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Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan 48823
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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We showed
recently that endothelin (ET)A receptors are involved in
the salt sensitivity of ANG II-induced hypertension. The objective of
this current study was to characterize the role of endothelin
ETB receptor activation in the same model. Male rats on
fixed normal (2 meq/day) or high (6 meq/day) salt intake received a
continuous intravenous infusion of ANG II or salt only for 15 days.
During the middle 5 days of the infusion period, rats were given either
the selective ETB receptor antagonist A-192621 or the
nonselective endothelin receptor antagonist A-182086 (both at 24 mg · kg
1 · day1
intra-arterially). Infusion of ANG II caused a greater rise in arterial
pressure in rats on high-salt intake. The administration of A-192621
increased arterial pressure further in all rats. The chronic
hypertensive effect of A-192621 was not significantly affected by salt
intake or ANG II. The administration of A-182086 lowered arterial
pressure chronically only in rats on normal salt intake receiving ANG
II. Thus the salt sensitivity of ANG II-induced hypertension is not
caused by changes in ETB receptor function.
blood pressure; salt-sensitive hypertension; kidney
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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THE OVERALL GOAL OF OUR RESEARCH was to define the mechanisms responsible for the salt sensitivity of ANG II-induced hypertension. Previous work by others has implicated the endothelial-derived peptide endothelin (ET)-1 in the pathophysiology of ANG II-induced hypertension (6, 12, 23). Two receptor subtypes, ETA and ETB, have been shown to mediate blood pressure effects of ET-1. Activation of the ETA receptor can increase blood pressure by a variety of mechanisms, including direct contraction of vascular smooth muscle and alteration of the pressure-natriuretic function of the kidney (11). Conversely, ETB receptor activation tends to lower blood pressure by causing release of endothelial vasodilators, removing ET-1 from the extracellular space, and promoting renal loss of sodium and water (11). Both ETA-selective and nonselective ET-1 receptor antagonists have been shown to attenuate the development of ANG II-induced hypertension (6, 12, 23), but the influence of salt intake was not investigated. We recently reported (1) that selective blockade of ETA receptors in rats with ANG II-induced hypertension caused a larger and more sustained fall in arterial pressure when the rats were on high- versus a normal salt intake. We concluded that the salt sensitivity of ANG II-induced hypertension is mediated in part by endogenous ET-1 acting at ETA receptors. Recent studies showed that a naturally occurring deletion of the ETB receptor gene (9) and chronic blockade of ETB receptors with A-192621 cause salt-sensitive hypertension in rats (21). Therefore, in this study, we conducted experiments to test the role of ETB receptors in the salt sensitivity of ANG II-induced hypertension.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Animals. Male Sprague-Dawley rats (Charles River Laboratories; Portage, MI) weighing 350-450 g were used in these experiments. On arrival at our facility, the rats were maintained according to standards approved by the Michigan State University All-University Committee on Animal Use and Care. All experimental procedures were carried out in accordance with the "Guiding Principles in the Care and Use of Animals" of the American Physiological Society. Rats were acclimatized for at least 2 days before surgical procedures in clear plastic boxes and were allowed access to standard rat chow (22/5 Rodent Diet W 8640, Teklad; Madison, WI) and tap water ad libitum.
Surgical procedures. All surgical procedures were performed after the administration of pentobarbital sodium (50 mg/kg ip; Nembutal, Abbott Laboratories; N. Chicago, IL) and atropine sulfate (0.2 mg ip; Sigma, St. Louis, MO). If necessary, anesthesia was supplemented using methohexital sodium (5-10 mg/kg iv; Brevital, Eli Lilly; Indianapolis, IN). At least 2 days before initiation of the experimental protocol, rats were catheterized via the femoral artery and vein as previously described (22).
Chronic rat maintenance and measurements. The metabolism cages housing the rats during the experiments were located in a climate-controlled room with a 12:12-h light-dark cycle. Rats were allowed access to distilled water and sodium-deficient rat chow (170950, Teklad) ad libitum, depending on the experimental protocol. Half of the rats were maintained on a daily sodium intake of 2 meq/day (normal salt intake), and the remaining rats were maintained on 6 meq/day (high salt intake). All sodium chloride was delivered by continuous (24 h/day) intravenous infusion in a volume of 5 ml/day. Catheters were flushed daily to maintain patency, and the arterial catheters were filled with a heparinized saline solution and occluded when not in use.
Systolic, diastolic, and mean arterial pressures (MAPs) and heart rate were recorded via the femoral arterial catheter each morning of the protocol between 8:00 and 11:00 AM. Arterial catheters were connected to low-volume displacement pressure transducers that were first zeroed at the level of the rat heart. The transducers were connected to digital pressure monitors (Digi-Med blood pressure analyzer; Micro-Med, Louisville, KY) that provided input directly to a computerized digital pressure monitoring system. Data were collected once every second for 15-30 min. The daily value recorded was the average of the 1-s recordings taken over the last 5 min of the recording session.Experimental protocol.
After blood pressure, heart rate, and other variables were recorded for
two control days, ANG II was continuously infused intravenously at a
rate of 5 ng/min for 15 days. On day 5, rats began receiving
intra-arterial injections of the selective ETB receptor
antagonist A-192621 (12 mg/kg, Abbott Laboratories), or the
nonselective ET-1 receptor antagonist A-182086 (12 mg/kg; Abbott
Laboratories) every 12 h during ANG II infusion days
5-10 (total dose = 24 mg · kg1 · day1). The dose
of antagonists was shown to be efficacious in preliminary studies, in
which antagonists were tested against acute and chronic pressor actions
of ET-1 and the selective ETB receptor agonist sarafatoxin
6c (data not shown). Blood pressure and heart rate recordings were
obtained for 1 h immediately after the first injection of ET-1
receptor antagonist and then once each subsequent day of the protocol.
Urine (daily) and blood (control day 2 and ANG II infusion
days 5, 7, 10, and 14)
samples were collected and electrolyte and metabolite concentrations
were measured using ion-selective electrodes (Nova electrolyte 16+
analyzer; Nova Biomedical). Plasma volumes were determined periodically
by Evans blue dye dilution, and blood volume was calculated according
to the standard formula. Total volume of blood withdrawn for
electrolyte and volume determination was 1.3 ml/measurement. Daily
electrolyte balance, water balance, and other variables were calculated
as previously described (22). Briefly, water intake was
measured from calibrated drinking tubes, and urine volume was
determined by collection into calibrated cylinders. Water balance was
calculated by subtracting urine volume from the sum of voluntary water
intake and the 5.0 ml/day infused fluid volume. Voluntary water intake during the control period was 25 ± 3 ml/day in normal salt intake rats, and 30 ± 4 ml/day in high salt intake rats. Water intake did not change consistently throughout the protocol in any group; thus
changes in water balance represent changes in urine volume. Sodium
balance was calculated as the difference between the amount of daily
sodium infused (2.0 or 6.0 meq/day) and the urinary sodium excretion
(urine volume times urinary sodium concentration). In both balance
measurements, nonrenal loss of sodium and water was discounted.
Recovery of sodium and water in our collection system averages 90%.
Reported values were not corrected for recovery.
Statistical analysis. Results are expressed as means ± SE. Within-group differences were analyzed using repeated measures ANOVA. Between-group differences were analyzed using one-way ANOVA. Post hoc comparisons were performed using the protected least-significant difference test. Criterion for statistical significance was a probability level of <0.05.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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ETB receptor antagonism using A-192621.
As shown in Fig. 1, during
the first 5 days of ANG II infusion, MAP rose significantly in rats on
high salt intake (115 ± 3 to 130 ± 7 mmHg) but was not
significantly increased in rats on normal salt intake (110 ± 3 to
116 ± 3 mmHg). The increment in MAP was significantly
larger in rats on high salt intake. MAP did not change over the same
time period in rats not receiving ANG II. There was no change in water
balance (Fig. 2). However, in rats on
normal salt intake there was a significant sodium retention on
day 1 of ANG II infusion followed by a significant loss of sodium on day 3 (Fig. 3). No
significant changes occurred in rats on high salt intake.
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1 · day1. There was
a significant increase in MAP in all groups compared with the predrug
values recorded on day 5 of ANG II infusion (Fig. 1). The
increases in MAP during chronic A-192621 treatment (difference between
days 5 and 10) were 23 ± 8 mmHg in high
salt intake rats receiving ANG II, 24 ± 5 mmHg in high salt
intake control rats, 9 ± 3 mmHg in normal salt intake rats
receiving ANG II, and 14 ± 4 mmHg in normal salt intake control
rats. The increases in MAP during chronic treatment with A-192621 were
not significantly different in any of the four groups. All four groups
demonstrated a decrease in water balance (Fig. 2) on the first day of
A-192621 treatment, but this change was statistically significant only in high salt intake rats receiving ANG II. A similar decrease in sodium
balance was observed (Fig. 3) in all rats on the first day of A-192621
treatment, but this change was significant only in normal salt intake
rats receiving ANG II.
After stopping A-192621, MAP returned to predrug values over a period
of 1 to 4 days in all groups (Fig. 1) although recovery was faster in
animals on normal salt intake. Water balance increased on the first day
after stopping A-192621 in all groups except normal salt controls, but
this change was significant only in high salt controls. There were no
changes in sodium balance in any of the four groups after A-192621
administration was terminated.
There were no significant differences in body weight among the four
groups (high salt ANG II, 405 ± 8 g; high salt control, 393 ± 5 g; normal salt ANG II, 407 ± 7 g; normal
salt control, 385 ± 26 g). Resting heart rate was 355 ± 5 beats/min in rats on high salt intake and 388 ± 7 beats/min
in rats on normal salt intake. No significant changes in heart rate
occurred in response to ANG II or A-192621. There were also no
significant differences in initial blood volume among the four groups
(high salt ANG II, 55 ± 5 ml/kg; high salt control, 53 ± 4 ml/kg; normal salt ANG II, 58 ± 2 ml/kg; and normal salt control,
57 ± 5 ml/kg). Blood volume decreased significantly during the
experiment (averaging 5.6 ml), however, but to a similar degree in all
four groups. This probably reflects the ~4 ml of blood withdrawn
during the protocol without red blood cell replacement. There were no
significant changes in plasma sodium or blood urea nitrogen (BUN)
during the protocol; however, plasma potassium increased slightly but
significantly in all four groups.
ETA/B receptor antagonism using
A-182086.
As shown in Fig. 4, during the first 5 days of ANG II infusion, MAP rose significantly in rats on high salt
intake (109 ± 2 to 126 ± 5 mmHg) and in rats on normal salt
intake (107 ± 2 to 116 ± 4 mmHg). The increment in MAP was
significantly larger in rats on high salt intake. MAP did not change
over the same time period in rats not receiving ANG II. There were no
significant changes in water balance (Fig.
5) or sodium balance (Fig.
6) over this time period.
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1 · day1. There was
a statistically significant fall in MAP (9 ± 3 mmHg) during this
time period (compared with day 5 of ANG II infusion) only in
ANG II-infused rats on normal salt intake. There were no significant
changes in water (Fig. 5) or sodium balance (Fig. 6) during A-182086
administration compared with predrug values on day 5 of ANG
II infusion.
In normal salt intake rats receiving ANG II, cessation of A-182086
treatment resulted in a recovery of MAP to hypertensive levels 3 days later.
There were no significant differences in body weight among the four
groups (high salt ANG II, 403 ± 12 g; high salt control, 397 ± 8 g; normal salt ANG II, 405 ± 9 g; and
normal salt control, 408 ± 13 g). Resting heart rate was
366 ± 4 beats/min in rats on high salt intake, and 349 ± 5 beats/min in rats on normal salt intake. No significant changes in
heart rate occurred in response to ANG II or A-182086. There were also
no significant differences in initial blood volume between the two high
salt groups (high salt ANG II, 56 ± 3 ml/kg; high salt control,
47 ± 2 ml/kg) or between the two normal salt groups (normal salt
ANG II, 45 ± 3 ml/kg; normal salt control, 45 ± 3 ml/kg).
However, initial blood volume was significantly larger in the high salt
ANG II group versus both normal salt groups. Blood volume decreased
significantly during the experiment, but did so to a similar degree in
all four groups (averaging 3.5 ml). There were no significant changes
in plasma sodium, potassium, or BUN during the protocol.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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It has been shown numerous times (5, 13, 19) and confirmed in the current study that ANG II-induced hypertension is potentiated by increased daily salt intake. Although these earlier studies showed a larger degree of potentiation by high salt than observed here, we used smaller increments in salt intake and lower infusion rates of ANG II than employed previously. Nonetheless, ANG II infusion produced a consistently greater rise in MAP in rats on high salt intake in these experiments. An important goal of this study was to investigate the role of ETB receptors in this phenomenon.
This is the first report on the effects of a selective ETB receptor antagonist in ANG II-induced hypertension. Previous studies have demonstrated that ETB receptor activation opposes increases in MAP in some forms of hypertension, including deoxycorticosterone acetate-salt rats (16, 20), and humans with essential hypertension (3). Proposed mechanisms have included both ETB-mediated diuretic and natriuretic actions (20) and the release of endothelial cell-derived vasodilators (3). Therefore, in this study, we investigated the effects of acute and chronic ETB, as well as combined ETA and ETB receptor antagonism on blood pressure and sodium and water balance in rats with ANG II-induced hypertension. We used changes in MAP 1 h after acute intra-arterial injection of ET-1 receptor antagonists as an index of the vascular component of ET-1 action. Because long-term changes in MAP require a shift in the renal pressure-natriuresis relationship (10), we also assessed the effects of ET-1 receptor antagonism on renal sodium and water handling. The main findings of this study were that chronic ETB receptor blockade increases MAP similarly in rats on fixed 2 and 6 meq/day sodium intakes, and that this effect is not altered in rats receiving chronic infusion of ANG II.
After 5 days of continuous ANG II infusion, ET-1 receptor antagonists were injected intra-arterially, and the resulting acute changes in MAP were measured. These changes are summarized in Fig. 7. Selective blockade of ETB receptors by A-192621 resulted in a significant increase in MAP in all four groups of rats. This pressor response is due to impaired release of endothelial vasodilators (nitric oxide and prostacyclin) and/or increased ETA receptor stimulation, possibly due in part to diminished ET-1 clearance (11). The acute increase in MAP we observed in control rats was larger under high salt conditions, consistent with earlier work showing that A-192621-treated rats exhibit salt-sensitive hypertension (21), and thus confirms that a high salt diet enhances acute ETB receptor-mediated effects on blood pressure. Because the acute pressor response to A-192621 in high salt rats receiving ANG II was significantly less than in high salt control rats, chronic ANG II infusion appears to attenuate ETB receptor-mediated blood pressure effects in this setting. On the other hand, ANG II infusion augmented ETB receptor-mediated blood pressure effects in rats on normal salt intake. The mechanism for this salt-dependent difference in ANG II effects on ETB receptor-mediated activity is unknown.
On day 5 of ANG II infusion, combined blockade of ETA and ETB receptors with A-182086 produced a significant acute decrease in MAP in all groups except normal salt control rats. This change in MAP was presumably due to the net effect of inhibiting both ETA-mediated vasoconstriction and ETB-mediated vasodilation and/or ET-1 clearance. We (1) previously reported that injection of the selective ETA receptor antagonist ABT-627 in ANG II-induced hypertension caused significant acute falls in MAP of similar magnitude in rats on both high- and normal salt intake. This indicates that ETA-mediated vasoconstriction is augmented equally by ANG II under conditions of normal and high salt intake. This could be a consequence of either increased vascular ET-1 synthesis (7, 23) or increased vascular reactivity to endogenous ET-1 (11). In normotensive control rats in this study, the acute changes in MAP produced by A-182086 were small and not significantly different in rats on high- versus normal salt intake. This confirms other reports that endogenous ET-1 exerts only modest net effects on basal vascular tone in normotensive animals, regardless of salt intake (1, 11). Rats on high salt intake receiving ANG II showed a larger fall in MAP to bolus injection of A-182086 than high salt controls, presumably due to increased ETA receptor-mediated vasoconstriction (1, 6, 23) and decreased ETB receptor-mediated blood pressure effects in the ANG II-infused rats (as discussed above). Rats on normal salt intake receiving ANG II infusion also showed a larger acute fall in MAP to A-182086 compared with normal salt controls. This effect is likely due predominately to increased ETA receptor-mediated vasoconstriction in ANG II-infused rats (1, 6, 23), because acute ETB receptor-mediated blood pressure effects are augmented by ANG II under normal salt conditions (as discussed above). Taken together, these observations of acute responses to ET-1 receptor antagonists indicate that ETA-mediated vasoconstriction plays an important role in ANG II-induced hypertension at any salt intake. Acute effects of ETB receptors on blood pressure, on the other hand, are affected in a complex way by salt and ANG II.
Sustained alterations in MAP require a shift in the renal pressure-natriuresis relationship, and ET-1 shifts the pressure-natriuresis relationship to higher pressure levels predominately via activation of ETA receptors (14). ETB receptor activation generally causes natriuresis and diuresis (4, 15). Therefore during chronic dosing with ET-1 receptor antagonists, we measured changes in sodium and water balance to assess the specific contributions of ETA and ETB receptors to controlling renal function in ANG II-induced hypertension. Published reports show chronic ANG II infusion increases renal ET-1 content (2), whereas the effect of salt intake on renal ET-1 formation is controversial (8, 17, 18, 21). Chronic effects of the endothelin antagonists on blood pressure are summarized in Fig. 7 as the difference in MAP between days 5 and 10 of the infusion period (the day before treatment and the last day of treatment).
During the first 24 h of chronic ETB receptor blockade with A-192621, MAP rose significantly, and modest sodium and water loss occurred, presumably via the pressure-natriuresis mechanism. Subsequently, however, sodium and water balances were restored, whereas MAP was elevated to a similar degree in all four groups of rats. The fact that A-192621 did not have a large effect on salt and water balance was reflected by a failure to observe significant changes in blood volume or plasma electrolytes during the drug treatment period. Overall these data show that A-192621 produces a similar chronic shift in pressure-natriuresis to a higher pressure level in all groups. Thus ANG II does not change the ETB-mediated contribution to chronic blood pressure regulation.
During the first 24 h of chronic combined blockade of ETA and ETB receptors with A-182086, MAP fell slightly (but only significantly in normal salt rats receiving ANG II), and modest sodium and water retention occurred (but only significantly in high salt control rats), presumably via the pressure-natriuresis mechanism. Subsequently, however, sodium and water balances were restored, whereas MAP remained significantly lower than pretreatment values only in normal salt rats receiving ANG II. A-182086 also produced no significant changes in blood volume or plasma electrolytes during the drug treatment period. Overall these data indicate that A-182086 produced a chronic shift in pressure-natriuresis to a lower pressure level only in normal salt rats receiving ANG II infusion.
The contribution of ET-1 to ANG II-induced changes in the chronic pressure-natriuresis relationship occurs through a balance of ETA (antinatriuretic)- and ETB (natriuretic)-mediated actions. In a previous study (Ref. 1, summarized in Fig. 7), we showed that chronic blockade of ETA receptors alone caused a significant decrease in MAP in ANG II-induced hypertension that was well sustained over 5 days in rats on high salt intake. In rats on normal salt intake, however, MAP fell initially during ETA receptor blockade but then returned to pretreatment levels by day 5 of drug treatment. Recently published work using much larger differences in salt intake than employed here (>10×) indicated that chronic hypertension during selective ETB receptor blockade is significantly larger in rats on high salt intake (21). However, the difference was completely eliminated by concomitant blockade of ETA receptors. We have recently obtained similar results (unpublished observations). Thus most of the chronic MAP response to ETB receptor blockade appears to be caused by activation of ETA receptors (21). Taken together, these results suggest that increased salt intake does not significantly alter ETB-mediated effects on pressure-natriuresis, but that ETA-mediated effects are potentiated by high salt, probably as a result of increased renal ET-1 synthesis during high salt intake (21).
In summary, on the basis of our results with ET-1 receptor antagonists and the work of others (1, 6, 12, 23), we conclude that ET-1 plays a major role in the development of ANG II-induced hypertension and that both vascular and renal actions of ET-1 are important factors. Furthermore, our data indicate that some contributions of ETA and ETB receptors in this model of hypertension are influenced by changes in salt intake. ETA-mediated acute blood pressure effects are increased by ANG II infusion, but are similar under conditions of high and normal salt intake. However, ETB-mediated acute blood pressure effects (enhanced under high salt conditions in control rats) are either increased (normal salt rats) or decreased (high salt rats) by ANG II. The effects of ANG II on ETA receptor-mediated shifts in the pressure-natriuresis relationship are increased by high salt intake. On the other hand, ETB-mediated natriuretic effects are not influenced by ANG II infusion or high salt intake. We conclude that together these actions of ANG II on predominantly ETA-mediated vascular and renal responses to ET-1 are important factors in the salt sensitivity of ANG II-induced hypertension.
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ACKNOWLEDGEMENTS |
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The authors thank Barbara Grant and Evan Brown for their excellent technical assistance and Abbott Laboratories (Abbott Park, IL) for the generous gift of A-192621 and A-182086.
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FOOTNOTES |
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This work was supported by National Heart, Lung, and Blood Institute Grant HL-24111.
Address for reprint requests and other correspondence: G. D. Fink, Dept. of Pharmacology and Toxicology, B-327 Life Science Bldg., Michigan State Univ., East Lansing, MI 48824 (E-mail: finkg{at}msu.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 8 August 2000; accepted in final form 27 July 2001.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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 G. Fink, M. Li, Y. Lau, J. Osborn, and S. Watts Chronic Activation of Endothelin B Receptors: New Model of Experimental Hypertension Hypertension, September 1, 2007; 50(3): 512 - 518. [Abstract] [Full Text] [PDF]
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M. Barton, J. J. Mullins, M. A. Bailey, and M. Kretzler Role of Endothelin Receptors for Renal Protection and Survival in Hypertension: Waiting for Clinical Trials Hypertension, November 1, 2006; 48(5): 834 - 837. [Full Text] [PDF]
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R. A. Khalil Dietary salt and hypertension: new molecular targets add more spice Am J Physiol Regulatory Integrative Comp Physiol, March 1, 2006; 290(3): R509 - R513. [Full Text] [PDF]
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C. Zeng, U. Hopfer, L. D. Asico, G. M. Eisner, R. A. Felder, and P. A. Jose Altered AT1 Receptor Regulation of ETB Receptors in Renal Proximal Tubule Cells of Spontaneously Hypertensive Rats Hypertension, October 1, 2005; 46(4): 926 - 931. [Abstract] [Full Text] [PDF]
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 H. T. Yu Progression of Chronic Renal Failure Arch Intern Med, June 23, 2003; 163(12): 1417 - 1429. [Abstract] [Full Text] [PDF]
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J. F. Reckelhoff and J. C. Romero Role of oxidative stress in angiotensin-induced hypertension Am J Physiol Regulatory Integrative Comp Physiol, April 1, 2003; 284(4): R893 - R912. [Abstract] [Full Text] [PDF]
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 G. A. Reinhart, L. C. Preusser, S. E. Burke, J. L. Wessale, C. D. Wegner, T. J. Opgenorth, and B. F. Cox Hypertension induced by blockade of ETB receptors in conscious nonhuman primates: role of ETA receptors Am J Physiol Heart Circ Physiol, October 1, 2002; 283(4): H1555 - H1561. [Abstract] [Full Text] [PDF]
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