(Hypertension. 1999;33:1420-1424.)
© 1999 American Heart Association, Inc.
Scientific Contributions |
Stimulation of the Renin-Angiotensin System by Endothelin Subtype A Receptor Blockade in Conscious Dogs
From the I. Physiologisches Institut der Ruprecht-Karls-Universität Heidelberg (H.B., A.J., H.R.K., H.E.), and Knoll AG, Ludwigshafen (K.M.), Germany.
Correspondence to Dr Heimo Ehmke, I. Physiologisches Institut der Ruprecht-Karls Universität, Im Neuenheimer Feld 326, D-69120 Heidelberg, Germany. E-mail ehmke{at}novsrv1.pio1.uni-heidelberg.de
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Abstract |
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Abstract—Previous studies in dogs have shown additive or even synergistic effects of combined angiotensin-converting enzyme inhibition and either nonselective endothelin subtype A/B (ETA/B) or selective endothelin subtype A (ETA) receptor blockade on renal vascular resistance and mean arterial blood pressure. A possible mechanism underlying this interaction may be a stimulation of the renin-angiotensin system during endothelin (ET) receptor blockade. We therefore investigated whether plasma renin activity and renin release are regulated by the ETA receptor. Experiments were made in conscious, chronically instrumented dogs receiving either saline or the selective ETA receptor antagonist LU 135252 (10 mg/kg IV). Eighty to 100 minutes after the administration of LU 135252 (n=5), heart rate (99±7 versus 81±6 bpm; P<0.05) and renal blood flow (327±40 versus 278±36 mL/min; P<0.05) were increased significantly, whereas mean arterial blood pressure tended to be lower (93±5 versus 105±7 mm Hg). These changes were associated with a 2-fold increase in plasma renin activity (0.74±0.12 versus 0.37±0.10 ng angiotensin I per milliliter per hour; P<0.05). Measurements of renin release at various renal perfusion pressures (n=5) with the use of a vascular occluder implanted around the left renal artery revealed that ETA receptor blockade did not alter renin release at resting renal perfusion pressure (78±25 versus 71±39 U/min) but strongly enhanced the sensitivity of pressure-dependent renin release <80 mm Hg
2.2-fold. In conclusion, selective ETA receptor blockade
is associated with a stimulation of the circulating
renin-angiotensin system, which results from both a
sensitization of pressure-dependent renin release and a larger
proportion of blood pressure values falling into the low pressure
range, where renin release is stimulated. These find-ings strengthen
the view that ET and the renin-angiotensin system closely
interact to regulate vascular resistance and provide a
physiological basis for synergistic hypotensive
effects of a combined blockade of both pressor systems.
Key Words: endothelin • receptors, endothelin • renal blood flow • renin-angiotensin system • renin
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Introduction |
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Exogenous endothelin (ET), predominantly by activating endothelin subtype A (ETA) receptors, is a strong constrictor of renal and systemic vessels, but the relevance of endogenous ET for the maintenance of basal vascular tone and blood pressure is still controversial. In healthy subjects, short-term blockade of ETA receptors1 had no effects on blood pressure and renal blood flow (RBF). In addition, nonselective blockade of ETA and endothelin subtype B (ETB) receptors did not affect blood pressure in anesthetized dogs.2 In contrast, intra-arterial infusion of an ETA receptor blocker in normotensive humans caused strong increases in forearm blood flow, indicating a pronounced reduction in vascular resistance.3 4
An interaction of ET and the renin-angiotensin system could account for the lack of large blood pressure changes during systemic ET receptor blockade. In 2 recent investigations in normotensive dogs, we observed significant falls in mean arterial blood pressure (MAP)5 6 and large increases in RBF5 when the ETA receptor blockade was combined with angiotensin-converting enzyme (ACE) inhibition. Similarly, nonselective ETA/B receptor blockade by bosentan exerted an additional hypotensive effect in hypertensive dogs during ACE inhibition.7 Combined administration of bosentan and an ACE inhibitor also resulted in pronounced hypotensive effects in rats with chronic heart failure.8 The mechanisms underlying this interaction between ET receptor blockade and the renin-angiotensin system are still unclear. Because previous investigations have demonstrated that exogenous ET may inhibit basal or stimulated renin release in isolated perfused kidneys9 and in anesthetized rats10 and dogs,11 it is conceivable that ETA receptor blockade may have stimulatory effects on renin release. Consequently, elevated angiotensin II concentrations may take over the vasoconstrictor effects of ET, thus allowing for maintenance of vascular tone and blood pressure during ETA receptor blockade. Accordingly, the aim of the present study was to investigate the influence of a selective ETA receptor blockade on the renin-angiotensin system in conscious, normotensive dogs.
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Methods |
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Animals
Experiments were performed in 6 conscious foxhounds of either sex weighing 28 to 31 kg. The dogs received a commercially available dog diet (SSniff Spezialdiäten GmbH) containing
100 mEq
sodium per day and had free access to water. At least 10 days were
allowed for recovery after the implantation surgery. All experiments
were done in accordance with the national law for the care and use of
research animals.
Surgical Procedures
The dogs were premedicated with atropine (0.5 mg SC; Braun) and
propionylpromazine (Combelen, 0.64 mg/kg SC; Bayer).
Anesthesia was introduced with sodium pentobarbital
(Nembutal, 20 mg/kg IV; Sanofi) and maintained with halothane
(Fluothane, 0.8% to 1.0%; Zeneca) and N2O (0.5
L/min). Surgery was performed under sterile conditions. Through a left
flank incision, polyurethane catheters were implanted into the
abdominal aorta and left renal artery. A silicone elastomer catheter
was implanted into the left renal vein. The ovarian or
spermatic vein was ligated. An inflatable cuff was placed around the
renal artery proximal to the tip of the renal artery catheter. An
ultrasound transit-time flow probe (6-mm diameter; Transonic Systems)
was fixed around the left renal artery between the origin of the artery
from the aorta and the cuff. The flow probe was wrapped with synthetic
polyester velour material (Protgraft; Braun-Dexon) to prevent ingrowth
of fatty tissue and enhance probe stabilization after healing. No
surgery was performed on the right kidney. The catheters and cuff leads
were led subcutaneously to the dog's neck and brought out through the
skin. The first 9 days after surgery, the dogs received a combination
of benzathine benzylpenicillin and sulfatolamide (Tardomyocel, 3
mL SC; Bayer) every third day. The arterial catheters were
flushed every third day with sterile saline and filled with a solution
of heparin (1700 IU/mL; Braun). The venous catheter was flushed and
filled daily.
Circulatory Measurements and Blood Sampling
Blood pressure was measured in the abdominal aorta and the renal
artery with the use of Statham pressure transducers (P23Db) and Gould
pressure processors. Heart rate (HR) was recorded instantaneously
with a rate meter (Gould pressure processor). RBF was measured with the
implanted flow probe connected to a flowmeter (Transonic T 106 or T
108). The flow probe signals were passed through a 10-Hz filter
(Transonic). An analog recorder (Gould 2600) was used to directly
display the measured variables. All data were sampled at 20 Hz and
stored as 1-second mean values online (IBM PC 386) after
analog-to-digital conversion.
For the determination of plasma renin activity (PRA) and renin release,
blood samples (1 mL) were taken from the arterial and
venous catheters simultaneously and collected in chilled
tubes containing 6 µmol EDTA. For the estimation of PRA, the
amount of generated angiotensin I was determined by
radioimmunoassay. Renin release was calculated according to the
equation
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Drugs
LU 135252 is a nonpeptide, selective ETA
receptor antagonist with a plasma half-life in dogs of
12 hours. The selectivity for ETA receptors,
expressed as the ratio of the affinities for ETA
over ETB receptors, is 131.12 LU
135252 was used at a dose of 10 mg/kg. Preliminary experiments in
anesthetized dogs showed that this dose completely inhibits the
vasoconstrictor response (+26±4 mm Hg) to an
intravenous injection of 0.75 nmol/kg ET-1, which increases
plasma ET-1 concentrations into the nanomolar range (ie, 100- to
1000-fold higher than normal).
Experimental Protocols
All experiments were performed in conscious dogs lying quietly
on their right side on a bench. The dogs were connected to the
recording instruments by extension cables. The renal cuff could
be inflated without distracting the dog's attention. The experiments
started between 8 and 9 AM, 16 to 20 hours after the last
feeding. Two experimental protocols were followed, as described
below.
Time Course Experiments (n=5)
MAP, HR, RBF, and arterial PRA were examined 20
minutes before the administration of LU 135252 and for the following
100 minutes. Arterial blood samples for the determination
of PRA were taken every 20 minutes. LU 135252 was given slowly as a
bolus (10 mg/kg IV), dissolved in 10 mL saline. Experiments with bolus
infusions of 10 mL saline served as time controls. Time control
experiments were performed in the same dogs with at least 2 days left
between the 2 experiments. Experiments were done in random order.
Determination of Pressure-Dependent Renin Release (n=5)
Renin release experiments were done 100 minutes after the
administration of LU 135252 and saline, respectively. The renal artery
catheter and the cuff lead were connected to an extracorporal
electropneumatic control system. By controlled inflation of the cuff,
renal perfusion pressure (RPP) was reduced to defined levels below the
systemic blood pressure. The precision of the servo-control system was
<±1 mm Hg. A 5-minute control period was allowed before RPP was
servo-controlled. Then RPP was reduced in steps of 5 or 10 mm Hg
to 60 mm Hg. The duration of each pressure step was 5 minutes. In
the last 30 seconds, arterial and venous blood samples were
taken for the determination of renin release.
Data Analysis and Statistics
For the analysis of the time course, mean values of MAP,
HR, and RBF were calculated over 20-minute periods. The effects of LU
135252 versus saline were analyzed by 2-way ANOVA. If
significant changes were detected, mean values obtained during the last
experimental period (80 to 100 minutes) were analyzed by the
paired Student t test.
For the analysis of pressure-dependent renin release, renin release was calculated for each pressure step in single dogs. Then mean values over all dogs were calculated. Two-way ANOVA was used to determine whether significant changes occurred between renin release during control conditions and during ETA receptor blockade.
Differences at the 5% level were considered statistically significant. All data are presented as mean±SEM.
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Results |
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Baseline values before the administration of either LU 135252 or saline were not different in the 2 experimental groups (Table).
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The effects of acute ETA receptor blockade on MAP, HR, and RBF are summarized in Figure 1. LU 135252 induced renal vasodilation (RBF, 327±40 versus 278±36 mL/min; P<0.05) together with an increase in HR (99±7 versus 81±6 bpm; P<0.05). MAP tended to be lower during ETA receptor blockade compared with saline infusion, but the difference failed to reach statistical significance.
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The time course of arterial PRA in response to acute ETA receptor blockade is depicted in Figure 2. Whereas in the control experiments arterial PRA remained unchanged, it started to increase immediately after the administration of LU 135252 and remained elevated over the entire observation period. One hundred minutes after the administration of LU 135252, arterial PRA was doubled (0.74±0.12 versus 0.37±0.10 ng angiotensin I per milliliter per hour; P<0.05). Renin release was transiently elevated after ETA receptor blockade in each dog, reaching maximum values between 20 and 80 minutes after the administration of LU 135252, and then returned to control levels. Because of the high interindividual variability of renin release and the different time courses, however, this effect did not reach statistical significance (P=0.09).
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The effects of acute ETA receptor blockade on
renin release at rest and at reduced RPP are shown in Figure 3. At resting RPP, renin release was
unaffected by ETA receptor blockade (78±25
versus 71±39 U) and remained unaltered down to a RPP of 80
mm Hg. Below 80 mm Hg, however, a strong enhancement of renin
release was observed during ETA receptor
blockade, indicating a sensitization of pressure-dependent renin
release by a factor of 2.2.
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Discussion |
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Previous studies have shown pronounced hypotensive effects of a blockade of ET receptors combined with an ACE inhibition in normotensive dogs5 6 and in animal models of chronic heart failure8 and hypertension.7 In contrast, both nonselective ETA/B or selective ETA receptor blockade2 5 and ACE inhibition alone5 13 had only minor hypotensive effects in normal dogs. From the results of a recent study, we proposed a close interaction of ET and the renin-angiotensin system, such that during blockade of ETA receptors an increased effect of angiotensin II may compensate for the lack of vasoconstrictor activity of ET.5 Therefore, the aim of the present study was to test the hypothesis that the renin-angiotensin system is stimulated during ETA receptor blockade. In accordance with this hypothesis, we observed an increase of arterial PRA during ETA receptor blockade; 100 minutes after the administration of LU 135252, PRA was doubled. Until now, only a few studies have been performed to determine the effects of ET receptor blockade on the renin-angiotensin system. Schricker et al14 investigated the effects of administration of bosentan for 2 days on PRA in 2-kidney, 1 clip hypertensive rats. Neither renal mRNA nor PRA was found to be altered. Similar results after bosentan were obtained in patients with mild to moderate essential hypertension.15 A possible explanation for the discrepancy to the present study may be the different selectivities of the ET receptor blockade. It is conceivable that ET exerts an inhibitory effect on renin release via the ETA receptor subtype and a stimulatory effect via the ETB receptor subtype, secondary to the release of nitric oxide. During nonselective ETA/B receptor blockade, the removal of both inhibitory and stimulatory effects may be balanced, leading to an unchanged PRA. In a recent in vitro investigation, however, bosentan has been shown to increase renin secretion from isolated afferent arterioles even after nitric oxide synthase inhibition by NG-nitro-L-arginine methyl ester (L-NAME).16 Therefore, a more likely explanation for the discrepant results of the present investigation and those of Schricker et al14 and Krum et al15 appears to be that in the latter studies the ET system was blocked chronically, which may result in secondary adaptive changes in the regulation of renin release. Differences between acute and chronic effects of ET receptor blockade on the renin-angiotensin system may also explain the failure of ACE inhibition to sensitize blood pressure to the hypotensive effects of ETA receptor antagonists in hypertensive rats.17 18 Furthermore, species differences may exist in the regulation of renin release by ET.
Surprisingly, renin release at resting RPP was only transiently affected by ETA receptor blockade. Only when RPP was reduced was a strong enhancement of the sensitivity of pressure-dependent renin release disclosed, suggesting a more prominent regulatory role of renal ET at low perfusion pressures. This interpretation would be in accordance with the results from a study in anesthetized dogs, in which ET infused intrarenally into denervated kidneys inhibited renin release prestimulated by renal artery constriction.11 Similarly, in the isolated rat kidney9 and the nonfiltering canine kidney,19 ET elicited an inhibitory effect on renin release at a constant renal artery pressure of 80 mm Hg, which was abolished if the kidney was perfused with a Ca2+-free solution.9 In contrast, in some early studies ET had been found to stimulate renin release,20 21 although at pharmacological concentrations. Thus, this stimulatory action may not reflect the physiological effect of ET.
The mechanism by which renin release is altered by ETA receptor blockade is not clear. Because ETA receptor blockade was associated with an increase in HR and a reduction in MAP, the enhancement of renin release may be mediated by a reflex increase in sympathetic activity due to an unloading of arterial baroreceptors. However, several studies have shown that both direct22 23 and reflex24 25 stimulation of renal sympathetic nerve activity as well as humoral activation of intrarenal adrenoceptors25 26 27 cause a parallel shift of the relation between RPP and renin release without affecting the sensitivity of renin release in the lower pressure range. By contrast, ETA receptor blockade increased the sensitivity of the pressure-dependent mechanism of renin release without major effects on the threshold pressure of renin release. Therefore, it seems more likely that the enhancement of renin release resulted from a direct effect of renal ET at the level of juxtaglomerular cells. One possibility may be the release of a direct inhibitory effect of ET on juxtaglomerular cells at lower perfusion pressures. For example, ET may tonically antagonize the effects of nitric oxide on renin release. Previous studies have demonstrated that endogenously generated nitric oxide increases the sensitivity of pressure-dependent renin release.28 29 Alternatively, it is conceivable that the renal ET production may be enhanced at low perfusion pressures, but it remains to be shown whether this actually occurs under physiological conditions. Finally, the macula densa mechanism of renin release may be altered during ETA receptor blockade. Low, nonpressor doses of ET induced a natriuresis in dogs30 and in rats,31 an action that may be mediated by an inhibition of proximal tubular sodium reabsorption.31 Accordingly, if ETA receptor blockade should cause an increase in sodium reabsorption, the reduced sodium chloride concentration at the macula densa would be expected to stimulate renin release. However, if ET exerted a tonic inhibitory action on renin release by this mechanism, one would rather expect an elevation of renin release over the entire pressure range during the ETA receptor blockade. Nevertheless, in any case the slight decrease in MAP will contribute to the increase in PRA, inasmuch as a greater proportion of pressure values are falling into the lower pressure range and consequently stimulate renin release.
Taken together, the present study shows that selective ETA receptor blockade is associated with a stimulation of the renin-angiotensin system, which results from both a sensitization of pressure-dependent renin release and a larger proportion of pressure values falling into the lower pressure range. These findings are in agreement with the suggestion of a strong interaction of ET and the renin-angiotensin system in the maintenance of basal vascular tone and provide a physiological basis for the synergistic hypotensive effects of a combined blockade of both vasoconstrictor systems.
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Acknowledgments |
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We thank Inge Keller and Lucie Mahl for excellent technical assistance.
Received October 19, 1998; first decision November 5, 1998; accepted February 12, 1999.
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