(Hypertension. 1995;25:501-506.)
© 1995 American Heart Association, Inc.
Articles |
ETA and ETB Receptors Mediate Contraction to Endothelin-1 in Renal Artery of Aging SHR
Effects of FR139317 and Bosentan
Presented at the 48th Annual Fall Conference and Scientific Sessions of the Council for High Blood Pressure Research of the American Heart Association, Chicago, Ill, September 27-30, 1994.
From the Department of Research, University Hospital, Basel (B.S., T.F.L.); Cardiology, Cardiovascular Research, University Hospital, Bern (T.F.L.), Switzerland; and the Department of Medicine, Gyeongsang National University Hospital, Chinju, Korea (B.S.).
Correspondence to Thomas F. Lüscher, MD, Division of Cardiology, University Hospital/Inselspital, CH-3010 Bern, Switzerland.
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Abstract |
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Abstract We characterized vascular endothelin receptors of the renal artery from adult (12 to 16 weeks of age) and old (72 to 76 weeks) spontaneously hypertensive rats (SHR) and age-matched Wistar-Kyoto rats (WKY). Vessels were suspended in organ chambers (37°C, aerated with 95% O2/5% CO2), and isometric tension was recorded. The endothelin-A (ETA) receptor antagonist FR139317, the combined ETA/ETB receptor antagonist bosentan, and the ETB-selective agonist sarafotoxin S6c were used. In old (and less so in adult) SHR, cumulative concentration-contraction curves to endothelin-1 showed a small contraction resistant to FR139317 (10-5 mol/L) at 3x10-9 to 10-8 mol/L endothelin-1, which was completely inhibited by bosentan (10-5 mol/L). This FR139317-resistant contraction to endothelin-1 was not present in WKY. Furthermore, in the presence of FR139317 (10-5 mol/L), sarafotoxin S6c induced a stronger contraction in old SHR than in WKY (P<.05). In rings contracted with norepinephrine, sarafotoxin S6c caused endothelium-dependent relaxations in both strains; these relaxations were blocked by N
-nitro-L-arginine methyl
ester, indicating that nitric oxide is the mediator. In WKY but not
SHR, release of nitric oxide by sarafotoxin S6c increased with age
(P<.05). Thus, both ETA and ETB
receptors mediate contraction to endothelin-1 in the renal artery from
SHR but not WKY. ETB receptors on vascular smooth muscle
seem to be unmasked with age in SHR, whereas those on endothelium
(mediating nitric oxide release) exhibit more efficient responses with
age in WKY.
Key Words: renal artery • receptors, endothelin • endothelins • aging
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Introduction |
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Endothelin-1 (ET-1) is a potent vasoconstrictor peptide synthesized by vascular endothelium.1 The vascular actions of ET-1 are mediated by specific receptors on endothelium and vascular smooth muscle cells.2 3 ETA receptors4 are present on vascular smooth muscle cells and mediate vasoconstriction, and ETB receptors5 on endothelium mediate transient vasodilation through the release of nitric oxide or prostacyclin.6 7 The presence of a third receptor specific for ET-3 has been suggested.8 A cDNA encoding for the so-called ETC receptor has recently been cloned.9 We recently found that in addition to ETA receptors, vasoconstrictor ETB receptors are also present on the smooth muscle of human internal mammary vessels and porcine coronary artery.10 ETB receptors also were reported to mediate renal vasoconstriction to ET-1 in rats.11 12 13 ET-1 seems to play a role in pathophysiological states, as its plasma levels are increased in myocardial infarction,14 renal failure,15 and some patients with hypertension.16 17 18 Furthermore, endothelin receptor antagonists, the endothelin-converting enzyme inhibitor phosphoramidone, and antibody against ET-1 lower blood pressure in some animal models of hypertension.19 20 21 22
The spontaneously hypertensive rat (SHR) is frequently used as an animal model of essential hypertension. However, the difference, if any, between hypertensive rats and normotensive Wistar-Kyoto rats (WKY) concerning endothelin receptor subtypes has not been studied comprehensively. Furthermore, studies on the contractile response to ET-1 have yielded conflicting results; increased, normal, and reduced contractile responses to ET-1 have been reported.18 Therefore, we investigated pharmacologically the endothelin receptor subtypes mediating vasodilation and contractile responses to ET-1 in the renal artery of hypertensive and normotensive rats. For this purpose, we used the selective ETA receptor antagonist FR139317,23 the combined ETA/ETB receptor antagonist bosentan,24 and the ETB-selective agonist sarafotoxin S6c.25
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Methods |
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Blood Vessels and Experimental Setup
Male rats (Charles River, Germany) of two age groups (adult, 12 to 16 weeks of age; old, 72 to 76 weeks of age) were used in this study. The animals were housed according to the guidelines of the Basel commission for animal research, which approved all protocols. In the adult group, 17 SHR (345±4 g) and 18 age-matched normotensive WKY (345±4 g) were used. In the old group, 10 SHR (378±9 g) and 11 age-matched WKY (597±12 g) were used. Arterial blood pressure was measured by the tail-cuff method. Rats were anesthetized with sodium pentobarbital (50 mg/kg IP), and the kidneys were removed together with the renal arteries and abdominal aorta and immediately immersed in cold modified Krebs-Ringer bicarbonate solution of the following composition (mmol/L): NaCl 118, KCl 4.7, CaCl2 2.5, MgSO4 1.2, KH2PO4 1.2, NaHCO3 25.0, edetate calcium disodium 0.026, and glucose 1.1 (control solution). Both main renal arteries were cleaned of adherent soft tissue and cut into 2-mm rings under a dissection microscope. Vascular rings were suspended between two stirrups in organ chambers filled with 12.5 mL control solution (37°C) and were aerated with 95% O2/5% CO2, and isometric tension was measured. Optimal resting tension of the rings (approximately 2.5 g in all rat groups26 ) was determined by repeated contraction to 100 mmol/L KCl before the beginning of the experiments. In some vascular rings, the endothelium was removed by perfusion with saponin (500 µg/mL) for 15 seconds through the abdominal aorta, both ends of which had been closed by ligation. Endothelium removal was confirmed by relaxation to acetylcholine (10-6 mol/L) of less than 10% of the contraction to norepinephrine (3x10-7 mol/L).
Protocols
After contraction of each vascular ring with 100 mmol/L KCI
(control response), the following protocols were performed.
Effect of FR139317 and Bosentan on Contractions to ET-1 (Protocol
1)
To characterize differences between ETA and combined
ETA/ETB antagonist, we preincubated
vascular rings for 30 minutes with the ETA antagonist
FR139317 (10-5 mol/L, to unmask the effects of contractile
ETB receptors on vascular smooth muscle10 ) or
the combined ETA/ETB antagonist bosentan
(10-5 mol/L) and constructed cumulative
concentration-contraction curves to ET-1. In old rats, this protocol
was performed in rings with endothelium, and in adult rats, vessels
both with and without endothelium were tested.
Contractions to Sarafotoxin S6c (Protocol 2)
To test the contractile responses to the
ETB-selective agonist sarafotoxin S6c, we preincubated
vascular rings with FR139317 (10-5 mol/L) for 30 minutes
(to block vasoconstrictor ETA receptors on smooth muscle
cells) and observed contractions to cumulative concentrations
(10-9 to 10-7 mol/L) of sarafotoxin S6c in
the renal arteries with (in old rats) and without (in adult rats)
endothelium.
Endothelium-Dependent Relaxation to Sarafotoxin S6c (Protocol
3)
To examine relaxations in response to stimulation of endothelial
ETB receptors, we constructed cumulative
concentration-relaxation curves to acetylcholine (10-9 to
3x10-7 mol/L) first in vascular rings with endothelium
after precontraction with norepinephrine (3x10-7 mol/L).
Thereafter, vascular rings were preincubated with FR139317
(10-5 mol/L, 30 minutes), again contracted with
norepinephrine (3x10-7 mol/L), and then sarafotoxin S6c
(3x10-8 mol/L) was added. Some vascular rings were
preincubated with
N-nitro-L-arginine methyl ester
(L-NAME, 10-4 mol/L for 30 minutes) in addition to
FR139317 to determine whether the relaxations were mediated by nitric
oxide.
Drugs
The following drugs were used (all from Sigma Chemical Co unless
otherwise stated): ET-1, sarafotoxin S6c (Bachem), FR139317 (Fujisawa
Pharmaceutical Co), bosentan (F. Hoffmann–La Roche),
acetylcholine, norepinephrine, and L-NAME. ET-1 and sarafotoxin
S6c were dissolved in 0.1% bovine serum albumin. FR139317 was
dissolved in 50% ethanol (stock solution, 10-5 mol/L) and
diluted with distilled water. The final concentration of ethanol in the
organ chamber was less than 0.3%. All other drugs were dissolved in
distilled water.
Data Analysis and Statistics
Contractions are expressed as absolute values (in grams)
or a percentage of the control response to 100 mmol/L KCl. In some
contraction studies, the ET-1 concentrations (expressed as negative log
molar) exhibiting either 35% of the response to 100 mmol/L KCl
(PD35) or 50% of the maximal response to ET-1
(EC50) were calculated separately for each ring. The
acetylcholine concentration (negative log molar) required to relax the
vessels by 50% of the contraction to norepinephrine (IC50)
was also calculated in protocol 3. The amount of relaxation to
sarafotoxin S6c was expressed as the percentage of the maximal
relaxation to cumulative acetylcholine concentrations. A paired
t test was used in protocol 1 to compare each point of the
concentration-contraction curves in the presence of FR139317 or
bosentan. An unpaired t test was used to compare the values
between the two strains in the same age group or between the two age
groups in the same strain. ANOVA followed by Scheffé's F test
was used to compare the PD35 values in the same rat group.
For comparison of the concentration shift induced by FR139317 and
bosentan, the Wilcoxon rank sum test was used for the different rat
groups and Wilcoxon signed rank test for the same rat group. All values
are expressed as mean±SEM. Three vascular rings obtained from the same
rat were used in parallel for protocol 1.
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Results |
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Sensitivity and Maximal Contraction to ET-1
In renal arteries with endothelium from WKY, the sensitivity to ET-1 (EC50) was higher in the younger group. In SHR, however, the EC50 was not different by age (Table 1 and Fig 1). In addition, the difference in sensitivity between WKY and SHR was not significant in adult and old rats (Table 1 and Fig 1).
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Maximal contractions to ET-1 in vessels with endothelium were significantly smaller in SHR than WKY, regardless of age (Table 1). In addition, maximal contraction to ET-1 was increased with age in WKY but not in SHR (Table 1).
Effect of Endothelin Receptor Antagonists on the Contraction to
ET-1
In renal arteries with endothelium of adult rats, ET-1
(10-12 to 10-6 mol/L) caused
concentration-dependent contractions (Fig 2). Both
FR139317 (10-5 mol/L) and bosentan (10-5
mol/L) shifted the concentration-response curves to the right, whereas
the maximal contraction was maintained, thus confirming the competitive
antagonism of both compounds (Fig 2 and Table 2). The
degree of shift was not significantly different in the vessels
preincubated with FR139317 or bosentan (Table 2).
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In adult WKY, endothelium removal did not alter the sensitivity or the maximal response to ET-1 (Table 1). In contrast, in adult SHR, endothelium removal significantly enhanced the sensitivity but not the maximal response to ET-1 (Table 1). In adult WKY without endothelium, the effect of FR139317 or bosentan was still similar (Fig 3, left). In contrast, in renal arteries without endothelium and preincubated with FR139317 (10-5 mol/L) of adult SHR, ET-1 did cause small contractions at 3x10-9 mol/L, but this did not differ significantly compared with the response in the presence of bosentan (Fig 3, right).
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In renal arteries with endothelium from old rats, FR139317 and bosentan also shifted the concentration-contraction curves to the right (Fig 4 and Table 2). However, the contractions at 3x10-9 to 10-8 mol/L ET-1 were resistant to the effect of FR139317 (10-5 mol/L) in old SHR but not in old WKY (Fig 4). This high-sensitivity portion of the concentration-contraction curve was prevented by preincubation of the vessels with the ETA/ETB antagonist bosentan (P<.05, Fig 4, right). Bosentan also was more effective than FR139317 in inhibiting ET-1–induced contraction in old SHR (Table 2, P<.05 for both PD35 and concentration shift). In addition, the concentration shift to the right induced by bosentan was greater in SHR compared with old WKY (Table 2, P<.05).
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Contraction to Sarafotoxin S6c in the Presence of FR139317
In the renal arteries of both SHR and WKY, sarafotoxin S6c caused
concentration-dependent contractions (Fig 5, left).
Maximal contractions to sarafotoxin S6c (usually obtained at
10-8 to 3x10-8 mol/L, in the presence of
FR139317) showed a significant difference in the renal arteries with
endothelium from old SHR compared with those from old WKY
(P<.05, Fig 5, right).
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Endothelium-Dependent Relaxations to Sarafotoxin S6c
Endothelium-dependent relaxations to cumulative concentrations of
acetylcholine (10-9 to 3x10-7 mol/L) were
well preserved in all rat groups. The maximal relaxation and
IC50 averaged 105±4% and 7.8±0.1, respectively, in adult
WKY, 110±9% and 8.0±0.1 in adult SHR, 110±3% and 7.9±0.1 in old
WKY, and 97±7% and 7.7±0.1 in old SHR. Maximal relaxations did not
show any significant difference between groups. However, the
IC50 values were significantly higher in adult compared
with old SHR (P<.05).
Sarafotoxin S6c (3x10-8 mol/L) induced relaxations in all four groups tested (Fig 6). Old WKY showed more pronounced relaxations compared with adult WKY (P<.05, Fig 6). The relaxations were almost completely inhibited by L-NAME, averaging 12±5% before and 1±1% after L-NAME preincubation in adult WKY (n=7). The corresponding values were 29±14% and 0% (no relaxation) in adult SHR (n=5), 45±8% and 2±1% in old WKY (n=5), and 22±10% and 1±1% in old SHR (n=3) (P<.05 in all groups).
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Discussion |
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The most important finding of our study is that two endothelin receptors, ETA and ETB, are present and mediate vasoconstriction in the renal artery of SHR, whereas only ETA receptors are involved in the vasoconstriction to ET-1 in both adult and old WKY. An additional finding is that the release of nitric oxide by endothelial ETB receptor stimulation increases with age in WKY but not in SHR.
Endothelins have potent biological activities, ie, transient vasodilation followed by sustained vasoconstriction and mitogenic effects.17 They may be involved in many cardiovascular diseases, as suggested by increased plasma levels of ET-1 in these situations.14 15 16 27
The sensitivity to ET-1 was higher in adult compared with old WKY. This is consistent with other reports that aging reduces the sensitivity to ET-1 in the aorta28 and mesenteric circulation29 of the rat. However, this age-related difference in ET-1 sensitivity was not seen in SHR. In addition, the ET-1 sensitivity was not different between SHR and WKY, regardless of age. The sensitivity of vascular smooth muscle to ET-1 in hypertension as reported in the literature varies depending on the vascular bed studied and experimental conditions and methods used. In certain studies, hypertension did not affect the contractile sensitivity to ET-1 as in our experiments.30 However, an increased31 or decreased32 ET-1 sensitivity has also been reported in hypertension, the latter results in particular in the aorta28 33 and mesenteric resistance arteries.7 The maximal contractions to ET-1 were significantly greater in old compared with adult WKY in the present study. A similar trend, albeit not significant, also was seen in SHR. The cause of this finding is not clear. Although not tested in the present study, one possible explanation may be more release of endothelium-derived contracting factor (such as thromboxane A2) to high ET-1 concentrations33 in old compared with adult rats. Endothelium removal significantly enhanced the sensitivity (but not the maximal contraction) to ET-1 in adult SHR but not in adult WKY, suggesting that the role of endothelium-derived relaxing factor(s) in modulating the contractile response to ET-1 is more important in renal artery of hypertensive rats. Indeed, although not significant, the renal artery showed a trend toward releasing more nitric oxide in response to ET-1 in adult SHR than in WKY (Fig 6).
The effects of endothelins are mediated by at least two specific receptors, ie, ETA and ETB.4 5 ETA receptors, mainly present on vascular smooth muscle cells, mediate vasoconstriction, and ETB receptors on the vascular endothelium evoke nitric oxide or prostacyclin release.6 7 Recently, we (in human blood vessels10 ) and others (in experimental animals34 35 36 37 38 39 ) found that in addition to ETA receptors, vasoconstrictor ETB receptors are also present on vascular smooth muscle. ETA receptors have a higher affinity to ET-1 than ET-3 and sarafotoxin S6c, whereas ETB receptors show nearly the same affinity to all isoforms of endothelin and sarafotoxin peptides.4 5 Sarafotoxin S6c, derived from snake venom, has a much higher affinity to ETB than ETA receptors and can be used as an ETB-selective agonist,25 particularly if ETA receptors are blocked by coincubation with an appropriate antagonist (ie, FR13931710 ). Endothelin receptor antagonists for the ETA and for both ETA/ETB receptors have recently been developed; these tools may help in the understanding of the role of endothelins in these pathophysiological states.34 35 36 37 38 39 40 41 42 43
In renal arteries with endothelium of adult SHR, no functional evidence for contractile ETB receptor could be obtained. This could be related to the masking effect of nitric oxide released by concomitant endothelial ETB receptor stimulation6 (see below). Indeed, renal arteries without endothelium and incubated with FR139317 obtained from adult SHR showed a small contraction at low ET-1 concentrations. Furthermore, these preparations did contract quite markedly to sarafotoxin S6c, although the response varied considerably within the group. Finally, endothelium-dependent relaxations decreased with age in the SHR (also see below). Hence, it is likely that the release of endothelium-derived nitric oxide either masks ETB receptor activation in the adult SHR or downregulates the ETB receptor. In contrast, WKY did not show this phenomenon at either an adult or old age.
In old SHR, the ET-induced contraction resistant to FR139317 that occurred at low ET-1 concentrations was pronounced. This response was abolished by the combined ETA/ETB antagonist bosentan, suggesting that ETB receptors mediate this high-sensitivity portion of the contraction to ET-1. In line with this interpretation, the rightward shift of the concentration-contraction curves was greater with bosentan than with FR139317. As in adult WKY, old WKY did not show this phenomenon and exhibited a smaller rightward shift to bosentan than old SHR. Consistent with these observations, the contraction to sarafotoxin S6c was also significantly greater in old SHR than in old WKY. Thus, in the renal artery from hypertensive but not from normotensive rats, aging is associated with an increasing contribution of contractile ETB receptors to the response to ET-1; hence, both ETA and ETB receptors mediate contraction to ET-1 in old SHR. These results are also consistent with those of Batra et al,40 who suggested the presence of ETB receptors in aortic smooth muscle cells from hypertensive rats by measuring cytosolic calcium transients. This phenomenon may be related to an upregulation of ETB receptors and/or enhanced postreceptor transduction mechanism(s) in old hypertensive rats. It is unlikely that endothelium-derived thromboxane A2 contributes to this contraction, because thromboxane A2 is known to be released only at high ET-1 concentrations (10-8 to 10-7 mol/L).44
We used a rather high concentration of endothelin receptor antagonists (10-5 mol/L). However, it is unlikely that this concentration of FR139317 blocked ETB as well as ETA receptors. Indeed, it actually unmasked ETB receptors, as it did in our previous study10 in human and porcine arteries.10 41
In contrast to our results, some in vivo studies suggested that non-ETA, probably ETB, receptors mediate renal vasoconstriction to ET-1 even in normotensive rats, because BQ-123, a selective ETA receptor antagonist, did not inhibit the renal vasoconstriction to infused ET-1.11 12 13 However, it is possible that the ET-1 concentrations used in those in vivo studies were too high for BQ-123 to block ETA receptors completely. Indeed, when lower ET-1 concentrations were used, BQ-123 effectively blocked the renal vasoconstriction to ET-1.37 In the rabbit kidney, ETA receptors also seem to be important in mediating contraction to ET-1.42 Even though endothelin receptor subtypes may differ between the main renal artery and arterioles, our results suggest that ETB receptors, in addition to ETA, are more important in hypertensive rats than in normotensive rats in mediating ET-1–induced contraction in the renal artery.
Although the relative importance of vasoconstrictor ETB receptors compared with ETA receptors is small, ETB receptors seem to contribute to the maintenance of vascular tone in hypertension. Indeed, in renal arteries, the combined ETA/ETB antagonist bosentan was more effective in old SHR than in WKY. Furthermore, bosentan is quite effective in lowering blood pressure in hypertensive rats,24 whereas the effect of ETA antagonists is controversial.21 23 45 Our results therefore suggest that combined ETA/ETB antagonism rather than ETA antagonism may be effective in controlling blood pressure in this genetic model of hypertension.
In renal arteries of SHR, endothelium-dependent relaxation to acetylcholine was reduced with age but unaffected in WKY. In the present study, renal vessels with endothelium from both age groups showed relaxation to sarafotoxin S6c that was almost completely inhibited by L-NAME, suggesting that endothelial ETB receptors linked to the release of nitric oxide are present in the rat renal artery. This is consistent with most in vivo and in vitro studies in the aorta of hypertensive rats,46 47 48 although in mesenteric resistance arteries, the release of prostacyclin is more important.7 In contrast to our result, in vivo and isolated perfused kidney studies failed to show endothelium-dependent relaxation to endothelins in the rat.11 12 This discrepancy may be due to the difference in the vessel size (conduit versus resistance) or the rat strains studied. Interestingly, the release of nitric oxide stimulated by sarafotoxin S6c increased with age in WKY. One possible explanation may be an age-related increase in the number of endothelial ETB receptors and/or enhanced postreceptor signal transduction linked to the release of nitric oxide.
In conclusion, both ETA and ETB receptors mediate vasoconstriction in vascular smooth muscle of the renal artery from SHR but not from WKY. If endothelin receptors in the resistance vessels also show this characteristic, combined ETA/ETB receptor antagonists may be more effective in reducing blood pressure in genetic hypertension. The contraction mediated by ETB receptors is enhanced with age in SHR, whereas the release of nitric oxide by endothelial ETB receptor stimulation increases with age in WKY.
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Acknowledgments |
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This work was supported by grants of the Swiss National Research Foundation (No. 32-32541.91), the Karl Mayer Foundation, Vaduz/Liechtenstein, and Hoffmann–La Roche AG, Basel, Switzerland.
Received April 18, 1994; first decision May 9, 1994; accepted November 7, 1994.
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