(Hypertension. 1995;26:752.)
© 1995 American Heart Association, Inc.
Articles |
Endothelial AT1–Mediated Release of Nitric Oxide Decreases Angiotensin II Contractions in Rat Carotid Artery
From the Center for Experimental Therapeutics, Baylor College of Medicine, Houston, Tex (C.M.B.), and Institut National de la Santé et de la Recherche Médicale (INSERM), Unité 141, Hôpital Lariboisière, Paris, France.
Correspondence to Chantal M. Boulanger, PhD, INSERM U141, Hôpital Lariboisière, 41, Bd de la Chapelle, F-75475 Paris cedex 10, France.
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Abstract |
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Abstract The purpose of this study was to examine whether angiotensin II (Ang II) stimulates the release of endothelium-derived nitric oxide, which then impairs the contractions of vascular smooth muscle caused by the peptide, and to determine the receptor subtypes mediating these responses. Experiments were performed on isolated rings of rat carotid artery either incubated in the presence of phosphodiesterase inhibitor for the measurement of intracellular levels of cGMP or suspended in organ chambers for recording of changes in isometric force. Ang II (10-7 mol/L) caused a twofold increase in intracellular cGMP level in preparations with but not in those without endothelium. The presence of endothelium impaired the contractions evoked by the peptide and caused approximately 50% inhibition of the maximal response to Ang II (3x10-8 mol/L); pD2 values for Ang II were 8.9±0.1 and 9.6±0.2 in rings with and without endothelium, respectively. In rings with endothelium the contractions to Ang II were augmented by nitro-L-arginine (an inhibitor of nitric oxide synthase) but not indomethacin (an inhibitor of cyclooxygenase), to reach a response comparable to that of preparations without endothelium. In rings without endothelium losartan (a preferential angiotensin type 1 receptor antagonist) displayed competitive antagonism toward Ang II (pA2=9.5); PD 123319 (a preferential angiotensin type 2 receptor antagonist; up to 10-7 mol/L) did not affect the response to the peptide. Losartan (3x10-9 mol/L) but not PD 123319 (10-7 mol/L) impaired the endothelium-dependent component of the response to the peptide. These results suggest that in the rat carotid artery stimulation of an Ang II type 1 receptor causes the release of nitric oxide, which in turn inhibits the contractions to Ang II also mediated by type 1 receptors.
Key Words: angiotensin II • nitric oxide • cyclic GMP • endothelium • losartan
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The response of vascular smooth muscle to contractile agonists may be modulated by endothelial relaxing factors released both under basal conditions and after activation of endothelial receptors.1 2 3 4 The major relaxing factor produced by endothelial cells is NO, or a closely related compound, formed during oxidation of the guanidino-nitrogen atom of L-arginine.5 6 7
Ang II is a potent vasoconstrictor peptide produced by angiotensin-converting enzyme and plays an important role in blood pressure regulation.8 Ang II causes contractions of a number of vascular smooth muscle preparations by activating AT1 receptors9 ; however, the vasoconstrictor response to Ang II shows marked regional differences.10 The heterogeneity in response to Ang II may be due to a different modulatory effect of the vascular endothelium, depending on the preparations and species studied. Indeed, the contractions evoked by Ang II are augmented by the presence of the endothelium in canine basilar and cerebral arteries and in the aorta of rat with coarctation-induced hypertension.11 12 13 However, in rat and rabbit aortas and in the porcine femoral, bovine coronary, and canine mesenteric arteries, the presence of endothelium impairs the contractions evoked by Ang II.13 14 15 16 17 In other blood vessels, such as the bovine intrapulmonary artery and vein, the response to the peptide is not affected by the presence of the endothelium.15 Endothelium-dependent relaxations to Ang II have been reported in the fowl aorta18 and in canine renal and cerebral arteries.19 In addition, Ang II degradation products evoke endothelium-dependent relaxations in rat and rabbit cerebral arterioles, presumably after activation of AT2 receptor subtypes.20 21 22
Although the contractions evoked by Ang II are impaired by endothelium-derived NO,13 16 17 23 it is uncertain whether this impairment is due to the basal release of NO or to stimulation of the endothelial cells by Ang II. The hypothesis that Ang II causes the release of endothelium-derived NO is supported by the observations that endothelial cells express angiotensin receptors24 25 26 and that Ang II causes the release of endothelial vasoactive factors other than NO (such as prostacyclin and endothelin27 28 ). In addition, in a cultured endothelial cell line Ang II augments the intracellular level of cGMP, suggesting that the peptide may stimulate NO release.29 30 Furthermore, Ang II causes an endothelium-dependent increase in cGMP in isolated rat carotid artery.31
The purpose of the present study was to examine in the rat carotid artery whether Ang II–stimulated NO release impairs the direct contractile effect of the peptide and if so to determine the receptor subtypes mediating these responses.
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Methods |
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Experiments were performed on the common carotid artery of normotensive Wistar-Kyoto rats (10 to 12 weeks old; 260 to 290 g; Harlan Sprague Dawley, Inc, Indianapolis, Ind). All procedures were in accordance with the guidelines of the Animal Protocol Review Committee of Baylor College of Medicine. Systolic arterial pressure was measured by the tail-cuff method and averaged 140±1 mm Hg (n=68). Rats were anesthetized with pentobarbital sodium (50 mg/kg IP). The common left and right carotid arteries were dissected free, excised, and placed in modified Krebs-Ringer bicarbonate solution of the following composition (mmol/L): NaCl 118.3, KCl 4.7, MgSO4 1.2, KH2PO4 1.2, CaCl2 2.5, NaHCO3 25.0, calcium disodium edetate (EDTA) 0.026, and glucose 11.1 (control solution). Blood vessels were cleaned of adherent connective tissue and cut into rings (5 to 6 mm long). In some preparations the endothelium was removed by gentle rubbing of the intimal surface with the tip of a pair of small forceps. In the remaining rings care was taken not to touch the inner surface of the blood vessel.
cGMP Measurements
Rings with and without endothelium were
incubated in control solution (37°C, 60 minutes) gassed with a
mixture of 95% O2/5% CO2 in the
presence of isobutylmethylxanthine
(10-4 mol/L; a nonspecific
inhibitor of phosphodiesterases). The preparations were
then exposed to either Ang II (10-7
mol/L) or solvent (distilled water) for 1 minute and immediately frozen
in liquid nitrogen. The preparations were homogenized in
trichloroacetic acid (6%) and centrifuged for 15 minutes at
2000g. The supernatant was extracted with 4 vol
water-saturated ether and lyophilized. The cGMP content of each
sample was determined after acetylation with a cGMP
125I assay system (Amersham) and is expressed as femtomoles
per milligram tissue.
Organ Chamber Experiments
Rings with and without endothelium were
suspended horizontally between two stainless steel wires in organ
chambers that contained 25 mL control solution (37°C) aerated with
95% O2/5% CO2. The preparations were
connected to force transducers (Scaime) for recording of
isometric force. Before experimentation the rings were stretched
progressively and exposed to KCl (40 mmol/L) at each level of force
until the optimal point of the length–active force relationship
was reached (rings with endothelium: 1.50±0.02 g,
n=42; without endothelium: 1.48±0.02 g, n=62). After
the procedure the rings were allowed to equilibrate for 30 minutes. All
rings were then exposed to phenylephrine
(3x10-5 mol/L) for determination
of their maximal responsiveness. Experiments were performed in parallel
rings with and without endothelium. The incubation
period for losartan, PD 123319, indomethacin,
and aminoguanidine was 45 minutes before the concentration-response
curve to Ang II was obtained. NLA and dexamethasone were
added to the preparations (with or without endothelium)
30 minutes before stretching. NLA and dexamethasone did not
significantly affect the optimal point of the length–active force
relationship of rings with endothelium (data not
shown). The presence or absence of functional
endothelial cells was confirmed by the presence or
absence, respectively, of a relaxation to acetylcholine
(10-6 mol/L) during contraction
evoked by prostaglandin F2
(1 to
2x10-6 mol/L).32 In
rings exposed to NLA the presence or absence of
endothelium was confirmed by histology (data not
shown).
Drugs
The followings drugs were used: acetylcholine HCl, Ang II, Ang
III, dexamethasone, 5-hydroxytryptamine
(serotonin), indomethacin,
isobutylmethylxanthine, and
phenylephrine (Sigma Chemical Co); Ang-(1-7) (Bachem
Biosciences Inc); endothelin-1 (Peninsula Laboratories Inc); NLA
(Aldrich Chemical Co); prostaglandin
F2 (Upjohn Co); and losartan (DuP
753; DuPont). PD 123319 was a kind gift from Dr J.P. Vilaine (Institut
de Recherches Servier, Suresnes, France). Drug concentrations are
expressed as final molar concentrations in the bath solution. Drugs
were prepared daily in distilled water, except for
indomethacin, which was dissolved in distilled water
containing Na2CO3
(3x10-5 mol/L) and sonicated
before use, and isobutylmethylxanthine stock
solution (0.1 mol/L), which was prepared in pure dimethyl sulfoxide and
further diluted in control solution. A stock solution of Ang II (1
mmol/L) was prepared in distilled water and frozen in aliquots
(-20°C).
Statistical Analysis
Results are given as mean±SEM. Data are expressed as percentage
of the contraction evoked by phenylephrine
(3x10-5 mol/L); n
represents the number of rats used. The pD2 values
represent the negative logarithm of the concentration of Ang II
that elicits 50% of the contraction to phenylephrine.
Experiments with Ang II antagonists (losartan and PD 123319) were performed on rings from the same rat studied in parallel. The pA2 value (estimates of the equilibrium dissociation constant) for losartan was determined from the graph of log concentration ratios minus 1 (CR-1) versus log concentration of the antagonist.33 CR is defined as the concentration of angiotensin required to induce 50% of the response to phenylephrine in the presence of losartan divided by the concentration of Ang II that elicits the same degree of response in the absence of the antagonist. The pA2 value was calculated only if the slope of the plot was not significantly different from unity.
Subtraction of the data obtained in paired rings with and without endothelium from the same artery was performed for evaluation of the endothelium-dependent component of the response to Ang II; this was done either under control conditions or in the presence of angiotensin receptor antagonists.34
Statistical evaluation was done by Student’s t test for paired and unpaired observations. When more than two means were compared, a two-way ANOVA was used, followed by a Bonferroni test (GRAPHPAD, Instate Software).35 Means were considered significantly different at a value of P<.05.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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cGMP Measurements
The intracellular level of cGMP was significantly greater in preparations with endothelium than in those without (Fig 1). Exposure to Ang II (10-7 mol/L) for 1 minute increased the cGMP content of carotid arteries with but not of those without endothelium (Fig 1).
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Organ Chamber Experiments
Effect of the Endothelium
In quiescent preparations the presence of
endothelium significantly impaired the
concentration-dependent contractions caused by Ang II
(10-12 to
10-7 mol/L) (Fig 2). The pD2 value for Ang II
was significantly smaller in preparations with
endothelium than in those without (8.9±0.1 and
9.6±0.2, respectively; n=6). The impairment by the
endothelium of the maximal response to agonists was
observed with Ang II but not with endothelin-1 or serotonin
(Table 1).
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In rings with endothelium the contractions evoked by Ang II were augmented significantly by NLA (10-4 mol/L; an inhibitor of NO synthase) but not by indomethacin (10-5 mol/L; an inhibitor of cyclooxygenase) (Fig 2). The pD2 value and maximal response to Ang II in rings with endothelium exposed to NLA were 9.6±0.2 and 130.4±15.1%, respectively (n=6), and were not significantly different from those of control preparations without endothelium (Table 2). Neither aminoguanidine (10-6 mol/L; a preferential inhibitor of the inducible form of NO synthase36 ) nor NLA affected the response to Ang II in preparations without endothelium (Table 2). Dexamethasone (10-6 mol/L; to prevent induction of NO synthase37 ) impaired moderately but significantly the maximal response to Ang II but did not affect the pD2 value to the peptide (Table 2).
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Ang II, Ang III, and Ang-(1-7) (all from
10-13 to
10-7 mol/L) did not cause
relaxations of rings with or without endothelium during
contractions to prostaglandin F2
(10-6 mol/L; causing approximately
50% of the contraction to 3x10-5
mol/L phenylephrine; n=4; data not shown).
Angiotensin Receptor Subtype on Vascular Smooth
Muscle
In rings without endothelium losartan
(10-8 to
3x10-7 mol/L; a preferential
AT1 receptor antagonist) caused a parallel
rightward displacement of the contraction-response curve to Ang II
without affecting the maximal response to the peptide (Fig 3). The slope of the Arunlakshana-Schild
plot was not different from unity (slope=1.003; n=6), and the
pA2 value for losartan was estimated to be 9.5±0.2
(n=6). PD 123319 (10-8 and
10-7 mol/L; a preferential
AT2 receptor antagonist) did not significantly
affect the response to Ang II in preparations without
endothelium (Table 3).
However, higher concentrations of PD 123319
(10-6 mol/L; a concentration
affecting AT1 receptors9 38 ) caused a
significant rightward displacement of the concentration-response
curve to Ang II (Table 3). Neither losartan nor
PD 123319 (up to 10-6 mol/L)
affected the basal tension of rings without endothelium
of rat carotid arteries (data not shown).
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Endothelial Angiotensin Receptor
Subtype
The effect of losartan
(3x10-9 mol/L) on the response to
Ang II was examined in quiescent rings with and without
endothelium. Losartan caused a significant
rightward shift of the concentration-response curve to the peptide
in rings both with (pD2 control: 9.2±0.2; with
losartan: 8.2±0.1; n=6) and without (pD2 control:
9.6±0.1; with losartan: 8.9±0.1; n=6)
endothelium but did not affect the maximal response to
the peptide (data not shown). The difference in pD2 values
between control and losartan-treated preparations was not
affected by the presence of endothelium (with:
1.0±0.2; without: 0.7±0.1; P=NS). The
endothelium-dependent inhibitory
component of the response to Ang II was estimated to be the difference
in response between preparations with and those without
endothelium34 ; this was assessed under
control conditions and in the presence of losartan
(3x10-9 mol/L) (Fig 4). The maximal inhibitory
effect of the endothelium was observed at
3x10-9 mol/L Ang II and reached
approximately 50% of the contraction to phenylephrine
(3x10-5 mol/L) (Fig 4). Losartan
(3x10-9 mol/L) significantly
impaired the endothelial component of the response to
low concentrations of Ang II
(3x10-11 and
10-10 mol/L).
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The preferential angiotensin AT2 receptor antagonist PD 123319 (10-8 and 10-7 mol/L) did not affect the response to the peptide in preparations without or with endothelium (Table 3); at these concentrations, PD 123319 did not affect significantly the endothelial inhibitory component of the response to Ang II (Fig 4). However, a higher concentration of PD 123319 (10-6 mol/L; not preferentially selective for the AT2 receptor subtype38 ) caused a significant rightward shift of the contraction response to Ang II in preparations without endothelium, without affecting the maximal response (Table 3). In rings with endothelium PD 123319 (10-6 mol/L) significantly augmented the maximal response to Ang II (from 50.5±5.1% to 71.9±6.1%, n=6) without affecting the pD2 values (control: 9.0±0.1; with PD 123319: 9.0±0.1; n=6), whereas PD 123319 (10-6 mol/L) significantly impaired the endothelial component of the response to high concentrations of Ang II (from 10-10 to 3x10-9 mol/L) (Fig 4).
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Discussion |
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The present study shows that in the rat carotid artery contractions to Ang II are decreased by an AT1-stimulated release of endothelium-derived NO. This conclusion is based on the observation that in the rat carotid artery the presence of the endothelium significantly shifted to the right the concentration-response curve to Ang II and decreased the maximal response to the peptide. This impairment was not mediated by relaxing prostaglandins because an inhibitor of cyclooxygenase was without effect on the response to Ang II.38 However, the endothelial impairment of the contraction to Ang II was abolished by NLA, an inhibitor of NO synthase.39 A contribution of NO formed after induction of NO synthase in the vessel wall under the present experimental conditions can be ruled out because aminoguanidine, a preferential inhibitor of the inducible form of NO synthase, and dexamethasone, a glucocorticoid that prevents the induction of NO synthase, did not augment the response to Ang II.36 37 40 Therefore, the impairment by the presence of endothelial cells of the response to Ang II observed in the present study may be mediated by the constitutive endothelial NO synthase.13 16 17 23
In the rat carotid artery Ang II likely activates the endothelial NO synthase. Indeed, the peptide causes an endothelium-dependent increase in cGMP as observed for other endothelium-dependent agonists,41 42 thus confirming our previous preliminary observations.31 This conclusion is supported further by the finding that angiotensin receptor antagonists impaired the endothelium inhibitory component of the response to the peptide, suggesting that Ang II activates endothelial receptors to release NO. The fact that Ang II failed to induce endothelium-dependent relaxations in the rat carotid artery could imply that the stimulated release of endothelium-derived NO by Ang II is not potent enough to overcome the strong direct contractile effect of the peptide on the smooth muscle. A selective blockade of the angiotensin receptor(s) on vascular smooth muscle could unmask an endothelium-dependent relaxation in this preparation; however, this is unlikely because the response to Ang II of isolated rat carotid artery appears to be mediated by activation of AT1 receptors on both endothelial and vascular smooth muscle cells.
Indeed, in preparations without endothelium the preferential nonpeptidic AT1 receptor antagonist losartan displayed a competitive antagonism toward the response to Ang II, with a pA2 value in the range of that reported for AT1 receptor subtypes.9 43 This interpretation is reinforced further by the absence of effect of PD 123319, a preferential AT2 receptor antagonist, at concentrations selective for the AT2 binding site.9 38 A similar conclusion may be reached for the endothelial angiotensin receptor mediating NO release from rat carotid artery, although both AT1 and AT2 receptor subtypes are expressed in cultured endothelial cells from the rat coronary artery.26 Indeed, the present study shows that the endothelial inhibitory component of the response to Ang II is impaired by losartan at concentrations selective for the AT1 receptor subtype. The observation that losartan caused a comparable shift of pD2 in rings with and without endothelium is consistent with the finding that the antagonist impaired the endothelial inhibitory component only at low Ang II concentrations. The sensitivity of this endothelial response to Ang II to a low losartan concentration suggests that the endothelial receptor is of the AT1 subtype. This interpretation is also supported by the absence of effect of the AT2 receptor antagonist PD 123319 in a range of concentrations preferentially affecting this receptor subtype.9 38 Further studies investigating Ang II receptor subtypes expressed by endothelial cells in the rat carotid artery may reinforce this interpretation.
In conclusion, the present study suggests that the response of rat carotid arteries to Ang II results from the combined activation of endothelial and smooth muscle AT1 receptors. The endothelium-dependent production of NO on stimulation of AT1 receptors likely contributes to the impairment of the direct vasoconstriction caused by the peptide. This effect may favor blood flow when plasma levels of Ang II are elevated. The stimulated release of NO may also downregulate the endothelial production of the potent vasoconstrictor peptide endothelin induced by Ang II.28 44 45 46 Finally, the Ang II–induced release of NO may interact with the long-term effect of the peptide on vascular remodeling because this endothelial mediator has antiproliferative effects on vascular smooth muscle.47 48
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was supported in part by a grant from the National Institutes of Health (HL-35614), an IRIS-INSERM grant, and a grant-in-aid from the "Fondation pour la Recherche Medicale" (Paris, France). The authors wish to thank Drs Jean-Vivien Mombouli and Paul M. Vanhoutte for stimulating discussion, Dr Jean Paul Vilaine for kindly supplying PD 123319, and Barnabas Desta and Nusret Didzik for superb technical assistance.
Received March 27, 1995; first decision May 10, 1995; accepted May 16, 1995.
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