Published online before print June 13, 2005, doi: 10.1161/01.HYP.0000171479.36880.17
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(Hypertension. 2005;46:107.)
© 2005 American Heart Association, Inc.
Original Articles |
Participation of Prostacyclin in Endothelial Dysfunction Induced by Aldosterone in Normotensive and Hypertensive Rats
From the Departamentos de Fisiología (J.B.-R., R.A.-L., I.M.-R., M.F., G.B.) y Farmacología (M.S.), Facultad de Medicina, Universidad Autónoma; Departamento de Fisiología (V.C., V.L.), Facultad de Medicina, Universidad Complutense, Madrid, Spain; and Programa de Pós-Graduação em Ciências Fisiológicas/ UFES (F.E.X.), Vitória-ES, Brazil.
Correspondence to G. Balfagón, Departamento de Fisiología, Facultad de Medicina, Universidad Autónoma, C/ Arzobispo Morcillo, 4, 28029, Madrid, Spain. E-mail gloria.balfagon{at}uam.es
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Abstract |
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The aim of the present study was to analyze the possible involvement of vasoconstrictors prostanoids on the reduced endothelium-dependent relaxations produced by chronic administration of aldosterone in Wistar Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). For this purpose, acetylcholine (ACh) relaxations in aortic segments from both strains were analyzed in absence and presence of the cyclooxygenase-1 (COX-1) and COX-2 inhibitor indomethacin, the specific COX-2 inhibitor NS-398, the TP receptor antagonist (SQ 29 548), the thromboxane A2 (TXA2) synthase inhibitor furegrelate, and the prostacyclin (PGI2) synthesis inhibitor tranylcypromine (TCP). In addition, COX-2 protein expression was studied by Western blot analysis. Release of prostaglandin E2 (PGE2) and the metabolites of PGF2
, TXA2, and PGI2, 13,14-dihydro-15-keto PGF2a, TXB2, and 6-keto-PGF1, respectively, were measured. Treatment with aldosterone did not modify blood pressure levels in any strain. However, aldosterone markedly reduced (P<0.05) ACh-induced relaxations in segments from both strains in a similar extent. Indomethacin, NS-398, SQ 29 548, and TCP enhanced (P<0.05) ACh relaxations in both strains treated with aldosterone. Aortic COX-2 protein expression was higher in both strains of rats treated with aldosterone. In normotensive animals, aldosterone increases the ACh-stimulated aortic production of 13,14-dihydro-15-keto PGF2a, PGE2, and 6-keto-PGF1 (P<0.05). In SHR, ACh only increased the 6-keto-PGF1 production (P<0.05). It could be concluded that chronic treatment with aldosterone was able to produce endothelial dysfunction through COX-2 activation in normotensive and hypertensive conditions. PGI2 seems to be the main factor accounting for endothelial dysfunction in hypertensive rats, whereas other prostanoids besides PGI2 appear to be involved in endothelial dysfunction under normotensive conditions.
Key Words: aldosterone • endothelium • prostacyclin • normotension • hypertension
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Introduction |
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Aldosterone is a mineralocorticoid that participates in electrolyte balance and plays an important physiological role in the long-term regulation of Na+ and K+ in the distal tubule and collecting duct.1–4 To date, several studies suggested that aldosterone plays a larger role than once appreciated in the regulation of vascular tone as well as in cardiovascular alterations such as endothelial dysfunction, vascular fibrosis, and inflammation, left ventricular hypertrophy, congestive heart failure, and cardiac arrhythmias.5–12 Furthermore, aldosterone has also been shown to be involved in the pathogenesis of hypertension.13–15
In general terms, endothelial dysfunction is characterized by reduced endothelium-dependent relaxations, suggesting a reduced availability of NO attributable to a reduction of NO production or enhanced NO inactivation.16,17 In addition, an increased production of vasoconstrictor factors could be also responsible for the reduced endothelium-dependent relaxations.13 Diminished endothelium NO synthase expression or activity has been proposed as an important mechanism leading to reduced NO availability and endothelial dysfunction in aldosterone-treated animals.18–20 Furthermore, enhanced vascular production of reactive oxygen species, specifically superoxide anions, has been reported as another important mechanism contributing to endothelial dysfunction in aldosterone-treated animals.21,22 However, the role of vasoconstrictor prostanoids prostaglandin F2 (PGF2a) and thromboxane A2 (TXA2), as well as prostacyclin (PGI2) and PGE2, which can act as vasoconstrictors under certain conditions,23,24 is not well established in the endothelial dysfunction produced by aldosterone. Thus, the aim of the present study was to analyze the possible involvement of endothelium-derived vasoconstrictors prostanoids on the reduced endothelium-dependent relaxations produced by chronic administration of aldosterone under normotensive and hypertensive conditions in rats.
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Methods |
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Male 6-month-old Wistar Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) weighing 200 to 250 g were obtained from colonies maintained at the animal quarters of the Facultad de Medicina of the Universidad Autónoma de Madrid.
Rats were divided into 2 groups: untreated and aldosterone treated (0.05 mg/kg per day). Controlled time-release pellets (Innovative Research of America) containing aldosterone or vehicle were subcutaneously implanted. At the end of the treatment period (3 weeks), systolic blood pressure (BP) was measured by a tail-cuff method. After death by CO2 inhalation, aorta was carefully dissected out, cleaned of connective tissue, and placed in Krebs–Henseleit solution (KHS; in mmol/L: 115 NaCl, 2.5 CaCl2, 4.6 KCl, 1.2 KH2PO4, 1.2 MgSO4.7H2O, 25 NaHCO3, 11.1 glucose, and 0.03 Na2 EDTA) at 4°C. Animals were kept in the animal facility of the Universidad Autónoma de Madrid (registration No. EX-021U) according to the directives 609/86 CEE and R.D. 233/88 of the Ministerio de Agricultura, Pesca y Alimentación.
Endothelium-Dependent Relaxations
Thoracic aorta was cut transversally in ring segments (4-mm long). Each ring was placed inside a 5-mL heated bath filled with KHS (37°C) bubbled with a 95% O2–5%CO2 mixture, pH 7.4, and suspended between 2 L-shaped stainless steel hooks. The top one was attached to a force transducer (Grass FTO3C); in turn, this was connected to a model 7D Grass polygraph for measurement of isometric tension. Rings were allowed to equilibrate for 90 minutes, with changes of buffer every 15 minutes and with several adjustments of length until baseline tension stabilized at 1 g to obtain comparable acetylcholine (ACh) relaxation in both strains. In previous studies, we found that 2 g but not 1 g of resting tension evidenced reduction of ACh relaxation in SHR compared with WKY.25 When tension was stable, experiments were initiated by obtaining a reference contractile response to 75 mmol/L KCl. Endothelium-dependent relaxations were studied by evaluating relaxations to ACh (10–10 to 10–5 mol/L) in noradrenaline precontracted rings (1.5±0.18 g). In pilot studies, we found that treatment of rats with aldosterone reduced endothelium-dependent relaxation to ACh.
To investigate the possible participation of prostanoids in the reduction of ACh relaxations produced by aldosterone treatment, aortic segments from both strains were incubated with the cyclooxygenase-1 (COX-1)/COX-2 inhibitor indomethacin (10–5 mol/L; Sigma-Aldrich). To clarify whether COX-1 or COX-2 was involved in the effect of aldosterone on ACh relaxation, aortic segments were incubated with the specific COX-2 inhibitor NS-398 (10–5 mol/L; Calbiochem-Novabiochem GmbH). In another set of experiments, segments were incubated with SQ 29 548 (TP receptor antagonist; 10–6 mol/L; ICN Iberica) to evaluate the possible participation of vasoconstrictor prostanoids. Finally, segments were incubated with the thromboxane (TXA2) synthase inhibitor furegrelate (10–6 mol/L; Sigma-Aldrich), the PGI2 synthesis inhibitor tranylcypromine (TCP; 10–5 mol/L; Sigma-Aldrich), or the cytochrome P450 inhibitor 1-aminobenzotriazole (ABZ; 5x10–4 mol/L; Sigma-Aldrich) to analyze the possible involvement of these prostanoids in the effect of aldosterone on ACh relaxations.
Western Blot Analysis
Aorta samples from control and aldosterone-treated WKY and SHR were homogenized in a boiling buffer composed of 1 mmol/L sodium vanadate (Sigma-Aldrich), 1% SDS and pH 7.4, 0.01 mol/L Tris-HCl, and protein content was measured with a DC protein assay kit (Bio-Rad). Homogenates containing 20 µg protein were fractionated in a 10% SDS-PAGE and transferred to a polivinilifluoride membrane (Bio-Rad). Membranes were blocked in 5% nonfat milk in Tris-HCl buffered saline 0.1% Tween 20 (TBS-T). Subsequent washes were done in TBS-T, and the membranes were incubated with antibody against COX-2 (1:1000; Cayman Chemical) or -actin (1:3000; Sigma-Aldrich) proteins and individual horseradish peroxidase–conjugated secondary antibodies in blocking buffer. Immunoreactive proteins were detected by chemiluminescence with ECL-Plus (Amersham).
Prostanoid Production
To measure the release of PGE2 and the metabolites of PGF2, TXA2, PGI2, 13,14-dihydro-15-keto PGF2, thromboxane B2 (TXB2), and 6-keto-PGF1, we used PGE2 enzyme immunoassay (EIA) Kit-Monoclonal, EIA kit, 13,14-dihydro-15-keto PGF2 EIA kit (Cayman Chemical), TXB2 immunoassay, and 6-keto-PGF1 immunoassay (R & D Systems), respectively. Segments of rat aorta arteries were preincubated for 30 minutes in 5 mL of KHS at 37°C and continuously gassed with a 95% O2–5% CO2 mixture (stabilization period). Afterward, 2 washout periods of 7 minutes in a bath of 0.3 mL of KHS were made before incubation with ACh (10–10 to 10–5 mol/L). The different assays were made following manufacturer instructions. Results were expressed as pg prostanoid/mL mg tissue.
Statistical Analysis
Results are expressed as mean±SEM of the number of rats indicated. Differences were analyzed using Student t test for unpaired experiments or 2-way ANOVA to compare groups. A P value <0.05 was considered significant.
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Blood Pressure
As expected, SHR presented higher BP levels than WKY (175±3.2 versus 115±2.8 mm Hg; P<0.05). Chronic aldosterone administration did not substantially modify BP levels in any strain (SHR 181±6; WKY 121±7.9).
Endothelium-Dependent Relaxations
ACh-induced relaxations were comparable in untreated WKY and SHR (Emax WKY 76.0±5.7 versus SHR 73.0±2.8; percent noradrenaline contraction; negative logarithm of effective concentration 50 (pD2) WKY 7.7±0.2 versus SHR 7.6±0.1). Treatment with aldosterone markedly reduced (P<0.05) ACh-induced relaxations in both strains in a similar extent (Figure 1A and 1B).
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Incubation of aortic rings with indomethacin or the COX-2 inhibitor NS-398 enhanced (P<0.05) ACh relaxations in both strains treated with aldosterone in a comparable manner (Figure 2A and 2B). Incubation with SQ 29 548 or ABZ also increased (P<0.05) ACh relaxations in both strains treated with aldosterone in a comparable manner (Figure 3A and 3B). However, incubation with the thromboxane synthase inhibitor furegrelate did not modify endothelium-dependent relaxations in any group treated with aldosterone (Figure 3A and 3B). Incubation with PGI2 synthesis inhibitor TCP increased (P<0.05) ACh relaxations in both strains treated with aldosterone (Figure 3A and 3B), this enhancement being higher in SHR.
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COX-2 Protein Expression
COX-2 protein expression was higher in aortic segments from SHR compared with WKY. In both rat strains, this parameter was increased after chronic aldosterone treatment (Figure 4).
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Prostanoid Production
In normotensive animals, aldosterone increased ACh-stimulated aortic production of 13,14-dihydro-15-keto PGF2a, PGE2, and 6-keto-PGF1 (Figure 5A through 5C; P<0.05) and did not modify TXB2 levels (untreated 68±14 pg/mL mg tissue; aldosterone 78±11 pg/mL mg tissue). However, in SHR, aldosterone did not modify 13,14-dihydro-15-keto PGF2 (untreated 1.5±0.3 pg/mL mg tissue; aldosterone 1.2±0.2 pg/mL mg tissue); PGE2 (untreated 8±0.4 pg/mL mg tissue; aldosterone 8.3±0.8 pg/mL mg tissue), and TXB2 release (untreated 185±21 pg/mL mg tissue; aldosterone 179±33 pg/mL mg tissue) but increased the 6-keto-PGF1 production induced by ACh (Figure 5D; P<0.05). Treatment with aldosterone increased 6-keto-PGF1 levels in a similar extent in segments from both strains (WKY 1.83±0.23; SHR 1.89±0.3).
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Discussion |
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The present results show that in our experimental conditions, aldosterone alters endothelial function because its chronic administration diminished the ACh-induced relaxation in normotensive and hypertensive animals. These data confirm previous observations indicating that aldosterone was able to produce endothelial dysfunction in experimental and clinical studies.20,26,27 This effect appears to be independent of previous BP levels because the reduction in ACh relaxation was similar in normotensive and hypertensive rats. Moreover, this deleterious effect induced by aldosterone on endothelial function is not mediated by hemodynamic changes induced by this mineralocorticoid because no differences in BP levels were observed between treated and untreated animals in both strains. Because an increase in BP associated with aldosterone administration has been reported,7,15 the lack of effect observed in this study could be a consequence of differences in experimental conditions (dose and period treatment).
Several mechanisms have been implicated in the endothelial dysfunction associated with different pathological situations (hypertension, diabetes, aging, and hypercholesterolemia)17,18,28–30 including a reduced NO availability and an increase in vasoconstrictor factors.28,29,31,32 Similarly, in aldosterone-treated animals, decreased NO levels have also been implicated in the alteration of endothelial function, mainly because of an increase in oxidative stress.22 In addition, the present results show that arachidonic acid–derived vasoconstrictor prostanoids are involved in endothelial dysfunction produced by aldosterone treatment in normotensive and hypertensive rats. This is demonstrated by the normalization of ACh relaxation in aortic segments of aldosterone-treated rats in the presence of the COX-1/COX-2 inhibitor indomethacin. Because the presence of the specific COX-2 inhibitor NS 398 increased the ACh response in a similar extent, then indomethacin, the vasoconstrictor factors are derived from COX-2. Supporting this role is the observation that COX-2 is overexpressed in the aorta from aldosterone-treated animals in normotensive and hypertensive rats, reaching higher levels in SHR. This is in agreement with a previous study showing that the aldosterone antagonist eplerenone was able to reduce COX-2 expression in hearts from rats treated with angiotensin II and a high-salt diet.33 Therefore, the data suggest that there are interactions between aldosterone and COX that can be relevant in the regulation of vascular function.
It has been reported that through the activation of TP receptors, vasoconstrictor prostanoids such as TXA2 can participate in the endothelial dysfunction associated with different cardiovascular risk factors.30,32,34 Incubation with SQ 29 548, a TP receptor antagonist, increased ACh relaxations in both strains of rats treated with aldosterone in a comparable manner, suggesting the participation of vasoconstrictor prostanoids through TP receptors. However, the present results showed that in aorta from WKY and SHR treated with aldosterone, TXA2 is not an important candidate responsible for the reduction of endothelium-dependent relaxations. This affirmation is based on the fact that the thromboxane synthase inhibitor furegrelate did not modify this response in any strain. These data are in agreement with previous results indicating that ACh did not release TXA2 in aorta from normotensive and hypertensive rats.23,35 Likewise, ACh was unable to increase TXA2 release in aorta from aldosterone-treated animal. Consequently, the participation of other prostanoids such as PGF2, PGE2, and PGI2, which can be synthesized through COX-2 and can act as vasoconstrictors under certain conditions,23,24 can be proposed. The present results showed that the presence of PGI2 synthesis inhibitor TCP was able to increase the reduced ACh relaxation in both strains, although it was only normalized in SHR. Moreover, aldosterone increased aortic production of 6-keto-PGF1 induced by ACh in both strains.
Therefore, it seems that PGI2 plays a major role in the alterations in endothelial function produced by aldosterone in normotensive and hypertensive conditions, supporting that the vasoconstrictor action of PGI2 observed23,24,36,37 could be relevant in hyperaldosteronism. TP receptor could be the main receptor implicated in this vasoconstrictor action of PGI2 because SQ 29 548 increased ACh relaxation in aorta from both strains treated with aldosterone. However, PGI2 or a metabolite of PGI2 would activate EP1 or EP3 receptors that are coupled to contraction in vascular smooth muscle. In this sense, it has been described that EP1 and EP3 receptors bound IP ligands such as iloprost with Ki values comparable to those for IP receptor.38,39 In addition, the participation of vasoconstrictor derivated from cytochrome P450 family can also be proposed because the presence of the cytochrome P450 inhibitor ABZ reversed the alterations in ACh relaxation in both strains.40 Because PGI2 synthase is a member of the P450 family,38 it could be postulated that the effect of ABZ is mediated by PGI2 synthesis inhibition.
It should be mentioned that under normotensive conditions, besides PGI2, other vasoconstrictor prostanoids such as PGF2 and PGE2 seem to participate in the reduced ACh-induced relaxations, as demonstrated by the results on prostanoid release. These differences could explain why endothelial dysfunction is comparable in both strains in addition to the higher expression of COX-2 in SHR.
In conclusion, the results of the study demonstrated that chronic treatment with aldosterone was able to produce endothelial dysfunction through COX-2 activation in normotensive and hypertensive conditions. PGI2 seems to be the main factor accounting for endothelial dysfunction in hypertensive rats, whereas other prostanoids besides PGI2 appear to be involved in endothelial dysfunction under normotensive conditions.
Perspectives
Aldosterone has been involved in vascular damage recently through direct effects on vascular wall at several levels (hypertrophy, inflammation, fibrosis, endothelial dysfunction, and atherosclerosis). The present results showed that vasoconstrictor prostanoids account for endothelial dysfunction induced by aldosterone in rats. Because endothelial dysfunction is involved in the development and complications of atherosclerosis, it could be hypothesized that treatment with anti-inflammatory drugs, and specifically COX-2 inhibitors, could ameliorate vascular damage and progression of atherosclerosis in patients with elevated aldosterone production.
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Acknowledgments |
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This research was supported by the Fondo de Investigaciones Sanitarias (PI020335 and C03/01) and the Comisión de Ciencia y Tecnología (BFI2001-1324, SAF 2003-006333 and SAF-2004-01884). We thank Rocio Baena for her technical help and the veterinarian Dr María del Carmen Fernández Criado for the care of animals.
Received February 22, 2005; first decision March 15, 2005; accepted April 25, 2005.
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J. Blanco-Rivero, I. Marquez-Rodas, F. E. Xavier, R. Aras-Lopez, I. Arroyo-Villa, M. Ferrer, and G. Balfagon Long-term fenofibrate treatment impairs endothelium-dependent dilation to acetylcholine by altering the cyclooxygenase pathway Cardiovasc Res, July 15, 2007; 75(2): 398 - 407. [Abstract] [Full Text] [PDF]
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E. L. Schiffrin Effects of Aldosterone on the Vasculature Hypertension, March 1, 2006; 47(3): 312 - 318. [Full Text] [PDF]
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M. Hermann, H. Krum, and F. Ruschitzka To the Heart of the Matter: Coxibs, Smoking, and Cardiovascular Risk Circulation, August 16, 2005; 112(7): 941 - 945. [Full Text] [PDF]
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F. K. Johnson, R. A. Johnson, and W. Durante Aldosterone Promotes Endothelial Dysfunction Via Prostacyclin Independent of Hypertension Hypertension, July 1, 2005; 46(1): 29 - 30. [Full Text] [PDF]
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