Published online before print September 12, 2005, doi: 10.1161/01.HYP.0000173426.06832.b5
(Hypertension. 2005;46:969.)
© 2005 American Heart Association, Inc.
Part 2 Original Articles |
Early Endothelin-A Receptor Blockade Decreases Blood Pressure and Ameliorates End-Organ Damage in Homozygous Ren-2 Rats
kováensk
ervenkaFrom Center for Experimental Medicine (I.V., Z.V., M.O., L.C.), Institute for Clinical and Experimental Medicine, Prague, Czech Republic; Cardiovascular Research Center (I.V., Z.V., M.O., L.C.), Prague, Czech Republic; Section of Nephrology (H.J.K., A.B.), Medical Policlinic, University of Bonn, Germany; Department of Pathology (Z.V.), 3rd Medical Faculty, Charles University, Prague, Czech Republic.
Correspondence to Ivana Vanêková, PhD, Center for Experimental Medicine, Institute for Clinical and Experimental Medicine, Videnska 1958/9, CZ-140 21, Prague 4, Czech Republic. E-mail ivvn{at}medicon.cz
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
We have recently found that nonselective endothelin ETA/ETB receptor blockade markedly improves survival rate and ameliorates end-organ damage in male homozygous rats transgenic (TGR) for the mouse Ren-2 renin gene without lowering blood pressure. Because activation of the ETA receptor may be responsible for the detrimental effects of ET in the development of hypertension, this study was performed to determine whether ETA or ETA/ETB receptor blockade exerts these beneficial effects. TGR and age-matched normotensive Hannover Sprague-Dawley rats fed a high-salt diet received either vehicle or bosentan and atrasentan (ABT-627) as nonselective ETA/ETB and selective ETA receptor blockers, respectively, from 29 until 90 days of age. The survival rate of 48% in untreated TGR was significantly (P<0.01) improved to 79% by bosentan and to 92% by ABT-627 (ABT-627 versus bosentan P<0.05). Proteinuria, glomerulosclerosis, and cardiac hypertrophy, as well as ET-1 content in left ventricular tissue, were significantly reduced by bosentan and to a greater degree by ABT-627, which also significantly attenuated the rise in blood pressure (P<0.05). Our data indicate that the ET system, especially via ETA receptors, plays an important role in the development of hypertensive end-organ damage and confirm the concept that the predominant role of ETB receptors within the peripheral vasculature is to mediate the vasorelaxant actions of ET-1. They also demonstrate that selective blockade of ETA receptors is superior to nonselective ETA/ETB in attenuating hypertension, hypertensive organ damage, and survival rate.
Key Words: hypertension • kidney • antihypertensive drugs • end-organ damage • systolic • experimental models
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Endothelin-1 (ET-1) has been described as one of the most powerful vasoconstrictors1,2 that also plays a role in the regulation of renal hemodynamics and salt and water excretion.3 Moreover, numerous studies have shown that the ET system plays an important role in the pathogenesis of salt-sensitive models of hypertension and in associated end-organ damage.4 The nephroprotective effect of ET receptor blockade in these models is comparable with blockade of the renin-angiotensin system.5 The beneficial effects of ET receptor blockers in modulating target-organ damage arises from their antiproliferative actions.6 There is, however, a large discrepancy in the effect of ET between various models of hypertension. Animal models with exogenously administered angiotensin II (ANG II) exhibit an ET-dependent component, whereas hypertensive models with endogenously enhanced production of ANG II do not.7
In our previous study, we showed that bosentan treatment substantially improved the survival rate in homozygous rats transgenic (TGR) for the mouse Ren-2 renin gene fed either normal-salt or high-salt diet without blood pressure (BP)-lowering effect.8 Whereas the protective action of nonselective ET blockade has attracted much attention in homozygous TGR,8,9 there is no information available concerning the effect of selective ETA blockade on the course of hypertension and end-organ damage in homozygous TGR and little information is available in heterozygous animals.10,11 It is well-known that young animals are more susceptible to various hypertensive stimuli12 and also that interventions made in these early periods are more effective than when adopted lately in the life.13 However, in Dahl-sensitive rats it has been shown that ETA receptor blockade was efficient in adult but not in young animals.14
The transgenic hypertensive TGR(mRen2)27 rat model15 is a valuable monogenetic model of renin-dependent (and thus ANG II-dependent) hypertension, which exhibits functional and structural changes of the kidney usually found in hypertension, ie, reduced glomerular filtration rate and proteinuria associated with glomerulosclerosis.16,10 Because it is generally accepted that ET is involved in elevating blood pressure (BP) principally in experimental models of salt-sensitive hypertension and in TGR who exhibit a salt-sensitive component of hypertension,17 we evaluated the effects of either nonselective ET receptor blockade or selective ETA receptor blockade in TGR on survival and BP on a high-salt regimen.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
The protocols in the present study were designed according to the Guiding Principles in the Care and Use Animals approved by the Council of the American Physiological Society and are in adherence to the Guide for the Care and Use of Laboratory Animals as published by the National Institutes of Health and were approved by Czech Animal Care and Use Committee (protocols 79/2001 and 923/2003).
Animals
Homozygous TGR (strain name TGR(mRen2)27) and their normotensive Hannover Sprague-Dawley (HanSD) control rats were kept at room temperature (25°C) with 12-hour light–dark cycle. All animals used in this study were bred at the Center for Experimental Medicine of the Institute for Clinical and Experimental Medicine from stock animals supplied from Max Delbrück Center for Molecular Medicine of Berlin, Germany. The animals were switched to a high-salt diet (HS) (2% NaCl) immediately after weaning (29 days) and received tap water ad libitum. At the same time, either nonselective ETA/ETB blockade by bosentan or selective ETA receptor blockade by atrasentan (ABT-627, A-147627) was started. Bosentan (Actelion, Alschwil, Switzerland) was mixed to the high-salt diet depending on the real food intake to achieve a final consumption of 100 mg · kg–1 · day–1.4 ABT-627 was given with the drinking fluid, adjusted weekly to maintain proper dosage of 5 mg · kg–1 · day–1.18
The following experimental groups were investigated:
Male HanSD + HS (n=24)
Male TGR + HS (n=21)
Male TGR + HS + bosentan (n=16)
Male TGR + HS + ABT-627 (n=16)
Experimental Design and Functional Examination
Twice per week, rats were weighed and systolic BP (SBP) was measured by the tail-cuff method previously validated in our laboratory.19 At the age of 50 and 80 days, animals were individually housed in metabolic cages and measurements of fluid consumption, urine excretion, as well as proteinuria, were monitored over 24 hours.
On termination of the experiment (day 90), animals were weighed, anesthetized with thiopental sodium (50 mg · kg–1) and mean arterial pressure (MAP) was monitored directly in the carotid artery using data acquisition system PowerLab (ADInstruments, Mountain View, Calif). Kidneys and hearts were weighed. Ratios of kidney weight/body weight (KW/BW) and heart weight/body weight (HW/BW) were used as indices of organ hypertrophy. Right kidney cortex and left ventricles were frozen in liquid nitrogen (LN2) for ET-1 determination using enzyme-linked immunosorbent assay test (Amersham, Braunschweig, Germany). Left kidneys were fixed in 4% buffered formaldehyde, embedded, and taken for morphological examination. Paraffin sections were stained with hematoxylin eosin and periodic acid-Schiff reaction (PAS). Slides were evaluated in a blind manner. As described previously,20 50 glomeruli were examined on a semi quantitative scale: grade 0=all glomeruli normal; grade 1=1 to 2 glomeruli affected; grade 2=>2 but <17 glomeruli affected; and grade 3=17 or more glomeruli affected.
Statistical Analysis
Statistical analysis of data was performed using Graph-Pad Prism software (Graph Pad Software, San Diego, Calif). Group comparisons were determined by 2-way ANOVA. Statistical comparisons of the results obtained for heart and kidney weights and for ET-1 concentration were made by 1-way ANOVA. Unless noted, values are expressed as mean±SEM and n represents the number of animals. P<0.05 was considered significant.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
BP
SBP data are shown at a time point in which the survival rate of rats was still 100%. After weaning (day 29), SBP started to rise gradually in all 3 homozygous TGR groups on high-salt diet (Figure 1A). This increase was similarly steep in male TGR on HS diet without or with bosentan treatment reaching 236±5 and 228±5 mm Hg on day 50, respectively. Treatment with the selective ETA receptor blocker ABT-627 caused a strong attenuation of SBP increments, starting already at the age of 32 days. By day 50, SBP was substantially lower in ABT-627–treated TGR (190±5 mm Hg) when compared with male TGR without (236±5 mm Hg, P<0.01) or with bosentan treatment (228±5 mm Hg, P<0.01). No significant difference in MAP was found on termination of the experiment (day 90) between male TGR on high-salt diet without or with bosentan treatment (193±5 versus 198±5 mm Hg) (Figure 1B). With ABT-627 treatment, MAP was significantly lower (by 30±3 mm Hg, P<0.05) than in untreated TGR but did not decrease to values found in HanSD (129±4 mm Hg).
|
Survival Rate
All male HanSD on high-salt diet survived until the end of experiment. Starting from day 50, high-salt regimen caused a substantial and progressive increase in mortality in untreated animals, with survival rate being only 48% by day 90 (Figure 2A). Both bosentan and ABT-627 treatment decreased mortality in homozygous animals fed the high-salt diet with survival rates of 79% and 92%, respectively (P<0.01), with a significantly greater effect of ABT-627 (P<0.05).
|
Proteinuria
Because there were no statistically significant differences in proteinuria between groups at the age of 50 days, results are not shown. At the age of 80 days, male HanSD on high-salt diet exhibited a significantly smaller proteinuria than all homozygous TGR groups (Figure 2B). Untreated TGR fed HS exhibited a 4-fold higher proteinuria in comparison with control HanSD animals (78.4±2.3 versus 19.4±0.9 mg/24 hours; P<0.01). Bosentan treatment partly decreased proteinuria, whereas ABT-627 markedly ameliorated proteinuria to (52.4±1.6 and 36.8±1.4 mg/24 hours, respectively; both P<0.01).
Body and Kidney Weight
All survivors of male homozygous groups of TGR gained weight until 6 to 7 weeks of age; thereafter, body weight remained stable until the end of the experiments. In HanSD, body weight increased gradually and was significantly higher when compared with homozygous TGR. There was no difference in kidney/body weight ratio between all 4 groups (data not shown).
Left Cardiac Ventricular Hypertrophy
The ratio of left heart ventricular weight to body weight was significantly increased in all homozygous TGR on high-salt diet when compared with control HanSD rats on the same diet (HS) (Figure 3A). In untreated TGR, it rose to 4.07±0.07, ie, to a level that was 63% higher than that of HanSD. Bosentan treatment caused a substantial decrease in LW/BW ratio (3.71±0.01). With ABT-627, the development of left ventricular hypertrophy was significantly attenuated (LW/BW ratio 3.39±0.06; P<0.01).
|
Glomerulosclerosis
According to renal histological changes, glomerulosclerosis indices were calculated and are shown in Figure 3B. Figure 4A to 4D shows morphological changes of renal injury. HanSD on a HS diet showed no signs of renal damage, ie, there was only focal segmental pattern of glomerular sclerosis. On the contrary, after HS diet, glomeruli of homozygous TGR showed advanced sclerotic changes and widespread vascular sclerosis. Thus, in TGR on HS, glomerulosclerosis index was strongly elevated when compared with kidneys from HanSD. Glomerulosclerosis indices in homozygous TGR without or with bosentan treatment were almost the same; vascular changes were slightly milder in TGR with bosentan treatment. This renal injury, however, was substantially attenuated by ABT-627, showing no significant abnormalities of vessels and glomeruli, thus histological changes resembled those of HanSD.
|
ET-1 Tissue Concentration
As shown in Figure 5A, kidney cortex ET-1 levels in male homozygous TGR on HS diet exceeded almost 4-fold values of HanSD on the same diet (0.68±0.11 versus 0.22±0.03 fmol/mg protein, P<0.05). After bosentan treatment, ET-1 content in TGR decreased to levels seen in HanSD (0.20±0.02 fmol/mg protein), whereas after ABT-627 treatment, ET-1 content was only moderately below values seen in untreated TGR (0.56±0.02 fmol/mg protein, not significant).
|
Left ventricular ET-1 content in untreated homozygous TGR fed a HS diet was almost 4-fold that of HanSD (2.15±0.21 versus 0.62±0.06, P<0.05) (Figure 5D). Both bosentan and ABT-627 treatment substantially decreased these levels to those of HanSD (0.89±0.12 and 0.42±0.03, respectively, not significant).
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
To our knowledge this is the first study addressing the effects of early treatment with selective ETA receptor blockade versus nonselective ETA/ETB receptor blockade in homozygous TGR on HS. We have recently found that the nonselective ETA/ETB receptor blocker bosentan markedly improved the survival rate and ameliorated end-organ damage in male homozygous TGR without lowering BP.8 The current study extends these findings to investigate the role of ETA receptors in the pathogenesis and treatment of end-organ damage in conditions of HS intake. Both bosentan and ABT-627 markedly improved survival rates of homozygous TGRs. Only treatment with ABT-627 but not with bosentan induced a significant decrease in BP. Moreover, whereas nonselective ET receptor blockade was moderately effective in heart and kidney protection, selective ETA receptor blockade was found to have substantial nephroprotective and cardioprotective effects, ie, reduce proteinuria, glomerulosclerosis index, and also left ventricular hypertrophy. The difference between the efficacy of ABT-627 and bosentan may be questionable because it could be a matter of potency. It has been found that ABT-627 as ET receptor antagonist is more potent than bosentan and their potency is greatly influenced by binding to serum albumin.21,22 Although we did not evaluate the efficacy of ABT-627 in TGR, the dose used in our experiments is generally accepted and confirmed by other authors,23,24 although both higher doses (35 and 70 mg per kg per day),13 and even the lower dose (2 mg per kg per day25) were used. However, higher doses may have unspecific side effects; therefore, a greater benefit may be obtained with an intermediate dose.13 Concerning bosentan, we have previously performed the experiments in homozygous male TGR and HanSD in which a dose of bosentan (100 mg per kg per day) completely blocked BP responses to an intravenous bolus dose of ET-1 (250 ng).8 Also, this dose resembles that used by other authors.26,11,27
Our present results are in agreement with our previous findings that nonselective ET receptor blockade with bosentan improved survival rate but had no effect on the course of hypertension in homozygous8 or heterozygous TGR.11,10 Similarly, Karam et al28 also found that the renoprotective actions of bosentan were independent of any BP-lowering effect. However, regarding the role of selective ETA receptor blockade conflicting data have been reported. Whereas some authors reported that ETA blockade lowers BP in various hypertensive models, ie, in Sabra salt-sensitive rats,29 DOCA-salt rats,30 salt-loaded SHR-SP,31 or rats transgenic for human angiotensinogen and renin genes.32 Rothermund et al10did not find a protective effect of ETA blockade in heterozygous Ren-2 animals. Although quite opposite to our findings, their results could be explained by different timing of the experiments, ie, different age of animals, and by using heterozygous instead of homozygous animals. First, although we have started treatment immediately after weaning, their results were obtained in animals between 10 to 30 weeks of age. Moreover, Blezer et al13 found in stroke-prone SHR that early-onset but not late-onset of ETA receptor blockade prevented the development of cerebral edema, decreased BP and proteinuria, and increased the survival rate. Thus it is possible that only early ETA receptor blockade is effective in reducing end-organ damage. The implication that ET plays a role in the pathogenesis of hypertension and proteinuria but not in the maintenance of established target-organ damage, however, needs further examination. Second, the difference between heterozygous and homozygous animals is probably related to the severity of hypertension, which is accompanied by higher ET-1 production in homozygous animals.9 Whitworth et al33 found that only heterozygous animals with severe hypertension have significantly higher preproET-1 mRNA expressions in kidney tissue when compared with rats with benign hypertension. Moreover, only in those models of malignant hypertension that have been shown to have elevated plasma levels of ET-1, ETA receptor blockade exhibited a hypotensive effect suggesting a role for ET in this condition.34 Third, although not very likely, the possibility cannot be fully excluded that various ETA receptor blockers may produce different effects.
The role of ET in end-organ damage appears to be quite clear, because both bosentan, and especially ABT-627, significantly reduced overall mortality rates. There exist, however, conflicting data regarding the nephroprotective and cardioprotective effects of ETA receptor blockade. Beneficial effects were found in rats with congestive heart failure,35 in Sabra salt-sensitive hypertension,29 or stroke-prone SHR,36 whereas Rothermund et al10 or Rossi et al11observed no beneficial effect in the Ren2 model. We cannot offer a satisfying explanation for these discrepant findings except for the use of heterozygous instead of homozygous animals since Rossi et al11 used animals of the same age as we did.
The beneficial effects of ETA receptor blockade can be clearly demonstrated by our histological findings. The most striking changes were found in the vasculature. They are characterized by hyaline sclerosis of afferent arterioles and fibrotic intimal thickening of preglomerular arteries caused by hypertrophy and hyperplasia of smooth muscle cells. The extent of glomerular involvement was directly proportional to the severity of vascular changes. Glomerular structural changes ranged from slight basement membrane wrinkling and mild mesangial matrix expansion to total glomerular collapse and sclerosis. Treatment with bosentan slightly attenuated the vascular damage but did not substantially reduce the glomerulosclerosis index, whereas ABT-627 fully prevented kidney parenchyme from hypertensive damage.
There still remains the crucial question of why this difference exists between the efficacy of selective versus nonselective ET receptor blockade in lowering BP and what is the underlying mechanism(s). A possible explanation could be the different actions of ET-1 via ETA and ETB receptors and their respective blockers at the molecular level. Whereas binding of both ABT-627 and ET-1 results in partial receptor internalization, only ET-1 is capable of triggering intracellular functional responses.37 Moreover, in rat aortic rings, ABT-627 is even able to reverse an ET-1 induced contraction. However, whether these observations offer a correct explanation for our findings remains speculative. With special emphasis on HS intake, one should keep in mind an additional role of ETB receptors, which bind and remove ET-1 from the circulation and thus reduce ETA receptor activation. Thus, in Sprague-Dawley rats Pollock and Pollock38 found that ETB receptor blockade produced an increase in mean arterial pressure that was significantly higher in rats on the high-salt diet. These authors hypothesized that in response to salt loading ET-1 participates in BP regulation through ETB receptors. Also, it is possible to assume that nonselective blockade not only reduces deleterious effects of ETA receptor blockade but is detrimental due to blockade of beneficial vasorelaxant actions of ETB receptors, which is mediated through the release of nitric oxide and prostaglandins.39 The question is even more complicated because, first, 2 distinct ETB receptors were identified40,41 (ETB1 present on vascular endothelium cause vasodilation whereas ETB2 on vascular smooth muscle cells mediate vasoconstriction) and, second, different actions of these receptors are reported in various species40,42,43 (in contrary to other species, Brooks found no ETB2-mediated vasoconstriction in dogs). Moreover, Just et al41 speculated that not only dual (constrictor and dilator) actions of ETB receptors have to be considered but also interactions with ETA receptors evaluating their physiological function. This topic therefore needs further examination.
Taken together, the aforementioned findings imply that the ET system may be activated secondary to an activation of the renin-angiotensin system. But only in conditions of severe hypertension or exogenously increased ANG II levels, when ET-1 expression is stimulated to a significantly elevated tissue level, ET-1 appears to play a major role in cardiovascular and renal damage. Moreover, our data clearly show that selective blockade of ETA receptors is superior to nonselective ETA/B receptor blockade in attenuating hypertension, hypertensive organ damage, and survival rate.
Perspectives
It is not yet well-understood whether the beneficial effect of early selective ETA blockade on BP and end-organ damage observed in homozygous Ren-2 transgenic rats on HS diet will also be effective in animals with already-established hypertension. This question together with the participation of ETB receptors on BP regulation needs further evaluation. However, when considering the therapeutic implication of our findings, our data clearly support the idea that selective ETA blockade may be preferable to nonselective one in protecting from hypertension and hypertension-associated organ damage.
|
Acknowledgments |
|---|
This study was supported by grant NR/7826-3 awarded to I.V. by the Ministry of Health of the Czech Republic. H.J.K. is supported by the German Research Foundation (Kra 433/14). We thank to Drs Detlev Ganten and Michael Bader for providing us with breeders of our Ren-2 transgenic colony. We also greatly appreciate the help of Abbot Laboratories (North Chicago, Ill) for generously providing us with ABT-627.
Received April 26, 2005; first decision May 9, 2005; accepted June 1, 2005.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
1. Yanagisawa M, Kurihara, H, Kimura, S, Tomobe, Y, Kobayashi, M, Mitsui, Y, Yazaki, Y, Goto, K, and Masaki, T. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature. 1988; 332: 411–415.[CrossRef][Medline] [Order article via Infotrieve]
2. Maguire JJ, Davenport, AP. Is urotensin-II the new endothelin? Br J Pharmacol. 2002; 137: 579–588.[CrossRef][Medline] [Order article via Infotrieve]
3. Simonson MS. Endothelins: multifunctional renal peptides. Physiol Rev. 1993; 73: 375–411.
4. Roux S, Breu, V, Ertel, SI, Clozel, M. Endothelin antagonism with bosentan: a review of potential applications. J Mol Med. 1999; 77: 364–376.[CrossRef][Medline] [Order article via Infotrieve]
5. Schiffrin EL Beyond blood pressure: the endothelium and atherosclerosis progression. Am J Hypertens. 2002; 15: 115S–122S.[CrossRef][Medline] [Order article via Infotrieve]
6. Mohacsi A, Magyar J, Tamas B, Nanasi PP. Effects of endothelins on cardiac and vascular cells: new therapeutic target for the future? Curr Vasc Pharmacol. 2004; 2: 53–63.[CrossRef][Medline] [Order article via Infotrieve]
7. Moreau P, Schiffrin EL. Role of endothelins in animal models of hypertension: focus on cardiovascular protection. Can J Physiol Pharmacol. 2003; 81: 511–521.[CrossRef][Medline] [Order article via Infotrieve]
8. Dvorak P, Kramer HJ, Backer A, Maly J, Kopkan L, Vaneckova I, Vernerova Z, Opocensky M, Tesar V, Bader M, Ganten D, Janda J, Cervenka L. Blockade of endothelin receptors attenuates end-organ damage in homozygous hypertensive ren-2 transgenic rats. Kidney Blood Press Res. 2004; 27: 248–258.[CrossRef][Medline] [Order article via Infotrieve]
9. Opocensky M, Dvorak P, Maly J, Kramer HJ, Backer A, Kopkan L, Vernerova Z, Tesar V, Zima T, Bader M, Ganten D, Janda J, Vaneckova I. Chronic endothelin receptor blockade reduces end-organ damage independently of blood pressure effects in salt-loaded heterozygous Ren-2 transgenic rats. Physiol Res. 2004; 53: 581–593.[Medline] [Order article via Infotrieve]
10. Rothermund L, Kossmehl P, Neumayer HH, Paul M, Kreutz R. Renal damage is not improved by blockade of endothelin receptors in primary renin-dependent hypertension. J Hypertens. 2003; 21: 2389–2397.[CrossRef][Medline] [Order article via Infotrieve]
11. Rossi GP, Sacchetto A, Rizzoni D, Bova S, Porteri E, Mazzocchi G, Belloni AS, Bahcelioglu M, Nussdorfer GG, Pessina AC. Blockade of angiotensin II type 1 receptor and not of endothelin receptor prevents hypertension and cardiovascular disease in transgenic (mREN2)27 rats via adrenocortical steroid-independent mechanisms. Arterioscler Thromb Vasc Biol. 2000; 20: 949–956.
12. Zicha J, Kunes J. Ontogenetic aspects of hypertension development: analysis in the rat. Physiol Rev. 1999; 79: 1227–1282.
13. Blezer EL, Nicolay K, Goldschmeding R, Jansen GH, Koomans HA, Rabelink TJ, Joles JA. Early-onset but not late-onset endothelin-A-receptor blockade can modulate hypertension, cerebral edema, and proteinuria in stroke-prone hypertensive rats. Hypertension. 1999; 33: 137–144.
14. Dobe
ová Z, Kune J, Zicha J. Less important role of endothelin in salt hypertension of young than adult Dahl rats. Physiol Res. 2003; 52: 49P.
15. Mullins JJ, Peters J, Ganten, D. Fulminant hypertension in transgenic rats harbouring the mouse Ren-2 gene. Nature. 1990; 344: 541–544.[CrossRef][Medline] [Order article via Infotrieve]
16. Bachmann S, Peters J, Engler E, Ganten D, Mullins J. Transgenic rats carrying the mouse renin gene–morphological characterization of a low-renin hypertension model. Kidney Int. 1992; 41: 24–36.[Medline] [Order article via Infotrieve]
17. Callahan MF, Li P, Ferrario CM, Ganten D, Morris M. Salt-sensitive hypertension in (mREN-2)27 transgenic rats. Hypertension. 1996; 27: 573–577.
18. Mulder P, Boujedaini H, Richard V, Derumeaux G, Henry JP, Renet S, Wessale J, Opgenorth T, Thuillez C. Selective endothelin-A versus combined endothelin-A/endothelin-B receptor blockade in rat chronic heart failure. Circulation. 2000; 102: 491–493.
19. Heller J, Hellerova S. Long-term effect on blood pressure of early brief treatment by different antihypertensive agents: a study in the prague hypertensive rat. Kidney Blood Press Res. 1998; 21: 445–451.[CrossRef][Medline] [Order article via Infotrieve]
20. Yagil C, Sapojnikov M, Katni G, Ilan Z, Zangen SW, Rosenmann E, Yagil Y. Proteinuria and glomerulosclerosis in the Sabra genetic rat model of salt susceptibility. Physiol Genomics. 2002; 9: 167–178.
21. Wu-Wong JR, Chiou WJ, Hoffman DJ, Winn M, von Geldern TW, Opgenorth TJ. Endothelins and endothelin receptor antagonists: binding to plasma proteins. Life Sci. 1996; 58: 1839–1847.[CrossRef][Medline] [Order article via Infotrieve]
22. Wu-Wong JR, Dixon DB, Chiou WJ, Opgenorth TJ. Endothelin receptor antagonists: effect of serum albumin on potency and comparison of pharmacological characteristics. J Pharmacol Exp Ther. 1997; 281: 791–798.
23. D’Angelo G, Pollock JS, Pollock DM. Endogenous endothelin attenuates the pressor response to acute environmental stress via the ETA receptor. Am J Physiol Heart Circ Physiol. 2005; 288: H1829–H1835.
24. Opgenorth TJ, Adler AL, Calzadilla SV, Chiou WJ, Dayton BD, Dixon DB, Gehrke LJ, Hernandez L, Magnuson SR, Marsh KC, Novosad EI, von Geldern TW, Wessale JL, Winn M, Wu-Wong JR. Pharmacological characterization of A-127722: an orally active and highly potent ETA-selective receptor antagonist. J Pharmacol Exp Ther. 1996; 276: 473–481.
25. Ballew JR, Fink GD. Role of ET(A) receptors in experimental ANG II-induced hypertension in rats. Am J Physiol Regul Integr Comp Physiol. 2001; 281: R150–R154.
26. Muller DN, Mervaala EM, Schmidt F, Park JK, Dechend R, Genersch E, Breu V, Loffler BM, Ganten D, Schneider W, Haller H, Luft FC. Effect of bosentan on NF-kappaB, inflammation, and tissue factor in angiotensin II-induced end-organ damage. Hypertension. 2000; 36: 282–290.
27. Seccia TM, Belloni AS, Kreutz R, Paul M, Nussdorfer GG, Pessina AC, Rossi GP. Cardiac fibrosis occurs early and involves endothelin and AT-1 receptors in hypertension due to endogenous angiotensin II. J Am Coll Cardiol. 2003; 41: 666–673.
28. Karam H, Heudes D, Bruneval P, Gonzales MF, Loffler BM, Clozel M, Clozel JP. Endothelin antagonism in end-organ damage of spontaneously hypertensive rats: comparison with angiotensin-converting enzyme inhibition and calcium antagonism. Hypertension. 1996; 28: 379–385.
29. Rothermund L, Traupe T, Dieterich M, Kossmehl P, Yagil C, Yagil Y, Kreutz R. Nephroprotective effects of the endothelin ET(A) receptor antagonist darusentan in salt-sensitive genetic hypertension. Eur J Pharmacol. 2003; 468: 209–216.[CrossRef][Medline] [Order article via Infotrieve]
30. Allcock GH, Venema RC, Pollock DM. ETA receptor blockade attenuates the hypertension but not renal dysfunction in DOCA-salt rats. Am J Physiol. 1998; 275: R245–R252.[Medline] [Order article via Infotrieve]
31. Okada M, Kobayashi M, Maruyama H, Takahashi R, Ikemoto F, Yano M, Nishikibe M. Effects of a selective endothelin A-receptor antagonist, BQ-123, in salt-loaded stroke-prone spontaneously hypertensive rats. Clin Exp Pharmacol Physiol. 1995; 22: 763–768.[Medline] [Order article via Infotrieve]
32. Bohlender J, Gerbaulet S, Kramer J, Gross M, Kirchengast M, Dietz R. Synergistic effects of AT(1) and ET(A) receptor blockade in a transgenic, angiotensin II-dependent, rat model. Hypertension. 2000; 35: 992–997.
33. Whitworth CE, Veniant MM, Firth JD, Cumming AD, Mullins JJ. Endothelin in the kidney in malignant phase hypertension. Hypertension. 1995; 26: 925–931.
34. Nishikibe M, Tsuchida S, Okada M, Fukuroda T, Shimamoto K, Yano M, Ishikawa K, Ikemoto F. Antihypertensive effect of a newly synthesized endothelin antagonist, BQ-123, in a genetic hypertensive model. Life Sci. 1993; 52: 717–724.[CrossRef][Medline] [Order article via Infotrieve]
35. Sakai S, Miyauchi T, Kobayashi M, Yamaguchi I, Goto K, Sugishita Y. Inhibition of myocardial endothelin pathway improves long-term survival in heart failure. Nature. 1996; 384: 353–355.[CrossRef][Medline] [Order article via Infotrieve]
36. Orth SR, Esslinger JP, Amann K, Schwarz U, Raschack M, Ritz E. Nephroprotection of an ET(A)-receptor blocker (LU 135252) in salt-loaded uninephrectomized stroke-prone spontaneously hypertensive rats. Hypertension. 1998; 31: 995–1001.
37. Chiou WJ, Wessale JL, von Geldern T, Opgenorth TJ, Wu-Wong JR. Irreversible endothelin-1 binding does not prohibit ABT-627 from reversing endothelin-1-induced effects. J Cardiovasc Pharmacol. 2000; 36: S48–S52.[Medline] [Order article via Infotrieve]
38. Pollock DM, Pollock JS. Evidence for endothelin involvement in the response to high salt. Am J Physiol Renal Physiol. 2001; 281: F144–F150.
39. de Nucci G, Gryglewski RJ, Warner TD, Vane JR. Receptor-mediated release of endothelium-derived relaxing factor and prostacyclin from bovine aortic endothelial cells is coupled. Proc Natl Acad Sci U S A. 1988; 85: 2334–2338.
40. Gellai M, Fletcher T, Pullen M, Nambi P. Evidence for the existence of endothelin-B receptor subtypes and their physiological roles in the rat. Am J Physiol. 1996; 271: R254–R261.[Medline] [Order article via Infotrieve]
41. Just A, Olson AJ, Arendshorst WJ. Dual constrictor and dilator actions of ET(B) receptors in the rat renal microcirculation: interactions with ET(A) receptors. Am J Physiol Renal Physiol. 2004; 286: F660–F668.
42. Brooks DP, dePalma PD, Pullen M, Nambi P. Characterization of canine renal endothelin receptor subtypes and their function. J Pharmacol Exp Ther. 1994; 268: 1091–1097.
43. Cirino M, Martin E, Yano M, Rodger IW. Cardiovascular and renal actions of the endothelin(B) receptor in pigs. J Cardiovasc Pharmacol. 1997; 29: 704–712.[CrossRef][Medline] [Order article via Infotrieve]
This article has been cited by other articles:
 |
|
 |
|
  N. Dhaun, J. Goddard, D. E. Kohan, D. M. Pollock, E. L. Schiffrin, and D. J. Webb Role of Endothelin-1 in Clinical Hypertension: 20 Years On Hypertension, September 1, 2008; 52(3): 452 - 459. [Full Text] [PDF]
|
|
|
|
|
|
E. Raichlin, A. Prasad, V. Mathew, B. Kent, D. R. Holmes Jr, G. M. Pumper, R. E. Nelson, L. O. Lerman, and A. Lerman Efficacy and Safety of Atrasentan in Patients With Cardiovascular Risk and Early Atherosclerosis Hypertension, September 1, 2008; 52(3): 522 - 528. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Opocensky, H. J. Kramer, A. Backer, Z. Vernerova, V. Eis, L. Cervenka, V. Certikova Chabova, V. Tesar, and I. Vaneckova Late-Onset Endothelin-A Receptor Blockade Reduces Podocyte Injury in Homozygous Ren-2 Rats Despite Severe Hypertension Hypertension, November 1, 2006; 48(5): 965 - 971. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Barton, J. J. Mullins, M. A. Bailey, and M. Kretzler Role of Endothelin Receptors for Renal Protection and Survival in Hypertension: Waiting for Clinical Trials Hypertension, November 1, 2006; 48(5): 834 - 837. [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Zhou, S. Mitra, S. Varadharaj, N. Parinandi, J. L. Zweier, and N. A. Flavahan Increased Expression of Cyclooxygenase-2 Mediates Enhanced Contraction to Endothelin ETA Receptor Stimulation in Endothelial Nitric Oxide Synthase Knockout Mice Circ. Res., June 9, 2006; 98(11): 1439 - 1445. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||