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(Hypertension. 1996;27:1341-1345.)
© 1996 American Heart Association, Inc.
Articles |
Bosentan Ameliorates Cyclosporin A–Induced Hypertension in Rats and Primates
From the Departments of Surgery (B.B., K.J.H.) and Medicine (P.A.P.), University of Melbourne, Austin and Repatriation Medical Centre, Heidelberg, and Department of Obstetrics and Gynaecology (A.S.N.), University of Melbourne, Royal Women's Hospital, Carlton, Victoria, Australia.
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Abstract |
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Abstract Cyclosporine-induced hypertension is a major problem in transplant therapy. The pathophysiology of this disease is unclear. Cyclosporine increases endothelin synthesis and release, which may contribute to this hypertension. We examined the effects of chronic endothelin receptor blockade with the novel nonpeptide endothelin receptor antagonist bosentan in two animal models of cyclosporine-induced hypertension. Cyclosporine was administered daily to female Wistar rats (10 mg/kg per day SC for 30 days) and marmosets (30 mg/kg per day PO for 20 days). Control rats received vehicle. Tail-cuff systolic pressure was significantly elevated in the cyclosporine-treated animals before the last week of treatment. Bosentan (100 mg/kg) in arabic gum or arabic gum alone was given daily to the rats by gavage during the last 5 days of cyclosporine treatment and to the marmosets for the last 7 days of cyclosporine treatment. Tail-cuff systolic pressure was measured daily during bosentan treatment. Bosentan but not gum alone significantly lowered blood pressure in the cyclosporine-hypertensive rats from 134±1 to 122±3 mm Hg (P<.01) and in the cyclosporine-hypertensive marmosets from 156±2 to 139±4 mm Hg (P<.01). There were no differential effects on plasma creatinine concentration, endothelin concentration, or end-organ weights. Bosentan had no effect in the vehicle-treated rats. These data provide further evidence to support a role for endothelin in cyclosporine-induced hypertension and demonstrate the effectiveness of endothelin receptor antagonism as a novel treatment in cyclosporine-induced hypertension.
Key Words: cyclosporine • bosentan • endothelin • rats • primates
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Introduction |
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Cyclosporin A (CsA), a cyclic 11–amino acid peptide of fungal origin, is a potent immunosuppressant given to transplant patients to prevent organ rejection. However, its use in transplantation is complicated by the development of hypertension.1 2 3 CsA has been shown to damage the endothelium4 5 and may alter production of the endothelium-derived endothelin3 and nitric oxide systems.4 Although other immunosuppressants such as FK 506 (Fujisawa Pharmaceutical) show promise,6 7 CsA will be the main immunosuppressant in clinical use for some years to come.
The endothelins are a family of potent vasoconstrictor peptides produced by endothelial cells.8 Endothelin-1 (ET-1) is the major isoform in the vasculature and therefore is probably the most important member of this family for the local regulation of vascular tone.9 ET-1 is a 21–amino acid peptide produced by intracellular processing of preproendothelin via pro- or "big" endothelin. ET-1 acts on cell membrane–bound receptors. The endothelin type A (ETA) receptor mediates vasoconstriction, and the ETB receptor can mediate vasoconstriction or endothelium-dependent vasodilation.10 With CsA treatment, there is evidence for increased endothelin synthesis in vivo in the rat11 12 and from endothelial cells in vitro.7 13 We have recently demonstrated that acute ETA receptor antagonism with the peptide ETA receptor antagonist BQ-123 reduced blood pressure in CsA-hypertensive rats.14
The aim of this study was to examine the effects of chronic endothelin receptor blockade with bosentan,15 a novel orally active nonpeptide ETA and ETB receptor antagonist, on CsA-induced hypertension in rats and primates.
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Methods |
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Experimental procedures were approved by the Austin Hospital and Royal Women's Hospital Animal Research Ethics Committees and were performed according to the National Health and Medical Research Council of Australia guidelines for animal experimentation.
Polyvinylpyrrolidone (PVP) was obtained from Sigma Chemical Co and methohexital sodium from Eli Lilly. Bosentan (4-tert-butyl-M-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2,2/-bipyrimidin-4-yl]-benzene-sulfonamide) was a generous gift from F. Hoffmann–La Roche Ltd. Cyclosporine was kindly donated by Sandoz Pharmaceuticals.
Experiment 1: Rat Studies
Animals
Female Wistar rats (approximately 250 g) were obtained from
the Biological Research Laboratories, Austin and Repatriation Medical
Centre. Rats were housed at 24°C in a 12-hour light/dark cycle with
food (standard Norco rat chow, 0.6% NaCl) and water ad libitum.
CsA-Induced Hypertension
Rats received either CsA (10 mg/kg per day SC dissolved in PVP,
n=28) or PVP alone (0.4 mL/d SC, n=25) for 30 days according to
previously published methods.14 Tail-cuff
systolic pressure (model 229 amplifier and model 38L flatbed
recorder, IITC Life Science) was measured twice weekly, and body
weight was measured weekly. During the last 5 days of CsA or vehicle
treatment, rats received either bosentan (100 mg/kg per day in arabic
gum by gavage; CsA group, n=14; vehicle group, n=10) or arabic gum
alone (0.6 mL/d by gavage; CsA group, n=14; vehicle group, n=15).
Tail-cuff systolic pressure was measured daily during these
5 days. At the end of treatment, rats were anesthetized with
methohexital sodium (60 mg/kg IP, supplemented as required) for
insertion of a polyethylene carotid artery catheter (P45, Dural
Plastics and Engineering). At least 24 hours after surgery, mean
arterial pressure was measured in conscious rats with a
blood pressure transducer (model DPT 3003-S, Peter von Berg) calibrated
and attached to the intra-arterial catheter.
Transducer signals were preamplified before analog-to-digital
conversion (Maclab/8TM, Analog Digital Instruments Pty, Ltd) for data
recording and storage.
After blood pressure measurement, the rats were killed by decapitation, and trunk blood was taken for measurement of blood CsA concentrations with the Cyclo-Trac SP whole blood radioimmunoassay kit (Incstar Corp). Plasma creatinine was measured with an Automated Stat Routine Analyzer 8 (Beckman Instruments). Plasma sodium and potassium concentrations were measured with a sodium/potassium flame photometer (Instrumentation Laboratory). Plasma ET-1 concentrations were measured with an ET-1 radioimmunoassay kit (Nichols Institute Diagnostics SA). The mesenteric arterial bed and vascular cascade were removed in a standardized manner, and the fat was removed by blunt dissection in cold (4°C) normal saline. The mesenteric arteries, kidneys, and heart were weighed.
Experiment 2: Marmoset Studies
Animals
Male and female marmosets (Callithrix jacchus) bred
in an established marmoset colony (Department of Obstetrics and
Gynaecology, University of Melbourne, Royal Women's Hospital, Carlton,
Australia), between 3 and 8 years of age, and weighing 300 to 500
g were studied. Marmosets (n=10) were housed at 26°C and fed pellets
(standard cat chow, Whiskettes), fresh fruit, and vegetables ad
libitum.
So that marmosets became accustomed to blood pressure measurements, they were restrained in a specially designed chair for a few minutes each day for 1 to 2 weeks, and tail-cuff blood pressure was obtained according to previously published methods.14 16 After this acclimatization period, tail-cuff systolic pressure was recorded (model 229 amplifier and model 38L flatbed recorder, IITC Life Science) for 3 days before drug treatment began to obtain baseline readings. Body weight was measured weekly during the study.
CsA-Induced Hypertension
CsA (30 mg/kg per day dissolved in 0.5 mL olive oil) was given
orally to all marmosets for 20 days according to previously published
methods.16 Tail-cuff systolic pressure was
measured three times weekly during the first 14 days. During days 15
through 21 of CsA treatment, marmosets received either bosentan (100
mg/kg per day) in arabic gum or arabic gum alone as a control.
Systolic pressure was measured daily, and the average
recordings for days 16 through 18 and days 19 though 21 were
obtained for each animal. This average was taken as the value for that
animal at that time. At the end of treatment (day 21), approximately 2
mL blood was taken from the femoral vein for measurement of blood CsA
and plasma creatinine and ET-1 concentrations; body weight
was recorded before marmosets were killed by anesthetic overdose
with 9 mg alphaxalone IM (Saffan, Pitman-Moore).
Statistics
Values are expressed as mean±SE. The effects of bosentan
administration on tail-cuff systolic pressure were
subjected to a two-way repeated measures ANOVA. The factors were
treatment and time, with time the repeated measure. Post hoc
analysis of individual time points was performed with the
Newman-Keuls test. Mean arterial pressure; blood CsA
concentrations; plasma creatinine, ET-1, sodium, and
potassium concentrations; and tissue weights in the rat studies were
analyzed by two-factor ANOVA with CsA/control and
bosentan/gum being the factors. Tissue weights and blood CsA and plasma
creatinine concentrations in the marmoset study were
analyzed by unpaired t tests. Statistical
significance was taken at a value of P<.05.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Experiment 1: Rat Studies
Baseline blood pressures were similar for the control (126±1.6 mm Hg) and CsA-treated (127±2.4 mm Hg) rats. CsA significantly elevated systolic pressure in rats (Fig 1
) by week 3 of
treatment (134±1 mm Hg, n=14, P<.01, versus control
vehicle-treated rats, 125±2 mm Hg, n=15). Administration of 100
mg/kg bosentan lowered tail-cuff systolic pressure (Fig 1)
in the CsA-hypertensive rats to control rat levels (ie, from 134±1 to
122±3 mm Hg, P<.01). This fall in systolic
pressure was confirmed by measurement of intra-arterial
mean blood pressure in the four rat groups (Table 1,
P<.01).
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Blood CsA concentration was elevated in both CsA-treated groups (Table 1
, P<.01), whereas readings for the control rat groups were
below the sensitivity of the assay. Plasma creatinine,
sodium, potassium, and ET-1 concentrations and organ weights did not
differ between the four rat groups (Table 1).
Experiment 2: Marmoset Studies
By the end of week 2, CsA raised systolic pressure (Fig 2) in the marmosets from 133±3 (baseline reading) to
156±2 mm Hg (P<.01) in the gum-treated group and
151±7 mm Hg (P<.01) in the bosentan-treated group.
Blood pressure did not differ between these groups. Systolic
pressure remained elevated in the gum-treated group by the end of 7
days of treatment (157±5 mm Hg), whereas in the bosentan-treated
group, blood pressure was lowered to 139±4 mm Hg (P<.01
compared with the gum-treated group). This was not statistically
significantly different from baseline blood pressure before CsA
treatment.
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) or bosentan (
, 100 mg/kg)
for 7 days on tail-cuff systolic pressure in conscious
cyclosporin A–treated marmosets. Daily treatment with
bosentan significantly lowered systolic pressure compared with
arabic gum. Mean±SE is given; n=5 marmosets per group.
**P<.05 vs gum-treated group.
Blood CsA concentration was significantly lower in the
bosentan-treated group at the end of the experiment compared with
the gum-treated group (Table 2, 37.6±9.6 versus
14.4±2.0 nmol/L, P<.05). Plasma creatinine and
kidney and left ventricle weights were not significantly different
between the groups (Table 2). Plasma creatinine
concentrations from a group of normotensive marmosets (0.045±0.005
mmol/L, n=5) that did not receive CsA were not different from
concentrations in the CsA-treated group (0.052±0.002 mmol/L, n=5,
Table 2) or data from other investigations.16
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The present study examined the effects of chronic ET-1 receptor blockade with bosentan on CsA-induced hypertension in rats and marmosets. We found that bosentan lowered blood pressure in both CsA-hypertensive animal models and had no effect on blood pressure in the control rat group.
Plasma ET-1 was not significantly altered in the CsA-treated rats compared with the control rats. This is in agreement with our previous findings with Wistar rats.14 However, Carrier et al17 have shown an increase in plasma ET-1 concentration in the renal venous blood of a CsA-treated dog and in CsA-treated rats.18 Although some studies have shown that solid-organ transplant patients receiving CsA also have elevated circulating ET-1 levels,19 20 21 others have not confirmed increased circulating ET-1 concentrations in human transplant recipients.22 However, the endothelins are a tissue-based system produced and acting locally rather than as a circulating hormone. Therefore, the significance of any change or lack of change in plasma ET-1 concentrations is unclear.
Previous studies have shown that CsA damages endothelial cells1 2 3 and can induce endothelin synthesis and release in vitro in rat12 and human7 13 cultured endothelial cells as well as increase ET-1 peptide11 and mRNA synthesis in vivo23 in rats. These data provide compelling evidence for increased ET-1 synthesis as potentially pathogenetic in CsA-induced hypertension.
A potential role for ET-1 in CsA-induced hypertension was further supported by our previous demonstration that 24 hours after ETA receptor blockade with the ETA receptor antagonist BQ-123, intra-arterial blood pressure was lowered in the CsA-hypertensive rats to the same level as that in the control rat group.14 This was in the absence of any differences in 125I–ET-1 binding or vascular myographic responses to ET-1 in mesenteric resistance vessels of CsA-treated and control rats. However, because of the nature of the peptide and expense of this antagonist, long-term studies of the chronic effects of endothelin receptor antagonism were not possible.
Bosentan15 is a more potent analogue of Ro 46-2005,24 the first nonpeptide orally active endothelin receptor antagonist. It is a competitive antagonist at both the ETA and ETB receptors. The bosentan dose used has previously been shown by Clozel et al15 to inhibit the effect of 0.3 nmol/kg big ET-1 by 37% at 24 hours after its administration. Maximum inhibition of ET-1 binding by 100 mg/kg bosentan orally occurred at 1 hour in rat mesenteric arteries and at 4 hours in the rat liver with a prolonged duration of action for up to 16 hours in the liver probably because of hepatic excretion of bosentan.25
Previous studies demonstrating increased ET-1 synthesis and our studies of acute14 and now chronic endothelin receptor blockade effectively lowering blood pressure in CsA-hypertension in both rats and primates provide strong evidence that ET-1 is pathogenetic in CsA-hypertension.
Endothelin has also been implicated in CsA-induced nephrotoxicity.21 26 Studies have shown that endothelin may be an important mediator of renal vasoconstriction after CsA administration,21 27 28 and endothelin receptor blockade was effective in abolishing this effect. Kon et al28 have shown that CsA reduces creatinine clearance in rats and that ETA/ETB receptor blockade prevents this CsA effect. Improved renal excretion may explain the lower blood CsA concentrations seen with bosentan in the marmosets despite their being given the same dose as gum-treated CsA-hypertensive animals.
However, the CsA-treated rats and marmosets in our study had plasma creatinine concentrations similar to those of normotensive animals. These results confirm those from a previous study with CsA-treated marmosets.16 This is in contrast to the study of Kon et al,28 which showed that CsA significantly increased serum creatinine in rats after 5 weeks of CsA treatment; however, they used a higher dose and longer duration of CsA administration. Although plasma creatinine is a crude measure of glomerular filtration rate, our data suggest that there was no severe renal impairment with CsA. An upregulation of endothelin binding sites18 and increased endothelin mRNA29 in the kidneys from CsA-treated rats have also been demonstrated.
It has been suggested that ETA receptor activation could be involved in volume-dependent or low-renin hypertension,30 both of which are characteristic of CsA-hypertension.31 ET-1 has been implicated in the pathogenesis of deoxycorticosterone acetate–salt hypertension in rats,32 but evidence regarding its role in spontaneous genetic hypertension in rats is inconclusive.30 31 32 33 34
Whether ET-1 receptor blockade will be effective therapy in chronic CsA-hypertension in humans is unknown; however, bosentan is now entering trials in essential hypertension and has been shown to lower blood pressure in the short term in humans.35 Further studies of any beneficial effect of endothelin receptor antagonism in humans will elucidate whether this treatment will be useful.
In conclusion, all of these studies support the role of endothelin in the pathogenesis of CsA-induced hypertension and nephrotoxicity and the potential role of orally active nonpeptide endothelin receptor antagonism as treatment. Better management of CsA-induced hypertension, possibly with endothelin receptor antagonists, may further improve the long-term prognosis for transplant recipients.
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Acknowledgments |
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This research was supported by the Austin Hospital Medical Research Foundation. We would like to thank Prof Alex Lopata for providing access to the marmoset colony.
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Footnotes |
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Reprint requests to Briony Bartholomeusz, Department of Surgery, University of Melbourne, Austin and Repatriation Medical Centre, Austin Campus, Heidelberg, Victoria, 3084, Australia.
Received October 9, 1995; first decision January 11, 1996; accepted February 16, 1996.
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