(Hypertension. 1995;26:83-88.)
© 1995 American Heart Association, Inc.
Articles |
Heterogeneity in Vascular Smooth Muscle Responsiveness to Angiotensin II
Role of Endothelin
From the Cardiovascular Risk Factor Reduction Unit (CRFRU), Departments of Pharmacology and Medicine, University of Saskatchewan, Saskatoon (Canada).
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Abstract |
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Abstract We compared the role of endothelium and of endothelin in mediating the vasoconstrictor responses to angiotensin II (Ang II) in three vascular smooth muscle preparations—aorta, mesenteric artery, and tail artery—isolated from adult male Sprague-Dawley rats. The vasoconstrictor potency for Ang II in blood vessels with endothelium varied in the following rank order: aorta>mesenteric artery>tail artery. Although the maximal tension responses to Ang II were similar for mesenteric and tail arteries, it was significantly lower in aorta. Endothelium removal led to a leftward shift in the concentration-response curves to Ang II in the aorta but a rightward shift in the mesenteric artery. Strikingly, Ang II failed to evoke tension responses in tail artery in the absence of endothelium. The endothelin-A (ETA)–selective antagonist BQ-123 blocked the responses to Ang II in a noncompetitive manner, with partial and complete attenuation of responses in the endothelium-intact mesenteric and tail artery preparations, respectively. In contrast, BQ-123 did not affect the responses to Ang II in the aorta. BQ-123 also failed to affect the responses to Ang II in endothelium-denuded mesenteric artery rings. The Ang II type 1 (AT1) receptor–selective antagonist losartan competitively blocked the responses to Ang II in the three tissues (pA2, 8.3 to 8.7) when endothelium was present. These data suggest that there are endothelium-dependent regional variations in vascular tissue sensitivity to Ang II. The vasoconstrictor response to Ang II in rat aorta involves activation of AT1 receptors located on vascular smooth muscle cells, whereas the response in mesenteric artery involves activation of both vascular and endothelial AT1 receptors. In contrast, the responses to Ang II in the tail artery may be mediated by the indirect stimulation of vascular smooth muscle ETA receptors subsequent to the activation of endothelial AT1 receptors likely linked to the release of endothelins.
Key Words: angiotensin II • endothelium • endothelin • losartan • receptors, angiotensin • vasoconstriction
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Introduction |
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Although an important role for angiotensin II (Ang II) as an endogenous regulator of vascular smooth muscle (VSM) tone is well established,1 2 the vasoconstrictor responses to Ang II vary in different regional beds and among VSM preparations.3 4 5 6 7 As early as 1973, Bohr3 and later Toda and his colleagues4 6 described regional and species variations in the responses of isolated arteries to Ang II. Their studies focused on blood vessels derived from the rabbit, dog, or monkey. With the exception of studies using rat aortic preparations,5 6 7 8 9 very few studies have attempted to investigate the mechanism underlying any differences in the in vitro responsiveness to Ang II in isolated blood vessels from the different regions of the rat vasculature. Although a few studies have addressed the issue of changes in perfusion pressure in response to Ang II of the rat mesenteric vascular bed10 and perfused rat caudal artery preparation,11 12 these studies failed to provide potency (EC50) and efficacy (Emax) estimations for appropriate comparisons. Such differences in the vasoactive properties of Ang II among blood vessels may result from differences in the properties of vascular Ang II receptors. More importantly, Ang II via activation of endothelial receptors could also modulate VSM tone to a variable extent in different vascular beds. However, systematic investigations have not been undertaken to examine these issues with the use of different VSM preparations of the rat.
A few studies have shown that Ang II promotes the release of endothelin-1 (ET-1) from endothelial and rat mesangial cells in culture.13 14 15 Perfusion of the mesenteric arterial bed for 5 hours with Ang II (100 nmol/L) potentiated the vascular responses to norepinephrine via release of ET-1 in the spontaneously hypertensive rat (SHR) but not in the normotensive Wistar-Kyoto rat (WKY).16 More recently, it was demonstrated that Ang II could release ET-1 in a time- and concentration-dependent manner from human endothelial and mesangial cells.17 18 Despite these elegant observations, there are no reports implicating a role for ET-1 in Ang II–mediated changes in VSM tone. Therefore, the aim of this study was to examine the in vitro responsiveness to Ang II in the presence and absence of endothelium with the use of ring preparations of aorta, mesenteric artery, and tail artery isolated from adult rats. The study elucidates the likely participation of endothelin release contributing to an increase in VSM tone in response to Ang II in certain blood vessels.
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Methods |
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Tension Measurement
Ring preparations of the thoracic portion of the aorta (length, 5 mm), the superior mesenteric artery (3 mm), and the ventral caudal artery (2 mm) isolated from 14- to 16-week-old adult male Sprague-Dawley rats purchased from Charles River (St Constant, Montreal, Quebec, Canada) were set up for isometric tension measurements under resting preload conditions of 2.0, 1.0, and 0.5 g, respectively, in 20-mL organ baths containing modified Krebs' physiological salt solution (PSS) maintained under oxygenation with 95% O2/5% CO2 at 37°C. The composition of the PSS was (mmol/L) NaCl 118, KCl 4.7, KH2PO4 1.2, MgCl2 · 6H2O 1.2, CaCl2 · 2H2O 1.8, NaHCO3 25.0, and glucose 1.1.19
The increase in isometric tension under resting and agonist(s)-stimulated conditions was recorded on a Grass 7E polygraph using FT0.3 force transducers. After an initial 1-hour equilibration period with repeated washings every 20 minutes, the tissues were challenged with indicated concentrations of agonist(s). The presence or absence of endothelium was confirmed by relaxation responses to 1 µmol/L acetylcholine in the three VSM tissues precontracted with a standard concentration of 1 µmol/L phenylephrine. In separate experiments, endothelium was removed through chemical stripping by incubation of the tissues for approximately 3 seconds with Triton X-100 (0.5% in PSS) in the organ baths followed by repeated washings with normal PSS several times. Previous studies have shown that brief exposure to this detergent selectively destroys the endothelial layer of both vascular and cardiac preparations.20 Again, the absence of endothelium was confirmed by lack of relaxation responses to acetylcholine in tissues precontracted with phenylephrine.
The aorta, mesenteric artery, and tail artery isolated from the same rat were set up for tension measurements with either intact or denuded endothelium (on the same day) for comparison of differences in responsiveness to Ang II. Each tissue was exposed to only a single cumulative concentration-response (C-R) determination for Ang II (either in the presence or absence of endothelium) to avoid the possibility that receptor desensitization would affect subsequent determinations. Thus, all determinations were carried out only once, and a single cumulative C-R curve was generated with each preparation. To examine this issue further, we conducted preliminary experiments in parallel rings as follows. Each tissue was exposed to one single maximal concentration of Ang II (10 µmol/L), or a similar concentration was achieved in a cumulative fashion. There were no significant differences in the calculated values (mean±SEM) of maximal tension responses obtained by both procedures. These data confirmed that desensitization/tachyphylaxis did not occur in response to Ang II during stepwise increases within the first cumulative C-R curve. The likely desensitization/tachyphylaxis in response to Ang II has been characterized in aortic rings only for the second and third cumulative response determinations.21 All data shown in the present study relate to analyses of cumulative C-R curves, but we conducted a few experiments of single C-R studies using rat tail artery rings to compare the responses to fixed concentrations of Ang II, arginine vasopressin (AVP), ET-1, and phenylephrine before and after endothelium removal.
C-R curves to Ang II were also determined in the three VSM rings with intact endothelium in the presence of varying concentrations of either the endothelin-A (ETA)–selective antagonist BQ-123 (10, 50, and 100 nmol/L and 1 µmol/L) or varying concentrations of the Ang II type 1 (AT1) receptor–selective antagonist losartan (DuP 753; 1.0, 5.0, and 10 nmol/L). To verify that BQ-123 was indeed a competitive antagonist to ET-1, we also determined cumulative C-R curves to ET-1 determined in either the presence or absence of a maximal concentration of BQ-123 (1 µmol/L). These antagonists were maintained in the organ baths for 20 minutes before the addition of agonists. Ring preparations that did not receive any antagonist(s) set up in parallel served as controls. At the end of the experiment, tissues were blotted dry and weighed, and cross-sectional areas were calculated as described elsewhere.22 This was necessary to express the data of tension developed at each concentration of the agonist per unit area (as grams per millimeter squared) for each blood vessel.
Drugs Used
Ang II octapeptide, ET-1, and AVP were obtained from either
Peninsula Laboratories or Bachem Inc. The AT1
receptor–selective antagonist losartan and the
ETA-selective antagonist BQ-123 were obtained
from DuPont Merck Pharmaceutical Co and Bachem Bioscience,
respectively. Phenylephrine hydrochloride, acetylcholine
chloride, and Triton X-100 were purchased from Sigma Chemical Co. Drugs
were added to the organ baths in volumes between 40 and 100 µL to
provide the required final bath concentrations.
Data Analyses
Each cumulative C-R curve was analyzed individually for
the estimation of the concentration required to produce 50% of the
maximal response (EC50) and the maximal increase in tension
(Emax) by use of the ALLFIT
program.23 The pooled data of EC50 values are
expressed as geometric mean with 95% confidence limits. The
experimental values are expressed as mean±SEM. Comparison of mean
values between various groups was performed by ANOVA
(SUPERANOVA package, Macintosh). Simultaneous
multiple comparisons were examined by Scheffé's F test. The
method of Arunlakshana and Schild24 was used for
calculation of the pA2 values and determination of the
competitive nature of Ang II antagonism by losartan.
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Results |
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Comparison of C-R Curves to Ang II
In the presence of intact endothelium, Ang II evoked concentration-dependent increases in VSM tone with the following rank order of sensitivity: aorta>mesenteric artery>tail artery (Fig 1). In the endothelium-denuded preparations, the C-R curve to Ang II was shifted to the left in the case of aorta, with significant decreases (P<.01) in the EC50 value (Table 1). On the other hand, the C-R curve to Ang II in mesenteric artery was shifted significantly (P<.01) to the right, and the tail artery failed to respond to Ang II even at 10 µmol/L in the absence of endothelium (Fig 1 and Table 1). Although the actual tension generated (grams) seemed to be higher in aorta, when the tension values were normalized and expressed as maximal tension (Emax) generated per cross-sectional area (grams per millimeter squared), it was in fact significantly lower for aorta than observed with mesenteric artery and tail artery. Thus, the order of Emax for Ang II was mesenteric artery
tail artery>aorta
(Fig 1).
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Among the agonists tested, ET-1 showed the highest level of efficacy (Emax) in both the presence and absence of endothelium in all three preparations (data not shown). The Emax values for Ang II (10 µmol/L) were lower, and they were 55±3% (aorta), 64±5% (mesenteric artery), and 79±7% (tail artery) of the corresponding Emax values for ET-1 (100%) in these tissues with intact endothelium.
Selective Attenuation of Responses to Ang II
To examine whether the loss of responsiveness of tail artery is
selective to Ang II, we made single C-R determinations in tail artery
rings using near-maximal concentrations of Ang II (1 µmol/L), AVP
(100 nmol/L), phenylephrine (1 µmol/L), and ET-1 (10
nmol/L) before and after endothelium removal. Fig 2 shows the pooled data (mean±SEM) of tension generated
for each agonist from several experiments. Before
endothelium removal, tail artery responded to all
agonists including Ang II (Fig 2, left). After repeated washings, when
the same rings were stimulated again after 1 hour, similar levels of
tension response could be restored for all four agonists (Fig 2,
right). However, in parallel rings that were subjected to
endothelium removal by brief exposure to Triton X-100,
the tension responses to AVP, ET-1, and phenylephrine were
present, and even high concentrations of Ang II (10 µmol/L)
failed to enhance the tone (Fig 2, middle). These data confirmed that
endothelium removal led to selective loss of
responsiveness to Ang II in the ring preparations of rat tail
artery.
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Effects of the Endothelin Antagonist BQ-123
Inclusion of BQ-123 (1 µmol/L) led to rightward shifts in the
cumulative C-R curves to ET-1, with no significant changes in the
Emax values of the three blood vessels in the presence of
endothelium (data not shown). However, the
EC50 values for ET-1 were significantly higher
(P<.01) in the three preparations in the presence of BQ-123
(Table 2). These data confirmed the competitive nature
of BQ-123 for ET-1–evoked tension responses.
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Although BQ-123 (1 µmol/L) did not affect the tension responses of aorta, it shifted the C-R curve to Ang II of the mesenteric artery to the right, with decreases in its maximal response. In addition, the responses of tail artery to Ang II were completely attenuated by BQ-123 (Fig 3). Table 2 summarizes pooled EC50 and Emax values from several C-R curves. The inhibitory effects of increasing concentrations of BQ-123 (10 nmol/L to 1 µmol/L) were determined in both mesenteric and tail arteries. The data confirmed that BQ-123 exerts a concentration-dependent noncompetitive inhibition of responses to Ang II in endothelium-intact preparations of both blood vessels (Fig 3A and 3B). In contrast, Ang II–evoked partial responses of the mesenteric artery in the absence of endothelium remained unaffected by the inclusion of a high concentration of BQ-123 (data not shown). Thus, the responses of mesenteric and tail arteries to Ang II determined in the presence of BQ-123 in the endothelium-intact preparations were similar to those obtained for Ang II in these tissues in the absence of endothelium.
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, 10 nmol/L;
, 50 nmol/L; 
, 100 nmol/L; 
, 1 µmol/L) in rat
mesenteric artery ring (A) and rat tail artery ring (B) or the absence
of BQ-123 (
, control group) in preparations with intact
endothelium. Appropriate concentrations of BQ-123 shown
were maintained for 20 minutes in the organ baths before addition of
angiotensin II. Each data point is mean±SEM of six
separate determinations.
Responses to Ang II in the Presence of Losartan (DuP
753)
Incubation with varying concentrations of losartan in the
endothelium-intact preparations led to parallel
rightward shifts in the C-R curves to Ang II, with no significant
differences in the maximal responses to Ang II (Fig 4).
Moreover, the calculated pA2 values were closely similar in
the three preparations, with values of 8.65, 8.40, and 8.25 in aorta,
mesenteric artery, and tail artery, respectively. The slopes of these
plots were also closer to 1.0. These data suggest that Ang II–evoked
tension responses in these three VSM tissues (with intact
endothelium) were competitively blocked by the
AT1 antagonist losartan.
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, 5 nmol/L; |
Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The present study shows that Ang II evokes tension responses in rat aorta by stimulation of vascular Ang II receptors; the presence of endothelium in fact depresses the vascular response to Ang II in this tissue. On the other hand, in tail artery it evokes an increase in VSM tone only in the presence of endothelium, whereas in the case of mesenteric artery, it evokes tension responses via activation of both vascular (direct) and endothelial (indirect) Ang II receptors. Both vascular and endothelial Ang II receptors belong to the AT1 subtype, because losartan competitively blocked the responses to Ang II with closely similar pA2 values (8.3 to 8.7) in the three VSM preparations with intact endothelium. Since the ETA antagonist BQ-123 partly and completely attenuated the responses to Ang II in mesenteric artery and tail artery preparations, respectively, our findings indicate that the indirect vascular responses to Ang II involve endothelin release from the endothelial cells. Thus, the present work provides evidence that the heterogeneity in arterial responsiveness to Ang II could be due to differences in the distribution and activation of vascular and endothelial AT1 receptors in different blood vessels of the same species.
Destruction of endothelium significantly enhanced the sensitivity of the rat aorta to Ang II. Previous studies have demonstrated that in the presence of normal endothelium, constitutive release of endotheliumderived relaxing factor opposed the direct VSM contraction by Ang II. This was lost in endothelium-denuded preparations and was mimicked by agents that interfered with the generation of endothelium-derived relaxing factor in aorta.5 8 9 It has been shown that the tension responses to Ang II in rabbit aorta with intact endothelium were abolished by the inclusion of BQ-123, suggesting that Ang II receptor activation could evoke endothelin release.25 However, we did not observe a rightward shift in the C-R curve to Ang II in rat aorta in the presence of BQ-123, suggesting that endothelin release did not contribute to the evoked tension responses to Ang II in this preparation. In fact, in the absence of endothelium, Ang II responses of rat aorta were enhanced.
In contrast to rat aorta, both mesenteric artery and tail artery showed endothelium-dependent responses to Ang II. The abolition of Ang II–evoked tension responses in the tail artery either by removal of the endothelium or by the inclusion of BQ-123 in preparations with intact endothelium confirmed that Ang II–evoked responses are mediated by the activation of endothelial Ang II receptors that are likely coupled to processes capable of endothelin release. A recent report has shown that potentiation of norepinephrine-induced increases in rat tail artery perfusion pressure by Ang II was absent in preparations devoid of endothelium.12 These data confirm the observations made in the present study that Ang II responses of the tail artery depend on the presence of endothelium.
Two laboratories independently reported that Ang II and AVP stimulate the release of immunoreactive ET-1 from cultured bovine aortic endothelial cells and porcine aortic endothelial cells.13 14 These effects were also mimicked by phorbol esters and Ca2+ ionophore.13 Ang II also induced preproET-1 mRNA expression in cultured endothelial cells derived from the carotid artery.15 Similar observations were obtained with the use of rat mesangial cells as well as human mesangial and endothelial cells in culture.15 17 18 Despite such elegant observations with cultured cells, there is little evidence from intact VSM tissues supporting the notion of a direct ET-1–releasing role for Ang II. Recently, however, Dohi et al16 demonstrated that perfusion of the rat mesenteric vascular bed with Ang II (100 nmol/L) for 5 hours led to potentiation of norepinephrine-induced vasoconstriction via ET-1 release in the SHR. In contrast, short-term incubation with Ang II for 1 hour failed to potentiate norepinephrine responses. Importantly, Dohi et al failed to observe similar findings in the normotensive WKY strain. On the other hand, other researchers have shown that perfusion of the mesenteric artery bed of WKY with AVP (100 pmol/L to 1 nmol/L) for 3 to 6 hours led to significant increases in the release of ET-1 and induction of preproET-1 mRNA levels.26
Although it is suggested that VSM cells predominantly express ETA receptors, the existence of ETB receptors on VSM cells has been proposed recently. However, we have confirmed that the ETB-selective agonist IRL 1620 failed to evoke increases in VSM tone in the three preparations (unpublished observations, 1995). Moreover, ET-1–evoked tension responses were competitively blocked by the ETA antagonist BQ-123. These results confirmed that the VSM cells of the three blood vessels possess ETA receptors and that the released endothelins could evoke their tension responses via activation of these receptors. The observation that the ETA antagonist BQ-123 significantly attenuated the tension responses to Ang II in a concentration-dependent and noncompetitive manner in mesenteric artery (with intact endothelium) confirmed the involvement of endothelin release by Ang II and the likely stimulation of ETA receptors in this preparation. The present study does not provide direct evidence of endothelin release or induction of preproET-1 mRNA levels by Ang II. However, with the use of a well-established endothelin antagonist in functional studies, it supports the notion that endothelin released from the endothelium mediates the tension responses to Ang II in blood vessels such as mesenteric artery and tail artery. Although earlier studies have shown that incubation of Ang II or AVP for a longer time with endothelial cells in culture is required for the induction of endothelin mRNA, the present data show that the responses to Ang II had an immediate effect in both mesenteric and tail arteries. The possibility that Ang II and other agonists could be linked to activation of endothelin-converting enzyme, thereby liberating endothelin from big endothelin, could be considered in future studies. Thus, the exact site of action of Ang II on endothelial cells and the signal transduction pathway governing endothelin release in blood vessels such as rat mesenteric artery and rat tail artery need further study.
Despite differences in the distribution of Ang II receptors in aorta, mesenteric artery, and tail artery, the AT1-selective antagonist losartan competitively blocked the tension responses to Ang II in the three VSM preparations when endothelium was present. Moreover, the calculated pA2 values in these three VSM preparations were similar and in agreement with other reports. These findings confirmed that there were no differences in the characteristics of vascular and endothelial Ang II receptors and that they both belong to the AT1 subtype.27 28
In conclusion, the present study provides evidence that Ang II–induced VSM tone is predominantly governed by the direct activation of vascular AT1 receptors in conduit-type blood vessels such as rat aorta. In the tail artery the responses to Ang II may be mediated mainly by the release of endothelins from the endothelium. In contrast, the tension responses of rat mesenteric artery to Ang II are mediated by the activation of both vascular and endothelial AT1 receptors. Although the observed EC50 values for the exogenously added Ang II in mesenteric artery and tail artery rings were found to be higher in the present study, other studies have shown that locally generated Ang II plays an important role in the regulation of vascular tone.1 2 10 11 Therefore, it is possible that locally generated Ang II could enhance endothelin release in the mesenteric vascular bed and caudal arteries, thereby contributing to increased peripheral VSM tone.
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Acknowledgments |
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This work was supported by a grant-in-aid from the Heart & Stroke Foundation of Saskatchewan to Dr V. Gopalakrishnan, a Scholar of the Heart & Stroke Foundation of Canada during the tenure of this project. We thank Dr Ronald D. Smith, DuPont Merck Pharmaceutical Co, Wilmington, Del, for a generous supply of losartan.
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Footnotes |
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Reprint requests to Dr V. Gopalakrishnan, CRFRU, Department of Pharmacology, University of Saskatchewan, Saskatoon, SK, S7N 5E5, Canada.
Received October 19, 1994; first decision December 16, 1994; accepted March 13, 1995.
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M. Iglarz, J. Benessiano, I. Philip, S. Vuillaumier-Barrot, S. Lasocki, U. Hvass, G. Durand, J.-M. Desmonts, B. I. Levy, and D. Henrion Preproendothelin-1 Gene Polymorphism Is Related to a Change in Vascular Reactivity in the Human Mammary Artery In Vitro Hypertension, February 1, 2002; 39(2): 209 - 213. [Abstract] [Full Text] [PDF]
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 C. R. Rosenfeld Mechanisms regulating angiotensin II responsiveness by the uteroplacental circulation Am J Physiol Regulatory Integrative Comp Physiol, October 1, 2001; 281(4): R1025 - R1040. [Abstract] [Full Text] [PDF]
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 G. Petrescu, M. Costuleanu, S. M. Slatineanu, N. Costuleanu, L. Foia, and A. Costuleanu Contractile effects of angiotensin peptides in rat aorta are differentially dependent on tyrosine kinase activity Journal of Renin-Angiotensin-Aldosterone System, September 1, 2001; 2(3): 180 - 187. [Abstract] [PDF]
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K. F. Hilgers, R. Veelken, D. N. Muller, H. Kohler, A. Hartner, S. R. Botkin, C. Stumpf, R. E. Schmieder, and R. A. Gomez Renin Uptake by the Endothelium Mediates Vascular Angiotensin Formation Hypertension, August 1, 2001; 38(2): 243 - 248. [Abstract] [Full Text] [PDF]
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S. Shastri, J. R. McNeill, T. W. Wilson, R. Poduri, C. Kaul, and V. Gopalakrishnan Cysteinyl leukotrienes mediate enhanced vasoconstriction to angiotensin II but not endothelin-1 in SHR Am J Physiol Heart Circ Physiol, July 1, 2001; 281(1): H342 - H349. [Abstract] [Full Text] [PDF]
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A. Riggleman, J. Harvey, and C. Baylis Endothelin Mediates Some of the Renal Actions of Acutely Administered Angiotensin II Hypertension, July 1, 2001; 38(1): 105 - 109. [Abstract] [Full Text] [PDF]
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 R. M. Touyz and E. L. Schiffrin Signal Transduction Mechanisms Mediating the Physiological and Pathophysiological Actions of Angiotensin II in Vascular Smooth Muscle Cells Pharmacol. Rev., December 1, 2000; 52(4): 639 - 672. [Abstract] [Full Text] [PDF]
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B. E. Cox, C. E. Williams, and C. R. Rosenfeld Angiotensin II indirectly vasoconstricts the ovine uterine circulation Am J Physiol Regulatory Integrative Comp Physiol, February 1, 2000; 278(2): R337 - R344. [Abstract] [Full Text] [PDF]
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 K. G. Stewart, Y. Zhang, and S. T. Davidge Estrogen Decreases Prostaglandin H Synthase Products From Endothelial Cells Reproductive Sciences, November 1, 1999; 6(6): 322 - 327. [Abstract] [PDF]
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R. Choussat, L. Hittinger, F. Barbe, G. Maistre, A. Carayon, B. Crozatier, and J. Su Acute effects of an endothelin-1 receptor antagonist bosentan at different stages of heart failure in conscious dogs Cardiovasc Res, September 1, 1998; 39(3): 580 - 588. [Abstract] [Full Text] [PDF]
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 J. A. Borland, A. H. Chester, S. Crabbe, J. B. Parkerson, J. D. Catravas, and M. H. Yacoub Differential action of angiotensin II and activity of angiotensin-converting enzyme in human bypass grafts J. Thorac. Cardiovasc. Surg., August 1, 1998; 116(2): 206 - 212. [Abstract] [Full Text] [PDF]
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E. Thorin, P. Cernacek, and J. Dupuis Endothelin-1 Regulates Tone of Isolated Small Arteries in the Rat : Effect of Hyperendothelinemia Hypertension, April 1, 1998; 31(4): 1035 - 1041. [Abstract] [Full Text] [PDF]
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 M. E. Pueyo, J.-F. Arnal, J. Rami, and J.-B. Michel Angiotensin II stimulates the production of NO and peroxynitrite in endothelial cells Am J Physiol Cell Physiol, January 1, 1998; 274(1): C214 - C220. [Abstract] [Full Text] [PDF]
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 E. Thorin, T.-D. Nguyen, A. Bouthillier, and F. M. Faraci Control of Vascular Tone by Endogenous Endothelin-1 in Human Pial Arteries • Editorial Comment Stroke, January 1, 1998; 29(1): 175 - 180. [Abstract] [Full Text] [PDF]
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A. Herizi, B. Jover, N. Bouriquet, and A. Mimran Prevention of the Cardiovascular and Renal Effects of Angiotensin II by Endothelin Blockade Hypertension, January 1, 1998; 31(1): 10 - 14. [Abstract] [Full Text] [PDF]
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M. Barton, L. V. d'Uscio, S. Shaw, P. Meyer, P. Moreau, and T. F. Luscher ETA Receptor Blockade Prevents Increased Tissue Endothelin-1, Vascular Hypertrophy, and Endothelial Dysfunction in Salt-Sensitive Hypertension Hypertension, January 1, 1998; 31(1): 499 - 504. [Abstract] [Full Text] [PDF]
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E. Thorin, S. M. Shreeve, N. Thorin-Trescases, and J. A. Bevan Reversal of Endothelin-1 Release by Stimulation of Endothelial {alpha}2-Adrenoceptor Contributes to Cerebral Vasorelaxation Hypertension, October 1, 1997; 30(4): 830 - 836. [Abstract] [Full Text]
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 P. Moreau, L. V. d'Uscio, S. Shaw, H. Takase, M. Barton, and T. F. Luscher Angiotensin II Increases Tissue Endothelin and Induces Vascular Hypertrophy : Reversal by ETA-Receptor Antagonist Circulation, September 2, 1997; 96(5): 1593 - 1597. [Abstract] [Full Text]
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E. Thorin, M. A. Shatos, S. M. Shreeve, C. L. Walters, J. A. Bevan, and W. G. Mayhan Human Vascular Endothelium Heterogeneity: A Comparative Study of Cerebral and Peripheral Cultured Vascular Endothelial Cells Stroke, February 1, 1997; 28(2): 375 - 381. [Abstract] [Full Text]
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L. V. d'Uscio, P. Moreau, S. Shaw, H. Takase, M. Barton, and T. F. Luscher Effects of Chronic ETA-Receptor Blockade in Angiotensin II-Induced Hypertension Hypertension, January 1, 1997; 29(1): 435 - 441. [Abstract] [Full Text] [PDF]
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S. M. Balakrishnan, H. D. Wang, V. Gopalakrishnan, T. W. Wilson, and J. R. McNeill Effect of an Endothelin Antagonist on Hemodynamic Responses to Angiotensin II Hypertension, November 1, 1996; 28(5): 806 - 809. [Abstract] [Full Text]
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 T. L. Goodfriend, M. E. Elliott, and K. J. Catt Angiotensin Receptors and Their Antagonists N. Engl. J. Med., June 20, 1996; 334(25): 1649 - 1655. [Full Text] [PDF]
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