(Hypertension. 1995;26:932-936.)
© 1995 American Heart Association, Inc.
Articles |
Effects of an Endothelin Receptor Antagonist in Rats With Cyclosporine-Induced Hypertension
From the Second Department of Internal Medicine, School of Medicine, Kanazawa (Japan) University.
Correspondence to Yoshiyu Takeda, MD, Second Department of Internal Medicine, School of Medicine, Kanazawa University, 13-1 Takara-machi, Kanazawa 920, Japan.
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Abstract |
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Abstract Cyclosporine, a potent immunosuppressant, is associated with the development of hypertension and nephrotoxicity. We have previously shown that endothelin release from the arteries is increased in rats with cyclosporine-induced hypertension. We conducted the present study to determine whether the specific endothelin type A (ETA) receptor antagonist FR 139317 prevents cyclosporine-induced hypertension and whether cyclosporine increases ETA receptor mRNA in blood vessels. Cyclosporine (25 mg/kg per day) given for 4 weeks increased blood pressure from 98±12 to 156±14 mm Hg; this increase was blunted by coadministration of 10 mg/kg per day FR 139317 (ie, blood pressure was 138±14 mm Hg) in Wistar-Kyoto rats. Cyclosporine induced greater vasoconstrictor responses to norepinephrine and angiotensin II in isolated mesenteric arteries. FR 139317 normalized the vasoconstrictor responses to angiotensin II and norepinephrine. Cyclosporine (25 mg/kg per day) given for 4 weeks increased ETA receptor mRNA expression in the rat aorta and mesenteric artery (170% and 176%, respectively). Little change was observed in ETB receptor mRNA. These results indicate that cyclosporine may increase blood pressure by increasing not only endothelin production but also ETA receptor in the vasculature. The specific ETA receptor antagonist FR 139317 may prevent the hypertension induced by cyclosporine.
Key Words: receptors, endothelin • cyclosporine • hypertension • rat
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Introduction |
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Although CysA is an effective immunosuppressive agent, its clinical efficacy is complicated by substantial hypertension and nephrotoxicity.1 2 The exact mechanism for CysA-induced hypertension is unclear,3 but a growing body of evidence suggests that the primary pathogenic mechanism may be vascular.4 5 Recent evidence has supported a potentially important role for the potent vasoconstrictor peptide endothelin in the CysA-induced effect on vascular smooth muscle.6 7 The exact role played by endothelin in CysA-induced vasoconstriction remains uncertain. We have reported that CysA increased endothelin synthesis as well as endothelin mRNA expression in the vascular wall.8
The purpose of the present study was to determine whether the specific ETA receptor antagonist FR 139317 prevents the CysA-induced hypertension and whether CysA exposure directly increases ETA receptor mRNA in blood vessels.
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Methods |
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Male Wistar-Kyoto rats (weighing 200 to 220 g, Nippon Charles River, Kanagawa, Japan) were housed in metabolic cages with free access to tap water and normal rat chow (0.1 mmol/g sodium and 0.24 mmol/g potassium; Nippon Charles River). The rats were divided into four experimental groups. Group 1 received daily subcutaneous injections of CysA (Sandoz Ltd) solubilized in olive oil at a dose of 25 mg/kg per day for 4 weeks (n=18). Group 2 (n=18) was given FR 139317 [(R)2-[(R)-2-[(S)-2-[[1-(hexahydro-1H-azepinyl)]carbonyl]amino-4-methylpentanoyl]-amino-3-[3-(1-methyl-1H-indolyl)]-propionyl]amino-3-(2-pyridyl) propionic acid], an ETA-receptor antagonist (kindly donated by Fujisawa Pharmaceutical Co, Osaka, Japan),9 injected subcutaneously at a dose of 10 mg/kg per day for 4 weeks. Group 3 (n=18) received a combination of CysA (25 mg/kg per day) and FR 139317 (10 mg/kg per day) for 4 weeks. Group 4 (n=18) was injected daily with subcutaneous olive oil for 4 weeks. The protocol was approved by the Animal Research Committee of this institution.
Blood pressure was determined by the plethysmographic tail-cuff method and blood collected from the tail vein, both as previously reported.10 Plasma ET-1 concentrations were determined with a sandwich-type enzyme immunoassay after extraction with a Sep-Pak C18 cartridge column (Waters Associates).6 Serum creatinine levels were determined by the alkaline picrate method. FR 139317 plasma concentration was measured with a high-performance liquid chromatographic system (LKB 2249, Pharmacia Japan) (column, 5-µm TSK GEL 120T [Tosoh]; mobile phase, NaH2PO4·2H2O, H3PO4, CH3CN, H2O [3.11 g/0.15 mL/1L/1L]; flow rate, 1.0 mL/min).
Ten rats from each group were used for the experiments of mesenteric arterial perfusion. After the rat was put under pentobarbital anesthesia the mesenteric artery was immediately excised with the use of the method described by McGregor11 with minor modifications as we previously reported.12 Briefly, the isolated artery was perfused with Krebs-Ringer solution, pH 7.4, at a temperature of 37°C and was oxygenated with a 95% O2/5% CO2 gas mixture at a constant flow rate of 3 mL/min. Perfusion pressure was constantly monitored and recorded by means of a pressure transducer connected to a polygraph (RM 600, Nihon-Koden). After 30 minutes of equilibration l-norepinephrine (0.6x10-8 mol/L, 1.2x10-8 mol/L, Sankyo) or Ang II (1.0x10-9 mol/L, 2.0x10-9 mol/L, Peptide Institute) was administered by bolus injection through a cannula; the injection volume was less than 100 µL. Injection of an equal volume of isotonic saline had no effect on perfusion pressure.
Eight rats from each group were used for the quantification of ETA and ETB receptor mRNA in the mesenteric artery and aorta. Rat mesenteric arteries and aorta were removed immediately after rats were decapitated. The tissue was promptly weighed, frozen in liquid nitrogen, and stored at -80°C before use. Total RNA from rat mesenteric arteries was separated with guanidium thiocyanate followed by centrifugation in a cesium chloride solution. One microgram of total RNA was incubated at 42°C for 60 minutes with 2.5 U M-MLV reverse transcriptase (Perkin-Elmer Japan) in a 20-µL reaction mixture containing random hexanucleotide primer. After incubation for 5 minutes at 99°C the single-stranded cDNA in the 20-µL reaction mixture was amplified with the PCR mixture containing 0.2 mmol/L of each dNTP. The reaction was followed by incubation at 92°C for 3 minutes and 30 cycles of the following sequential steps: 92°C for 1 minute, 60°C for 1 minute, and 72°C for 2 minutes.
The ETA receptor primer (sense) was 5'-CTGTGCTGCTCGCCCTTGTA-3' and antisense primer was 5'-GAAGTCGTCCGTGGGCATCA-3'; the ETB receptor primer (sense) was 5'-CACGATAGAGGACAATGAAGAT-3' and antisense primer was 5'-TTACAAGACAGCCAAAGACT-3' according to the published sequence by Takeda et al.13 We performed RT-PCR of ß-actin as an internal standard. The primers were defined as previously reported by Krapf and Solioz.14 The RT-PCR products in 20-µL aliquots were electrophoresed on a 1.5% agarose gel and transferred to nylon membranes. The membranes were prehybridized in 50% formamide, 5x saline/sodium/phosphate/EDTA, 5x Denhardt's reagent, 1% SDS, and 0.5 mg/mL salmon sperm DNA at 50°C for 6 hours and hybridized in the same buffer at 50°C for 15 hours with specific oligoprobe for ETA receptor, ETB receptor, or ß-actin, which were end-labeled with [32P]ATP (6000 Ci/mmol, New England Nuclear) with the use of a 5'-end oligonucleotide labeling kit. The sequence of each oligonucleotide was 5'-CCCCTTGATTACCGCCATT-G-3' (ETA receptor) and 5'-TGTGCT-GCTGGTGCCAAACG-3' (ETB receptor).13 The membrane was washed twice in 2x SSC and 0.1% SDS at room temperature for 20 minutes, twice in 0.1x SSC and 0.1% SDS at 50°C for 20 minutes, and autoradiographed. The hybridized signals were analyzed with a BAS 2000 (Fuji Photo Film Co Ltd).
Data are expressed as mean±SEM. The significance of differences was assessed by one-way ANOVA and Wilcoxon's unpaired t test. Statistical significance was accepted at a value of P<.05.
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Results |
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Maximal plasma concentration of FR 139317 in rats after subcutaneous administration of 10 mg/kg FR 139317 was 7.0±0.5 µmol/L 2 hours after injection and gradually decreased to 33±2 nmol/L 16 hours after injection.
Chronic administration significantly increased blood pressure beginning at 2 weeks (Fig 1). Treatment with FR 139317 resulted in 60% and 70% decreases in the CysA-control difference in blood pressure at 3 and 4 weeks, respectively (Fig 1). The Table summarizes body weight, heart rate, and serum creatinine and plasma ET-1 concentrations in the experimental groups. Body weight and serum creatinine did not differ significantly between the experimental groups. Plasma ET-1 concentration was significantly higher in CysA-treated and FR 139317–treated rats compared with control rats at 2 and 4 weeks (P<.05). The increased pressor response to norepinephrine and Ang II by CysA was normalized by FR 139317 (Fig 2). FR 139317 slightly but significantly decreased the pressor response to norepinephrine and Ang II (P<.05).
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Fig 3 shows the results of RT-PCR products predicted for ETA receptor (216 bp) and ETB receptor (565 bp) in Southern blot analysis. When PCR was carried out in the absence of reverse transcription, bands were not seen at 216 or 565 bp. The amplification product of ß-actin (703 bp) served as an internal standard for the RT-PCR reaction.
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Fig 4 summarizes quantification of ETA receptor mRNA in the mesenteric arteries and aorta of CysA-induced hypertensive rats, FR 139317–treated rats, CysA plus FR 139317–treated rats, and control rats. ETA receptor mRNA concentrations in the mesenteric arteries and aorta of CysA-induced hypertensive rats were significantly increased compared with those of control rats or FR 139317–treated rats (P<.05). FR 139317 did not affect ETA receptor mRNA expression in CysA-induced hypertensive rats. ETB receptor mRNA concentrations did not differ significantly between the experimental groups (data not shown).
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Discussion |
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This study demonstrated that treatment with the selective ETA receptor antagonist FR 139317 for 4 weeks blunts the rise in blood pressure in CysA-induced hypertensive rats. This is associated with the changes in response to vasoconstrictors usually found in mesenteric resistance arteries in these hypertensive rats.
CysA-induced hypertension occurs frequently in solid organ transplantation and in autoimmune disease.15 Although renal dysfunction is usually also present, blood pressure elevations have been observed in the absence of detectable renal dysfunction in both animals and humans.16 In our experiments chronic administration of CysA (25 mg/kg per day) for 4 weeks did not increase serum creatinine. Numerous studies have been conducted in various animal models to elucidate the vascular changes that might be responsible for the blood pressure elevation. Rego et al17 showed that chronic administration of CysA induced a greater vasoconstrictor response to norepinephrine. Other reports obtained with the use of large vessels also documented increased adrenergic vascular reactivity, further supporting the sympathetic factor of CysA-induced hypertension.18 In our results FR 139317 improved the increased sensitivity to norepinephrine caused by CysA.
CysA has been shown to augment selectively the effects of Ang II in rat vascular smooth muscle.19 Auch-Schwelk et al20 reported that chronic angiotensin-converting enzyme inhibition prevents the augmentation of contractions to Ang II caused by CysA. In the present study the contractions to Ang II were augmented in rats treated with CysA. FR 139317 normalized this response to Ang II caused by CysA.
Endothelin is a potent vasoconstrictor produced by endothelial cells.21 Its putative role in the pathogenesis of hypertension is supported by several lines of evidence suggesting that endothelial damage is generally associated with the enhanced release of the vasoconstrictor peptide.22 23 We have reported that CysA increased endothelin production and endothelin mRNA levels in the rat mesenteric artery.24 Lanese and Conger25 reported that CysA exposure causes direct local release of endothelin from the endothelium of the renal microvasculature and that ETA receptor antagonist blocks the vasoconstrictor effect induced by CysA. Wong-Dusting and Rand26 have suggested that a low concentration of ET-1, which does not directly cause vasoconstriction, may increase the sensitivity of vascular smooth muscle to sympathetic stimulation. Ito et al27 also reported that endogenously stimulated ET-1 generated and secreted locally by cardiomyocytes contributes to Ang II–induced cardiac hypertrophy. Locally increased endothelin may contribute either directly or indirectly to vasoconstriction. This theory is supported by our findings that FR 139317 decreased the pressor responses to Ang II and norepinephrine.
FR 139317 is a novel and potent selective antagonist for ETA receptor.28 The effects of a selective ETA receptor antagonist observed in these experiments confirmed the important role for endothelin in CysA-induced hypertension. The dose of 10 mg/kg reportedly is enough to completely block the ETA receptor.29 The plasma concentration of FR 139317 from our experimental rats was more than 10 nmol/L, which is enough to cause an antagonistic effect.9 FR 139317 blunted the rise of blood pressure by CysA but did not completely prevent it. Factors other than endothelin have been reported for CysA-induced vasoconstriction.30 Auch-Schwelk et al20 suggested that CysA upregulates Ang II receptors in the vasculature. Recently, Diederich et al31 reported that CysA impairs relaxation mediated by endothelium-derived nitric oxide in mesenteric arteries via enhanced production of free radicals that inactivate endothelium-derived nitric oxide.
Our previous report32 and another33 suggest that CysA increases endothelin production from the endothelium. CysA-treated animals appear to have upregulated endothelin receptors, as suggested by observations of enhanced endothelin binding in glomeruli, renal medulla, and cardiac tissue.34 35 36 ETA receptors appear to be present mainly on vascular smooth muscle cells, mediating the vasoconstrictor effects of ET-1, whereas ETB receptors on the vascular endothelium mediate the transient vasodilator response to ET-1 and ET-3 through release of nitric oxide and/or prostacyclin.37 According to the development of the specific antagonist for ETA or ETB receptor, there are increasing reports that the function of endothelin receptors differs in species and vessels.38 Takeda et al13 reported that CysA increases ETB receptor mRNA but not that for ETA in rat mesangial cells. Our results showed that the ETA receptor mRNA concentration in the mesenteric artery and aorta of CysA-treated rats was higher than that of controls. However, ETB receptor mRNA levels did not differ significantly between CysA-induced hypertensive and control rats. ETB receptor mRNA levels are downregulated by endothelins by decreasing the intracellular stability of mRNA molecules.39 Seo et al40 reported that not only ETA receptor but also ETB receptor contributed to the vasoconstriction by ET-1 in human vessels. In spontaneously hypertensive rats chronic administration of the combined ETA/ETB receptor antagonist bosentan does not decrease blood pressure.41 The role of ETB receptors in blood vessels appears to be more complex than originally thought and is not well understood.
CysA may increase either directly or indirectly ETA receptor mRNA levels in the vessels. In addition to locally increased endothelin, the CysA-induced increase in ETA receptor in the resistant vessels may contribute to vasoconstriction and hypertension. In our results serum creatinine did not increase in CysA-treated rats; however, renal injury by CysA was not neglected. Benigni et al29 reported that a specific ETA receptor antagonist protects against injury in the progression of renal disease. Further study is necessary to understand the clinical implications of an ETA receptor antagonist in preventing the complications of CysA (ie, hypertension and nephrotoxicity).
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Selected Abbreviations and Acronyms |
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Received March 8, 1995; first decision April 13, 1995; accepted August 16, 1995.
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References |
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