(Hypertension. 1996;27:25-31.)
© 1996 American Heart Association, Inc.
Articles |
Antihypertensive Therapy Prevents Endothelial Dysfunction in Chronic Nitric Oxide Deficiency
Effect of Verapamil and Trandolapril
From Cardiology and Cardiovascular Research, University Hospital, Bern, Switzerland.
Correspondence to Thomas F. Lüscher, MD, Professor of Medicine, Cardiology, University Hospital, Inselspital, CH-3010 Bern, Switzerland.
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Abstract |
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Abstract The objective of this study was to examine the effects of long-term antihypertensive therapy on blood pressure and vascular responses of resistance arteries during prolonged inhibition of nitric oxide synthesis. Four groups of 6-week-old Wistar-Kyoto rats were treated with either placebo as controls or N
-nitro-L-arginine methyl ester
(L-NAME) alone or in combination with verapamil or with
trandolapril. Drugs were given orally for 6 weeks or short-term in
vitro to vessels obtained from untreated rats.
Endothelium-dependent and -independent relaxations
as well as contractions were studied in isolated perfused mesenteric
and renal arteries with an arteriograph. Kidney nitric oxide synthase
activity was also evaluated. Verapamil and trandolapril
prevented the increase in systolic blood pressure and the
blunted acetylcholine-induced relaxations that occurred with L-NAME
treatment without improving the nitric oxide synthase activity. Both
antihypertensive regimens also normalized sensitivity to sodium
nitroprusside, which was enhanced by L-NAME. In contrast,
short-term in vitro preincubation with verapamil or
trandolaprilat in the presence of L-NAME did not improve the impaired
relaxations to acetylcholine. Long-term but not short-term
therapy with a calcium antagonist or
angiotensin-converting enzyme inhibitor
improved the blunted endothelium-dependent
relaxations in nitric oxide–deficient hypertension. These findings
strongly suggest that the role of other vasodilator systems, which
normally do not regulate vascular tone, is enhanced with long-term
but not short-term treatment with these drugs. These observations
emphasize the potential importance of these treatments in the
management of hypertension in which nitric oxide production is
diminished.
Key Words: L-NAME • nitric oxide • antihypertensive therapy • endothelium-derived relaxing factors
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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NO is a widespread mediator of cell communication that plays a crucial role in the regulation of vascular tone and blood pressure.1 2 NO is synthesized from L-arginine by a family of NO synthases that are competitively inhibited by different L-arginine analogs.1 3 NO is released under both basal4 and stimulated conditions by a variety of humoral substances5 and by mechanical forces such as shear stress and blood flow.6 The in vitro administration of L-arginine analogues leads to the inhibition of endothelium-dependent relaxations induced by a variety of vasodilators.3 7 Furthermore, the short-term and long-term in vivo administration of NO synthase inhibitors produces an elevation in arterial pressure and increase in peripheral vascular resistance,4 8 9 indicating that NO is basally released and regulates vascular tone and blood pressure. Recent studies have shown that long-term oral administration of L-arginine analogues induces a dose- and time-dependent hypertension accompanied by bradycardia.10 11 12 13 The prolonged blockade of NO synthesis by long-term oral administration of these drugs provides a new experimental model of hypertension useful to study the effects of antihypertensive therapy on endothelial function.
Impaired endothelium-dependent relaxations occur in experimental models14 15 16 17 as well as in human essential hypertension.18 19 20 In human hypertension, basal NO production seems to be diminished,18 19 21 whereas recent evidence from our laboratory indicates that in genetic hypertension, the production of NO is higher than normal, but it is inefficient in maintaining the vasodilator tone.22 Antihypertensive therapy improves endothelial function in different models of hypertension.14 23 24 ACE inhibitors and calcium antagonists appear to be particularly effective in spontaneously hypertensive rats.23 24 25 Since these antihypertensive agents prevent the increase in blood pressure in NO-deficient hypertension,13 26 27 28 we were interested in determining whether their antihypertensive effect could be due to an improvement of the endothelial function. We investigated the effects of long-term treatments with two antihypertensive drugs, the calcium antagonist verapamil and the ACE inhibitor trandolapril, on blood pressure, endothelial function, and NO synthase activity in mesenteric and renal resistance arteries from L-NAME–induced hypertensive rats.
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Methods |
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TopAbstractIntroductionMethods Results Discussion References |
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Animal Preparation
Thirty-two 6-week-old male Wistar-Kyoto rats were obtained from IFFA CREDO (L'Arbresle, France) and randomly divided into the following four groups (8 rats in each group): (1) placebo (control), (2) L-NAME, (3) L-NAME plus verapamil, and (4) L-NAME plus trandolapril. The placebo group received normal chow and tap water. L-NAME and trandolapril were dissolved in the drinking water at concentrations of 50 mg/100 mL and 1 mg/100 mL, respectively, and a verapamil solution was sprayed on powdered chow (100 mg/100 g chow). The actual dose given for each drug was calculated according to the water or food intake measured three times weekly. The average intake of L-NAME in the L-NAME, L-NAME plus verapamil, and L-NAME plus trandolapril groups was 58±1, 54±1, and 61±1 mg·kg-1·d-1, respectively. The respective antihypertensive treatment groups received an average of 108±6 mg·kg-1·d-1 of verapamil and 1.2±0.1 mg·kg-1·d-1 of trandolapril. The treatments were performed for 6 weeks and were discontinued 2 or 3 days before the in vitro experiment so as to limit the short-term effects of the antihypertensive drugs. Before the treatments were started and each week thereafter, the rats were weighed and their systolic blood pressure and heart rate were measured by a tail-cuff method using a pulse transducer (model LE 5000, Letica). The average of three measurements was taken on each occasion.
Vessel Preparation
The rats were anesthetized with thiopental
sodium (50
mg/kg IP) and exsanguinated by decapitation. The mesentery and one
kidney were removed and immersed in a cold Krebs' solution of the
following composition (in mmol/L): NaCl 118.6, KCl 4.7,
CaCl2 2.5, KH2PO4 1.2,
MgSO4 1.2, NaHCO3 25.1, edetate calcium
disodium 0.026, and glucose 10.1. Segments 2 mm long of the second or
third branch of the mesenteric artery and of the interlobar renal
artery were isolated under a dissection microscope (intraluminal
diameters of both arteries, 170 to 280 µm). The artery was then
transferred to an arteriograph chamber filled with warmed
(37±0.5°C)
and oxygenated (95% O2/5%
CO2) Krebs' solution circulating from a 250-mL
oxygenated reservoir at a flow rate of 50 mL/min. The
chamber contained two glass microcannulas: one was fixed to the chamber
(efferent cannula), and the other was mounted on a manipulator to
facilitate positioning of the vessel (afferent cannula). The proximal
end of the artery was mounted on the afferent cannula and secured with
a surgical nylon suture (diameter, 50 µm). The distal end of the
vessel was positioned inside the efferent cannula as previously
described.17 The artery was then perfused intraluminally
with Krebs' solution containing 1.0% BSA and equilibrated under a
constant optimal perfusion pressure of 30 mm Hg for 45 minutes before
the experiments. The arteriographic chamber was placed on the stage of
a microscope equipped with a video camera attached to the viewing tube.
The signal derived from the video image of the vessel was processed by
a video dimension analyzer (Living Systems Instrumentation) for
continuous measurement and recording of the intraluminal
diameter.
Protocols
The intraluminal diameters of mesenteric and renal
arteries were
measured at the end of the equilibration period. The following
protocols were used in both the mesenteric and renal arteries. All
drugs were administered extraluminally, and each protocol was separated
by a 45-minute washout period. After an equilibration period, a
concentration-response curve to norepinephrine
(10-9 to
3x10-5 mol/L) was performed, followed by
concentration-response curves to acetylcholine
(10-10 to
3x10-5 mol/L) and sodium nitroprusside
(10-10 to
3x10-5 mol/L) in preparations
half-maximally precontracted with norepinephrine
(2x10-6 mol/L in mesenteric arteries,
2x10-7 to
10x10-7 mol/L in renal arteries). Then,
a concentration-response curve to endothelin-1
(10-11 to
3x10-8 mol/L) was obtained, and at the
top of this contraction, a single concentration of
L-arginine (10-4 mol/L) was
administered. Additionally, in a separate set of experiments using
mesenteric and renal arteries from untreated Wistar-Kyoto rats, we
studied the short-term effects of the two antihypertensive agents.
The vessels were preincubated with verapamil
(10-5 mol/L) or trandolaprilat (the
active form of trandolapril, 10-7 mol/L)
in the presence of L-NAME (10-4 mol/L)
for 30 minutes before acetylcholine-induced relaxation was
performed.
NO Synthase Activity
The contralateral kidney was removed
from each rat of all four
groups after the 6 weeks of treatment, immediately frozen in liquid
nitrogen, and then stored at -70°C until it was used for the
measurement. The frozen kidneys were homogenized in 3 vol
containing (in mmol/L): sucrose 320, Trizma base 50, edetate calcium
disodium 1, DL-dithiothreitol 1, leupeptin 0.019, and
phenylmethylsulfonyl fluoride 0.57 and (in µg/mL): soybean
trypsin inhibitor 10 and aprotinin 2, brought to pH 7 with
HCl. The homogenates were centrifuged at
12 000g for 20 minutes. NO formation was measured in the
supernatant by the rate of conversion of radiolabeled
[14C]L-citrulline from
[14C]L-arginine, as previously
described.29 30 Briefly, tissue extracts were
incubated in
a buffer containing, in mmol/L: potassium phosphate 50,
L-valine 60, NADPH 0.012, L-citrulline 1.2,
L-arginine 0.024, magnesium chloride 1.2, and calcium
chloride 0.24 and L-[14C]arginine (ul)
150 000 dpm (pH 7). Duplicate incubations were performed for 10
minutes at 37°C for each sample in the presence or absence of either
EGTA (1 mmol/L) or EGTA plus L-NAME (1 mmol/L each) to determine the
level of the Ca2+-dependent (constitutive) and
Ca2+-independent (inducible) NO synthase activities,
respectively. [14C]L-citrulline in the
supernatant was separated from
[14C]L-arginine by addition of a Dowex-50W
resin. Both interassay and intra-assay coefficients of variation
are less than 8%.
Drugs
Verapamil, trandolapril, and trandolaprilat were
kindly provided by Dr J. Griess and Dr M. Kirchengast of Knoll
Pharmaceuticals. All the following drugs were dissolved in distilled
water and diluted with Krebs' solution: acetylcholine chloride,
L-arginine, (-)-norepinephrine
bitartrate, sodium nitroprusside, and L-NAME (Sigma Chemical Co).
Endothelin-1 (Calbiochem-Novabiochem AG) was dissolved in distilled
water containing 0.1% BSA and then diluted with Krebs' solution
containing 0.05% BSA. Trandolaprilat was dissolved in slightly basic
aqueous solution and diluted with Krebs' solution. For NO synthase
activity measurement, all compounds were purchased from Sigma except
[14C]L-arginine monohydrochloride (ul) (318
mCi/mmol, Amersham Laboratories).
Calculations and Statistical Analysis
The contractions of the
vessels were expressed as a percentage
of the decrease in the basal intraluminal diameter, taken as 100%. The
relaxations were expressed as a percentage of the increase in
intraluminal diameter from the diameter obtained after precontraction
with either norepinephrine or endothelin-1. Data are
expressed as mean±SEM. The concentrations of the agonists causing
half-maximal response (EC50 value) and the maximal
response were calculated for both the contractions and relaxations
using a nonlinear regression analysis. The EC50
values were expressed as the negative logarithm of the molar
concentration (pD2 value). The pD2 values and
maximal responses were compared by one-way ANOVA with Bonferroni's
correction for multiple comparisons.31 The
concentration-response curves of the different groups were compared
by ANOVA for repeated measurements, with Bonferroni's correction to
compare the different groups. Where appropriate, a paired or unpaired
t test was used. A value of P<.05 was considered
significant.
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Results |
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TopAbstractIntroductionMethods Results Discussion References |
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Blood Pressure, Heart Rate, and Body Weight
The changes in systolic blood pressure, heart rate, and body weight are summarized in Table 1
. L-NAME treatment
alone markedly increased systolic blood pressure, whereas heart
rate was decreased. The increase in systolic blood pressure
produced by L-NAME was prevented by concomitant therapy with
verapamil or trandolapril. The bradycardia induced by
L-NAME was enhanced by these antihypertensive agents.
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All four groups
gradually gained weight during the 6 weeks of treatment
(Table 1
). However, at the end of treatment, the body weights
of both
the L-NAME plus verapamil and L-NAME plus trandolapril
groups were significantly lower than that of the control group, whereas
L-NAME treatment itself did not affect body weight significantly.
NO Synthase Activity
L-NAME treatment reduced the activity of
the constitutive NO
synthase in the kidney compared with the control group (59±18 and
133±17
pmol·min-1·g-1,
respectively; P<.05). Neither verapamil nor
trandolapril treatment modified the effects of L-NAME treatment on the
activity of the enzyme (42±17% and 52±23%, respectively;
P=NS versus L-NAME group) (Fig 1). No
inducible NO synthase activity was found in any group (data not
shown).
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Endothelium-Dependent Relaxations
In mesenteric arteries
half-maximally contracted with
norepinephrine, acetylcholine
(10-10 to
3x10-5 mol/L) elicited
concentration-dependent relaxations that were blunted by
long-term treatment with L-NAME (Table 2 and Fig
2a). Verapamil and trandolapril prevented
this inhibition of the relaxation induced by long-term L-NAME
treatment. In another set of experiments, mesenteric arteries obtained
from untreated rats were preincubated in vitro with L-NAME
(10-4 mol/L) alone or in the presence of
verapamil (10-5 mol/L) or
trandolaprilat (10-7 mol/L) for 30
minutes. Concentration-response curves to acetylcholine were then
performed and compared with a control response (without any
preincubation). Relaxations to acetylcholine were not improved by
short-term in vitro preincubation with the antihypertensive drugs
(Fig 2b).
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P<.05 vs L-NAME group (ANOVA+Bonferroni).
In renal arteries, L-NAME treatment also
inhibited
acetylcholine-induced relaxations, and this effect of L-NAME was
prevented by both antihypertensive regimens (Table 2 and Fig
3a). In each of the treatment groups, however, the
responses to acetylcholine were less pronounced in renal than in
mesenteric arteries. Short-term in vitro treatment of renal
arteries incubated with L-NAME (10-4
mol/L) with either verapamil
(10-5 mol/L) or trandolaprilat
(10-7 mol/L) for 30 minutes did not
affect endothelium-dependent relaxations to
acetylcholine (Fig 3b).
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In mesenteric resistance
arteries, a single concentration of
L-arginine (10-4 mol/L)
evoked a relaxation of preparations maximally contracted by
endothelin-1. The relaxation of the L-NAME group was greater than that
of the control group (P<.05), whereas in the two groups
receiving antihypertensive treatments, this response did not differ
from the control group (Table 2). A similar pattern of
responses to
L-arginine was obtained in the renal arteries of the four
different treatment groups, although trandolapril had a more important
effect than verapamil in normalizing this response in this
vascular bed (Table 2).
Endothelium-Independent Relaxations
Long-term L-NAME
treatment significantly increased the
sensitivity (pD2 value) of mesenteric resistance arteries
to sodium nitroprusside (10-10 to
3x10-5 mol/L) compared with the control
group (P<.05), whereas the sensitivities in both the L-NAME
plus verapamil and L-NAME plus trandolapril groups were
comparable to those of untreated animals (Table 2). The maximal
responses of mesenteric arteries to sodium nitroprusside were similar
in all groups.
In renal arteries, the sensitivity (pD2
value) to sodium
nitroprusside also tended to be enhanced by L-NAME treatment
(P=NS versus control), whereas the two antihypertensive
regimens decreased the sensitivity (Table 2). The maximal
responses to
sodium nitroprusside in the three different treatment groups were
greater than in the control group. The responses to sodium
nitroprusside of the control groups were not significantly different
between renal and mesenteric arteries.
Contractions
In mesenteric arteries, norepinephrine
(10-9 to
3x10-5 mol/L) evoked similar
concentration-dependent contractions in all the groups (Table
3). In renal arteries, the responses to
norepinephrine (10-9 to
10-5 mol/L) were not different among the
groups (Table 3). In the control groups, the renal arteries
were more
sensitive to norepinephrine than the mesenteric arteries,
but the maximal responses were similar (Table 3).
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Although long-term L-NAME treatment by itself did not alter the
responses of mesenteric arteries to endothelin-1
(10-11 to
3x10-8 mol/L), the maximal responses of
both the L-NAME plus verapamil and L-NAME plus trandolapril
treatment groups were slightly greater than that of the control group
(Table 3). This pattern of endothelin-1–induced
contractions was
similar in renal arteries, whereas the responses in the control groups
were less sensitive and efficacious in renal than in mesenteric
arteries (Table 3).
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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The present study shows that the increase in blood pressure and the impaired endothelium-dependent relaxation to acetylcholine in both small mesenteric and renal arteries caused by a prolonged inhibition of NO synthesis can be prevented by long-term treatment with verapamil or trandolapril. In contrast, short-term incubation of the blood vessels with these two antihypertensive agents could not prevent the endothelial impairment produced by a short-term blockade of NO synthase.
Endothelium-dependent relaxations are impaired in hypertension,32 and the ability of NO to maintain vascular tone has been shown to be deficient in this condition.8 22 Long-term inhibition of NO synthesis represents a new model of hypertension that creates a status of selective NO deficiency.11 12 13 18 19 21 Our present experiments show that blood pressure is increased and endothelium-dependent relaxations to acetylcholine in small mesenteric and renal arteries are blunted by long-term L-NAME treatment. Furthermore, we demonstrate that L-NAME treatment inhibits the constitutive NO synthase activity in the kidney, suggesting that the impaired endothelium-dependent relaxations to acetylcholine are related to a decreased formation of NO. An increased contractility of vascular smooth muscle or a reduced responsiveness to NO can be excluded, because the responses to norepinephrine and endothelin-1 were unaltered, whereas that to sodium nitroprusside actually tended to be enhanced.
The most intriguing observation of our study is that prolonged treatment with verapamil or trandolapril could prevent the increase in blood pressure caused by the loss of NO-dependent vasodilator tone. Since a reduction in blood pressure is not sufficient to improve endothelial function in hypertensive humans33 and rats,24 our findings suggest that the vasculature can compensate for a failure in the production of NO, possibly through alternative vasodilatory mechanisms. Several possible mechanisms for this effect can be considered. It is known that ACE inhibitors reduce the formation of angiotensin II and prevent the degradation of bradykinin,34 35 an endothelium-dependent relaxant that works by stimulating the release of NO.36 On this basis, it has been suggested that part of the antihypertensive action of ACE inhibitors is mediated by NO.37 38 In this model of hypertension, however, the production of NO is selectively inhibited, and trandolapril still reduces blood pressure. Furthermore, the beneficial effect of trandolapril is still present in vitro, whereas the influence of endogenous bradykinin is probably very limited. Alternative mechanisms (see below) may therefore operate either with or without an involvement of bradykinin.
The constitutive NO synthase is calcium dependent, and calcium antagonists may reduce the activity of this enzyme by blocking calcium influx into endothelial cells.39 However, this effect does not seem to be additive to the inhibition of the enzyme by L-NAME, as suggested by the direct measurement of NO synthase activity. Furthermore, this mechanism is not predominant during long-term verapamil treatment, since this study and a previous report in stroke-prone spontaneously hypertensive rats40 show an improvement of the endothelial function. Neither verapamil nor trandolapril improved the reduced activity of constitutive NO synthase caused by the prolonged administration of L-NAME. A compensatory activation of inducible NO synthase also can be excluded on the basis of our experiments. It is possible that the intracellular utilization of L-arginine, the precursor for the production of NO, is improved during antihypertensive therapy with verapamil or trandolapril. However, the relaxation induced by exogenous L-arginine—albeit enhanced during L-NAME treatment—was comparable in controls and those treated with verapamil or trandolapril. Therefore, these observations suggest that mechanisms that are not dependent on increased production of NO may be responsible for the improved endothelium-dependent relaxations. The processes by which verapamil and trandolapril improve NO-independent vasodilatory mechanisms are still obscure, but they appear to require a prolonged action of these drugs, since no enhancement of vascular reactivity to acetylcholine was observed when the drugs were applied for a short period of time in vitro. Furthermore, the effect seems to persist for a long time, considering that the antihypertensive therapies were withdrawn for 2 to 3 days. It is conceivable that in long-term NO deprivation, a variety of vasodilatory mechanisms that are normally downregulated progressively start to operate in the presence of calcium antagonists and ACE inhibitors. EDHF, prostaglandin E2, oxygen-derived free radicals, and adenosine are possible candidates.2 Prostacyclin is an unlikely candidate, since it is a weak vasodilator in the rat.32 However, an NO-independent component of the response to acetylcholine exists in mesenteric resistance arteries of this species.17 These endothelium-dependent relaxations have been attributed to an EDHF.2 Accordingly, trandolaprilat potentiates the release of EDHF in canine coronary artery.41 Inhibition of endothelium-derived contracting factors with antihypertensive therapy (C.F.K. et al, unpublished data, 1995) could also constitute a mechanism to improve the endothelial function. Alternatively, these antihypertensive agents could decrease the catabolism of NO, thus enhancing its effect on the vascular smooth muscle despite its smaller production.
Several studies in other models of experimental hypertension have shown beneficial effects of antihypertensive drugs either to prevent or to restore endothelial dysfunction.14 23 24 40 However, in hypertensive subjects, Creager and Roddy42 found no improvement of the impaired endothelial function after 2 months of therapy with ACE inhibitors. Although the duration of treatment may be relatively short, another study in humans with longer duration of treatment showed similar results.33 It must be kept in mind, however, that in the latter study several classes and different associations of antihypertensive drugs were used, making comparison to the present experiments more intricate. Nevertheless, it may be possible that in the forearm circulation, which is normally studied in patients, the alternative mechanisms that we propose cannot be upregulated. This discrepancy deserves further investigation.
In conclusion, our results demonstrate that endothelial function can be preserved with two widely used antihypertensive drugs by a mechanism independent of NO production. Our findings suggest that in long-term NO deprivation, verapamil and trandolapril can potentiate other alternative vasodilatory systems that normally do not play a crucial role in maintaining the vascular tone. These observations emphasize the importance and efficacy of calcium antagonists and ACE inhibitors in preventing endothelial dysfunction in hypertensive situations with diminished NO production.
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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 Research Foundation (32-32541.91 and 3100-039395.93-1) and from Knoll Pharmaceuticals, Ludwigshafen, Germany. Dr Moreau is the recipient of a fellowship from the Medical Research Council of Canada. Dr Küng holds a stipend from the Senglet Foundation, Basel/Switzerland. Dr Nava is the recipient of a stipend from the Roche Research Foundation, Basel, Switzerland.
Received February 20, 1995; first decision April 13, 1995; accepted August 21, 1995.
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