(Hypertension. 1997;30:1606-1612.)
© 1997 American Heart Association, Inc.
Articles |
Lacidipine Restores Endothelium-Dependent Vasodilation in Essential Hypertensive Patients
From the I Clinica Medica, University of Pisa, Pisa, Italy.
Correspondence to Dr Stefano Taddei, I Clinica Medica, University of Pisa, Via Roma, 67, 56100 Pisa, Italy.
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Abstract |
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Abstract Essential hypertension is characterized by impaired endothelium-dependent vasodilation. The present study was designed to test whether antihypertensive treatment with the calcium antagonist lacidipine can improve endothelium-dependent vasodilation in essential hypertensive patients. In 12 normotensive subjects (mean age, 47.8±8.6 years; blood pressure, 118.6±4.2/76.7±3.9 mm Hg) and 19 hypertensive patients (mean age, 49.4±10.2 years; blood pressure; 153.5±13.3/101.3±6.4 mm Hg), we studied forearm blood flow modifications (strain-gauge plethysmography) induced by intrabrachial infusion of acetylcholine (0.15, 0.45, 1.5, 4.5, and 15 µg/100 mL per minute) and bradykinin (5, 15, and 50 ng/100 mL per minute), two endothelium-dependent vasodilators that act through different receptors and signal transduction pathways, and sodium nitroprusside (1, 2, and 4 µg/100 mL per minute), an endothelium-independent vasodilator. In essential hypertensive patients, vascular reactivity was repeated during prolonged (8 weeks of oral treatment at 6 mg/d) lacidipine administration and 2 weeks after withdrawal of chronic (32-week) treatment. Hypertensive patients showed significantly (P<.01) blunted vasodilation in response to acetylcholine (vascular resistance, 31.5±4.9 to 7.6±2.4 SU) and bradykinin (vascular resistance, 32.3±5.8 to 8.5±3.0 SU) compared with control subjects (vascular resistance: acetylcholine, 24.3±3.9 to 3.7±1.2 SU; bradykinin, 24.7±0.4 to 4.1±1.3 SU), whereas the response to sodium nitroprusside was similar. After either 8 or 32 weeks of lacidipine treatment, the vasodilation in response to acetylcholine (30.6±7.7 to 5.7±1.5 and 34.3±6.6 to 5.9±1.9 SU, respectively) and bradykinin (31.3±7.2 to 6.4±1.6 and 33.7±5.4 to 6.1±1.5 SU, respectively), but not to sodium nitroprusside, proved to be significantly (P<.05) increased compared with baseline. In essential hypertensive patients, oral treatment with lacidipine increased forearm vasodilation in response to acetylcholine and bradykinin, suggesting that this drug can improve endothelial function in patients with essential hypertension.
Key Words: endothelium • acetylcholine • bradykinin • hypertension • essential
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Introduction |
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Endothelial cells have an imporant local regulatory role by secreting substances that affect the tone of the underlying smooth muscle cells as well as the adhesion and aggregation of platelets and smooth muscle cell proliferation; thus, endothelium can deeply affect vascular function and structure.1
The best characterized EDRF is NO,2 3 which is derived from L-arginine metabolism through NO synthase (a constitutive enzyme present in endothelial cells).4 5 NO causes relaxation of vascular smooth muscle and inhibition of platelet aggregation or cell proliferation through activation of soluble guanylate cyclase, which leads to augmented production of GMP.1 Endothelial cells can be stimulated to produce and release NO by agonists such as acetylcholine, bradykinin, substance P, serotonin, and others acting on specific receptors and different signal transduction pathways.1 The possibility that acetylcholine, bradykinin, and substance P may induce endothelium-derived NO-dependent vasodilation has been confirmed in humans.6 7 8
Although relaxing factors play an important physiological role in circulatory regulation, in several pathological states, such as hypertension, diabetes, atherosclerosis, vasospasm, and reperfusion injury, activation of endothelial cells can lead to the production and release of contracting factors.1 Such substances are mainly cyclooxygenase-derived EDCFs, which at this time are partially identified with prostanoids9 10 11 or superoxide anions,12 which counteract the relaxing activity of NO. Superoxide anions can also impair endothelial function by causing NO breakdown.13 14 15
Impaired endothelium-dependent relaxations occur in experimental models16 as well as in human essential hypertension. Thus, the response to specific endothelium-dependent vasodilators, such as acetylcholine, methacholine, bradykinin, and substance P, has been found to be impaired in the forearm vessels of essential hypertensive patients compared with control subjects.7 8 17 18 19 20 21 22 23 24 It is worth noting that these agonists act on different receptor and signal transduction pathways, indicating that in essential hypertension, endothelial dysfunction is a generalized phenomenon. Mechanisms responsible for endothelial dysfunction involve an alteration in the L-arginine–NO pathway20 21 23 24 25 and production of cyclooxygenase-dependent EDCFs.19 24 25 At least in experimental models, a dysfunctioning endothelium loses its ability to exert a protective effect on the cardiovascular system by keeping vessels in a dilatory state, preventing platelet adhesion, smooth muscle cell proliferation and migration, and adhesion molecule expression and therefore playing a pathophysiological role in the development of atherosclerosis.26 Hence, an important aim for antihypertensive treatment should be to not only normalize blood pressure values but also reverse endothelial dysfunction.
In experimental hypertension, antihypertensive therapy is able to reverse endothelial dysfunction,27 28 29 whereas in humans, this appears to be much more difficult to achieve. Thus, it is well documented that pharmacological blood pressure normalization per se is not a sufficient condition to normalize or improve the vascular effect of endothelium-dependent vasodilators such as acetylcholine or methacholine, at least in the forearm circulation.30 31 32
Calcium entry blockers are compounds that are used extensively in the treatment of cardiovascular disease. Previous investigations have demonstrated a positive effect of these compounds on endothelial dysfunction in animal models of experimental hypertension.33 34 35 Therefore, the present study was designed to evaluate the effect of a dihydropyridine calcium entry blocker, lacidipine, on endothelium-dependent vasodilation in essential hypertensive patients. To better explore endothelial function and the potential effect of treatment, we specifically studied forearm vascular response to different endothelium-dependent vasodilators, such as acetylcholine and bradykinin, after acute (intra-arterial), prolonged (8 weeks), and chronic (32 weeks) lacidipine treatment. In addition, the effect of the compound on response to sodium nitroprusside, an endothelium-dependent vasodilator,36 was evaluated.
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Methods |
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Patients
The study population consisted of 12 normotensive control subjects and 19 matched essential hypertensive patients. Subjects with severe hypercholesterolemia (total cholesterol, 6.2 mmol/L), diabetes mellitus, cardiac and/or cerebral ischemic vascular disease, impaired renal function, or other major pathologies were excluded from the study. In addition, subjects or patients smoking more than five cigarettes per day and/or consuming more than 60 g of ethanol (corresponding to 0.5 L of wine) per day were excluded from the study. In accordance with institutional guidelines, all patients were aware of the investigational nature of the study and gave written consent. Any pharmacological treatment was discontinued 4 weeks before performance of the study.
Subjects, defined as normal according to the absence of familial
history of essential hypertension and to blood pressure values of 140
to 90 mm Hg were characterized by a mean age of 46.9±4.5 years
and mean blood pressure values of 118.3±3.1/76.8±4.2 mm Hg.
Essential hypertensive patients were recruited from among the newly
diagnosed cases in our outpatient clinic if they reported the presence
of positive family history of essential hypertension, and supine
arterial blood pressure (after 10 minutes of rest),
measured with a mercury sphygmomanometer three times at 1-week
intervals, was consistently 140/90 mm Hg. Secondary forms
of hypertension were excluded by the use of routine
diagnostic procedures. Mean age was 49.4±10.2 years, and
mean blood pressure values were 153.5±13.3/101.3±6.4 mm Hg.
Patients were enrolled if never-treated (n=11) or reporting a history
of discontinued or ineffective pharmacological antihypertensive
treatment (n=8). Among the latter subgroup, no patient had previously
received a calcium antagonist. Moreover, to avoid possible
dropouts because of lack of blood pressure normalization by lacidipin
treatment, hypertensive patients were tested for response to the
compound 4 weeks before enrollment into the study. Blood pressure
response to a single dose of 4 mg lacidipine was evaluated; only
patients who showed a <10% blood pressure decrease induced by drug
administration were finally enrolled. After this procedure, we screened
33 essential hypertensive patients to select 19 patients who proved to
be responders to lacidipine treatment. The demographic and clinical
characteristics of the two groups are given in Table 1
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Experimental Model
The FBF studies were performed at 8:00 AM after
overnight fasting, with the subjects lying supine in a quiet
air-conditioned room (22° to 24°C). A polyethylene cannula (21
gauge, Abbot) was inserted into the brachial artery with the patient
under local anesthesia (2% lidocaine). The cannula was
connected through stopcocks to a pressure transducer (model MS20;
Electromedics) for determination of systemic mean arterial
blood pressure (one-third pulse pressure plus diastolic
pressure), heart rate (model VSM1; Physiocontrol), and
intra-arterial infusions. FBF was measured with the use of
strain-gauge venous plethysmography (LOOSCO; GL LOOS).37
Circulation to the hand was occluded 1 minute before each measurement
of FBF by inflation of a paediatric cuff around the wrist at
suprasystolic blood pressure. Earlier research established the
sensitivity and reproducibility of the method.38 Forearm
volume was determined according to the water-displacement method, and
the drug infusion rate was adjusted for each subject according to his
or her forearm volume. Thus, drug infusion rates were normalized to 100
mL forearm tissue through alteration of the drug concentration in the
solvent. Drugs were infused through three-way stopcocks at
concentrations that had no systemic effects.
Study Design
Endothelium-dependent forearm vasodilation was
evaluated with a dose-response curve to intra-arterial
acetylcholine (cumulative increase in infusion rates; 0.15, 0.45, 1.5,
4.5, and 15 µg/100 mL of forearm tissue per minute for 5 min each
dose) and bradykinin (cumulative increase in infusion rates, 1.5, 4.5,
and 15 ng/100 mL of forearm tissue per minute for 5 min each dose).
Endothelium-independent vasodilation was assessed with
sodium nitroprusside (1, 2, and 4 µg/100 mL of forearm tissue/min for
5 minutes each dose), a direct smooth muscle cell relaxant compound.
The three infusions were given in randomized sequence, and 30 minutes
of recovery was allowed between each experimental intervention.
In the essential hypertensive patients, acetylcholine, bradykinin, and sodium nitroprusside infusions were performed under basal conditions (saline infusion at 0.2 mL/min). After the first FBF study, patients were administered 4 mg lacidipine QD for 1 week. After ensuring that no adverse clinical or biochemical effects had occurred, the dose was increased to 6 mg QD for the remainder of the 32-week active treatment. Additional clinic visits were scheduled every 4 weeks for the duration of the study.
The FBF study was repeated after 8 weeks (prolonged treatment) of lacidipine administration, during active treatment, and then 2 weeks after the end of 32-week chronic active treatment. Blood pressure measurements were performed in our outpatient unit with the use of a standard mercury sphygmomanometer. Blood pressure was determined as the mean of three measurements made at 2-minute intervals after the patient had been seated for 10 minutes.
Data Analysis
Data were analysed in terms of changes in FBF and FVR
(calculated as the ratio between intra-arterial mean
pressure and FBF and expressed as SU). Because arterial
blood pressure did not change significantly during the FBF study,
increments in FBF were taken as evidence of local vasodilation.
Differences between two means were compared with the use of a paired or
unpaired Student's t test, as appropriate. Responses to
acetylcholine, bradykinin, and sodium nitroprusside were
analyzed with an analysis of variance for repeated
measures. Because basal FBF and FVR had different results in the
various experimental steps, data were also analyzed as percent
increase or decrease from baseline (see figures). In this case,
Wilcoxon's test was used to check the statistical significance
of the difference between non parametric values. Results are
expressed as mean±SD. Differences were considered statistically
significant at a level of P<.05. Computations for the
statistical method described were performed using the SAS Institute
system.
Drugs
Acetylcholine HCl (Farmigea SpA), bradykinin HCl (Clinalfa AG),
and sodium nitroprusside (Malesci) were obtained from commercially
available sources and diluted fresh to the desired concentration
through the addition of normal saline. Sodium nitroprusside was
dissolved in glucosate solution and protected from light with
aluminum foil.
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Results |
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Basal systemic demographic, hemodynamic, and humoral characteristics for normotensive subjects and essential hypertensive patients are summarized in Table 1
. Age, sex, plasma
cholesterol level, glycemia, and smoking history were
similar, and within a normal range, between the two study groups, but
blood pressure differed (Table 1).
In essential hypertensive patients, administration of lacidipine
significantly decreased blood pressure values from
153.5±13.3/101.3±6.4 to 138.6±12.2/87.9± 7.9 mm Hg
(P<.001 versus basal) and 136.4±11.4/87.2±7.3 mm Hg
(P<.001 versus basal) after 8 and 32 weeks of treatment,
respectively. However, when the final FBF study was performed, 2 weeks
after lacidipine withdrawal, blood pressure values were found to be
increased to 147.6±9.4/95.3±5.4 mm Hg (P<.001
versus active treatment). Heart rate was not modified by lacidipine
treatment (from 73.3±7.5 to 72.6±7.2 and 79.1±7.8 bpm after 8 and 32
weeks of treatment, respectively) (Table 2). Furthermore, body weight, lipid
profile, and glucose plasma levels were unchanged throughout the
treatment period (Table 2).
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FBF Study
Basal Vascular Responses
The dose-dependent increase in FBF and decrease in FVR induced by
acetylcholine were found to be significantly (P<.02)
reduced in essential hypertensive patients (FBF, from 3.7±0.5 to a
maximum of 16.3±5.2 mL/100 mL forearm tissue per minute; Fig 1; and FVR: from 31.5±4.9 to a minimum
of 7.6±2.4 SU) compared with normotensive subjects (FBF: from 3.7±0.5
to a maximum of 23.8±5.5 mL/100 mL forearm tissue per minute; Fig 1;
FVR: from 24.3±3.9 to a minimum of 3.7±1.2 SU). Similar to the
results obtained with acetylcholine, the increase in FBF and decrease
in FVR seen with bradykinin were significantly (P<.001)
blunted in essential hypertensive patients (FBF: 3.6±0.6 to a maximum
of 14.5±4.0 mL/100 mL forearm tissue per minute; Fig 1; FVR: from
32.3±5.8 to a minimum of 8.5±3.0 SU) compared with control subjects
(FBF: 3.6±0.4 to a maximum of 21.2±4.6 mL/100 mL forearm tissue per
minute; Fig 1; FVR: from 24.7±4.1 to a minimum of 4.1±1.3 SU). In
contrast, dose-dependent vasodilation in response to sodium
nitroprusside was found to be similar in normotensive subjects (FBF:
from 3.7±0.5 to a maximum of 17.4±5.3 mL/100 mL forearm tissue per
minute; Fig 1; FVR: from 24.1±3.9 to a minimum of 5.1±2.1 SU) and
hypertensive patients (FBF: from 3.6±0.5 to a maximum of 16.5±4.6
mL/100 mL forearm tissue per minute; Fig 1; FVR: from 32.3±5.6 to a
minimum of 7.3±1.8 SU). Contralateral FBF did not significantly change
during the study (data not shown).
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) and
essential hypertensive patients (n=19) (
). Data are shown as
mean±SD and expressed as percent increase above basal. *Significant
differences between infusions in normotensive subjects and essential
hypertensive patients.
Effect of Prolonged (8-Week) Lacidipine Administration
Lacidipine treatment for 8 weeks significantly (P<.01)
increased vasodilation in response to both acetylcholine (FBF: from
3.5±0.7 to a maximum of 19.1±5.1 mL/100 mL forearm tissue per minute;
Fig 2; FVR: from 30.6±7.7 to a minimum
of 5.7±1.5 SU; Fig 3) and bradykinin
(FBF: from 3.4±0.6 to a maximum of 16.8±4.9 mL/100 mL forearm tissue
per minute; Fig 2; FVR: from 31.3±7.2 to a minimum of 6.4±1.6 SU; Fig 3). In contrast, the response to sodium nitroprusside (FBF: from
3.4±0.6 to a maximum of 16.0±4.7 mL/100 mL forearm tissue per minute;
Fig 2; FVR: from 30.4±5.4 to a minimum of 6.8±1.9 SU; Fig 3) was
found to be similar to that observed under basal conditions.
Contralateral FBF did not significantly change during the entire study
(data not shown).
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). Data are shown as mean±SD and expressed as percent
increase above basal. *Significant differences between infusions under
basal conditions and in the presence of lacidipine treatment.
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Effect of Chronic (32-Week) Lacidipine Administration
Two weeks after chronic lacidipine treatment (32 weeks)
withdrawal, patients were found to be hypertensive again (Table 2).
However, vascular responses to acetylcholine (FBF: from 3.4±0.5 to a
maximum of 20.5±6.6 mL/100 mL forearm tissue per minute; Fig 2; FVR:
from 34.3±6.6 to a minimum of 5.9±1.9 SU; Fig 3) and bradykinin (FBF:
from 3.4±0.4 to a maximum of 19.7±6.5 mL/100 mL forearm tissue per
minute; Fig 2; FVR: from 33.7±5.4 to a minimum of 6.1±1.5 SU; Fig 3)
were still found to be significantly increased compared with
pretreatment values, whereas the vasodilating effect of sodium
nitroprusside (FBF: from 3.4±0.5 to a maximum of 17.1±4.1 mL/100 mL
forearm tissue per minute; Fig 2; FVR: from 33.6±5.5 to a minimum of
7.0±1.7 SU; Fig 3) was unchanged. Contralateral FBF did not
significantly change during the study (data not shown).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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In the present study, we tested the effect of lacidipine, a dihydropyridine calcium-entry blocker, on endothelium-dependent vasodilation in essential hypertensive patients. To better characterize endothelial dysfunction and the possible effect of antihypertensive treatment, we tested two different specific endothelium-dependent vasodilators, acetylcholine and bradykinin. These agonists, although acting on different receptor and signal transduction pathways,1 both induce NO-dependent relaxations.6 8 We observed that in line with previous evidence from Panza et al,8 vasodilation in response to both acetylcholine and bradykinin was impaired in the forearm circulation of essential hypertensive patients compared with control subjects. Because the response to sodium nitroprusside was similar in the two study populations, the present findings confirm the presence of generalized abnormality of endothelial vasodilator function, at least in this subset of essential hypertensive patients.
After either 8 or 32 weeks of treatment, lacidipine significantly increased the response to both acetylcholine and bradykinin, whereas the vasodilating effect of sodium nitroprusside remained unchanged. Therefore, the present results indicate that lacidipine can improve endothelial function in essential hypertensive patients. This effect is probably specific and not dependent on blood pressure reduction because previous evidence has suggested that blood pressure normalization per se is not a maneuver sufficient to increase endothelium-dependent vasodilation in the forearm circulation of essential hypertensive patients.30 31 32 In line with this hypothesis is the finding that lacidipine treatment still exerted a beneficial effect on endothelial function 2 weeks after withdrawal while the patients were reverting to a hypertensive state. Thus, although it is conceivable that the beneficial effect of lacidipine on endothelial function could be related to intrinsic properties of the compound, direct evidence addressing this major issue is lacking, and further studies are needed to investigate whether the mechanism through which lacidipine can restore endothelium-dependent vasodilation in essential hypertension is related to blood pressure reduction.
The present demonstration of a beneficial effect of lacidipine on endothelial function is in agreement with experimental data indicating that calcium entry blockers increase endothelium-dependent relaxation in different vessels from various animal models.33 34 35 In addition, Frielingsdorf et al39 recently reported that the chemically unrelated calcium antagonists nicardipine, a dihydropyridine, and diltiazem, a benzothiazepine, can improve the impaired endothelium-dependent vasomotor response induced by exercise in atherosclerotic stenotic coronary vessels of normotensive patients and in normal and stenotic vessels of essential hypertensive patients. Furthermore, Schiffrin and Deng40 demonstrated that treatment with the dihydropyridine calcium entry–blocker nifedipine, but not with the ß-blocker atenolol, prevents endothelial dysfunction, tested as relaxation induced by acetylcholine, in resistance-size small arteries dissected from a gluteal subcutaneous biopsy of essential hypertensive patients. Taken together, this evidence indicates that in different vascular beds such as coronary, muscle, and subcutaneous circulation, calcium entry blockers can restore endothelium-dependent responsiveness in essential hypertensive patients.
Several hypotheses can be put forward to clarify the mechanism through which lacidipine and possibly the other calcium antagonists can improve endothelial function. First, the present finding that the beneficial effect is exerted on both acetylcholine and bradykinin indicates that the mechanism involved is not related to an interaction with surface endothelial receptors or signal transduction pathways. Thus, acetylcholine and bradykinin agonists act on specific receptors and different signal transduction pathways involving a G1 protein that is sensitive and insensitive to pertussis toxin, respectively.41 42 Independent of the type of endothelial cell stimulation, both compounds induce endothelium-dependent vasodilation through activation of the L-arginine–NO pathway.6 7 8 Previous evidence has shown that in human essential hypertension, endothelial dysfunction is not caused by an alteration in receptor or signal transduction pathways7 8 but is probably related to a defect in the NO system, which can be primary20 21 23 25 or induced by the simultaneous production of cyclooxygenase-dependent EDCF,19 24 25 possibly oxygen free radicals. Potentially, calcium antagonists act directly on NO synthase because the enzyme activity is calcium dependent.43 Under this perspective, however, calcium antagonists should block and not increase NO production.44 This unfavorable possibility is excluded by the finding that endothelial cells do not express voltage-operated calcium channels.45
An alternative explanation is that calcium entry blockers could enhance NO-induced vasodilation by decreasing calcium influx into smooth muscle cells, in which voltage-operated channels are present.45 Although experimentally demonstrated, this possibility is unlikely under our experimental conditions because lacidipine was devoid of effect on vasodilation in response to sodium nitroprusside, which acts directly on smooth muscle cells as an NO donor. Finally, calcium antagonists, including lacidipine, have effects that differ from that of calcium influx blockade, and these could be beneficial in reversing endothelial dysfunction in hypertension. Thus, calcium entry blockers, including lacidipine, have been shown to have antioxidant effects,46 47 48 a mechanism through which this drug could protect endothelial cells against free radical injury. Such a hypothesis is supported by recent preliminary evidence showing that the antioxidant vitamin C restores vasodilation in response to acetylcholine in the forearm vasculature of essential hypertensive patients.49 Regardless of the mechanism involved, it is important to stress that the beneficial effect of lacidipine on endothelium-dependent vasodilation is still present 2 weeks after drug withdrawal, indicating that the compound causes deep modifications in the functional state of endothelial cells.
Assessment of the clinical relevance of the present results must include the increasing evidence that endothelial dysfunction is not a unique characteristic of human primary or secondary hypertension7 8 17 18 19 20 21 22 23 24 but rather has been documented to be associated with almost all cardiovascular risk factors and with atherosclerotic disease.22 50 51 52 53 54 Furthermore, the relationship between endothelial dysfunction and cardiovascular risk factors seems to be so strong that the simultaneous association of several risk factors further impairs endothelium-dependent relaxations.22 55 Thus, it is conceivable that endothelial dysfunction could be considered a promoter of the pathogenesis of atherosclerosis, suggesting that reversal of endothelial dysfunction could represent an important target for pharmacological prevention of atherosclerotic vascular disease associated with cardiovascular risk factors. At the present time, the long-term effect of treatment with lacidipine on carotid morphology in hypertensive patients who had been stratified according to the presence of plaque or wall thickening or of a normal carotid wall is under investigation in the European Lacidipine Study on Atherosclerosis (ELSA) study.56 If the study gives positive results, the finding that lacidipine can improve endothelium-dependent vasodilation could provide a plausible explanation for the possible beneficial effect of the calcium antagonist on the vessel wall.
In conclusion, the present study indicates that the dihydropyridine calcium entry–blocker lacidipine can improve impaired endothelium-dependent vasodilation in response to acetylcholine and bradykinin in the forearm circulation of essential hypertensive patients. These results indicate that lacidipine, and possibly other calcium antagonists, not only lower blood pressure values but also can have beneficial effects on vascular endothelium, thereby offering considerable potential in the prevention and/or treatment of atherosclerosis.
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Selected Abbreviations and Acronyms |
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Received March 27, 1997; first decision May 8, 1997; accepted June 16, 1997.
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