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CARDIOVASCULAR
Department of Internal Medicine, Section of Cardiology, Southern Arizona Veterans Affairs Health Care System (H.T., S.G., M.G.) and the Sarver Heart Center (H.T., J.W., S.G., M.G.), University of Arizona, Tucson, Arizona
Received May 22, 2003; accepted September 8, 2003.
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). In contrast, therapy that improves endothelial function also attenuates LV remodeling and enhances survival in heart failure (The SOLVD Investigators, 1988; Kubo et al., 1991; Katz et al., 1992; Drexler et al., 1993). Thus restoring abnormal endothelial-dependent vasorelaxation may be an important therapeutic goal in the treatment of heart failure.
Although it is well documented that angiotensin-converting enzyme inhibition reverses endothelial dysfunction in patients with heart failure and accentuates endothelial function in normal subjects, it is not clear what effect AT1 blockade has on endothelial function in heart failure. Given the ability of ANG II to promote endothelial NO synthesis through the stimulation of the angiotensin subtype 2 receptor (AT2) (Weimer et al., 1993; Olson et al., 1997; Hennington et al., 1998), we speculated that angiotensin receptor blockade could improve endothelial-dependent vasodilation, at least in part, via NO. This hypothesis is based on data in hypertensive animal models showing that AT1 receptor antagonism restores impaired NO-mediated endothelial vasorelaxation (Cachofeiro et al., 1995; Maseo et al., 1996). Furthermore, stimulation of the AT2 receptors by unbound ANG II has been reported to induce vasodilation (Maseo et al., 1996).
We designed this study to investigate the role of AT1 and AT2 on endothelial function in heart failure using angiotensin receptor blockade as a pharmacologic tool. In brief, we treated infarcted rats with candesartan and measured cardiovascular hemodynamics and vasorelaxation in aortic rings from these animals. To clarify the mechanism(s) underlying the hemodynamic responses at the cellular level, we examined the effects of candesartan and a specific AT2 receptor antagonist on endothelial nitric-oxide synthase (eNOS) protein expression in bovine pulmonary endothelial cells. Our data showed that AT1 receptor blockade enhances vasomotor relaxation in heart failure by improving endothelial-dependent vasorelaxation through increased NO bioavailability. Our data suggest that this may be accomplished by an AT2 receptor-mediated up-regulation of eNOS protein in the endothelium.
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Materials and Methods |
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Myocardial Infarction Model. Adult male Sprague-Dawley rats underwent experimental MI by standard techniques developed in our laboratory (Raya et al., 1989, 1991; Litwin et al., 1991; Gaballa and Goldman, 1999; Gaballa et al., 1999). In brief, rats were anesthetized with inactin and a left thoracotomy was performed, the heart expressed from the thorax, and a ligature placed around the proximal left coronary artery. The heart was then returned to the chest and the thorax closed.
Hemodynamics. At 7 days and 8 weeks after randomization to candesartan or placebo, rats were anesthetized with thiobutabarbitol (100 mg/kg, i.p.). A 1-mm micromanometer tipped catheter (Millar Instruments, Houston, TX) was inserted into the right carotid artery. The catheter was advanced into the aorta and then into the left ventricle under constant pressure monitoring. A zero pressure baseline was obtained by placing the pressure sensor in 37°C saline before measurements. After a 15-min stabilization period, LV pressures were recorded and digitized at 1000 Hz, using a computer equipped with an analog-to-digital converter and customized software. From these data, heart rate, the first derivative of LV pressure with respect to time (dP/dt), and systemic resistance (SR) was derived according to previously described methods (Raya et al., 1989, 1991; Litwin et al., 1991; Gaballa and Goldman, 1999; Gaballa et al., 1999). Phasic aortic pressure was measured, and the electronic mean was determined after withdrawal of the LV catheter into the aortic root.
Vasorelaxation in Arterial Segments. The vasorelaxation response of thoracic aortic segments was examined using standard techniques (Gaballa et al., 1998, 1999). In brief, a 3.0- to 3.5-mm section of the ascending thoracic aorta was mounted on a ring apparatus attached to a force transducer. The arterial segment was attached to stainless steel wire stirrups with one wire fixed in place and the other attached to the transducer. The tissue was suspended ina37°C bath of Krebs-Henseleit solution suffused with 95% oxygen and 5% carbon dioxide. Rings were stretched to a resting tension of 1 g and allowed to equilibrate for 45 min. Rings were precontracted with 60 mM KCl for 30 min and then returned to Krebs-Henseleit solution and allowed to equilibrate again for 45 min. Rings were constricted with phenylephrine (3 µM) until a steady-state constriction is obtained. Dose-response studies were performed with increasing concentrations of ACh (10–9–10–4 M), and the resulting vasorelaxation was recorded. The ACh dose-response studies were repeated in the presence of L-NAME (200 µM).
Endothelial Cell Culture. We used a bovine pulmonary artery endothelial cell line previously reported by our laboratory (Bates et al., 2002). Confluent bovine pulmonary artery endothelial cells were used between passages 10 and 16. These cells tested negative for Mycoplasma infection using Mycofluor Mycoplasma detection kit (Molecular Probes, Eugene, OR). Cells were grown in an incubator at 37°C in the presence of 7% CO2 in air and 100% humidity. When endothelial cells exhibited the cobble stone shape, confluent endothelial cells were treated with 10 and 20 µM concentrations of candesartan for 24 h with and without 20 µM PD. Cells were incubated at 37°C in the presence of 7% CO2 in air and 100% humidity. For protein analysis, cells were separated with trypsin, and protein was measured using the Lowry technique (Lowry et al., 1951).
Determination of eNOS Protein Levels. eNOS protein levels are measured using immunoblot techniques as previously described (Gaballa et al., 1998, 1999). In brief, after incubation for 24 h, untreated cells and cells treated with candesartan at 10 and 20 µM concentrations are collected along with cells treated with a combination of 20 µM candesartan and 20 µM PD. Cell lysates are centrifuged at 10,000g at 4°C for 20 min. The supernatant is fractionated using 8% SDS-polyacrylamide gel electrophoresis after mixing with an equal volume of 2% SDS/1% 
-mercaptoethanol. Proteins are then transferred to nitrocellulose membranes. After blocking the membranes for 1 h at room temperature with 5% nonfat dry milk and 0.1% Tween 20, the membranes are incubated with a mouse anti-eNOS IgG antibody (1:1000) (Transduction Laboratories, Lexington, KY). The eNOS is then detected with horseradish peroxidase-labeled rabbit anti-mouse IgG secondary antibody (1:2000).
Statistical Analysis. Data are expressed as mean ± S.D. In both physiological and biochemical measurements, the effects of candesartan and PD treatment on normal animals and animals with heart failure are determined by using two-way analysis of variance followed by the Student's t test to compare the candesartan- and PD-treated animals to the untreated animals.
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, 1991; Litwin et al., 1991; Gaballa and Goldman, 1999; Gaballa et al., 1999; Thai et al., 1999). In the present study, we infarcted 100 rats to obtain the 48 rats reported here. We did not measure infarct size in this report, but in our previous work, we have measured infarct size using histologically defined endocardial/epicardial infarct circumferences (Raya et al., 1989; Litwin et al., 1991). In those studies, we showed that rats with LV enddiastolic pressures in the range reported here (15–20 mm Hg) had infarct sizes ranging from 35 to 40% of the left ventricle (Thai et al., 1999). Effects of AT1 and AT2 Receptor Blockade on Systemic Hemodynamics in Normal Rats. To determine the hemodynamic effects of candesartan, we treated normal rats for 8 weeks. Compared with untreated normal rats, treatment for 8 weeks with candesartan lowered mean arterial pressure (MAP) (P < 0.05) from 121 ± 6 to 104 ± 8 mm Hg with no change in LV end-diastolic pressure; the addition of PD lowered MAP (P < 0.05) by an additional 31% (Fig. 1). To define the effects of stimulating the AT2 receptor, we infused ANG II in untreated animals and candesartan-treated normal animals. Angiotensin II infusion increased MAP (P < 0.05) in normal rats from 121 ± 6 to 134.7 ± 6 mm Hg; this response was increased (P < 0.05) by 10% with the addition of the NO synthase inhibitor, L-NAME. Angiotensin II infusion in normal rats treated with candesartan resulted in a similar response; an initial increase in MAP (P < 0.05) followed by a decrease with candesartan (P < 0.05) (Fig. 2). This response demonstrates that stimulation of the AT2 receptor increases the bioavailability of NO.
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The effects of candesartan in the heart are seen in Figs. 3, 4, 5. In normal rats, candesartan decreased LV dP/dt from 7938 ± 707 to 6489 ± 808 mm Hg/s (P < 0.05); the addition of PD further reduced LV dP/dt to 5124 ± 2260 mm Hg/s, (P < 0.05) (Fig. 3). In candesartan-treated normal rats, ANG II infusion (alone and with L-NAME) reduced LV dP/dt by 12 and 24%, respectively (P < 0.05; Fig. 4). In normal rats, the addition of ANG II and L-NAME increased SR by 58% (P < 0.05; Fig. 5). Candesartan resulted in a paradoxical lowering of SR (P < 0.05) in the presence of ANG II (Fig. 5).
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The effects of AT2 receptor blockade were evaluated in pilot dose-ranging studies of PD (0.02–20 mg/kg) in normal rats alone and during an ANG II infusion. There were no changes in LV systolic pressure, LV end-diastolic pressure, or LV dP/dt. Our interpretation of these data are that with increased circulating ANG II, in the absence of AT1 receptor blockade, the overwhelming effect of AT1 receptor stimulation masks any effect of AT2 receptor blockade. This is similar to what occurs in heart failure with ANG II inducing systemic vasoconstriction.
Effects of AT1 Receptor Blockade on Systemic Hemodynamics in MI Rats. These studies were done to define the hemodynamic effects of candesartan in infarcted rats in acute and chronic conditions. Candesartan at both 7 days and 8 weeks lowered systolic blood pressure (122 ± 22 versus 74 ± 16 and 73 ± 10 mm Hg) and LV dP/dt (5914 ± 1294 versus 2857 ± 1672 versus 3175 ± 769 mm Hg/s (P < 0.05) (Figs. 6 and 7). Candesartan lowered LV end-diastolic pressure only at 8 weeks (16.9 ± 9.7 versus 11.2 ± 5.7 versus 6.9 ± 5.3 mm Hg; Fig. 8).
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Effects of AT1 and AT2 Receptor Blockade on Endothelial-Dependent Vasorelaxation. The effects of AT1 and AT2 receptor blockade on endothelial-dependent vasorelaxation are seen in Figs. 9 and 10. In normal rats treated with candesartan, there was a dose-dependent endothelial-mediated vasorelaxation response to ACh (Fig. 9). The enhanced vasorelaxation response occurred at concentrations of ACh greater than 10–6 M with peak vasorelaxation observed at 10–4 M. In animals treated with a combination of PD + candesartan, the enhanced vasorelaxation response to ACh was reduced (P < 0.05) to baseline level in normal rats without candesartan (Fig. 9). The addition of L-NAME completely abolished the vasorelaxation response in rats treated with candesartan. Untreated MI rats had a decreased vasorelaxation response (P < 0.05) to ACh. Whereas 7 days of candesartan did not alter vasorelaxation, 8 weeks of candesartan increased ACh-mediated vasorelaxation (P < 0.05) in MI rats by 84 and 86% at 10–4 and 10–5 M ACh, respectively. This enhanced vasorelaxation seen with chronic candesartan therapy was abolished in the presence of L-NAME (Fig. 10).
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Effects of AT1 and AT2 Receptor Blockade on eNOS Protein. Figure 11 displays the levels of eNOS protein in endothelial cells treated with candesartan; increased levels of eNOS (P < 0.05) were demonstrated at the 20 µM dose (28.9 ± 2.6 versus 16.1 ± 3.7, intensity units/µg of protein, P < 0.05). Endothelial cells treated with 10 µM candesartan did not have any effect on eNOS (not shown). Cells incubated with both PD and candesartan had a reduction in eNOS protein content (P < 0.05).
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Our study illustrates the association between angiotensin receptor blockade of ANG II via binding to the AT2 receptor and improving endothelial function secondary to eNOS upregulation. The addition of PD, an AT2 antagonist, significantly reduced eNOS protein content. These findings are important and may be clinically relevant because afterload reduction alone with other arterial vasodilators that do not directly affect endothelial function have had minimal effect on LV remodeling and mortality in patients with congestive heart failure. In contrast, therapy that improves endothelial function, i.e., angiotensin-converting enzyme inhibition, clearly attenuates LV remodeling and enhances survival in patients with heart failure. The effect of candesartan on systolic function as reflected in changes in LV dP/dt is not clear. Since LV dP/dt is dependent on both afterload and preload, an expected result would be a decrease in LV dP/dt with afterload reduction with candesartan.
Our study demonstrates improvement in endothelial function due to eNOS up-regulation via angiotensin receptor blockade of ANG II binding to the AT2 receptor. This finding is consistent with previous studies that have shown that the decrease in the peripheral resistance with AT1 receptor antagonism is dependent on an intact AT2 receptor signaling mechanism (Ichiki et al., 1995; Munzenmaier and Greene, 1996; Gigante et al., 1998). Previous work has shown that AT2 receptor activation mediates NO production (Siragy and Carey, 1997). In rats on a salt-restricted diet, inducing a significant ANG II response, AT2 receptor blockade reversed the hypotensive effect of losartan therapy (Munzenmaier and Greene, 1996). In a similar attempt to evaluate the role of AT2 receptor blockade in an intact animal model simulating a hyper-renin state, we performed a dose-response study of PD (0.02–20 mg/kg) in normal animals with constant ANG II infusion. The usual increase in MAP and LV dP/dt response to ANG II was seen; however, the addition of PD had no additive effects on these hemodynamic variables. The data in our present study suggest that the beneficial hemodynamic effects of AT1 receptor antagonism in heart failure is mediated in part by AT2 receptor antagonism (Gigante et al., 1998). Whereas it is clear that previous investigators have demonstrated an improvement in endothelial function with the use of angiotensin-converting enzyme inhibition, particularly among patients with heart failure (Kubo et al., 1991; Ontkean et al., 1992), the mechanism has not been clearly defined, but NO was reported to play a role in this improvement. Furthermore, other clinical studies have demonstrated a benefit using pharmacologic therapy designed to improve NO activity in patients with heart failure and coronary artery disease by showing that either treatment with a NO precursor, such as L-arginine, or an angiotensin-converting enzyme inhibitor improved endothelial function (Hirooka et al., 1994; Mancini et al., 1996).
Our study demonstrated that the improvement in endothelial-dependent vasorelaxation from candesartan is possibly mediated via NO, because inhibition of NO synthesis with L-NAME abolishes vasorelaxation in both normal rats and candesartan-treated rats with heart failure. This effect appears to be associated with an up-regulation of eNOS, which has been previously described with AT2 receptor stimulation (Weimer et al., 1993; Cachofeiro et al., 1995; Maseo et al., 1996). We speculated that, since candesartan selectively inhibits AT1 receptors, it has the potential to promote selective binding of angiotensin II to the free AT2 receptors, effectively leading to AT2 receptor stimulation and potential up-regulation of eNOS. This possibility has been suggested by data that showed post-MI remodeling retarded by AT1 receptor blockade via increased stimulation of growth inhibitory AT2 receptors by displaced ANG II (van Kats et al., 2000). The stimulation of free AT2 receptors is magnified in ischemic heart failure patients since there is already an up-regulation of AT1 receptors. This up-regulation of AT1 receptor is accompanied by a sequestration of ANG II in the noninfarcted left ventricle, increasing the bioavailability of tissue ANG II to bind to unopposed AT2 receptors (Sun and Webber, 1994; Nio et al., 1995; van Kats et al., 1997). This hypothesis is consistent with our vasorelaxation data but may appear inconsistent with data obtained from cultured endothelial cells, since we found up-regulation of eNOS in endothelial cells incubated with candesartan, which implies a de novo effect directly from candesartan itself. The explanation for this finding is unclear, since ANG II was absent from the cell culture system to support the hypothesis of unopposed stimulation of free AT2 receptors. One potential explanation for the finding in cell culture may be due to ANG II receptor cross talk where overexpression of AT2 receptors leads to an attenuated pressor response from AT1 receptor stimulation, possibly from suppression of the AT1 receptor (Masaki et al., 1998). Conceivably, chronic inhibition of AT1 receptors may lead to increased vasorelaxation via the AT2 receptor pathway.
As opposed to angiotensin-converting enzyme inhibition, the effects of angiotensin receptor antagonism on NO-mediated endothelial function in heart failure have not been described in detail. In addition, the signaling pathway of the AT2 receptor is unclear. There appears to be two distinct signaling cascades that promote vasorelaxation via AT2 receptor stimulation. One pathway, similar to the angiotensin-converting enzyme inhibition-mediated prevention of bradykinin degradation, is thought to involve increased NO bioavailability. The evidence that this is mediated via AT2 receptor activation is supported by data showing that ANG II infusion in conscious rats resulted in a 2-fold increase in renal cortex interstitial fluid cGMP. This response was attenuated by coadministration of the same AT2 receptor antagonist used in this study or the nitric-oxide synthase inhibitor, L-NAME (Siragy and Carey, 1997). This increase in NO bioavailability may be mediated via bradykinin production because bradykinin receptor blockade in spontaneous hypertensive rats attenuated the increase in cGMP mediated by constant ANG II infusion (Gohlke et al., 1998). Other investigators have proposed a mechanism in which AT2 receptor activation leads to conformational alteration in the Na+/H+ pump promoting acidification of the intracellular environment, leading to activation of kininogenase and subsequently increased bradykinin bioavailability (Tsutsumi et al., 1999). A second pathway that has been proposed through which the AT2 receptor could promote vasorelaxation is via dephosphorylation of vascular contractile proteins, such as calcium calmodulin kinase and myosin light chain kinase, and by phospholipase A2 modulated activation of the serine/threonine phosphatase (Hayashida et al., 1996; Volpe and De Paolis, 2000). It is not clear whether this dephosphorylation pathway has a significant role in altering vasomotor tone in a homeostatic environment, specifically endothelial-mediated vasorelaxation.
The use of an angiotensin receptor blocker in heart failure has recently been examined in several clinical trials, the hallmark of which is the Val HeFT study (Cohn and Tognoni, 2001). In this trial, the addition of an angiotensin receptor blocker valsartan to standard therapy was shown to decrease the combined endpoint of mortality and morbidity in heart failure. These effects appear to be independent of blood pressure reduction; however, the issue of how much blood pressure reduction in heart failure is necessary remains controversial. The current clinical guidelines favor maintaining patients with heart failure in the normotensive range, with some clinicians advocating the maintenance of as low a systolic blood pressure as possible without causing significant symptoms among patients. The blood pressure reduction seen in our study is clearly beyond the normotensive range. We purposely chose this approach to achieve significant hemodynamic differences among the treated and untreated animals, since the untreated animals are within the normotensive range themselves. The significant differences in blood pressure served to reassure us that the treated animals clearly received candesartan. With the substantial reduction in blood pressure achieved among the treated animals in our study, there are concerns that the improvement in endothelial function with candesartan may only be achieved with very high plasma concentrations. In addition, since candesartan is a nanomolar AT1 receptor antagonist and very high concentrations (10 µM) were required to demonstrate a significant increase in eNOS from the endothelial cell cultures in our study, it raises the possibility that eNOS up-regulation would only be seen at high candesartan doses. This does not appear to be the case, since there are several recent clinical trials that demonstrate a significant improvement in endothelial function with therapeutic doses of angiotensin receptor blockade in hypertensive patients and normotensive volunteers (Ghiadoni et al., 2000; Tran et al., 2001; Phoon and Howes, 2002; Klingbeil et al., 2003). The improvement in endothelial function in several of these studies appear to be independent of effects on blood pressure.
It is clear that AT1 receptor blockade has beneficial effects in heart failure. Although the clinical concept is that this benefit is due to more neurohormonal blockade, our data would suggest that perhaps the benefit of angiotensin-receptor blockade might be related to AT2-mediated increase in NO bioavailability and improvements in endothelial function. We have previously demonstrated that an improvement in endothelial function, with eNOS gene transfer can decrease vascular resistance in heart failure (Gaballa and Goldman, 1999). Our current study shows how we can potentially affect the same response using pharmacologic agents that are widely available and easier to administer than gene therapy.
In conclusion, the findings from our study suggest that angiotensin-receptor blockade enhances vasomotor relaxation in normal and heart failure settings. This is accomplished by inhibiting ANG II and by a second mechanism of enhancing endothelial-dependent vasorelaxation through increased NO bioavailability, via up-regulation of eNOS protein. The possible mechanisms may be unopposed stimulation of free AT2 receptors as well as a possible de novo effect of candesartan on the endothelium, directly stimulating eNOS synthesis.
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Acknowledgements |
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Footnotes |
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ABBREVIATIONS: ANG II, angiotensin II; ACh, acetylcholine; AT1, angiotensin subtype 1; AT2, angiotensin subtype 2; NO, nitric oxide; eNOS, endothelial NO synthase; l-NAME, NG-nitro-l-arginine methyl ester; LV, left ventricular; MI, myocardial infarction; SR, systemic resistance; MAP, mean arterial pressure; PD, PD 123319.
Address correspondence to: Dr. Hoang M. Thai, Assistant Professor of Medicine, Cardiology Section, 1-111C, Southern Arizona Veterans Affairs Health Care System Hospital, 3601 S. 6th Avenue, Tucson, AZ 85723. E-mail: hoang.thai{at}med.va.gov
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