(Hypertension. 1997;30:22-28.)
© 1997 American Heart Association, Inc.
Articles |
Endogenous Endothelin Modulates Blood Pressure, Plasma Volume, and Albumin Escape After Systemic Nitric Oxide Blockade
From the Research Center, Maisonneuve-Rosemont Hospital, Department of Medicine, University of Montréal (Québec, Canada).
Correspondence to János G. Filep, MD, Research Center, Maisonneuve-Rosemont Hospital, Department of Medicine, University of Montréal, 5415 Boulevard de l'Assomption, Montréal, Québec, Canada H1T 2M4.
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Abstract |
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Abstract To assess whether acute nitric oxide (NO) blockade could unmask the vascular actions of endogenous endothelin, we tested the effects of the endothelin type A/type B (ETA/ETB) receptor antagonist bosentan and the selective ETA antagonist FR 139317 on blood pressure, plasma volume, and albumin escape after inhibition of NO synthesis with NG-nitro-L-arginine methyl ester (L-NAME). Conscious, chronically catheterized rats received L-NAME in the absence and presence of 17.4 µmol/kg (10 mg/kg) bosentan or 3.8 µmol/kg (2.5 mg/kg IV, 10 minutes before L-NAME) FR 139317. Red blood cell volume and plasma volume were determined with chromium-51–tagged erythrocytes and iodine-125–labeled albumin, respectively. L-NAME (0.46 to 7.42 µmol/kg [0.125 to 2 mg/kg]) induced a dose-dependent increase in blood pressure, which was attenuated by 60% and 48% with bosentan and FR 139317, respectively (P<.01). L-NAME (7.42 µmol/kg) also increased hematocrit. This effect was associated with an increase in total-body albumin escape, which is reflected by a 14% reduction in plasma volume. Red blood cell volume remained unchanged. L-NAME promoted albumin escape primarily in the lung, heart, liver, kidney, and gastrointestinal tract. Both bosentan and FR 139317 markedly reduced these effects of L-NAME. Furthermore, L-NAME increased plasma levels of immunoreactive endothelin-1 from 8.6±0.4 (n=10) to 14.7±1.4 pg/mL (n=9, P<.01). These results demonstrate that the pressor response, losses in plasma volume, and increase in albumin escape observed after inhibition of NO synthesis are in part the consequence of unmasking the actions of endogenous endothelin, which are mediated predominantly via ETA receptors. These findings suggest a role for endogenous endothelin in the regulation of vascular functions in conditions when NO formation by endothelial cells is impaired.
Key Words: endothelin • receptors, endothelin • nitric oxide • blood pressure • plasma volume
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Introduction |
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A growing body of evidence indicates complex interactions between endothelium-derived substances, including ET-11 and NO.2 3 ET-1 induces formation of NO, which is believed to mediate its vasodepressor action.4 Furthermore, endothelium-derived NO inhibits the synthesis5 6 and may also counteract the vasoconstrictor7 8 9 and vasopressor4 10 actions of ET-1. In addition, both NO and ET-1 have been implicated in the regulation of blood and plasma volume and albumin extravasation in various vascular beds,11 12 13 and inhibition of NO production enhanced albumin extravasation in response to ET-1 in the rat.10 However, these studies have used exogenous ET-1. Although low levels of immunoreactive ET-1 can be detected in the plasma,14 the role of endogenous ET-1 in the regulation of vascular functions remains uncertain because selective endothelin receptor antagonists fail to affect blood pressure15 and albumin extravasation16 in normal animals. One possible explanation for this apparent lack of vascular effects of endogenous ET-1 might be that its actions are antagonized by NO produced continuously by endothelial cells. Indeed, recent studies have indicated that endogenous endothelin partially mediates the pressor action of acute NO blockade in both anesthetized17 and conscious18 rats. In the present study, we investigated whether ET-1 could play a role in the regulation of blood and plasma volume and albumin escape after inhibition of NO synthesis in conscious rats. To address these issues, we evaluated the effects of the nonselective ETA/ETB receptor antagonist bosentan19 and the ETA receptor–selective antagonist FR 13931720 on these parameters in animals treated with the L-arginine analogue L-NAME.
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Methods |
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Experimental Protocols
The experiments were performed on conscious, chronically catheterized male Wistar rats weighing 210 to 300 g. The animals were housed in individual metabolic cages, and catheters were implanted into the abdominal aorta and vena cava as described previously.12 The experiments were performed between postoperative days 4 and 7. During the experiments, the animals could move freely and had free access to food and water. MABP and heart rate were monitored continuously by a blood pressure analyzer (Micro-Med) using a pressure transducer (COBE CDX III).
On the day of the experiment, after an equilibration period of 1 hour, basal cardiovascular parameters were measured for 20 minutes. In the first series of experiments, bosentan (17.4 µmol/kg [10 mg/kg], n=5), FR 139317 (3.8 µmol/kg [2.5 mg/kg], n=5), or saline (n=5) was injected as a bolus in 10 µL/100 g body wt IV. Ten minutes later, the animals were given increasing doses of L-NAME (0.46 to 7.42 µmol/kg [0.125 to 2 mg/kg]) at 20-minute intervals. In the second series of experiments, the animals first received 51Cr-tagged erythrocytes (approximately 0.5 µCi IV) and 10 minutes later, 125I-labeled human serum albumin (ICN Pharmaceuticals; 1 µCi in 100 µL saline). Five minutes later, bosentan (17.4 µmol/kg [10 mg/kg], FR 139317 (3.8 µmol/kg [2.5 mg/kg]), or their vehicle (saline) was given as a bolus (10 µL/100 g body wt IV) followed by an injection of 7.42 µmol/kg (2 mg/kg) L-NAME or its vehicle (saline) 10 minutes later as follows: group 1 (n=10): saline only; group 2 (n=9): saline followed by L-NAME; group 3 (n=5): bosentan followed by saline; group 4 (n=5): FR 139317 followed by saline; group 5 (n=8): bosentan followed by L-NAME; group 6 (n=6): FR 139317 followed by L-NAME; group 7 (n=6): saline followed by hydralazine plus L-NAME; and group 8 (n=6): bosentan followed by hydralazine plus L-NAME.
In the last two groups, L-NAME–induced elevation of MABP was titrated to baseline levels with hydralazine (1.3 to 1.5 µmol/kg IV). Variations in MABP of hydralazine-treated rats were similar to those observed in control animals, and no transient elevations were observed. Triplicate arterial blood samples were taken into glass capillary tubes calibrated to 15 µL for measuring hematocrit and 51Cr and 125I radioactivities at 5 and 50 minutes after the injection of 125I-labeled albumin. At the end of the experiments, blood (1 mL) was collected into prechilled tubes containing 100 µL of 3.8% sodium citrate for measurement of plasma ET-1 levels. Immediately after the last blood sample was taken, the rats were killed with an overdose of sodium pentobarbital, and the thoracic and abdominal viscera were dissected and portions of selected organs weighed and placed in separate vials for measurement of 51Cr and 125I radioactivities with a Wallac 1470 Wizard Automatic Gamma Counter. The system was programmed to correct for cross talk and spillover between detectors and counting channels. "Large-vessel" hematocrit (LVHct) was determined by a manual hematocrit reader. Erythrocytes were labeled with sodium-51–chromate in saline (DuPont-NEN) as previously described13 and were resuspended in 0.9% NaCl solution to a hematocrit of 45% to 50%.
All procedures were in accordance with the Guidelines of the Canadian Council of Animal Care and were approved by the local Animal Care Committee.
Red Blood Cell, Plasma, and Blood Volumes
For the first blood sample, red blood cell volume (RCV), plasma
volume (PV), and blood volume (BV) were determined according to the
following formulas: RCV=Total 51Cr Activity
InjectedxLVHct÷Blood 51Cr Activity Concentration;
PV=Total 125I Activity Injectedx(1-LVHct)÷Blood
125I Activity Concentration; and BV=RCV+PV. The ratio of
whole-body hematocrit to LVHct (Fcells ratio) was
calculated as (RCV÷BV)÷LVHct. For the second blood samples, the
following formulas were used: BV=[(51Cr Activity
Injected-Sampling Loss of 51Cr Activity)÷Blood
51Cr Activity Concentration]÷Fcells;
RCV=RCVfirst-RCVlost, where
RCVfirst and RCVlost are RCV measured during
the first sample and RCV lost through sampling, respectively;
RCVlost=51Cr Activity Lost Through
Sampling÷(51Cr Activity Injected÷RCVfirst);
and PV=BV-RCV.
125I-Albumin Escape Rate
The rate at which 125I-labeled human serum
albumin escaped from the circulation
(125I-AERt) was calculated as
125I-AERt=[(Net 125I Activity
Injected-Total Plasma 125I Activity in the Second Blood
Sample)÷Net 125I Activity Injected]÷50 minx100, where
net 125I activity injected is the total 125I
activity injected less the cumulative radioactivity removed from the
circulation by blood sampling, and Total Plasma 125I
Activity=Plasma 125I Activity Concentrationx Plasma Volume
at 50 min after injection of 125I-labeled
albumin.
The rate at which 125I-labeled albumin escaped from the circulation of each organ (125I-AERorgan) was determined with the formula 125I-AERorgan=(Tissue 125I-Albumin Activity÷Net 125I Activity Injected)÷50 min÷Corrected Organ Weightx100. Tissue 125I-albumin activity was calculated as the difference in total organ 125I and organ plasma 125I-albumin activity. Organ plasma 125I activity was the product of organ plasma volume and plasma 125I-albumin activity concentration. Organ plasma volume was determined as Organ Blood Volumex(1-LVHct) for heart, lung, liver, and kidney, where organ hematocrit is similar to that of LVHct or as Organ Blood Volumex[1-(FcellsxLVHct)] for gastrointestinal tract, where the ratio of organ hematocrit to LVHct is similar to the ratio of whole-body hematocrit to LVHct.13 Organ blood volume was calculated as (Organ 51Cr Activity÷Blood 51Cr Activity Concentration) for heart, lung, liver, and kidney and as (Organ 51Cr Activity÷Blood 51Cr Activity Concentration)÷Fcells for gastrointestinal tract. Organ weight was corrected by subtracting estimated organ blood weight (Organ Blood VolumexBlood Specific Gravity) from wet organ weight.
Measurement of Plasma ET-1
Plasma samples were assayed with an ET-1 enzyme-linked
immunosorbent assay (R&D Systems) after extraction on a C18 Sep-Pak
cartridge (Millipore) as previously described.21 The assay
has less than 1% cross-reactivity with big ET-1 and 45% and 14%
cross-reactivity with ET-2 and ET-3, respectively. The extraction
procedure yielded a recovery of 72±3% (n=4) as assayed by calculating
the recovery of 4 fmol (10 pg) exogenous ET-1 added to 1 mL normal rat
plasma. The intra-assay coefficient of variation was 4.5% at the
midpoint of the standard curve. All ET-1 values were corrected for
recovery and expressed as picograms per milliliter plasma.
Drugs
Bosentan (Ro 470203, sodium salt) was a gift from Hoffmann–La
Roche. FR 139317 was a gift from Fujisawa Pharmaceutical Co. L-NAME and
hydralazine hydrochloride were purchased from Sigma
Chemical Co.
Statistical Analysis
Results are expressed as mean±SEM. Results were compared by
one-way ANOVA using ranks (Kruskal-Wallis test) followed by Dunn's
multiple contrast hypothesis test when various treatments were compared
with the same control group or by the Wilcoxon signed rank test
and Mann-Whitney U test for paired and unpaired
observations, respectively. A level of P<.05 was considered
significant for all tests.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Effect of Bosentan and FR 139317 on the Pressor Response to L-NAME
Baseline MABP and heart rate were 102±1 mm Hg and 312±5 beats per minute (n=60). Neither bosentan nor FR 139317 affected significantly MABP or heart rate (MABP was 103±2 and 102±2 mm Hg 15 minutes after injection of bosentan and FR 139317, respectively; heart rate was 327±23 and 292±12 beats per minute, respectively; both n=5).
As expected, intravenous bolus injection of 0.46 to
7.42 µmol/kg (0.125 to 2 mg/kg) L-NAME produced dose-dependent
increases in MABP in conscious rats, with an estimated ED50
value of 1.85 µmol/kg (0.5 mg/kg) (Fig 1
). The
maximal increase in MABP that could be evoked by L-NAME was reached at
7.42 µmol/kg (2 mg/kg), as higher doses of L-NAME (18.54 and
37.08 µmol/kg) did not produce any further increase in MABP
(data not shown).
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Both bosentan and FR 139317 markedly attenuated the pressor action of
L-NAME (Fig 1
). For instance, 7.42 µmol/kg (2 mg/kg) L-NAME
produced maximal increases of 29±2 mm Hg in MABP, which were
reduced to increases of 11±2 (n=5, P<.01) and 15±3 (n=5,
P<.01) mm Hg in bosentan- and FR 139317–treated
animals, respectively. The pressor effect of L-NAME was accompanied
by a significant decrease in heart rate from 308±23 to 262±21 beats
per minute, n=5, P<.01). This action of L-NAME was not
affected by bosentan or FR 139317 (heart rate decreased from 315±21 to
281±20 beats per minute and from 323±19 to 286±16 beats per minute
in response to L-NAME in animals pretreated with bosentan and FR
139317, respectively). Although the degree of inhibition with bosentan
appeared to be greater than that of FR 139317, there were no
statistically significant differences between the effects of these two
antagonists at any L-NAME doses studied.
Effect of L-NAME on Blood Volume, Plasma Volume, and
Albumin Escape Rate
Intravenous injection of 7.42 µmol/kg (2 mg/kg)
L-NAME markedly increased hematocrit from 0.455±0.005 (vehicle,
n=10) to 0.489±0.013 (n=9, P<.01). Plasma volume decreased
from 57.1±2.8 to 50.4±2.9 mL/kg (n=9, P<.01), whereas no
changes were detected in red blood cell volume (Fig 2).
Total-body blood volume decreased from 86.1±2.9 to 77.7±3.0 mL/kg
(P<.01) (Fig 2). Similar changes were observed after L-NAME
in hydralazine-treated animals (Table).
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Fcells ratios were 0.76±0.02, 0.74±0.01, 0.75±0.01, and
0.73±0.02 in animals that received saline (control), L-NAME, bosentan
plus L-NAME, and FR 139317 plus L-NAME, respectively
(P>.1). The total-body albumin escape rate
increased on average by 114% and 85% in response to L-NAME in
untreated (Fig 2) and hydralazine-treated (Table) rats,
respectively (n=9 and n=6, respectively, P>.1). L-NAME
enhanced the albumin escape rate in the lung, heart, liver,
kidney, and duodenum (Fig 3).
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Effect of Bosentan and FR 139317 on L-NAME–Induced Changes in
Plasma Volume and Albumin Extravasation
Injection of bosentan or FR 139317 by itself had no significant
effect on blood volume (87.8±3.8 and 86.4±2.9 mL/kg, respectively),
plasma volume (60.6±3.2 and 59.9±2.9 mL/kg, respectively), and
total-body albumin escape rate (10.3±2.0 and 11.0±1.8% net
125I-albumin injected per 50 minutes,
respectively).
Pretreatment of the animals with either bosentan or FR 139317 markedly
attenuated the hemoconcentration and albumin escape elicited by
L-NAME. Bosentan resulted in a 65% reduction of L-NAME–induced plasma
volume and blood volume losses, whereas a 55% reduction was detected
with FR 139317 (Fig 2). Total-body albumin escape rates were
significantly lower in rats pretreated with bosentan or FR 139317 than
in untreated rats after L-NAME (Fig 2). Accordingly, bosentan and FR
139317 also significantly attenuated the organ albumin escape
rates in all organs studied (Fig 3). Both bosentan and FR 139317
appeared to be more potent inhibitors of L-NAME–induced
albumin escape in the heart, liver, and duodenum than in the
large airways and kidney (Fig 3). The degree of inhibition observed
with bosentan and FR 139317 was similar in all vascular beds studied,
with the exception of the kidney and trachea, in which bosentan
appeared to be a more potent inhibitor than FR 139317 (Fig 3).
In hydralazine-treated animals, bosentan also resulted in an
average 66% reduction in L-NAME–induced blood and plasma volume
losses and markedly attenuated total-body albumin escape rate
(Table).
Effect of L-NAME on Plasma Immunoreactive ET-1
Plasma immunoreactive ET-1 levels were significantly higher 35
minutes after injection of 7.42 µmol/kg (2 mg/kg) L-NAME
(14.7±1.4 pg/mL, n=9) than in control animals (8.6±0.4 pg/mL, n=10,
P<.01).
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Discussion |
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The present results, obtained in conscious chronically catheterized rats, demonstrate that inhibition of NO synthesis unmasks effects of endogenous endothelin on blood pressure and body fluid shifts. L-NAME–induced pressor responses, plasma volume losses, and albumin escape from the intravascular space were markedly, though not completely, inhibited by either the ETA/ETB receptor antagonist bosentan or the ETA receptor–selective antagonist FR 139317. The vascular effects of L-NAME are generally considered to result from inhibition of endothelial NO synthesis since they can be reversed by L-arginine but not D-arginine.
In conscious rats, L-NAME caused a modest, statistically significant increase in plasma immunoreactive ET-1 levels. Elevated plasma endothelin levels have previously been observed in anesthetized rats after L-NAME17 and in dogs after administration of NG-monomethyl-L-arginine.9 However, the magnitude of the increase in plasma ET-1 appears to be greater in conscious than anesthetized rats. Baseline plasma immunoreactive ET-1 concentrations were considerably higher in anesthetized than conscious rats (26.8±4.1 versus 8.6±0.4 pg/mL), probably because of anesthesia and surgical stress.22 The mechanism by which L-NAME increases plasma levels of ET-1 is not known. Experiments with cultured endothelial cells1 and isolated rat aorta5 have shown that a long period of time (up to 4 hours) is required for stimulation of endothelin gene expression and subsequent release of the mature peptide. Since the ET-1 precursor, big ET-1, is present in the plasma at concentrations comparable to those of ET-1,23 considerable amounts of substrate are available for a suitable endothelin-converting enzyme after activation. Whether NO could modulate the activity of this enzyme remains to be tested. An alternative possibility is that NO could regulate mobilization of ET-1 (or its precursor) stored in secretory vesicles.24
The profound pressor effect of several L-arginine analogues, including L-NAME, has been well characterized and is probably due to an increase in total peripheral resistance.25 The findings that endothelin receptor antagonism attenuates this pressor action in conscious rats are consistent with previous observations.17 18 The similar inhibitory effect of bosentan and FR 139317 suggests that endothelin exerted its pressor action predominantly via activation of ETA receptors. Although stimulation of ETB receptors located on vascular smooth muscle cells also leads to vasoconstriction26 and a pressor response,16 activation of vasoconstrictor ETB receptors appears to play a minor role in mediating the pressor action of endogenous endothelin in conscious rats. It is uncertain whether unmasking the pressor influence of endogenous endothelin could be due to increased endothelin production and/or removal of NO-mediated relaxation of vascular smooth muscle. Previous studies on isolated arteries have shown that inhibition of NO synthesis potentiates, whereas exogenous NO donors attenuate or reverse ET-1–induced contractions.7 8 9 Although L-NAME produced on average a 70% increase in plasma immunoreactive ET-1 levels, these concentrations were still below the threshold for inducing contractions of isolated vascular rings1 or a systemic pressor response.27 However, because release of ET-1 by endothelial cells is polarized toward the basolateral side,28 plasma levels of ET-1 may not correctly represent production rate, and local concentrations of the peptide might be much higher than in the plasma.
The pressor action of 7.42 µmol/kg (2 mg/kg) L-NAME was associated with hemoconcentration, as evidenced by the marked increase in hematocrit. Blood volume decreased by 10%. This resulted almost exclusively from a 14% decrease in plasma volume, since no change in red blood cell volume was detected. The present study demonstrates a marked increase in whole-body albumin escape after L-NAME. This likely reflects fluid transfer, because in most tissues, convection appears to be the dominant mechanism for transmicrocirculatory transport of molecules with dimension similar to albumin.29 The increases in albumin escape rates in the lung, heart, liver, kidney, and duodenum are consistent with previous studies that reported increases in microvascular permeability in the cat intestine11 and guinea pig airways30 and in microvascular albumin leakage in numerous vascular beds in the rat10 after L-NAME administration. The present study documents for the first time that endothelin receptor antagonists attenuate the marked fluid shifts and increases in albumin escape caused by L-NAME. The varying degree of inhibition of albumin escape observed with bosentan and FR 139317 in the lung, heart, liver, kidney, and gastrointestinal tract would indicate regional differences in the mechanisms by which L-NAME enhances albumin extravasation or differences in the local production of and/or sensitivity to endothelin. Comparison of the inhibitory potency of bosentan and FR 139317 revealed that these effects of endogenous endothelin are mediated predominantly via ETA receptors. This interpretation of the data is supported by studies from our laboratory that have shown that the selective ETB receptor agonist IRL-1620 is a considerably less potent agent than exogenous ET-1 in inducing albumin extravasation in the same vascular beds of conscious rats.16 Acute L-NAME injection with a rise in MABP results in a marked diuresis/natriuresis,31 32 which, in addition to fluid shifts from the vascular to extravascular spaces, could also contribute to the decreases in plasma and blood volume.
Inhibition of NO synthesis may increase albumin escape via transmission of increased systemic arterial pressure to the capillaries, thereby increasing capillary hydrostatic pressure, or via increasing vascular permeability. The observations that hydralazine treatment, which prevented the L-NAME increase in MABP, resulted in only a slight attenuation of whole-body albumin escape rates evoked by L-NAME are most consistent with an increased permeability rather than an increase in hydrostatic pressure. Furthermore, L-NAME was found to decrease rather than increase capillary hydrostatic pressure in the cat intestine.11 Elevation of perfusion pressure with another vasoconstrictor, norepinephrine, failed to promote albumin extravasation in various vascular beds, with the exception of the lung, in conscious rats.10 Rapid increases in pulmonary perfusion pressure secondary to acute generalized vasoconstriction and consequently to elevated left atrial end-diastolic pressure cause structural changes (widening and disruption of the endothelial junctions) in the lung capillaries, leading to increased albumin escape.33 Bosentan effectively attenuated albumin escape in hydralazine-treated rats, albeit the magnitude of inhibition appeared to be somewhat greater in animals in which the L-NAME increase in MABP was not prevented. This would indicate that inhibition of albumin extravasation by endothelin antagonists was primarily due to alterations in vascular permeability rather than to their blood pressure–lowering effect. Increases in vascular permeability can be attributed to an increase in the hydraulic conductivity of microvascular cell membrane secondary to formation of interendothelial cell gaps.34 However, an increase in systemic blood pressure and consequently in capillary hydrostatic pressure would facilitate albumin extravasation when gaps are formed.34 Since ET-1 is a more potent constrictor of venous than arterial vessels35 and ETA-like contractile receptors predominate on arterial and ETB-like contractile receptors on venous smooth muscle,36 attenuation of endogenous endothelin-induced vasoconstriction by bosentan and to a lesser extent by FR 139317 could affect microvascular hydrostatic pressure. Presumably, ET-1 has tissue-specific effects on large arterioles affecting systemic vascular resistance and small arterioles controlling capillary surface area. The relative participation of these two components of the microcirculation will determine the capillary hydrostatic pressure in various vascular beds and ultimately affect albumin escape rate.
Platelet-activating factor,37 a leukocyte–endothelial cell adhesive interaction,38 and H2O2 release from endothelial cells and/or activated leukocytes39 have been implicated as mediators of increased albumin extravasation elicited by L-NAME in the mesenteric circulation. It is possible that these events might be at least partly secondary to endothelin formation. Indeed, platelet-activating factor receptor antagonists effectively reduce ET-1–induced albumin extravasation,12 and ET-1 is capable of enhancing adhesion of neutrophil granulocytes to cultured endothelial cells.40 Furthermore, endothelin may either activate or prime neutrophil granulocytes to produce free oxygen radicals.41
The present findings may have relevance to pathological conditions associated with an impaired endothelial NO production and/or enhanced endothelin formation. This imbalance between NO and ET-1 production would unmask and amplify the vascular actions of endothelin. Thus, it is possible that by virtue of its vasoconstrictor, mitogenic, and vascular permeability–enhancing effects, ET-1 may contribute to vascular dysfunction and damage and consequently to the development of vascular diseases.
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Selected Abbreviations and Acronyms |
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-nitro-L-arginine methyl ester
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Acknowledgments |
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This work was supported by a grant from the Medical Research Council of Canada (MT-12573).
Received November 20, 1996; first decision December 13, 1996; accepted December 31, 1996.
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