The Influence of One‐Year Treatment by Angiotensin Converting Enzyme Inhibitor on Baroreflex Sensitivity and Flow‐Mediated Vasodilation of the Brachial Artery in Essential Hypertension—Comparison with Calcium Channel Blockers

Background. Both baroreflex sensitivity and flow‐mediated vasodilator function have been recognized to have prognostic significance in cardiovascular diseases. Long‐term antihypertensive treatment effects on these parameters, however, remain unclear. Subjects and Methods. We examined the effects of long‐term treatment by angiotensin converting enzyme inhibitors (ACEI) or calcium channel blockers (CCB) on baroreflex and flow‐mediated vasodilator function in patients with essential hypertension (EH). We recruited 36 patients aged 56 ± 11 years, with systolic blood pressure ≧160 mmHg and/or diastolic blood pressure ≧95 mmHg. Patients were assigned either to treatment by long‐acting ACEI (n = 12) or CCB (n = 24). All patients were followed for 12 months. Optimal BP was achieved by two optional increases in treatment: dose‐doubling of the primary drug during the first three months and the addition of diuretics or β‐blockers thereafter. Target blood pressure was 140/90 mmHg or a fall ≧20/10 mmHg. Baroreflex sensitivity was examined by spectral analysis of blood pressure and RR interval variabilities before treatment and after 3 and 12 months of treatment. The flow‐mediated vasodilator function was determined before and 12 months after treatment by measuring the change in brachial artery diameter during increases in flow induced by reactive hyperemia. Results. Baseline blood pressures were similar between the ACEI and CCB groups (172 ± 5/103 ± 2 vs. 172 ± 4/101 ± 3 mmHg). Blood pressures after 3 and 12 months of treatment also did not differ between the ACEI and CCB groups (149 ± 4/91 ± 2 vs. 145 ± 2/ 85 ± 2 mmHg, and 133 ± 5/84 ± 2 vs. 133 ± 2/81 ± 2 mmHg, respectively). Baseline baroreflex sensitivity was similar between the groups (6.7 ± 0.8 vs. 5.9 ± 0.6 msec/mmHg). This parameter remained unchanged at three months but increased after 12 months of treatment in both the ACEI (9.5 ± 1.6 msec/mmHg, p = 0.05) and CCB (9.1 ± 1.2 msec/mmHg, p = 0.006) groups. Percent increases in brachial arterial diameter and flow during reactive hyperemia increased in the group treated with ACEI (12.4 ± 3.5 vs. 25.8 ± 6.3% and 618 ± 72 vs. 953 ± 166, p < 0.05 for both) but both parameters remained unchanged in the group treated with CCB. Conclusion. These data suggest that long‐term blood pressure control with modern antihypertensive drugs improves baroreflex function. Treatment with ACEI may be more favorable for flow‐mediated vasodilator function than treatment with CCB.

Keywords: Antihypertensive treatment; Baroreflex; Vascular function; Hypertension

The purpose of antihypertensive treatment is to prevent the development of end organ damage and reduce cardiovascular morbidity and mortality. Results of large prospective trials using diuretics or β‐blockers showed a significant benefit with the use of these traditional antihypertensive treatments; however, further reduction in the incidence of coronary heart disease remains an important clinical goal [1]. Therefore, attention should focus not only on lowering blood pressure but also on other aspects that could affect the development of coronary atherosclerosis including metabolic, neural, and vascular factors. Metabolic effects of antihypertensive drugs usually are examined in their development process but the influences on neural or vascular functions are not routinely studied. There has been increasing evidence to suggest that both neural and vascular functions have prognostic significance in cardiovascular disease [2],[3]. Schachinger et al. have shown that impaired endothelial and endothelium‐independent coronary vasodilator functions were associated with a significantly higher incidence of cardiovascular events [3].

Many compelling issues have arisen concerning the role of the newer antihypertensive agents, particularly with respect to angiotensin converting enzyme inhibitors (ACEI) and calcium channel blockers (CCB). There are a few informations regarding potentially favorable neural and vascular effects in patients with essential hypertension treated with ACEI or CCB. The results of the Swedish Trial in Old Patients with Hypertension‐2 (STOP‐Hypertension‐2) has shown that relative risk of myocardial infarction was significantly lower in a group treated with ACEI than in a group treated with CCB even after adjustment of age, sex, diabetes, blood pressure, and smoking [4]. Therefore, it could be hypothesized that treatment with ACEI is more favorable for neural and/or vasodilator functions than that with CCB.

Recent technical developments have enabled us to examine neural cardiovascular and vascular functions. Baroreflex sensitivity can be examined by spectral analysis of blood pressure and RR interval variabilities spontaneously occurring in the resting condition [5],[6]. We have shown the clinical usefulness of this method in human hypertension [7],[8] as well as in autonomic disturbance [9]. Furthermore, clinical evaluation of vascular endothelial function has become available through high resolution ultrasonography [10]. The dilation of the vessel, obtained via release of nitric oxide, is impaired when endothelial dysfunction is present. Brachial artery dilator response to reactive hyperemia has been widely used as an indicator of endothelial function in humans [11], [12], [13]. The aim of the present study was to compare the effects of long‐term treatment by ACEI and by CCB on baroreflex sensitivity and brachial vasodilator response to reactive hyperemia in patients with essential hypertension.

We studied 36 untreated patients with essential hypertension who had initial, untreated blood pressure readings ≧160 mmHg systolic an/or ≧95 mmHg diastolic. Secondary causes of hypertension were excluded by standard clinical and laboratory tests. Subjects with severe end organ damage, diabetes mellitus (fasting blood glucose >126 mg/dL), severe hypercholesterolemia (fasting total cholesterol >300 mg/dL), or other major diseases were excluded from the study. Six patients were smokers. The study protocol was approved by the Ethics Committee of Tohoku Rosai Hospital. Informed consent to participate in our study was obtained from all subjects.

Patients were assigned to treatment with long‐acting ACEI [temocapril 2 mg once daily (n = 9) or cirazapril 0.5 mg once daily (n = 3)] or CCB [amlodipine 2.5 mg once daily (n = 10), benidipine 4 mg once daily (n = 9), or nifedipine‐retard 10 mg twice daily (n = 5)]. All patients were followed for 12 months. Suboptimal blood pressure was treated with two optional treatment regimen: dose‐doubling of the primary drug during the first three months and addition of diuretics or β‐blockers thereafter. Target blood pressure was 140/90 mmHg or a fall ≧20/10 mmHg. Four patients in the ACEI group (33%) and five in the CCB group (21%) received additional diuretics and β‐blockers.

Baroreflex sensitivity was examined by spectral analysis of blood pressure and RR interval variabilities at baseline and after 3 months and 12 months of treatment. Flow‐mediated vasodilation of the brachial artery was examined by the ultrasonic quantitative flow measurement system before and after 12 months of treatment. Studies were done in a temperature‐controlled laboratory room. All patients were placed in the supine position. The electrocardiogram (ECG) was monitored using precordial lead (V5). Blood pressure was monitored on the right middle finger with a digital photoplethysmographic device (Finapres 2300, Ohmeda, Englewood, CO). The diameter and blood flow of the right brachial artery was monitored by the ultrasonic quantitative flow measurement system (QFM‐1100 Hayashi‐denki, Kawasaki, Japan). This system is designed to use ultrasonic Doppler flowmetry with an ultrasonic pulse echo‐tracking method to trace and display simultaneous pulse patterns of absolute volume flow rate and wall displacement [14]. Absolute volume flow was calculated as the product of blood velocity and the cross‐sectional area of the blood vessels. The probe, which has a barium titrate transducer that measures wall displacement with three ceramic transducers that detect blood flow, was positioned over the brachial artery. Wall displacement was measured at an ultrasonic frequency of 6 MHz pulse wave by echo‐tracking method. Blood flow as measured by the ultrasonic Doppler method, which utilizes an ultrasonic frequency of 5 MHz continuous wave. The probe was placed perpendicularly 2–4 cm proximal to the antecubital fossa so as to demonstrate maximal arterial diameter and Doppler flow sound. The validity and clinical application of this system has been previously described [15],[16].

After hemodynamic stabilization, analog ECG and blood pressure signals were fed into a signal processor (7T‐18; NEC San‐ei, Tokyo, Japan) with an R‐wave detector accurate to within 1 msec. Systolic and diastolic blood pressures were measured at each R‐wave. The RR interval was calculated during this period and then digitized to be stored on a floppy disk. Data were collected for 10 min following a 15‐min rest in the supine position.

Off‐line analysis was later performed by computer (PC 9801‐RX; NEC, Tokyo, Japan). Computer‐generated displays of the RR interval and systolic and diastolic pressures were visually inspected. A 256‐sec segment without movement artifacts or premature ventricular contractions was selected for final analysis. Overall variability of systolic and diastolic blood pressures was expressed in absolute terms, as the within‐subject standard deviation. The sensitivity of the baroreceptor‐heart rate reflex was examined by the transfer function analysis between systolic blood pressure and RR interval variabilities [9]. In previous studies, gain in the mid‐ and high‐frequency (0.15–0.40 Hz) bands have been calculated separately [5],[6]. However, both gains correlated similarly with baroreflex sensitivity estimated using vasoactive‐drug and sequence methods [6],[7]. Furthermore, linear linkage with blood pressure and RR interval variabilities sometimes shifts to the low‐frequency band (0.02–0.06 Hz) [7]. Therefore, in this study, we calculated the total gain of the transfer function ranges from 0.02 to 0.40 Hz for those frequency points with a coherence >0.5 as an indicator of baroreflex sensitivity [9].

Following the assessment of baroreflex sensitivity, we studied brachial vascular function. Analog output of brachial flow velocity, arterial diameter, and blood flow from the QFM system were computerized (NEC 98 NOTE SX/E) and digitized. Trendgrams of these parameters were visualized on the computer display. We assessed flow‐mediated vasodilation by measuring the change in the caliber of the brachial artery during reactive hyperemia, a maneuver that increases flow through the conduit segment being studied [10], [11], [12], [13]. To create this stimulus, a cuff placed on the upper arm was inflated to suprasystolic pressure for 7 min, thereby occluding flow to the forearm. This results in dilation of downstream forearm resistance vessels. After cuff deflation, reactive hyperemia occurs, as brachial blood flow increases to accommodate the dilated resistance vessels. Trendgrams of blood flow, flow velocity, and arterial diameter were continuously monitored for 5‐min period after cuff deflation until basal conditions were reestablished. After the completion of the experiment, data were recorded on a floppy disk. The diameter and flow measurements were taken at maximal values after cuff deflation. The flow‐mediated dilation of the brachial artery (FMD) was expressed as the % of diameter change relative to the mean value obtaining during a 10‐sec interval at the baseline condition. The increase in brachial blood flow was calculated as the % blood flow change relative to the baseline 10‐sec mean flow value. Repeated scans were randomly recorded in 20 patients by two observers (A. A. and M. M.) and measured on two different occasions. Interobserver and intraobserver variability in repeated recordings of resting brachial diameter were 4.5% and 4.0% respectively. The mean difference in the percentage of the changes in diameter of the brachial artery in response to hyperemia was 5.0%.

All data are expressed as mean ± s.e. Differences between two groups were assessed by the unpaired t test with two tails. The effects of antihypertensive drugs were assessed by paired‐t test or by ANOVA with repeated measurements. All statistical analyses were performed with a commercially available statistical package (Stat Flex for Windows, Ver. 5.0, Artec, Osaka, Japan). A level of p < 0.05 was accepted as statistically significant.

Table 1 shows the demographic data of the ACEI and CCB groups. There were no significant differences in age, sex distribution, blood pressures, body mass index, smoking status or metabolic factors between the two groups.

Table 1. Clinical characteristics of ACEI and Ca groups

1 Note: ACEI, angiotensin converting enzyme inhibitors; CCB, calcium channel blockers; SBP, systolic blood pressure; DBP, diastolic blood pressure; FBS, fasting blood sugar; mean ± SEM; n.s., not significant.

Baseline blood pressures and heart rate were similar in the ACEI and CCB groups (172 ± 5.2/103 ± 1.9 vs. 172 ± 3.9/102 ± 3.1 mmHg and 79 ± 2.4 vs. 76 ± 2.1 bpm) (Fig. 1). Blood pressures were significantly lower after three months of treatment compared with baseline values in both ACEI (149 ± 4.4/91 ± 2.1 mmHg, p < 0.0001 for both) and Ca (145 ± 2.1/85 ± 1.8 mmHg, p < 0.0001 for both) groups. Blood pressures were further reduced after 12 months of treatment both in the ACEI (133 ± 4.9/84 ± 2.4, p < 0.0001 for SBP, p < 0.01 for DBP) and CCB (133 ± 1.8/81 ± 2.0, p < 0.0001 for both) groups (Fig. 1). There were no significant differences in blood pressures after 3 and 12 months of treatment between the two groups. Heart rate remained unchanged over the 12‐month period in both the ACEI and CCB groups (Fig. 1).

Graph: Figure 1. Systolic, diastolic blood pressures (SBP and DBP, respectively) and heart rate (HR) before, 3, and 12 months of treatment; closed and hatched bars indicate data of ACEI and CCB group, respectively. Key: *, p < 0.0001 vs. before treatment; +, p < 0.0001; ++, p < 0.01 vs. three months.

Baroreflex sensitivity remained unchanged after three months of treatment compared with baseline value both in the ACEI (6.7 ± 0.8 vs. 6.3 ± 0.9 msec/mmHg) and CCB (5.9 ± 0.6 vs. 6.3 ± 0.6 msec/mmHg) groups (Fig. 2). However, this parameter was increased after 12 months of treatment in both the ACEI (9.5 ± 1.6 msec/mmHg, p < 0.05) and CCB (9.1 ± 1.2 msec/mmHg, p < 0.01) groups. Standard deviations of both systolic and diastolic blood pressures were suppressed during the treatment with CCB (p = 0.006 for systolic and p = 0.02 for diastolic) (Fig. 3). This effect, however, was less pronounced in the ACEI group (p = 0.13 for systolic and p = 0.65 for diastolic).

Graph: Figure 2. Baroreflex sensitivity before, 3, and 12 months of treatment; closed and hatched bars indicate data of ACEI and CCB group, respectively. Key: *, p < 0.05 vs. before treatment.

Graph: Figure 3. Standard deviation of systolic and diastolic blood pressure (sBPSD and dBPSD, respectively) before, 3, and 12 months of treatment; closed and hatched bars indicate data of ACEI and CCB group, respectively.

Baseline diameter, blood flow, FMD, and reactive hyperemia (% increase in flow) did not differ between the ACEI and CCB groups (Fig. 4). Baseline blood flow increased after treatment compared with pretreatment values in the CCB group (73 ± 4 vs. 95 ± 10 mL/min, p < 0.05). Both FMD and hyperemic response increased after treatment with ACEI (12.4 ± 3.5 vs. 25.8 ± 6.3% and 618 ± 72 vs. 953 ± 166% p < 0.05 for both) (Fig. 4). The FMD tended to increase also in the group treated with CCB (18.8 ± 4.4 vs. 30.0 ± 5.1%, p = 0.07) (Fig. 4), while hyperemic response remained unchanged.

Graph: Figure 4. Papameters of brachial vascular functions before and 12 months after treatment; closed and hatched bars indicate data of ACEI and CCB group, respectively. Key: *, p < 0.05 vs. before treatment.

We comparatively examined the effects of long‐term antihypertensive treatment with ACEI and CCB on baroreflex sensitivity and flow‐mediated vasodilatory response of the brachial artery.

One‐year treatment was found to significantly increase baroreflex sensitivity compared with pretreatment values in both the ACEI and CCB groups. Pre‐ and post‐treatment values of the baroreflex sensitivity were similar between the two groups. These data suggest that long‐term blood pressure reduction by either ACEI or CCB could similarly improve baroreflex function in patients with essential hypertension.

There are two important issues to be mentioned. First, blood pressures were significantly lowered after three months of treatments in both the ACEI and CCB groups. At this stage, however, baroreflex sensitivity remained unchanged in both groups. This means that simple blood pressure reduction most likely does not improve baroreflex function. It was necessary to treat for longer than three months to improve baroreflex sensitivity, suggesting that structural rather than functional alterations are necessary to improve baroreflex sensitivity. Second, blood pressure variability, a main regulatory target of baroreflex, was significantly reduced in the group treated with CCB, but this effect was less clear in the group treated with ACEI. It is well established that both blood pressure and baroreflex sensitivity affect blood pressure variability. These parameters, however, did not differ between the ACEI and CCB groups during the course of the 12‐month treatment period. Present data suggest that blood pressure variability is mediated in part by the oscillation of vascular smooth muscle cell tone regulated by calcium channel.

Previous studies have provided us with varying evidence of the effects of chronic antihypertensive treatment on baroreflex sensitivity [17], [18], [19], [20], [21], [22], [23], [24], [25]. The inconsistent results obtained seem to be due in part to differences in length of treatment periods. In a study of spontaneously hypertensive rats, it has been shown that early initiation of antihypertensive treatment markedly improves baroreflex sensitivity when compared with a delayed start in treatment [26]. Thus timing appears to be a critical factor in determining the effects of antihypertensive treatment on baroreflex sensitivity.

There is another important issue to be mentioned. Treatment with ACEI significantly increased the FMD while this parameter remained unchanged in the group treated with CCB. The FMD is known to have an important role in the regulation of arterial tone [27]. It has been shown that the larger flow‐mediated dilatation of the coronary artery is associated with a lower incidence of future cardiovascular events in human [3]. Age, glucose, lipid metabolism, and smoking status did not differ between the ACEI and CCB groups. Furthermore blood pressure control between the two groups was similar. These results suggest that long‐term treatment with ACEI could exert more favorable effect on vasoreactivity than that with CCB.

The mechanisms of FMD are very complex but endothelium‐dependent vasorelaxation may be chiefly involved [27]. In fact, previous studies have also shown that treatment with ACEI could improve endothelial function in patients with essential hypertension [28], [29], [30]. Recently, Higashi et al. have performed a multicenter comparison of the effects of the treatment with ACEI, CCB, β‐blocker, and diuretics on forearm reactive hyperemia [31]. They found that treatment with ACEI augment reactive hyperemia but not with others, supporting our results.

Sener and Smith has shown that endogenous nitric oxide could modulate baroreflex sensitivity in conscious lambs [32]. Baroreflex sensitivity of one week‐aged lambs was significantly greater than that of six week‐aged ones. Administration of L‐NAME completely abolished the age‐related difference in baroreflex sensitivity, suggesting that endogenous nitric oxide potentiates baroreflex sensitivity. In our data, an increase in baroreflex sensitivity following ACEI treatment was not related to an improvement of FMD (r = 0.201, n.s.). We, therefore, believe that improvement of baroreflex sensitivity after ACEI treatment was due mainly to endothelium‐independent mechanisms.

Our data do not exclude the possibility that CCB can improve FMD in some patients because this parameter insignificantly increased even in a group treated with CCB. It has been reported that both lacidipine and nipedipine improve endothelial function in patients with essential hypertension [13],[33],[34] while amlodipine does not [29]. Thus various CCB may have different effects on endothelial function. Because this study included three separate CCB (amlodipine, nifedipine, and benidipine), the conclusion of the current study may not be generalized to all calcium channel blockers.

A recent trial, Appropriate Blood Pressure Control in Diabetes (ABCD), showed a significantly higher incidence of fatal and nonfatal myocardial infarction among diabetic hypertensives treated with the calcium‐channel blocker nisoldipine than those treated with the angiotensin converting enzyme inhibitor enarapril [35]. Furthermore, in the STOP‐Hypertension‐2, there were significantly fewer fatal and non‐fatal myocardial infarction during treatment with ACEI than during CCB [4]. Both hypertension and diabetes impair endothelial function and may be strong risk factors for coronary atherosclerosis. Therefore, antihypertensive medications having more favorable effects on vasoreactivity may offer a better prognosis in diabetic or old hypertensives. In this context, our data seem to be consistent with the results of the ABCD or STOP‐Hypertension‐2 trial.

Our study has two potential limitations. First, this study was performed retrospectively and thus baseline data were not randomized. The baseline blood flow tended to be lower and the FMD tended to be greater in the CCB group. This difference may have affected treatment outcome. To further confirm the conclusion of this study, we need to conduct randomized, prospective study. Second, four patients in the ACEI group (33%) and five in the CCB group (22%) received additional diuretics and β‐lockers, respectively. The combination therapy could modify the treatment effects of ACEI or CCB used alone. However, this possibility seems unlikely as it has been previously demonstrated that neither β‐blocker nor diuretics alter endothelial function in patients with essential hypertension.

In conclusion, the present data showed that adequate blood pressure control over a 12‐month period either with ACEI or CCB may improve baroreflex sensitivity in patients with essential hypertension. Furthermore, treatment with ACEI may improve vasoreactivity more than CCB, suggesting an additional benefit in the treatment of hypertension.