Abstract

We measured the effects of angiotensin II blockade on arterial stiffness, augmentation index (AI%), pulse wave velocity (PWV), and blood pressure (BP) in 12 hypertensive patients (mean 49 ± 11 years) in a 4-week, randomized, cross-over study comparing valsartan 160 mg/day with captopril 100 mg/day, with a 2-week washout period. Subsequently both therapies were combined. Reductions in PWV and AI% remained significant when corrected for BP. Combined therapy reduced PWV and AI% (P < .05) more than monotherapy, even when corrected for BP. The study shows that angiotensin receptor antagonists reduce arterial stiffness in hypertension comparable with and possibly additive to angiotensin converting enzyme inhibition.

Am J Hypertens 2002;15:321–325 © 2002 American Journal of Hypertension, Ltd.

Arterial stiffness is an independent marker of increased total and cardiovascular mortality and in hypertension,1 more closely related to risk than any single measure of blood pressure (BP). In patients with end-stage renal disease, a reduction in pulse wave velocity (PWV) was of greater prognostic significance than a reduction in BP.2

Angiotensin converting enzyme (ACE) inhibitors lower BP and decrease arterial stiffness both in humans and in experimental animals beyond that expected from the reduction in BP alone.3,4 More recently, we have shown that in poorly controlled hypertension, an angiotensin II (ATII) receptor antagonist added to a regimen of more than three antihypertensive agents, including an ACE inhibitor, has a beneficial effect on arterial wave reflection and pulse pressure (PP) amplification.5 The effect of monotherapy with an ATII receptor antagonist on large artery function, however, has not been described. Furthermore, although both ATII receptor antagonists and ACE inhibitors target the same pressor system, because of their different sites of action they may have additive or synergistic effects. The purpose of the study was to explore the effects of an ATII receptor antagonist valsartan on large artery properties, particularly arterial stiffness, in comparison and in combination with an ACE inhibitor, captopril.

Methods

Subjects

Twelve otherwise healthy white patients (aged 49 ± 11 [SD] years, range 27 to 72 years) with essential hypertension (>140/90 mm Hg) and confirmed by ambulatory BP monitoring (>135/85 mm Hg), who were not on any medication, were studied after a supine rest of 15 min in a quiet room at 23°C. Informed consent was obtained from all subjects and the study was approved by the Institutional Ethics Committee.

In a crossover randomized study, patients received valsartan, initially 80 mg/day for 2 weeks, increased to 160 mg/day for the subsequent 2 weeks, or captopril 50 mg/day, initially for 2 weeks and increased to 100 mg/day for the subsequent 2 weeks. At the end of 4 weeks of treatment the patients had a 2-week washout period, followed by crossover with treatment continued for another 4 weeks and at the end of this period, valsartan 160 mg/day and captopril 100 mg/day, respectively, were combined for an additional 2 weeks in all patients.

Patients were studied while fasting in the morning (apart from medication, which was taken as a single morning dose at a standardized time 2 to 4 h earlier), and having abstained from smoking or from consuming caffeine or alcohol in the previous 12 h.

Derivation of arterial pressure waveform

After recording BP (mean of three readings) using an automated digital oscillometric BP monitor (Omron model HEM 705-CP; Omron Healthcare, Inc., Vernon Hills, IL) the same arm was used for applanation tonometry with a high-fidelity micromanometer (PWV Medical Sphygmocor, Sydney, NSW, Australia) to derive the aortic pressure waveform from which the augmentation index (AI%) is calculated.5 The validity of the derived AI%, a measure of wave reflection, has been confirmed and is highly reproducible.6 The time taken by the reflected wave to return from the peripheral reflecting sites to the ascending aorta was calculated from the foot of the pressure wave to the shoulder as ΔTr. The left ventricular ejection duration (LVED) was measured from the foot of the pressure wave to the diastolic incisura.

Measurement of pulse wave velocity

Carotid-femoral PWV, an index of arterial stiffness, was determined by the simultaneous recording of waveforms by two pressure sensitive transducers, according to the foot-to-foot method using the validated Complior device (Colson, Dupont Medical, Paris, France). The observer was blind to the form of therapy.

Statistical evaluation

Statistical analysis is performed using JMP software, version 3.0 (SAS Institute, Cary, NC). Results are presented as mean ± SEM at baseline and follow-up visits. Hemodynamic changes are studied by analysis of covariance for repeated measures applied to a crossover design. Randomized group and period effects were examined. However, as there was no significant difference found, it was assumed that no carryover effect existed, and further analyses were based on ignoring the order in which subjects received their treatment. Dependent variables included in the analysis are changes in PWV and AI% from baseline. The effect of monotherapy (follow-up data on valsartan 160 mg and captopril 100 mg were considered as two replicates on the same individual) versus combined therapy are examined with and without adjustment for absolute level of diastolic blood pressure (DBP), as minimum distending pressure is a more appropriate index of pressure dependence than systolic blood pressure (SBP), which itself is contributed by systolic pressure augmentation in the aorta. Significance at P < .05 is assumed.

Results

There was no significant difference in the baseline values between the two groups (Table 1).

Table 1

Changes in hemodynamic parameters after valsartan 160 mg, captopril 100 mg, and in combination in hypertensive patients (n = 12)

 Valsartan Captopril Combined 
 Before 80 mg 160 mg Before 50 mg 100 mg 160/100 mg 
Brachial SBP (mm Hg) 157 ± 4 144 ± 3.8* 134 ± 4 157 ± 3 142 ± 5* 138 ± 4 129 ± 3 
Brachial DBP (mm Hg) 96 ± 2 90 ± 2.9* 83 ± 2 98 ± 3 88 ± 2.9* 85 ± 2 80 ± 2 
Brachial PP (mm Hg) 61 ± 2 54 ± 2.1* 51 ± 3 59 ± 3 54 ± 2.8* 53 ± 3 49 ± 3 
Aortic SBP (mm Hg) 147 ± 4 132 ± 5* 123 ± 5 148 ± 4 130 ± 5* 124 ± 4 118 ± 3 
Aortic DBP (mm Hg) 97 ± 3 91 ± 3* 83 ± 2 99 ± 3 89 ± 3* 86 ± 2 81 ± 2 
Aortic PP (mm Hg) 50 ± 3 41 ± 3* 37 ± 3 49 ± 3 41 ± 4* 38 ± 2 37 ± 2 
Heart rate (min−175 ± 4 74 ± 4.3 75 ± 4 75 ± 4 73 ± 3.4 74 ± 4 74 ± 4 
Tr (msec) 133 ± 4 138 ± 5 143 ± 4* 135 ± 4 136 ± 3 140 ± 3 142 ± 5 
LVED (msec) 330 ± 6 321 ± 5 335 ± 8 312 ± 7 329 ± 8 320 ± 9 327 ± 9 
 Valsartan Captopril Combined 
 Before 80 mg 160 mg Before 50 mg 100 mg 160/100 mg 
Brachial SBP (mm Hg) 157 ± 4 144 ± 3.8* 134 ± 4 157 ± 3 142 ± 5* 138 ± 4 129 ± 3 
Brachial DBP (mm Hg) 96 ± 2 90 ± 2.9* 83 ± 2 98 ± 3 88 ± 2.9* 85 ± 2 80 ± 2 
Brachial PP (mm Hg) 61 ± 2 54 ± 2.1* 51 ± 3 59 ± 3 54 ± 2.8* 53 ± 3 49 ± 3 
Aortic SBP (mm Hg) 147 ± 4 132 ± 5* 123 ± 5 148 ± 4 130 ± 5* 124 ± 4 118 ± 3 
Aortic DBP (mm Hg) 97 ± 3 91 ± 3* 83 ± 2 99 ± 3 89 ± 3* 86 ± 2 81 ± 2 
Aortic PP (mm Hg) 50 ± 3 41 ± 3* 37 ± 3 49 ± 3 41 ± 4* 38 ± 2 37 ± 2 
Heart rate (min−175 ± 4 74 ± 4.3 75 ± 4 75 ± 4 73 ± 3.4 74 ± 4 74 ± 4 
Tr (msec) 133 ± 4 138 ± 5 143 ± 4* 135 ± 4 136 ± 3 140 ± 3 142 ± 5 
LVED (msec) 330 ± 6 321 ± 5 335 ± 8 312 ± 7 329 ± 8 320 ± 9 327 ± 9 

SBP = systolic blood pressure; DBP = diastolic blood pressure; PP = pulse pressure; Tr = time for return of reflected wave; LVED = left ventricular ejection duration.

Data are given as mean ± SEM.

*

P < .01 v baseline;

P < .001 v baseline;

P < .05 v monotherapy.

Blood pressure and pulse wave velocity

Brachial SBP and DBP decreased significantly and similarly with both valsartan and captopril (P < .001) from baseline (Table 1). Although there was evidence of a dose-response relationship, the reductions after 160 mg and 100 mg, respectively, were greater than that after 80 mg and 50 mg; this did not achieve statistical significance. At baseline PWV was significantly correlated to brachial SBP (r = 0.52, P < .0001) and DBP (r = 0.48, P < .0001). The PWV decreased significantly (P < .001) after both drugs (Fig. 1). The decrease in PWV with captopril and valsartan was independent of BP (P < .05). There was a further significant decrease in brachial SBP, DBP, and PWV with the combination therapy compared with monotherapy (P < .05). Also, when corrected for the absolute level of BP, the reduction in PWV with combination therapy was significantly (P < .05) greater than with monotherapy.

Pulse wave velocity and augmentation index after treatment with valsartan 80 and 160 mg and with captopril 50 and 100 mg as well as their combination in 12 hypertensive subjects. *P < .001 from baseline; fP < 0.5 monotherapy v combined (mean ± SEM). Val = valsartan; Cap = captopril.

Pulse pressure and augmentation index

At baseline the aortic PP was much lower compared with brachial PP (P < .001). Brachial and aortic PP decreased significantly with both drugs (P < .001), as shown in Table 1; however, the decrease occurred to the same extent in both the brachial and aortic PP.

The AI% decreased after both captopril (P < .001) and valsartan (P < .001) from baseline (Fig. 1), again in a nonsignificant dose-related fashion. However, there was no statistically significant difference between the two treatments and the fall in AI% was independent of BP (P < .05). The decrease in AI% after combination therapy was significant compared to monotherapy (P < .05) and still significant when corrected for BP (P < .05). The reduction in AI% was not related to changes in PWV or ΔTr. There was a significant increase in the ΔTr after valsartan but not after captopril (P < .05). There was no change in LVED or heart rate with either monotherapy or with the combination.

Discussion

The novel finding in our study is that in hypertensive subjects, after use of an ATII receptor antagonist, there was a significant reduction in AI% and PWV. As the relationship between BP and arterial stiffness is nonlinear, we also analyzed the changes in AI% and PWV corrected for BP. The fact that the reduction in PWV and AI% was independent of BP suggests the decrease in arterial stiffness may occur both by the direct effect of the drug on vascular wall as well as BP reduction. The ATII receptor blocker was as effective as an ACE inhibitor in reducing arterial stiffness. Finally, there may be an additive effect of the ATII receptor blocker and ACE inhibitor in combination, not only on BP but also on arterial stiffness.

Effect of angiotensin II blockade on arterial wave reflection

Reduction in wave reflection may be achieved by the following: 1) increased time taken for the reflected wave to return from the periphery to aorta, ΔTr; 2) shortening of LVED; or 3) reducing the intensity of wave reflection (decreased reflection coefficient).7 As valsartan did not change LVED, the improvement in timing presumably was partly related to the longer ΔTr in association with the decreased PWV. Nevertheless, the reduction in AI% was not related to changes in aortic PWV and ΔTr, suggesting that the decreased intensity of wave reflection at medium-sized muscular arteries was the principal mechanism.

Effect of angiotensin II blockade on pulse wave velocity

The other important effect of valsartan was a significant decrease in aortic PWV in parallel to the decrease in arterial wave reflection and PP in central arteries. These changes in PWV were independent of BP and were observed even after adjustment for baseline values of PWV and BP.

The arterial pressure-volume relationship is curvilinear, arteries being stiffer at high pressure, and arterial stiffness decreases with BP reduction. Therefore it is often difficult to ascertain whether the improvement in PWV with antihypertensive therapy is the “passive” result of BP reduction or is a consequence of pressure-independent alterations of the arterial wall. ACE inhibition improves large artery compliance independently of BP changes,4 probably by acute functional changes of vascular smooth muscle relaxation and in the long-term by decreased arterial wall thickness, collagen content, and reversion of smooth muscle cell hypertrophy.3 In addition, ATII blockade has been shown to reduce the viscosity index and aortic stiffness in rats with renovascular hypertension.8

There is evidence that ATII blockade may reduce vascular stiffness by both structural and functional changes. In hypertensive patients with left ventricular hypertrophy, valsartan was as effective as enalapril in causing regression.9 In normotensive volunteers, ATII infusion increased the AI% and aortic PP but not the brachial PP.10 The ATII receptor blocker candesartan improved tonic nitric oxide (NO) release and reduced vasoconstriction to endogenous endothelin 1 in the forearm of hypertensive patients after 12 months therapy.11 As it is unlikely that structural changes would occur after 4 weeks of therapy, the likely mechanism may involve functional changes in vascular relaxation possibly by improved endothelial dysfunction, increasing the bioavailability of NO,12 as was seen in the case of 4 weeks therapy with losartan.

ACE inhibition and angiotensin II receptor blockade in combination

For both valsartan and captopril, we saw evidence of a dose-response relationship (Table 1 and Fig. 1), although this did not achieve significance presumably due to the relatively small number of subjects. Both ATII receptor antagonists and ACE inhibitors affect the same pressor system; however, because they act on different sites, they may have additive or synergistic effects producing a more complete blockade including local and non-ACE pathways. Also, the ancillary properties of both ACE inhibitors (eg, interruption of bradykinin metabolism and interaction with NO) and of angiotensin II receptor antagonists (eg, interaction with prostaglandins and NO) may be synergistic when the two groups are combined.13 In addition, the recommended doses of ACE inhibitors may provide only partial inhibition of ACE.14 However, because of the small number of subjects, the lack of a washout period before studying combined therapy, and the observation of only peak effects, the additive effects must be interpreted with caution. Nonetheless, the latter was intentional, as we wished to see the combined effect (including any carry-over effect), reflecting clinical practice in which treatment is added on. However, given the shorter duration of action seen with captopril, studying the effects at trough may help to separate BP– independent effects on stiffness. Although favorable effects of combined therapy have been seen in heart failure and diabetic proteinuria,15 the benefits of such dual therapy must be established in hypertension. In addition, a long-term study is also required to separate the likely functional and structural mechanisms underlying the changes in stiffness. Nonetheless, these data do suggest an important role for the renin-angiotensin system in the control of large arterial function.

Acknowledgments

We thank Dr. K. Bennett for statistical advice.

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