because of angiotensin II (Ang II) are attributable to the action of endothelin (ET)-1, which is released/produced by Ang II. We investigated whether Ang II elicits its positive inotropic effect (PIE) by the action of endogenous ET-1, in addition to the role played by reactive oxygen species (ROS) in this mechanism. Cat cardiomyocytes were used for: (1) sarcomere shortening measurements; (2) ROS measurements by epifluorescence; (3) immunohistochemical staining for preproET-1, BigET-1, and ET-1; and (4) measurement of preproET-1 mRNA by RT-PCR. Cells were exposed to 1 nmol/L Ang II for 15 minutes. This low concentration of Ang II increases sarcomere shortening by 29.2±3.7% (P<0.05). This PIE was abrogated by Na+/H+ exchanger or Na+/Ca2+ exchanger reverse mode inhibition. The production of ROS increased in response to Ang II treatment (
ROS respect to control: 68±15 fluorescence units; P<0.05). The Ang II–induced PIE and ROS production were blocked by the Ang II type 1 receptor blocker losartan, the nonselective ET-1 receptor blocker TAK044, the selective ETA receptor blocker BQ-123, or the ROS scavenger N-(2-mercapto-propionyl)glycine. Exogenous ET-1 (0.4 nmol/L) induced a similar PIE and increase in ROS production to those caused by Ang II. Immunostaining for preproET-1, BigET-1, and ET-1 was positive in cardiomyocytes. The preproET-1 mRNA abundance increased from 100±4.6% in control to 241.9±39.9% in Ang II–treated cells (P<0.05). We conclude that the PIE after exposure to 1 nmol/L Ang II is due to endogenous ET-1 acting through the ETA receptor and triggering ROS production, Na+/H+ exchanger stimulation, and Na+/Ca2+ exchanger reverse mode activation.
Key Words: membranes • ion channels • oxidative stress • receptors, angiotensin
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
There is a large amount of evidence to demonstrate that several effects believed to be attributed to angiotensin II (Ang II) are caused by the release/production of endothelin (ET) from different cells. Ito et al1 reported Ang II–induced hypertrophy in neonatal rat cardiomyocytes via the release/production of ET-1. The resulting hypertrophy was prevented by blocking ETA receptors or by using antisense oligonucleotides directed against preproET mRNA.1 In addition, Liang and Gardner,2 also working with rat neonatal myocytes, reported that the increase in brain natriuretic peptide (BNP) gene promoter activity induced by Ang II was prevented by blocking ETA receptors. Furthermore, in vivo studies have also shown that several effects of Ang II can be attenuated or abolished by blocking ET receptors.3,4 These findings strongly suggest that Ang II induces the release/production of ET-1 from cells which, acting in an autocrine fashion on ET receptors, trigger intracellular signals.
Ang II is a classical stimulus for NADPH oxidase and superoxide production,5–7 and a role for this intracellular signaling pathway has been proposed to explain several physiological effects of this peptide.5,8 Alternatively, the stimulation of NADPH oxidase by ET-19,10 and the involvement of this mechanism in determining some of its physiological effects11 have also been reported. The aim of the present study, which was performed in isolated adult cat ventricular myocytes was to determine: (1) whether the release/production of ET-1 by Ang II could be detected in adult cardiomyocytes, (2) its implications in cardiac contractility, and (3) the role played by reactive oxygen species (ROS) in this mechanism.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
The investigation conforms to the Guide for the Care and Use of Laboratory Animals published by the National Institutes of Health (Publication No. 85-23, revised 1996).
Myocytes Isolation
Cat ventricular myocytes were isolated according to the technique described previously.12
Sarcomere Shortening
To measure sarcomere length (SL), myocytes were placed in a perfusion chamber on the stage of an inverted microscope (Nikon) and continuously superfused with a solution containing (mM) 5 KCl, 118 NaCl, 1.2 MgSO4, 0.8 MgCl2, 1.35 CaCl2, 10 glucose, and 20 NaHCO3 (pH 7.4) after continuous bubbling with 5% CO2 and 95% O2. The myocytes were stimulated via 2-platinum electrodes on either side of the bath at 0.5 Hz. The SL was recorded by a specific software (Ion Wizard). The myocytes were observed using a video camera connected to the microscope. The SL was measured in a determined region of the myocyte. The software estimated the most frequent SL in that region using fast Fourier transform analysis (Ion Optix). The SL was measured at 30°C (TC2, Cell micro controls).
RNA Measurements by RT-PCR
Total RNA was isolated from the cardiomyocytes suspension using the RNeasy kit (Qiagen) according to the manufacturer’s instructions. RNA (0.8 µg) was reverse-transcribed using the Omniscript RT kit (Qiagen). A dilution of the resulting cDNA was used to quantify the relative content of mRNA by real-time PCR (iCycler iQ Real-Time PCR Detection System, Bio-Rad) using appropriate primers and SYBR Green as fluorescent probe.13 The following primers designed using Primer3 software were used: GAPDH: forward primer 5'-GGGTGTGAACCACGAGAAAT-3'; reverse primer 5'-CCACAGTCTTCTGAGTGGCA-3'; preproET-1: forward primer 5'-CAGACAAAGAACTCCGAGCC-3'; reverse primer 5'-GGTCTTGATGCTGTTGCTGA-3'; preproET-3: forward primer 5'-TCTCCACAGACACGCTTACG-3'; reverse primer 5'-TGACTTCAGCCTTTGACGTG-3'; and ET converting enzyme 1 (ECE-1): forward primer 5'-ACAAGCTCCTTTCTCGACCA-3'; 3'-GCCCAGGTTGTTTTCTGTGT-5'. PCR reactions were performed with TaqDNA polymerase (Invitrogen). Fluorescence data were acquired at the end of extension. A melt analysis was run for all of the products to determine the specificity of the amplification. The cycle threshold values for each gene were measured and calculated by computer software (iCycler IQ OSS, version 3.0a, Bio-Rad). The cycle threshold values for each gene were normalized by those GAPDH in the same sample. The primers for preproET-1 and GAPDH amplification were designed against the feline sequences. With respect to preproET-3 and ECE-1, the primers were designed against the rat sequence for these genes, because the feline sequences have not been published yet. For every experiment of real-time RT-PCR we obtained a melting curve of the amplified gene where it could be appreciated that only a specific product was amplified in each case with no primer-dimer formation.
Reactive Oxygen Species Measurements
Intracellular reactive oxygen species (ROS) production was measured by epifluorescence.14 The myocytes were incubated with 20 µmol/L dichloride-hydrofluorescein diacetate at room temperature for 1 hour. After washing with extracellular solution, the myocytes were placed on a perfusion chamber of an inverted microscope and excited at 480 nm. The emitted light was collected at 530 nm by a photomultiplier connected to a digital converter and stored in a computer (Ionoptix system). Before obtaining the signal, background fluorescence was subtracted.
Immunohistochemistry
Myocyte suspensions were fixed with 4% paraformaldehyde in phosphate buffer during 30 minutes and washed in 5% sucrose in phosphate-buffered saline (PBS). They were additionally incubated for 48 hours with antibodies against preproET (preproET-1, Bachem T-4306, rabbit polyclonal against fragment 94-09 or Bachem T-4751, rabbit polyclonal against fragment 110-30), BigET-1 (Bachem T-4572, rabbit polyclonal), and ET-1 (rabbit polyclonal, Bachem T-4050 or mouse monoclonal, clone TR.ET.48.5., Oncogene). Epitopes recognized by the antiserum against preproET-1 are not present in the smaller peptides. On the other hand, mature peptides are recognized by antibodies directed against their folded tertiary structure, which requires cleavage of the precursor molecules. Bound antibodies were detected with fluorescein-5-isothiocyanate–conjugated or lissamine rhodamine–conjugated anti-rabbit or anti-mouse IgGs (Jackson Immunoresearch Laboratories, West Grove, PA). Negative controls were made by replacing the primary antibody with its diluent.15
Glycerol mounted specimens were observed with the Laser Scanning System Radiance 2000 (BioRad) using the 488 line of the argon laser followed by the 543 line of a helium-neon laser and the emission filters HQ515/30 and HQ590/70, respectively. Optical sections (1 µm) were performed in the z axis, and images were processed using Lasersharp 2000 (BioRad) and Confocal Assistant Software (BioRad).
Statistics
Data are expressed as mean±SEM. Paired t test or repeated-measures 1-way ANOVA followed by Student–Newman–Keuls as post-hoc test were used as appropriate. A P<0.05 was considered to indicate significant differences.
Drugs
BQ123 and N-(2-mercapto-propionyl)glycine (MPG) were purchased from Sigma Chemical. TAK044 and HOE642 were kindly donated by Takeda Chemical and Aventis Pharma, respectively. KB-R7943 and Losartan were purchased from Tocris and Merk, Sharp, and Dhome, respectively.
The drugs used in the present study did not significantly affect basal contractility, with the exception of KB-R7943, which slightly but statistically significantly decreased basal contractility (SL shortening relative to initial SL were 5.1±0.4% in control and 4.2±0.5% in KB-R7943; P<0.05). Although the nonselective actions of this compound were mainly reported to be present at higher doses than that used in this study,16,17 we cannot rule out completely an action of this compound mediated through mechanisms other than the inhibition of the Na+/Ca2+ exchanger (NCX) reverse mode.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Figure 1A and 1B shows the positive inotropic effect (PIE) induced by 1 nmol/L Ang II on a continuous recording of a myocyte SL. The overall results obtained using 11 myocytes are shown in Figure 1C. Ang II induced an increase in SL shortening of
30% over basal levels, a PIE similar to that observed previously in cat papillary muscles.18 Figure 1D shows the concentration-effect curve of Ang II before and after the inhibition of the ET receptors by the nonselective blocker (blocks ETA/ETB) TAK044 (1 µmol/L). These results indicate that Ang II induces a concentration-dependent increase in sarcomere shortening, reaching the maximal effect at concentrations of 100 nmol/L (70% increase in basal contractility). The PIE induced by 500 nmol/L Ang II was lower than that observed with 100 nmol/L. ET receptor blockade induces a downward shift in the concentration–effect curve. This shift decreased the maximal effect of Ang II by 30% and cancelled the effect of 1 nmol/L Ang II. Therefore, these findings demonstrate that the PIE induced by 1 nmol/L Ang II is entirely attributable to an autocrine pathway involving an ET isoform. Concentrations >1 nmol/L are, perhaps, also acting through mechanisms other than the autocrine signals triggered by ET and are beyond the scope of the present study. Therefore, based on these results, we decided to analyze in detail the PIE induced by 1 nmol/L Ang II, which is mediated by the autocrine effect of ET.
|
Figure 2 shows that the PIE induced by 1 nmol/L Ang II was totally prevented by pretreatment of the myocytes with losartan (1 µmol/L) indicating that the release/production of ET is entirely attributable to stimulation of the Ang II type 1 (AT1) receptors. The effect of Ang II was also blunted by TAK044 and by the ETA blocker BQ123 (10 µmol/L; Figure 2). Therefore, 1 nmol/L of Ang II induces an increase in inotropism through release/production of ET after stimulation of its AT1 receptor.
|
We have shown previously that the PIE produced by 1 nmol/L Ang II in cat papillary muscles was totally prevented by the inhibition of the Na+/H+ exchanger (NHE)-1 or of the reverse mode of the NCX with the selective blockers HOE642 and KB-R7943, respectively.18 Results similar to those we reported previously in papillary muscles were obtained in the isolated myocytes (Figure 2). These results indicate that the activation of the NHE-1 and the stimulation of the NCX reverse mode are the only mechanisms by which that concentration of Ang II increases contractility.
To provide additional evidence that Ang II induces the release/production of ET from the myocyte, a number of experiments were performed in which isolated cat myocytes were exposed to 1 nmol/L Ang II, and preproET-1, preproET-3, and ECE-1 mRNAs were measured. After 15 minutes of exposure to Ang II, isolated cat ventricular myocytes showed a significant increase in the expression of preproET-1 mRNA (Figure 3A) but not in preproET-3 or ECE-1 mRNAs (Figure 3B and 3C). The Ang II–induced increase in preproET-1 mRNA was blocked by losartan (Figure 3A).
|
The concentrated cardiomyocyte suspension used in RT-PCR experiments could possibly be contaminated with nonmyocytes (fibroblasts, endothelial cells, etc), leading to a misinterpretation of the above results. Since the presence of the synthetic and processing machinery for ET in adult cardiomyocytes is controversial,19,20 and species differences might exist, we examined the potential presence of preproET-1, BigET-1, and ET-1 in cat cardiomyocytes by immunohistochemistry. The signal for preproET-1, BigET-1, and ET-1 was positive in cardiac myocytes (Figure 4). Positive staining was observed in 5 of 5 preparations. Immunostaining of isolated myocytes was obtained with all of the tested antibodies. No significant differences were observed with monoclonal or polyclonal anti-ET1 antibodies or with antibodies against different fragments of preproET-1. Immunoreactivity was present in the myocyte cytoplasm and absent from myocyte nuclei. The presence of immunoreactivity for preproET-1, BigET1, and ET-1 indicates that myocytes contain the synthetic and processing machinery for ET.
|
Since the generation of ROS by Ang II and/or ET-1 is well established,5–11 the effect of the ROS scavenger, MPG (1 mmol/L), on the PIE induced by the autocrine pathway of Ang II/ET was examined. This compound has been confirmed previously as a scavenger of the hydroxyl radical.21,22 The Ang II–induced PIE was totally prevented by pretreatment of myocytes with MPG (Figure 2).
To determine whether the ROS generated by Ang II results in the release/production of ET or whether ROS are acting downstream of ET, we examined the effect of the scavenger MPG on the PIE induced by exogenous ET-1 applied at a concentration (0.4 nmol/L) that resulted equipotent to the effect of 1 nmol/L Ang II. The PIE induced by 0.4 nmol/L ET-1 was inhibited by MPG (Figure 5), suggesting that the ROS are acting downstream to the activation of the ETA receptors by ET-1. Therefore, it appears that Ang II–induced ET-1 release stimulates an increase in ROS generation, which, in turn, triggers the increase in contractility. To evaluate this hypothesis, we assessed the role that ET-1 plays in ROS generation using epifluorescence techniques. Figure 6 shows that Ang II increased ROS production and that this increase was blunted by the nonselective blockade of ET receptors. A representative time course of these experiments is shown in Figure 6A. Figure 6B depicts the average increase in ROS after 15 minutes of Ang II treatment and the blocking effect of MPG, losartan, TAK044, or BQ123 on ROS production. The suppression of ROS production is consistent with the lack of Ang II–induced PIE in the presence of MPG. The possibility that TAK044 was acting as a scavenger was eliminated, because this compound failed to prevent the H2O2 (5 µmol/L)-induced increase in contractility (H2O2: 112±9%, n=4; H2O2+TAK044: 112±20%, n=4) and in ROS production (n=2, data not shown). Finally, we detected that 0.4 nmol/L ET-1 induced a similar increase in ROS production (ROS with respect to the control: 101±36 fluorescence units, n=5) to that produced by 1 nmol/L Ang II (Figure 6B). Thus, the data indicate that the production of ROS by Ang II is downstream to the Ang II–mediated release/production of ET-1.
|
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
The present study shows that Ang II induces the release/production of ET, which acts in an autocrine fashion to trigger ROS production and the intracellular signaling that leads to the Ang II–induced PIE. Herein, we detected the presence of preproET-1, BigET-1, and ET-1 in cardiomyocytes and found that Ang II was able to increase the preproET-1 mRNA level in the cardiomyocyte suspension. These results, together with the results of contractility and epifluorescence, which were performed in isolated myocytes in a flow-superfusing chamber, suggest that the interaction between Ang II and ET-1 involves an autocrine mechanism. It was reported recently that the hypertrophic action of tri-iodothyronine was completely abolished by cardiomyocyte-specific disruption of the ET-1 gene, which supports the autocrine action of this peptide.20 However, the potential presence of endothelial cells in the cardiomyocyte suspension used in the present study does not allow us to unequivocally disregard cells other than myocytes as putative sources of this peptide. Therefore, although unlikely, the possibility exists that the increase in ET-1 mRNA detected in response to Ang II could be produced, at least in part, by those nonmyocyte cells.
Although the RT-PCR experiments performed in the present work do not elucidate the mechanism by which Ang II induces the release/production of ET, they suggest that Ang II increases the de novo production of ET-1 in the isolated myocytes. It seems unlikely that the increase in preproET-1 mRNA levels in 15 minutes on Ang II exposure could explain the acute PIE induced by this peptide during that time frame, because production of mature ET-1 to be released by the myocyte would require a greater time period. However, it appears valid to assume, if the translation efficiency is not altered, that the Ang II–induced release of preformed ET-1 may be followed by an increase in its mRNA abundance to restore the intracellular pools. On the other hand, we were unable to detect changes in ECE-1 mRNA after 15 minutes of Ang II. This finding in adult cat myocytes is in accordance with the report of Xia and Karmazyn23 in cultured neonatal rat cardiomyocytes treated with Ang II in which an increase in preproET-1 mRNA without any change in ECE mRNA was detected.
In the present study, we have shown that TAK044 was able to completely block the PIE induced by 1 nmol/L Ang II and to partially inhibit the PIE induced by higher concentrations of this peptide. Two alternative explanations can be proposed for the inability of this blocker to suppress the PIE induced by the higher concentrations of Ang II tested: (1) incomplete blockade of ET receptors by TAK044, or (2) an inotropic effect mediated through a different mechanism than that triggered by the autocrine effect of ET-1. The latter possibility appears more likely considering that we12,24 and others25,26 have reported the stimulation of L-type calcium channels by concentrations of Ang II >1 nmol/L. Nevertheless, we would like to emphasize that concentrations of 1 nmol/L are similar to the physiological concentration range of Ang II in the interstitial myocardium27 and are perhaps the most relevant concentrations involved in pathophysiological actions.
It was reported recently that the production of ROS is not involved in the negative inotropic effect of 1 mmol/L Ang II observed in rat cardiomyocytes.28 The discrepancy in the opposite inotropic effects and in the involvement of ROS in these Ang II–induced effects could be attributed to species differences and/or to the significantly higher doses (1000-fold) used in rat myocytes.28 Furthermore, it is important to mention that ET receptors do not appear to play any role in the contractile effects of Ang II on rodent cardiomyocytes.29,30
The experiments in the present study were performed in the presence of extracellular HCO3–. Thus, the activation of the NHE would lead to an increase in intracellular Na+ in the absence of changes in intracellular pH,18,31,32 making it unlikely that changes in intracellular pH are the cause of the inotropic changes. The reverse mode of the NCX appears to be the mechanism playing a pivotal role in the Ang II–induced PIE, considering previous data obtained in papillary muscles18 and the data presented herein. In addition, the fact that the Ang II/ET pathway induced similar inotropic responses in multicellular preparations and in isolated myocytes and that, in both cases, these responses were prevented by NHE or NCX reverse-mode inhibition, enable us to suggest that the mechanism involved is of an autocrine nature, with the myocyte being the source and target of endogenous ET-1.
The finding that Ang II increases ROS production was expected according to several reports, which indicate that Ang II stimulates NADPH oxidase.5–7 Surprisingly, this augmented ROS production induced by Ang II was abolished by blocking ETA receptors. Nevertheless, the stimulation of NADPH oxidase by ET-1 has been reported previously9,10 in addition to the role played by ROS generation after ET-1 in determining the increase in contractility in the atria.11 Furthermore, in smooth muscle, vasopressin exerts the increase in superoxide levels through the action of endogenous ET-1.33 It remains currently unknown whether or not every effect of Ang II on ROS level is mediated through ET-1. However, based on the present findings and those of Ortiz et al,34 it appears that at least the effects of subpressor doses of Ang II are mediated through ET-1.
The mechanism by which Ang II releases/produces ET was not investigated in the present study. A recent study performed in smooth muscle myocytes suggested that Ang II induces the synthesis of ET-1 through the production of superoxide and the stimulation of extracellular-regulated kinase 1/2.8 However, in the present study, ROS production and the PIE induced by Ang II were abolished by blocking the ET receptors. However, the possibility that a certain amount of superoxide not detected in our ROS measurements is inducing ET synthesis and that the ET released by this mechanism is additionally increasing the production of the same or another ROS from the same or another source cannot be completely ruled out. In relation to this, Kimura et al7 suggested recently that low levels of superoxide produced by Ang II–induced NADPH oxidase activation might be responsible for triggering the production of a greater level of ROS by mitochondria (ROS-induced ROS-release mechanism). Moreover, in smooth muscle, it was reported that Ang II increases ROS production by the stimulation of the NADPH oxidase, whereas ET-1 increases ROS production through mitochondrial-derived pathways.35 In summary, although we can certainly conclude that the ET released/produced by Ang II is promoting the production of ROS, we cannot disregard the possibility that, in the Ang II/ET autocrine pathway described in the present work, ROS may be involved in multiple steps.
Perspectives
Our results in adult cat ventricular myocytes are, perhaps, relevant to the hypertrophic effect of Ang II. In the present work, we present evidence that Ang II, through its AT1 receptors, increased the release/production of ET-1, which enhances the activity of the NHE-1 through ROS generation. The central role of ET-1 in cardiac hypertrophy is well established. Inactivation of the genes for G
11 and Gq, which transduce the signal from the ET receptors, produces mice resistant to pressure-overload hypertrophy.36 Furthermore, cardiac hypertrophy induced by tri-iodotironine was inhibited by selective disruption of the myocytes ET-1 gene, suggesting that the mechanism involved the action of myocyte-derived ET-1.20 Finally, it is important to note that, after myocardial stretch, an activation of the Ang II/ET system occurred, leading to an enhanced activity of the NHE-1, which increases intracellular Na+ that promotes Ca2+ influx through the NCX reverse mode.37 This phenomenon, possibly the basis for the Anrep effect, might be one of the links between myocardial stretch and hypertrophy.
|
Acknowledgments |
|---|
This study was partly supported by grants (PICT 05-08512 to H.E.C. and PICT 12412 to M.C.C.d.H.) of the Agencia Nacional de Promoción Científica y Tecnológica de Argentina. HOE642 and TAK044 were kindly provided by Aventis Pharma (Germany) and Takeda Pharmaceuticals (Japan), respectively. H.E.C., I.L.E., M.C.C.d.H., A.M.S., and E.A.A. are Established Investigators of Consejo Nacional de Investigaciones Científicas y Técnicas, Argentina. M.C.V.-A., V.T., and C.G. are Fellows of Consejo Nacional de Investigaciones Científicas y Técnicas, Argentina. M.V.C. is a Fellow of the Agencia de Promoción Científica de Argentina.
Received December 7, 2005; first decision December 16, 2005; accepted January 24, 2006.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
- Ito H, Hirata Y, Adachi S, Tanaka M, Tsujino M, Koike A, Nogami A, Murumo F, Hiroe M. Endothelin-1 is an autocrine/paracrine factor in the mechanism of angiotensin II-induced hypertrophy in cultured rat cardiomyocytes. J Clin Invest. 1993; 92: 398–403.[Medline] [Order article via Infotrieve]
- Liang F, Gardner DG. Autocrine/paracrine determinants of strain-activated brain natriuretic peptide gene expression in cultured cardiac myocytes. J Biol Chem. 1998; 273: 14612–14619.
[Abstract/Free Full Text] - Rajagopalan S, Laursen JB, Borthayre A, Kurz S, Keiser J, Haleen S, Giaid A, Harrison DG. Role for endothelin-1 in angiotensin II-mediated hypertension. Hypertension. 1997; 30: 29–34.
[Abstract/Free Full Text] - Ortiz MC, Sanabria E, Manriquez MC, Romero JC, Juncos LA. Role of endothelin and isoprostanes in slow pressor responses to angiotensin II. Hypertension. 2001; 37: 505–510.
[Abstract/Free Full Text] - Lavigne MC, Malech HL, Holland SM, Leto TL. Genetic demonstration of p47phox-dependent superoxide anion production in murine vascular smooth muscle cells. Circulation. 2001; 104: 79–84.
[Abstract/Free Full Text] - Giordano FJ. Oxygen, oxidative stress, hypoxia, and heart failure. J Clin Invest. 2005; 115: 500–508.[CrossRef][Medline] [Order article via Infotrieve]
- Kimura S, Zhang GX, Nishiyama A, Shokoji T, Yao L, Fan YY, Rahman M, Suzuki T, Maeta H, Abe Y. Role of NAD(P)H oxidase- and mitochondria-derived reactive oxygen species in cardioprotection of ischemic reperfusion injury by angiotensin II. Hypertension. 2005; 45: 860–866.
[Abstract/Free Full Text] - Hong HJ, Chan P, Liu JC, Juan SH, Huang MT, Lin JG, Cheng TH. Angiotensin II induces endothelin-1 gene expression via extracellular signal-regulated kinase pathway in rat aortic smooth muscle cells. Cardiovasc Res. 2004; 61: 159–168.
[Abstract/Free Full Text] - Li L, Fink GD, Watts SW, Northcott CA, Galligan JJ, Pagano PJ, Chen AF. Endothelin-1 increases vascular superoxide via endothelin(A)-NADPH oxidase pathway in low-renin hypertension. Circulation. 2003; 107: 1053–1058.
[Abstract/Free Full Text] - Callera GE, Touyz RM, Teixeira SA, Muscara MN, Carvalho MH, Fortes ZB, Nigro D, Schiffrin EL, Tostes RC. ETA receptor blockade decreases vascular superoxide generation in DOCA-salt hypertension. Hypertension. 2003; 42: 811–817.
[Abstract/Free Full Text] - Sand C, Peters SL, Pfaffendorf M, van Zwieten PA. The influence of endogenously generated reactive oxygen species on the inotropic and chronotropic effects of adrenoceptor and ET-receptor stimulation. Naunyn Schmiedebergs Arch Pharmacol. 2003; 367: 635–639.[CrossRef][Medline] [Order article via Infotrieve]
- Aiello EA, Cingolani HE. Angiotensin II stimulates cardiac L-type Ca2+ current (ICa) by a Ca2+ and protein kinase C-dependent mechanism. Am J Physiol. 2001; 280: H1528–H1536.
- Ennis IL, Garciarena CD, Perez NG, Dulce RA, Camilion de Hurtado MC, Cingolani HE. Endothelin isoforms and the response to myocardial stretch. Am J Physiol. 2005; 288: H2925–H2930.
- Keller A, Mohamed A, Drose S, Brandt U, Fleming I, Brandes RP. Analysis of dichlorodihydrofluorescein and dihydrocalcein as probes for the detection of intracellular reactive oxygen species. Free Radic Res. 2004; 38: 1257–1267.[CrossRef][Medline] [Order article via Infotrieve]
- Torbidoni V, Iribarne M, Ogawa L, Prasanna G, Suburo AM. Endothelin-1 and endothelin receptors in light-induced retinal degeneration. Exp Eye Res. 2005; 81: 265–275.[Medline] [Order article via Infotrieve]
- Hobai IA, O’Rourke B. The potential of Na+/Ca2+ exchange blockers in the treatment of cardiac disease. Expert Opin Investig Drugs. 2004; 13: 653–664.[CrossRef][Medline] [Order article via Infotrieve]
- Watano T, Kimura J, Morita T, Nakanishi H. A novel antagonist, No. 7943, of the Na+/Ca2+ exchange current in guinea-pig cardiac ventricular cells. Br J Pharmacol. 1996; 119: 555–563.[Medline] [Order article via Infotrieve]
- Pérez NG, Villa-Abrille MC, Aiello EA, Dulce RA, Cingolani HE, Camilión de Hurtado MC. A low dose of angiotensin II increases inotropism through activation of reverse Na+/Ca2+ exchange by endothelin release. Cardiovasc Res. 2003; 60: 589–597.[CrossRef][Medline] [Order article via Infotrieve]
- Preisig-Muller R, Mederos y Schnitzler M, Derst C, Daut J. Separation of cardiomyocytes and coronary endothelial cells for cell-specific RT-PCR. Am J Physiol. 1999; 277: H413–H416.[Medline] [Order article via Infotrieve]
- Shohet RV, Kisanuki YY, Zhao XS, Siddiquee Z, Franco F, Yanagisawa M. Mice with cardiomyocyte-specific disruption of the endothelin-1 gene are resistant to hyperthyroid cardiac hypertrophy. Proc Natl Acad Sci U S A. 2004; 101: 2088–2093.
[Abstract/Free Full Text] - Takano H, Tang XL, Qiu Y, Guo Y, French BA, Bolli R. Nitric oxide donors induce late preconditioning against myocardial stunning and infarction in conscious rabbits via an antioxidant-sensitive mechanism. Circ Res. 1998; 83: 73–84.
[Abstract/Free Full Text] - Tanonaka K, Iwai T, Motegi K, Takeo S. Effects of N-(2-mercaptopropyonil)-glycine on mitochondrial function in ischemic-reperfused heart. Cardiovasc Res. 2003; 57: 416–425.
[Abstract/Free Full Text] - Xia Y, Karmazyn M. Obligatory role for endogenous endothelin in mediating the hypertrophic effects of phenylephrine and angiotensin II in neonatal rat ventricular myocytes: evidence for two distinct mechanisms for endothelin regulation. J Pharmacol Exp Ther. 2004; 310: 43–51.
[Abstract/Free Full Text] - Petroff MG, Aiello EA, Palomeque J, Salas MA, Mattiazzi A. Subcellular mechanisms of the positive inotropic effect of angiotensin II in cat myocardium. J Physiol. 2000; 529: 189–203.
[Abstract/Free Full Text] - Freer RJ, Pappano AJ, Peach MJ, Bing KT, McLean MJ, Vogel S, Sperelakis N. Mechanism for the postive inotropic effect of angiotensin II on isolated cardiac muscle. Circ Res. 1976; 39: 178–183.
[Abstract/Free Full Text] - Ichiyanagi O, Ishii K, Endoh M. Angiotensin II increases L-type Ca2+ current in gramicidin D-perforated adult rabbit ventricular myocytes: comparison with conventional patch-clamp method. Pflugers Arch. 2002; 444: 107–116.[CrossRef][Medline] [Order article via Infotrieve]
- Dell’Italia LJ, Meng QC, Balcells E, Wei CC, Palmer R, Hageman GR, Durand J, Hankes GH, Oparil S. Compartmentalization of angiotensin II generation in the dog heart. Evidence for independent mechanisms in intravascular and interstitial spaces. J Clin Invest. 1997; 100: 253–258.[Medline] [Order article via Infotrieve]
- Palomeque J, Sapia L, Hajjar RJ, Mattiazzi A, Vila Petroff MG. Agiotensin II-induced negative inotropy in rat ventricular myocytes: Role of reactive oxygen species and p38 MAPK. Am J Physiol. 2006; 290: H96–H106.
- Delbridge LM, Morgan TO, Harris PJ. Effects of endothelin-1 on the contractility of cardiomyocytes from the spontaneously hypertensive rat. Clin Exp Pharmacol Physiol. 1995; 22: 755–762.[Medline] [Order article via Infotrieve]
- Kedzierski RM, Grayburn PA, Kisanuki YY, Williams CS, Hammer RE, Richardson JA, Schneider MD, Yanagisawa M. Cardiomyocyte-specific endothelin A receptor knockout mice have normal cardiac function and an unaltered hypertrophic response to angiotensin II and isoproterenol. Mol Cell Biol. 2003; 23: 8226–8232.
[Abstract/Free Full Text] - Camilion de Hurtado MC, Alvarez BV, Perez NG, Ennis IL, Cingolani HE. Angiotensin II activates Na+-independent Cl–HCO3- exchange in ventricular myocardium. Circ Res. 1998; 82: 473–481.
[Abstract/Free Full Text] - Luers C, Fialka F, Elgner A, Zhu D, Kockskamper J, von Lewinski D, Pieske B. Stretch-dependent modulation of [Na+]i, [Ca2+]i, and pHi in rabbit myocardium-a mechanism for the slow force response. Cardiovasc Res. 2005; 68: 454–463.
[Abstract/Free Full Text] - Li L, Galligan JJ, Fink GD, Chen AF. Vasopressin induces vascular superoxide via endothelin-1 in mineralocorticoid hypertension. Hypertension. 2003; 41: 663–668.
[Abstract/Free Full Text] - Ortiz MC, Manriquez MC, Romero JC, Juncos LA. Antioxidants block angiotensin II-induced increases in blood pressure and endothelin. Hypertension. 2001; 38: 655–659.
[Abstract/Free Full Text] - Touyz RM, Yao G, Viel E, Amiri F, Schiffrin EL. Angiotensin II and endothelin-1 regulate MAP kinases through different redox-dependent mechanisms in human vascular smooth muscle cells. J Hypertens. 2004; 22: 1141–1149.[CrossRef][Medline] [Order article via Infotrieve]
- Wettschureck N, Rutten H, Zywietz A, Gehring D, Wilkie TM, Chen J, Chien KR, Offermanns S. Absence of pressure overload induced myocardial hypertrophy after conditional inactivation of Gq/G11 in cardiomyocytes. Nat Med. 2001; 7: 1236–1240.[CrossRef][Medline]
[Order article via Infotrieve]
- Cingolani HE, Pérez NG, Aiello EA, Camilión de Hurtado MC. Intracellular signaling following myocardial stretch: An autocrine/paracrine loop. Regulatory Peptides. 2005; 128: 211–220.[CrossRef][Medline] [Order article via Infotrieve]
This article has been cited by other articles:
 |
|
 |
|
  Q. Zeng, Q. Zhou, F. Yao, S. T. O'Rourke, and C. Sun Endothelin-1 Regulates Cardiac L-Type Calcium Channels via NAD(P)H Oxidase-Derived Superoxide J. Pharmacol. Exp. Ther., September 1, 2008; 326(3): 732 - 738. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. J. Welch Angiotensin II-Dependent Superoxide: Effects on Hypertension and Vascular Dysfunction Hypertension, July 1, 2008; 52(1): 51 - 56. [Full Text] [PDF]
|
|
|
|
 |
|
 F. Syeda, E. Tullis, A. S. Slutsky, and H. Zhang Human neutrophil peptides upregulate expression of COX-2 and endothelin-1 by inducing oxidative stress Am J Physiol Heart Circ Physiol, June 1, 2008; 294(6): H2769 - H2774. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. J. de Beer, O. Sorop, D. A. Pijnappels, D. H. Dekkers, F. Boomsma, J. M. J. Lamers, D. J. Duncker, and D. Merkus Integrative control of coronary resistance vessel tone by endothelin and angiotensin II is altered in swine with a recent myocardial infarction Am J Physiol Heart Circ Physiol, May 1, 2008; 294(5): H2069 - H2077. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Defer, A. Azroyan, F. Pecker, and C. Pavoine TNFR1 and TNFR2 Signaling Interplay in Cardiac Myocytes J. Biol. Chem., December 7, 2007; 282(49): 35564 - 35573. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. I. Caldiz, C. D. Garciarena, R. A. Dulce, L. P. Novaretto, A. M. Yeves, I. L. Ennis, H. E. Cingolani, G. Chiappe de Cingolani, and N. G. Perez Mitochondrial reactive oxygen species activate the slow force response to stretch in feline myocardium J. Physiol., November 1, 2007; 584(3): 895 - 905. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. E. Cingolani and I. L. Ennis Sodium-Hydrogen Exchanger, Cardiac Overload, and Myocardial Hypertrophy Circulation, March 6, 2007; 115(9): 1090 - 1100. [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||