(Hypertension. 1995;26:332-336.)
© 1995 American Heart Association, Inc.
Articles |
Chronic Nitric Oxide Synthase Inhibition and Carotid Artery Distensibility in Renal Hypertensive Rats
From the Division of Hypertension, University Hospital, Lausanne, Switzerland.
Correspondence to Bernard Waeber, Division of Hypertension, CHUV, CH-1011 Lausanne, Switzerland.
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Abstract |
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Abstract The goal of the present study was to examine the viscoelastic properties of the carotid artery in genetically identical rats exposed to similar levels of blood pressure sustained by different mechanisms. Eight-week-old male Wistar rats were examined 2 weeks after renal artery clipping (two-kidney, one clip [2K1C] Goldblatt rats, n=53) or sham operation (n=49). One half of the 2K1C and sham rats received the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME, 1.48 mmol/L) in their drinking water for 2 weeks after the surgical procedure. Mean blood pressure increased significantly in the 2K1C-water (182 mm Hg), 2K1C–L-NAME (197 mm Hg), and sham–L-NAME (170 mm Hg) rats compared with the sham-water rats (127 mm Hg). Plasma renin activity was not altered by L-NAME but significantly enhanced after renal artery clipping. A significant and similar increase in the cross-sectional area of the carotid artery was observed in L-NAME– and vehicle-treated 2K1C rats. L-NAME per se did not modify cross-sectional area in the sham rats. There was a significant upward shift of the distensibility-pressure curve in the L-NAME– and vehicle-treated 2K1C rats compared with the sham–L-NAME rats. L-NAME treatment did not alter the distensibility-pressure curve in the 2K1C rats. These results demonstrate that the mechanisms responsible for artery wall hypertrophy in renovascular hypertension are accompanied by an increase in arterial distensi-bility that is not dependent on the synthesis of nitric oxide.
Key Words: carotid artery • hypertension, renovascular • nitric oxide • ultrasonography • hypertrophy • nitro compounds
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Introduction |
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The close correlation that exists between vascular structure and BP is well known.1 There is strong evidence that BP itself plays a major role in vascular remodeling,2 but growth factors might also be involved.3 At the level of conductance arteries, a noticeable increase in arterial distensibility and compliance has been recently reported in hypertensive animals4 5 6 and humans5 7 8 9 10 compared with their normotensive counterparts. Further studies11 demonstrated that carotid distensibility was enhanced despite an increase in wall IMT in SHR compared with normotensive WKY. It can be assumed that concurrent changes in composition or organization of the arterial wall are the prerequisite for the development of increased distensibility in the face of vascular wall hypertrophy.12 However, SHR differ from their normotensive counterparts by characteristics other than BP alone.
The aim of this study was to examine the viscoelastic properties of the carotid artery in genetically identical rats exposed to similar levels of BP sustained by different mechanisms. The 2K1C model of hypertension was chosen because of its propensity for developing severe cardiac and vascular hypertrophy. This model was compared with rats made hypertensive by long-term oral administration of the NO synthase inhibitor L-NAME. Furthermore, an additional group of 2K1C rats was treated with L-NAME for assessment of the effect of the combined hypertensive mechanisms on arterial distensibility. The distensibility-pressure curves of the common carotid artery were established in intact rats with the use of an echotracking device combined with intra-arterial BP monitoring.13 14 15 Morphometric examination was carried out for the determination of IMT and CSA of the common carotid artery.
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Methods |
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Male Wistar rats weighing 170 to 210 g were obtained from Iffa-Credo (Lyon, France). Animal care, surgical preparation, and experimental procedures were approved by the Government Review Committee for animal experiments. A clip (0.2-mm ID) was placed on the left renal artery with rats under halothane (Halothane BP, Arovet AG) anesthesia in half of the rats (2K1C, n=53). A sham operation was performed in the other rats (n=49). All rats were housed during 2 weeks at a constant temperature of 23°C. Ordinary rat chow (UAR, A04) containing 100 µmol sodium per gram and drinking fluid were provided ad libitum. One half of the 2K1C rats (n=26) received L-NAME (1.48 mmol/L, Sigma Chemical Co) in their drinking water for the 2 weeks after the surgical procedure (2K1C–L-NAME group), and the remaining 2K1C rats were maintained on tap water for the same period (2K1C-water group, n=27). Sham-operated rats were given either L-NAME (sham–L-NAME group, n=26) or tap water (sham-water group, n=23) for 2 weeks.
The four groups were divided into two subgroups for two distinct experiments. In experiment A, BP, heart rate, plasma sodium, creatinine, and PRA were measured. In experiment B, the viscoelastic properties of the common carotid artery were determined. For the morphometric evaluation of the carotid artery, all rats of both experiments were used.
Experiment A (n=47)
At the end of the two treatment periods an
intra-arterial catheter (PE-50, Portex) was inserted into
the right femoral artery and exteriorized at the back of the neck. This
was done with rats under halothane anesthesia the day
before hemodynamic measurements were performed. On the
study day the awake rats were placed in a plastic tube for partial
restriction of their movements. Intra-arterial pressure and
heart rate were monitored after 1 hour of rest with the use of a
computerized data-acquisition system.16 Blood samples were
then drawn through the arterial line for serial
determinations of PRA and plasma sodium and creatinine
concentrations (1.2, 0.5, and 0.5 mL, respectively). The plasma was
separated immediately and frozen at -20°C until assayed. PRA was
determined by radioimmunoassay of generated Ang I.17 18
Once the samples were obtained, the rats were killed with a lethal dose
(90 mg/kg IV) of pentobarbital (CHUV). The common carotid artery was
pressurized and fixed at 100 mm Hg with the intra-arterial
infusion during 30 minutes of a 4% paraformaldehyde
solution. The left common carotid artery was then excised and processed
for histological examination. Paraffin-embedded tissue
blocks were sectioned at a thickness of 5 µm and stained by
hematoxylin and eosin. Histometric measurements were performed with a
laser-scanned confocal microscope (MRC 500 confocal imaging system,
Bio-Rad). The scanner and detectors were attached to an inverted
microscope (Diaphot, Nikon). IMT and internal diameter measurements
were performed with a 200-fold magnification in a blinded fashion. The
measurements carried out on two carotid sections and six fields per
section were averaged. The intima-media CSA of the fixed arteries was
determined according to the formula CSA=
[(Internal
Radius+IMT)2-(Internal Radius)2]. The heart
was also obtained after the rats were killed. It was washed with
phosphate-buffered saline, squeezed, and fixed with 4%
paraformaldehyde. The left ventricle was dissected
after fixation and weighed.
Experiment B (n=55)
On the day of the experiment anesthesia was given
and maintained with halothane at a concentration of 1.5%. The right
common carotid artery was cannulated with a catheter (PE-50) filled
with a heparinized 0.9% NaCl solution. Intra-arterial
pressure and heart rate were monitored with the use of a computerized
data-acquisition system as described previously.16 The
internal diameter of the left common carotid artery was measured at the
same time with the use of an A-mode ultrasonic echotracking device
(Diarad, Asulab) that has already been used in humans and
animals.5 6 10 19 Briefly, the apparatus
consists of an A-mode ultrasonic echotracking device that measures
variations in the diameter in the common carotid artery with a
precision close to 1 µm. The high resolution reached with this device
is made possible by oversampling (5000 arterial diameter
measurements per second) and averaging 16 consecutive values. A 10-MHz
focalized transducer is placed perpendicular to the
arterial axis using Doppler mode, and an ultrasonic gel
is used for signal transduction. Arterial wall movements
that produce echoes of larger amplitudes than those of surrounding
tissues are visualized on a screen and tagged by electronic tracers.
Ten successive diameter-pressure recordings were determined for
each rat in a given 5-minute period and then averaged for
analysis. The simultaneous arterial
diameter and BP measurements were processed on-line for calculation of
a diameter-pressure relationship, which is subsequently converted into
an arterial cross-sectional compliance-pressure curve
characterized over the entire range of operating BP values. This curve
fits best with an arctangent function described by Langewouters et
al.20 Cross-sectional compliance in the case of a
cylindrical vessel is given by 
S/P, where S is the change in
cross section and P is the change in BP. Arterial
cross-sectional distensibility (D) is the inverse of the Peterson
elastic modulus,21 ie, the compliance value normalized for
the cross section (S). It is defined as D=(1/S)x(S/P).
At the end of the experiment the heart and common carotid arteries were excised, processed, and analyzed as in group A.
Statistical Analysis
Between-groups comparison of body weight, left
ventricular weight index, diameter of the carotid artery in
vitro, CSA, IMT, BP, heart rate, sodium, creatinine, and
PRA was made by one-way ANOVA followed when required by
Scheffé's test. The diameter- and distensibility-pressure curves
were established within operating pressures, the upper and lower limits
representing the mean systolic and diastolic
values for the group, respectively. For the statistical evaluation of
the diameter- and distensibility-pressure curves, two different
approaches were used. The curves were first compared with a
multivariate analysis, based on Hotelling's
T2, considering diameter and
distensibility values at three arbitrarily defined BP values in the
proximity of measured pressures (120, 160, and 200 mm Hg). The
diameter- and distensibility-pressure curves were also statistically
analyzed by comparing the areas under the curves of the
respective groups with a Student's t test for unpaired
data. The areas under the curves were calculated taking the limits of
the overlapping BP ranges between the groups compared as lower and
upper limits. Results are given as mean±SEM.
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Results |
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Part A: Hemodynamics and Hormonal Profile
Table 1 gives the characteristics of the four study groups of conscious rats. Heart rate was not different in the 2K1C rats compared with sham-operated rats. L-NAME given for 2 weeks increased heart rate in both sham (sham–L-NAME) and 2K1C (2K1C–L-NAME) rats.
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Mean intra-arterial pressure was 127±1 mm Hg in sham-water rats (Table 1). Two weeks after renal artery clipping the 2K1C-water rats exhibited a significant elevation of mean BP at 182 mm Hg. In both sham-operated and 2K1C rats the 2-week L-NAME treatment significantly increased mean intra-arterial BP, which reached 170±4 mm Hg in sham–L-NAME rats and 197±5 mm Hg in 2K1C–L-NAME rats. Pulse pressure was increased in both groups of clipped rats. In both sham-operated and clipped rats the 2-week L-NAME treatment did not change the differential BP.
Sham-operated rats maintained on tap water had a PRA of 2.2±0.9 ng Ang I/mL per hour (1 ng/mL per hour=0.77 nmol/L per hour). L-NAME given for 2 weeks had no effect on PRA (Table 1). In clipped rats PRA increased to 23.8±4.0 ng Ang I/mL per hour. L-NAME given to 2K1C rats had no additional effect on PRA (Table 1). Creatinine increased significantly in all hypertensive rats compared with the sham-water rats. Sodium was slightly but significantly decreased in the two groups treated with L-NAME (Table 1).
Part B: Diameter- and Distensibility-Pressure Curves During
Halothane Anesthesia
Table 2 presents BP parameters
during halothane anesthesia. All BP levels during
anesthesia were lower than those in the rats examined awake
after 1 hour of rest (Table 1). Two weeks after clipping the 2K1C-water
rats had a significant elevation of mean BP. In both sham and 2K1C rats
the 2-week L-NAME treatment significantly increased mean BP (Table 2).
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The diameter-pressure curves of the four groups of intact rats (Fig 1) show the expected increase in arterial diameter with the rise of operating intra-arterial pressure. Comparison of the diameter-pressure curves demonstrates a smaller diameter of the carotid artery in the sham–L-NAME and 2K1C–L-NAME rats versus the sham-water rats (P<.05 and P<.01, respectively).
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) or
without (
) NO synthase inhibition and in sham-operated rats
with (
) or without (
) NO synthase inhibition with L-NAME.
Mean±SEM.Fig 2 shows arterial distensibility-pressure curves established in intact rats. Since there is no overlap in operational pressure between normotensive and hypertensive rats, the curves cannot be compared. There was a significant upward shift in the curves of the 2K1C-water and 2K1C–L-NAME rats compared with those of the sham–L-NAME rats, indicating an increased distensibility for a given level of pressure. The difference was significant as assessed either by comparison of the area under the curve (P<.05) or by ANOVA (P<.05).
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Morphometric Analysis
Table 3 depicts the results of the morphometric
studies. There was no difference in internal diameter of the common
carotid artery in the four rat groups. Both IMT and CSA were increased
in 2K1C-water and 2K1C–L-NAME rats compared with sham rats
(P<.05 versus sham-water and sham–L-NAME). L-NAME
administered for 2 weeks did not induce any IMT or CSA increase in
sham-operated or clipped rats. Similar results were obtained with
regard to the left ventricular weight index. Left
ventricular weight index was markedly increased in
2K1C-water and 2K1C–L-NAME rats compared with sham-water and
sham–L-NAME rats (P<.001 versus sham-water and
sham–L-NAME). In sham and 2K1C rats left ventricular
weight index was not modified by 2 weeks of L-NAME treatment.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The aim of the present study was to evaluate the effect of vascular hypertrophy on the geometry, morphology, and viscoelastic properties of the common carotid arteries in genetically identical rats exposed to similar levels of BP sustained by different mechanisms. At the level of conductance arteries a striking increase in arterial distensibility has been recently reported in SHR compared with control WKY,11 despite an increased wall IMT. However, in SHR changes in composition or organization of the arterial wall might precede the development of high BP or may be related to factors other than BP per se, such as genetic characteristics differing from those of WKY. This prompted us to study the viscoelastic properties of hypertrophied vessels in rats with renovascular hypertension (2K1C renal hypertension), ie, a renin-dependent model of hypertension. Cardiac and vascular hypertrophy are known to develop very early in this type of hypertension and may be caused by the high BP per se as well as by the very high levels of Ang II. Our rats developed a severe hypertension within 2 weeks, exhibited a more than 10-fold rise in PRA when compared with sham-operated rats, and produced a significant cardiac and carotid artery hypertrophy. Since there was no overlap in the operating BP values between 2K1C and sham rats, the viscoelastic properties of the carotid artery could not be compared in the range of their respective operating BP values. Indeed, we have previously demonstrated the necessity to compare the viscoelastic properties of conductance vessels at a similar level of BP because distensibility varies in a nonlinear fashion with intra-arterial operating pressure.15
The 0.4-g/L drinking water dose of L-NAME provides a very marked inhibition of NO synthase, as assessed by the persistent blockade of the vasodilator response to acetylcholine in isolated mesenteric arteries taken from rats having received L-NAME in vivo in conditions similar to those described here.22 Blockade of NO synthase during the 2 weeks after the sham operation (sham–L-NAME) increased BP to a level comparable to that of 2K1C rats without modifying renin secretion and without inducing cardiac or carotid artery hypertrophy. These findings are in accordance with previous studies demonstrating a rise in PRA and the development of cardiac hypertrophy after only 4 weeks of NO synthase inhibition.23 The absence of measurable cardiac or vascular hypertrophy in sham–L-NAME rats can be attributed to a slower increase in arterial pressure, a lower pulse pressure, or the absence of activation of the renin-angiotensin system and therefore the lack of a heightened Ang II stimulus on growth. Finally, a growth retardation has to be considered in our rats under L-NAME treatment because the weight gain of the L-NAME–treated rats was lower than that of the control rats. However, the absence of cardiac and vascular hypertrophy after 2 weeks of L-NAME treatment is probably not a direct consequence of this growth retardation. Thus, cardiac hypertrophy can occur despite a reduced weight gain in young rats, as observed after 8 weeks of L-NAME treatment.24 This hypertrophy has been shown to be delayed compared with 2K1C renal hypertensive rats and to be positively correlated with the elevation of PRA, which occurs after several weeks of L-NAME treatment.24 We also gave L-NAME to 2K1C rats to investigate the effect of NO synthase blockade per se on the viscoelastic properties of the carotid artery. When given to 2K1C rats, L-NAME did not increase PRA further and had no influence on the degree of cardiac or carotid hypertrophy.
The internal diameter of the common carotid artery in vivo was reduced in both L-NAME–treated groups (sham–L-NAME and 2K1C–L-NAME rats, Fig 1). This may reflect an enhanced arterial tone under NO synthesis inhibition. However, a confounding factor is that the body weight gain in L-NAME–treated rats was reduced compared with rats having received the vehicle. The difference in arterial diameter therefore might also be accounted for by the difference in growth.
The striking feature of the present study resides in the viscoelastic properties characterizing the carotid artery of renal hypertensive rats. Despite an increased IMT and CSA compared with hypertensive sham-operated rats under NO blockade, this conductance vessel shows a significantly increased distensibility in 2K1C rats. L-NAME given to 2K1C rats did not modify the carotid artery distensibility compared with that of 2K1C-water rats. Thus, NO synthase blockade per se did not alter the carotid artery distensibility of 2K1C rats. Consequently, the difference of distensibility between 2K1C-water and sham–L-NAME rats exclusively results from the vascular growth and remodeling occurring in 2K1C rats. Such an increased distensibility despite an enhanced thickness of the vessel wall implies a decreased elastic modulus of the carotid artery wall, ie, a difference in intrinsic viscoelastic wall properties. The change in the intrinsic mechanical properties of the arterial wall may be consecutive to structural modifications in arterial smooth muscle mass and/or in the ratio of elastin to collagen. This rearrangement could result in an adaptive protective mechanism in renal hypertensive rats because the increased distensibility leads to an increased buffering capacity of the carotid artery wall.
In conclusion, the 2K1C model of renal hypertension is characterized 2 weeks after renal artery clipping by a sustained hypertension, a high level of PRA, and the presence of cardiac and vascular hypertrophy. These characteristics are not altered by NO synthase inhibition. In contrast, there is no hypertrophy of the carotid arterial wall in rats rendered hypertensive by 2 weeks of NO synthase inhibition. Arterial distensibility of the carotid artery is increased in the 2K1C model of hypertension compared with that of rats presenting chronic NO synthase inhibition. These results suggest that in rats with 2K1C hypertension of 2 weeks' duration the carotid artery wall exhibits a thickening accompanied by an increase in distensibility and by deduction a decrease in the incremental elastic modulus.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was supported by grants from the Swiss National Science Foundation.
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