(Circulation. 1995;91:771-775.)
© 1995 American Heart Association, Inc.
Articles |
In Vivo Evidence of an Endothelin-Induced Vasopressor Tone After Inhibition of Nitric Oxide Synthesis in Rats
From the Department of Pharmacology, VACOMED, IFRMP, Rouen University Medical School and Rouen University Hospital, France (V.R., M.H., C.T.), and the Pharma Division, Preclinical Research, F. Hoffmann-La Roche Ltd, Basel, Switzerland (M.C., B-M.L.).
Correspondence to Vincent Richard, PhD, Service de Pharmacologie, Hôpital de Bois Guillaume, CHU de Rouen, 76031 Rouen CEDEX, France.
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Abstract |
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 Top Abstract IntroductionMethods Results Discussion References |
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Background Continuous production of nitric oxide (NO) from endothelial cells permanently inhibits the synthesis and the vasoconstrictor effects of endothelin. Thus, inhibition of NO synthesis might unmask a vasopressor response to endothelin. To assess whether endothelin contributes to the pressor response induced by inhibition of NO synthesis, we tested whether bosentan, a nonpeptide antagonist of ETA and ETB endothelin receptors, affected the hypertensive response induced by the NO synthase inhibitor NG-nitro L-arginine methyl ester (L-NAME).
Methods and Results Anesthetized rats received increasing doses of L-NAME (0.1 to 3 mg · kg-1) in the absence or the presence of bosentan (3 mg · kg-1 IV 15 minutes before L-NAME). Bosentan itself did not affect blood pressure. L-NAME induced a dose-dependent increase in mean arterial pressure (percent increase from baseline after 3 mg · kg-1, 25±5%), and this was reduced by bosentan (13±3%; P<.05) or by the selective ETA antagonist BQ-123 (3 mg · kg-1: controls, 25±4%; BQ-123, 14±5%; P<.01). In contrast, bosentan did not affect the pressor response to phenylephrine (1 to 100 µg · kg-1). The response to L-NAME (3 mg · kg-1) was also reduced by bosentan in ganglion-blocked (chlorisondamine 2.5 mg · kg-1: controls, 89±10%; bosentan, 45±7%) or pithed rats (controls, 165±9%; bosentan, 85±12%; P<.01). Bosentan also inhibited the pressor response to another inhibitor of NO synthesis, NG-nitro L-arginine (3 mg · kg-1) in normal (controls, 24±5%; bosentan, 10±3%; P<.01) or ganglion-blocked (controls, 86±13%; bosentan, 25±8%; P<.01) rats. Finally, L-NAME induced a modest increase in plasma levels of endothelin-1 (controls, 26.8±4.1 pg · mL-1; L-NAME, 38.5±3.3 pg · mL-1; P<.05).
Conclusions These experiments demonstrate that inhibition of NO synthesis unmasks a tonic pressor influence of endothelin, suggesting that this peptide could play a major role in pathophysiological situations associated with an impaired formation of NO.
Key Words: endothelin • endothelium-derived factors • blood pressure
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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Although there is considerable evidence that vascular endothelial cells synthesize and release endothelin,1 the precise role of this vasoconstrictor peptide in the control of vascular tone in vivo remains elusive. Plasma concentrations of endothelin are low,2 and specific antagonists of endothelin receptors do not induce hypotension in normal animals.3 4 This apparent absence of endothelin-induced modification of vasomotor tone could be at least in part because the continuous production of nitric oxide (NO) from endothelial cells5 6 permanently inhibits the synthesis7 8 9 10 and/or the vasoconstrictor effects of endothelin.11 12 13 14 15 Thus, the vasoconstrictor effects of endogenous endothelin might be evidenced only in situations of impaired NO synthesis. If this were true, then it is possible that part of the vasoconstrictor and hypertensive effect induced by inhibitors of NO synthesis would be in fact the consequence of an unmasking of a vasomotor tone by endothelin.
Thus, the present study was designed to assess whether endogenous endothelin exerts a tonic pressor influence after inhibition of NO synthesis in rats. For this purpose, we tested whether the pressor effects induced by the L-arginine analogues NG-nitro L-arginine and NG-nitro L-arginine methyl ester (L-NAME)16 are affected by the mixed ETA/ETB receptor antagonist bosentan17 or by the selective ETA antagonist BQ-123.18
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Methods |
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TopAbstractIntroductionMethods Results Discussion References |
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Animal Preparation
Experiments were performed in male Wistar rats (Charles River) weighing between 300 and 400 g that were anesthetized with 50 to 100 mg · kg-1 IP thiopental sodium. A tracheotomy was performed after midline neck incision, and the rats were mechanically ventilated with room air supplemented with low-flow oxygen with a small-rodent ventilator (MDI) at a rate of 60 cycles per minute and a tidal volume of 10 mL · kg-1 body weight. The respiratory rate and tidal volume were adjusted to maintain arterial blood gases within a normal range. Body temperature was maintained at 37°C with a thermostatted heating blanket connected to a rectal thermometer. The right jugular vein was cannulated for injection of drugs. The left carotid artery was cannulated, and a small Millar Mikrotip catheter (model SPR407, Millar) was inserted into the artery to measure arterial blood pressure. An ECG was also obtained with standard limb electrodes. ECG and arterial pressure were continuously recorded on a Gould Windowgraph recorder.
Protocols
Effect of Bosentan on the Pressor Response to
L-NAME in Normal Rats
Experiments were performed in 24 rats. Bosentan
(3
mg · kg-1, n=12) or saline (n=12) was
given as
a bolus (0.2 mL IV). Fifteen minutes later, increasing doses of L-NAME
(0.1 to 3 mg · kg-1 IV) were administered. A 15-minute
period elapsed between each dose of L-NAME, and arterial pressure was
measured 15 minutes after administration of each dose.
Effect of BQ-123 on the Pressor Response to L-NAME
Experiments were performed in 20 rats. BQ-123 (3
mg · kg-1, n=10) or saline (n=10) was
given as
a bolus (0.2 mL IV). Fifteen minutes later, increasing doses of L-NAME
(0.1 to 3 mg · kg-1 IV) were administered. A 15-minute
period elapsed between each dose of L-NAME, and arterial pressure was
measured 15 minutes after administration of each dose.
Effect of Bosentan on the Pressor Response to L-NAME in
Ganglion-Blocked and Pithed Rats
Experiments were performed in 32
rats. The experimental protocol
was identical to that of the previous protocol, except that rats were
either ganglion-blocked by use of chlorisondamine (2.5
mg · kg-1 IV) given 15 minutes before saline
(n=10) or
bosentan (3 mg · kg-1; n=10) or were pithed
mechanically by use of a metal rod (n=6 for saline and bosentan).
Effect of Bosentan on the Pressor Response to Phenylephrine
To verify that the effect of endothelin antagonists was not the
consequence of a nonspecific inhibition of vasopressor responses, the
effect of bosentan on the hypertension induced by increasing doses of
the 
-adrenergic agonist phenylephrine was tested in 22 rats. Fifteen
minutes after administration of bosentan (3
mg · kg-1, n=11) or saline (n=11),
increasing
doses of phenylephrine (1 to 100 µg · kg-1) were
administered through the jugular catheter. A 15-minute period elapsed
between each dose of phenylephrine, and mean arterial pressure was
measured at the peak hypertensive effect of each dose.
Effect of Bosentan on the Pressor Response to
NG-Nitro L-Arginine
To verify
that the effect of endothelin antagonists on the
pressor response to L-NAME was not specific to one inhibitor of NO
synthesis, we tested the effect of bosentan on the response to another
L-arginine analogue,
NG-nitro L-arginine, both
in normal and in ganglion-blocked rats (n=8 in each group). Since
NG-nitro L-arginine had a
low solubility in water, we had to dissolve it in a large volume (0.5
mL) of saline. Thus, to avoid excessive hemodilution after injection of
saline, only one single dose of the inhibitor (3
mg · kg-1) was used. The pressor response to
NG-nitro L-arginine was
assessed 30 minutes after administration.
Effect of L-NAME
on Plasma Levels of Endothelin
Experiments were performed in 18 rats.
Fifteen minutes after
administration of bosentan (n=11) or saline (n=7), animals
received
increasing doses of L-NAME (0.1 to 3 mg · kg-1).
Fifteen minutes after the last dose, 5 mL of arterial blood was removed
from the carotid artery. Blood samples were immediately centrifuged,
and plasma samples were frozen for later analysis. Plasma
endothelin was assessed by a specific radioimmunoassay, as described
previously.19
Drugs
Bosentan (Ro 47-0203, sodium salt) was obtained from F.
Hoffmann-La Roche Ltd. Chlorisondamine was a gift from Ciba-Geigy.
Phenylephrine, L-NAME, NG-nitro
L-arginine, and big endothelin-1 were purchased from
Sigma. BQ-123 (sodium salt) was purchased from Neosystem.
Data Analysis
All results are expressed as mean±SEM.
Results were compared by
unpaired t tests or by repeated-measures ANOVA. A value of
P
.05 was considered statistically significant.
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Results |
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TopAbstractIntroductionMethods Results Discussion References |
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Basal Values and Effect of Bosentan or BQ-123 on Blood Pressure
Baseline mean arterial blood pressure (MAP) was 122±4 and 120±4 mm Hg in saline- and bosentan-treated rats, respectively (both n=31). Neither saline nor bosentan affected blood pressure (MAP 15 minutes after treatment: saline, 124±4 mm Hg; bosentan, 125±3 mm Hg; both n=31). BQ-123 was also itself devoid of any effect on blood pressure (MAP before BQ-123, 116±3 mm Hg; 15 minutes after BQ-123, 116±3 mm Hg; n=10). Neither bosentan nor BQ-123 affected baseline heart rate.
In ganglion-blocked rats, baseline MAP was 61±3 and 58±3 mm Hg in saline and bosentan rats, respectively (both n=18). Neither saline nor bosentan affected blood pressure (MAP 15 minutes after treatment: saline, 62±3 mm Hg; bosentan, 60±3 mm Hg; both n=18). Bosentan also did not affect blood pressure in pithed rats (MAP 15 minutes after treatment: saline, 48±3 mm Hg; bosentan, 49±3 mm Hg).
Effect of Bosentan or BQ-123 on the Pressor Response to L-NAME in
Normal Rats
The effect of bosentan or BQ-123 on the pressor response
induced
by increasing doses of L-NAME (0.1 to 3 mg · kg-1) in
normal rats is shown in Fig 1
. In control rats, L-NAME
induced a dose-dependent increase in MAP, which reached 25±5% at the
highest dose (n=12). Previous experiments showed that a higher dose of
L-NAME (10 mg · kg-1) did not induce any further
increase in arterial blood pressure in these experimental conditions
(data not shown).
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) or in rats pretreated by bosentan (
) or BQ-123 (
).
Values are mean±SEM.The pressor effect of L-NAME was markedly reduced by bosentan (ANOVA: F=3.21; P<.05). After bosentan, the maximal increase in MAP induced by L-NAME (3 mg · kg-1) was reduced to 13±3% (n=12).
In control rats, the hypertensive effect of L-NAME was accompanied by a significant decrease in heart rate (from 405±13 to 365±13 beats per minute after 3 mg · kg-1 L-NAME; P<.05). The bradycardic effect of L-NAME was not affected by bosentan (from 398±7 to 349±12 beats per minute after 3 mg · kg-1 L-NAME).
The pressor effect of L-NAME was also markedly reduced by BQ-123 (ANOVA: F=5.36; P<.01). After BQ-123, the maximal increase in MAP induced by L-NAME (3 mg · kg-1) was reduced to 14±5% (n=10). BQ-123 did not affect the bradycardic effect of L-NAME (controls: from 404±14 to 335±11 beats per minute; BQ-123: from 387±15 to 310±26 beats per minute).
Effect of Bosentan on the Pressor Response to L-NAME in
Ganglion-Blocked and in Pithed Rats
The effect of bosentan on the
pressor response induced by
increasing doses of L-NAME (0.1 to 3 mg · kg-1) in
ganglion-blocked and in pithed rats is shown in Fig 2.
In control rats, L-NAME induced a dose-dependent increase in MAP, which
reached 89±10% (n=10) and 165±9% (n=6) in
ganglion-blocked and in
pithed rats, respectively. In both cases, the pressor effect of L-NAME
was markedly reduced by bosentan (ANOVA: F=5.42, P<.01 and
F=16.48, P<.001 for ganglion-blocked and pithed rats,
respectively). After bosentan, the maximal increase in MAP induced by
L-NAME (3 mg · kg-1) was reduced to 45±7%
(n=10) and
80±12% (n=6) in ganglion-blocked and in pithed rats,
respectively.
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Effect of Bosentan on the Pressor Response to Phenylephrine
The effect of bosentan on the pressor response induced by
increasing doses of the -adrenergic agonist phenylephrine (1 to 100
µg · kg-1) in normal rats is shown in Fig
3. In control rats, phenylephrine induced a
dose-dependent increase in MAP, which reached 72±11% at the highest
dose (n=11). The pressor effect of phenylephrine was not affected by
bosentan (ANOVA: F=0.82; P=.47). After bosentan, the
maximal
increase in MAP induced by phenylephrine (100
µg · kg-1) was 63±10% (n=11).
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In control and bosentan-treated rats, the hypertensive effect of phenylephrine was accompanied by a significant decrease in heart rate (from 383±15 to 299±12 beats per minute after 100 µg · kg-1 phenylephrine; P<.01). The bradycardic effect of phenylephrine was not affected by bosentan (from 385±11 to 305±19 beats per minute; P<.01).
Effect of Bosentan on the Pressor Response to
NG-Nitro L-Arginine
The effect of bosentan
on the pressor response induced by
NG-nitro L-arginine (3
mg · kg-1) in normal and ganglion-blocked rats is
shown in Fig 4. NG-nitro
L-arginine induced an increase in MAP that reached
24±5% and 86±13% in normal and ganglion-blocked rats,
respectively
(both n=8). This pressor response was reduced to 10±3%
(P<.05) and 25±8% (P<.01) in normal and
ganglion-blocked rats, respectively (both n=8).
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Effect of L-NAME on Plasma Levels of Endothelin-1
The effect
of L-NAME (3 mg · kg-1) on plasma
levels of endothelin-1 is shown in Fig 5. L-NAME induced
a modest increase in circulating endothelin-1 (controls, 26.8±4.1
pg · mL-1, n=7; L-NAME, 38.5±3.3
pg · mL-1, n=11; P<.05).
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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Our results, obtained in vivo from experiments performed in different rat models and in two independent laboratories, suggest that part of the hypertensive response induced by NO synthase inhibitors, which is generally considered to reflect removal of the tonic vasodilatory influence of NO, is in fact due to the unmasking of an endothelin-induced vasopressor response, since this response was reduced by the ETA-ETB endothelin receptor antagonist bosentan.17 Furthermore, the similar inhibitory effect obtained with the ETA antagonist BQ-12318 suggests that this pressor response is mediated at least in part by ETA receptors present on vascular smooth muscle.
The L-arginine analogues L-NAME and NG-nitro L-arginine both induce significant increases in arterial pressure. Such an effect appears to be mediated by an increase in total peripheral resistance20 and is consistent with the hypothesis of a permanent release of NO from vascular endothelial cells in vivo.6 Moreover, the hypertensive effect of L-NAME was maintained and even augmented when the animals were pretreated with the ganglion-blocking agent chlorisondamine or were mechanically pithed. This maintenance of the pressor response to L-arginine analogues after chlorisondamine or pithing is consistent with previous rat experiments21 22 and suggests that tonic release of NO does not require the presence of an intact nervous system.
Two receptor subtypes, ETA and ETB, mediate the biological effect of endothelin.23 24 Although it was initially assumed that ETA receptors were present on vascular smooth muscle and induced vasoconstriction, whereas ETB receptors were present on vascular endothelium and mediated the vasodilatory effect of endothelin,25 recent experiments showed that ETB receptors are in fact also present on smooth muscle cells and contribute to the vasoconstrictor effect of endothelin; indeed, in rats, the ETA antagonists BQ-123 and FR-139317 are unable to fully antagonize the vasoconstrictor effect of endothelin-1,26 27 suggesting that part of this response could be due to stimulation of smooth muscle cell ETB receptors. In our experiments, however, the pressor effect of NO synthase inhibitors was inhibited by BQ-123, suggesting that this response is at least in part the consequence of the stimulation of the ETA receptors.
One possible mechanism by which inhibition of NO synthesis unmasks a
tonic pressor influence of endothelin is that removal of the inhibitory
effect of NO on endothelin synthesis might lead to an increased
synthesis and/or release of endothelin. Indeed, experiments performed
in cultured endothelial cells or in isolated arteries suggest that NO
donors or agents that increase the production of NO from endothelial
cells decrease the cellular production of endothelin, whereas
inhibition of NO synthesis increases the release of the
peptide,7 8 9 10 28
although this regulatory mechanism may be
lost in certain culture conditions.29 30 In the
present experiments, we found that L-NAME induced an increase in
plasma endothelin (Fig 5
). Thus, part of the hypertensive
effect of
this L-arginine analogue might indeed be due to a removal
of the inhibitory effect of NO on endothelin production. It must be
noted that the increase in plasma endothelin observed in the
present experiments was modest, averaging only 44% of basal
values. Whether such a modest increase in plasma endothelin is
sufficient in itself to induce an increase in blood pressure is not
known. However, plasma levels of endothelin might only partially
reflect the biological activity of the peptide, since endothelin is
probably preferentially released toward the vascular smooth muscle
rather than toward the lumen.31 Indeed, the
vasoconstrictor effects of big ET-1 (whose activity requires conversion
to endothelin by the endothelin-converting enzyme present in the
tissue) can be observed at doses for which no increase in plasma
endothelin can be detected.32
The mechanism by which L-NAME induces an increase in plasma levels of endothelin is not known. In isolated arteries and in cultured endothelial cells, basal and agonist-induced production of endothelin requires de novo protein synthesis, since this process is inhibited by cycloheximide.1 7 33 The time course of this response, which suggests a stimulation of the production of the peptide rather than its release from intracellular stores,1 is incompatible with the short time period during which the present experiments were performed. It must be noted, however, that a modest increase in plasma endothelin was also observed after short-term administration of the L-arginine analogue NG-monomethyl-L-arginine (L-NMMA) in dogs.15 One possibility to explain this modest increase in plasma levels of endothelin after acute inhibition of NO synthesis would be that a small amount of endothelin or its precursors is indeed stored within the endothelial cells and that mobilization of this endogenous store is negatively regulated by NO (for example, if NO could inhibit the activity of the endothelin-converting enzyme) or that NO somehow inhibits the plasma degradation of endothelin. However, to the best of our knowledge, none of these hypotheses have been tested experimentally.
Another mechanism that could explain the pressor influence of endothelin in the present experiments is that this response is the consequence of the removal of the inhibitory effect of NO on endothelin-induced smooth muscle contraction.11 12 13 14 15 Indeed, in isolated arteries of various species, agents that stimulate the release of NO, as well as exogenous NO donors such as nitroglycerin, sodium nitroprusside, and SIN-1, fully reverse contractions induced by endothelin.1 11 12 13 14 In isolated human mammary arteries (which do not express endothelial ETB receptors coupled to the release of NO and/or prostacyclin34 ), endothelium removal potentiates the contractile response to endothelin.11 Furthermore, in dogs, inhibition of endogenous release of NO by L-NMMA potentiates the vasoconstrictor response to endothelin, administered at a dose that doubles plasma levels of the peptide, and this effect was evident in all vascular beds studied (ie, coronary, pulmonary, and renal circulations).15
The unmasking of a tonic pressor influence of endothelin after inhibition of NO synthesis might have important physiological and pathophysiological implications. First, our experiments suggest that the acute pressor action of L-arginine analogues cannot be fully attributed to a removal of an NO-dependent vasodilator tone. Second, various pathological situations, such as ischemia, hypercholesterolemia, atherosclerosis, hypertension, and aging, are associated with an impaired formation of NO from endothelial cells. In these conditions, the unopposed biological effects of endothelin could favor smooth muscle contraction and proliferation, thus increasing the risk of subsequent vasospasm and vascular diseases.
Received July 5, 1994; accepted September 23, 1994.
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 F. Vargas, J. M. Moreno, R. Wangensteen, I. Rodriguez-Gomez, and J. Garcia-Estan The endocrine system in chronic nitric oxide deficiency Eur. J. Endocrinol., January 1, 2007; 156(1): 1 - 12. [Abstract] [Full Text] [PDF]
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 G. O. Ogungbade, L. A. Akinsanmi, H. Jiang, and A. O. Oyekan Role of epoxyeicosatrienoic acids in renal functional response to inhibition of NO production in the rat Am J Physiol Renal Physiol, November 1, 2003; 285(5): F955 - F964. [Abstract] [Full Text] [PDF]
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 H. C.D. Souza, H. C. Salgado, G. Ballejo, and M. C. O. Salgado SR141716A-Sensitive Enhancement of ET-1 Hypotensive Effect by Chronic NOS Inhibition Hypertension, October 1, 2003; 42(4): 802 - 805. [Abstract] [Full Text] [PDF]
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H. C Hercule, M.-H. Wang, and A. O Oyekan Contribution of cytochrome P450 4A isoforms to renal functional response to inhibition of nitric oxide production in the rat J. Physiol., September 15, 2003; 551(3): 971 - 979. [Abstract] [Full Text] [PDF]
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 I. Hubloue, D. Biarent, S. A. Kafi, G. Bejjani, F. Kerbaul, R. Naeije, and M. Leeman Endogenous endothelins and nitric oxide in hypoxic pulmonary vasoconstriction Eur. Respir. J., January 1, 2003; 21(1): 19 - 24. [Abstract] [Full Text] [PDF]
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 H. C. Hercule and A. O. Oyekan Role of NO and cytochrome P-450-derived eicosanoids in ET-1-induced changes in intrarenal hemodynamics in rats Am J Physiol Regulatory Integrative Comp Physiol, December 1, 2000; 279(6): R2132 - R2141. [Abstract] [Full Text] [PDF]
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 M. Takamura, R. Parent, P. Cernacek, and M. Lavallee Influence of dual ETA/ETB-receptor blockade on coronary responses to treadmill exercise in dogs J Appl Physiol, November 1, 2000; 89(5): 2041 - 2048. [Abstract] [Full Text] [PDF]
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C. Cardillo, C. M. Kilcoyne, R. O. Cannon III, and J. A. Panza Interactions Between Nitric Oxide and Endothelin in the Regulation of Vascular Tone of Human Resistance Vessels In Vivo Hypertension, June 1, 2000; 35(6): 1237 - 1241. [Abstract] [Full Text] [PDF]
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 E. Haapaniemi, T. Tatlisumak, K. Hamel, L. Soinne, C. Lanni, T. J. Opgenorth, and M. Kaste Plasma Endothelin-1 Levels Neither Increase nor Correlate With Neurological Scores, Stroke Risk Factors, or Outcome in Patients With Ischemic Stroke Stroke, March 1, 2000; 31(3): 720 - 725. [Abstract] [Full Text] [PDF]
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 R. Parent and M. Lavallee Endothelin-dependent effects limit flow-induced dilation of conductance coronary vessels after blockade of nitric oxide formation in conscious dogs Cardiovasc Res, January 14, 2000; 45(2): 470 - 477. [Abstract] [Full Text] [PDF]
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 P. J. M. Best, L. O. Lerman, J. C. Romero, D. Richardson, D. R. Holmes Jr, and A. Lerman Coronary Endothelial Function Is Preserved With Chronic Endothelin Receptor Antagonism in Experimental Hypercholesterolemia In Vitro Arterioscler. Thromb. Vasc. Biol., November 1, 1999; 19(11): 2769 - 2775. [Abstract] [Full Text] [PDF]
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J. C. Romero and J. F. Reckelhoff Role of Angiotensin and Oxidative Stress in Essential Hypertension Hypertension, October 1, 1999; 34(4): 943 - 949. [Abstract] [Full Text] [PDF]
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E. Thorin, R. Parent, Z. Ming, and M. Lavallee Contribution of endogenous endothelin to large epicardial coronary artery tone in dogs and humans Am J Physiol Heart Circ Physiol, August 1, 1999; 277(2): H524 - H532. [Abstract] [Full Text] [PDF]
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 T. F. Luscher and G. Noll Is It All in the Genes... ? : Nitric Oxide Synthase and Coronary Vasospasm Circulation, June 8, 1999; 99(22): 2855 - 2857. [Full Text] [PDF]
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P.-L. Tharaux, C. Chatziantoniou, D. Casellas, L. Fouassier, R. Ardaillou, and J.-C. Dussaule Vascular Endothelin-1 Gene Expression and Synthesis and Effect on Renal Type I Collagen Synthesis and Nephroangiosclerosis During Nitric Oxide Synthase Inhibition in Rats Circulation, April 27, 1999; 99(16): 2185 - 2191. [Abstract] [Full Text] [PDF]
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A. O. Oyekan, K. McAward, J. Conetta, L. Rosenfeld, and J. C. McGiff Endothelin-1 and CYP450 arachidonate metabolites interact to promote tissue injury in DOCA-salt hypertension Am J Physiol Regulatory Integrative Comp Physiol, March 1, 1999; 276(3): R766 - R775. [Abstract] [Full Text] [PDF]
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K. Munter, H. Ehmke, and M. Kirchengast Maintenance of blood pressure in normotensive dogs by endothelin Am J Physiol Heart Circ Physiol, March 1, 1999; 276(3): H1022 - H1027. [Abstract] [Full Text] [PDF]
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J. A. M. Avontuur, F. Boomsma, A. H. van den Meiracker, F. H. de Jong, and H. A. Bruining Endothelin-1 and Blood Pressure After Inhibition of Nitric Oxide Synthesis in Human Septic Shock Circulation, January 19, 1999; 99(2): 271 - 275. [Abstract] [Full Text] [PDF]
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A. Broere, A. H. Van Den Meiracker, F. Boomsma, F. H. M. Derkx, A. J. Man In'T Veld, and M. A. D. H. Schalekamp Human renal and systemic hemodynamic, natriuretic, and neurohumoral responses to different doses of L-NAME Am J Physiol Renal Physiol, December 1, 1998; 275(6): F870 - F877. [Abstract] [Full Text] [PDF]
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 E. Wight, C. F. Kung, P. Moreau, H. Takase, and T. F. Luscher Chronic Blockade of Nitric Oxide Synthase and Endothelin Receptors During Pregnancy in the Rat: Effect on Reactivity of the Uterine Artery In Vitro Reproductive Sciences, November 1, 1998; 5(6): 288 - 295. [Abstract] [PDF]
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Z. Ming, R. Parent, E. Thorin, and M. Lavallee Endothelin-Dependent Tone Limits Acetylcholine-Induced Dilation of Resistance Coronary Vessels After Blockade of NO Formation in Conscious Dogs Hypertension, November 1, 1998; 32(5): 844 - 848. [Abstract] [Full Text] [PDF]
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C. E. King-VanVlack, S. E. Curtis, J. D. Mewburn, S. M. Cain, and C. K. Chapler Endothelial modulation of neural sympathetic vascular tone in canine skeletal muscle J Appl Physiol, October 1, 1998; 85(4): 1362 - 1367. [Abstract] [Full Text] [PDF]
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P. Moreau Endothelin in hypertension: A role for receptor antagonists? Cardiovasc Res, September 1, 1998; 39(3): 534 - 542. [Abstract] [Full Text] [PDF]
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S. Prie, D. J. Stewart, and J. Dupuis EndothelinA Receptor Blockade Improves Nitric Oxide–Mediated Vasodilation in Monocrotaline-Induced Pulmonary Hypertension Circulation, June 2, 1998; 97(21): 2169 - 2174. [Abstract] [Full Text] [PDF]
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E. Wight, C. F. Kung, P. Moreau, H. Takase, and T. F. Luscher Chronic Blockade of Nitric Oxide-Synthase and Endothelin Receptors During Pregnancy in the Rat: Effect on Pregnancy Outcome Reproductive Sciences, May 1, 1998; 5(3): 132 - 139. [Abstract] [PDF]
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J.-P. Gratton, G. Cournoyer, B.-M. Loffler, P. Sirois, and P. D'Orleans-Juste ETB Receptor and Nitric Oxide Synthase Blockade Induce BQ-123–Sensitive Pressor Effects in the Rabbit Hypertension, November 1, 1997; 30(5): 1204 - 1209. [Abstract] [Full Text]
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J. D. Banting, K. E. Thompson, P. Friberg, and M. A. Adams Blunted Cardiovascular Growth Induction During Prolonged Nitric Oxide Synthase Blockade Hypertension, September 1, 1997; 30(3): 416 - 421. [Abstract] [Full Text]
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 X. COMBES, M. MAZMANIAN, H. GOURLAIN, and P. HERVÉ Effect of 48 Hours of Nitric Oxide Inhalation on Pulmonary Vasoreactivity in Rats Am. J. Respir. Crit. Care Med., July 1, 1997; 156(2): 473 - 477. [Abstract] [Full Text]
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J. G. Filep Endogenous Endothelin Modulates Blood Pressure, Plasma Volume, and Albumin Escape After Systemic Nitric Oxide Blockade Hypertension, July 1, 1997; 30(1): 22 - 28. [Abstract] [Full Text]
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G. Ahlborg and J. M. Lundberg Nitric oxide-endothelin-1 interaction in humans J Appl Physiol, May 1, 1997; 82(5): 1593 - 1600. [Abstract] [Full Text] [PDF]
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P. Moreau, H. Takase, C. F. Kung, S. Shaw, and T. F. Luscher Blood Pressure and Vascular Effects of Endothelin Blockade in Chronic Nitric Oxide–Deficient Hypertension Hypertension, March 1, 1997; 29(3): 763 - 769. [Abstract] [Full Text]
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P. Sventek, A. Turgeon, and E. L. Schiffrin Vascular Endothelin-1 Gene Expression and Effect on Blood Pressure of Chronic ETA Endothelin Receptor Antagonism After Nitric Oxide Synthase Inhibition With L-NAME in Normal Rats Circulation, January 7, 1997; 95(1): 240 - 244. [Abstract] [Full Text]
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E. D. Frohlich Influence of Nitric Oxide and Angiotensin II on Renal Involvement in Hypertension Hypertension, January 1, 1997; 29(1): 188 - 193. [Abstract] [Full Text] [PDF]
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 L. Puybasset, M.-L. Bea, B. Ghaleh, J.-F. Giudicelli, and A. Berdeaux Coronary and Systemic Hemodynamic Effects of Sustained Inhibition of Nitric Oxide Synthesis in Conscious Dogs: Evidence for Cross Talk Between Nitric Oxide and Cyclooxygenase in Coronary Vessels Circ. Res., August 1, 1996; 79(2): 343 - 357. [Abstract] [Full Text]
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C. F. Kung, P. Moreau, H. Takase, and T. F. Luscher L-NAME Hypertension Alters Endothelial and Smooth Muscle Function in Rat Aorta : Prevention by Trandolapril and Verapamil Hypertension, November 1, 1995; 26(5): 744 - 751. [Abstract] [Full Text]
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C. M. Boulanger, L. Caputo, and B. I. Levy Endothelial AT1-Mediated Release of Nitric Oxide Decreases Angiotensin II Contractions in Rat Carotid Artery Hypertension, November 1, 1995; 26(5): 752 - 757. [Abstract] [Full Text]
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R. Kramp, P. Fourmanoir, and N. Caron Endothelin resets renal blood flow autoregulatory efficiency during acute blockade of NO in the rat Am J Physiol Renal Physiol, December 1, 2001; 281(6): F1132 - F1140. [Abstract] [Full Text] [PDF]
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