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. 2001 Feb 1;530(Pt 3):541–550. doi: 10.1111/j.1469-7793.2001.0541k.x

Changes in the derived central pressure waveform and pulse pressure in response to angiotensin II and noradrenaline in man

Ian B Wilkinson *, Helen MacCallum *, Patrick C Hupperetz *, Caspar J van Thoor *, John R Cockcroft †, David J Webb *
PMCID: PMC2278423  PMID: 11158283

Abstract

  1. Peripheral pulse pressure provides a surrogate measure of arterial stiffness. Analysis of the central pressure waveform allows assessment of central pulse pressure and arterial stiffness. The aim of the present study was to assess the effect of vasoconstrictor drugs on pulse pressure amplification and arterial stiffness in vivo.

  2. Eight healthy male subjects (mean age 30 years) received an infusion of angiotensin II (1, 3, 6 and 10 ng kg−1 min−1), noradrenaline (10, 30, 60 and 100 ng kg−1 min−1) and matching placebo, in random order, on separate occasions. Peripheral blood pressure and cardiac index were recorded non-invasively. Pulse wave analysis was used to determine augmentation index (AIx), which provides a measure of systemic arterial stiffness, aortic stiffness and central arterial pressure.

  3. Infusion of both active drugs resulted in a significant increase in peripheral mean arterial pressure (PMAP), peripheral vascular resistance, AIx, aortic stiffness and central pulse pressure, but only angiotensin II reduced cardiac index.

  4. Peripheral pulse pressure was unaffected by infusion of angiotensin II but increased with noradrenaline, which also produced a greater reduction in pulse pressure amplification than angiotensin II. However, the linear relationship of PMAP with both AIx and aortic stiffness did not differ significantly between drugs.

  5. These results demonstrate that intravenous infusion of angiotensin II and noradrenaline increase aortic and systemic arterial stiffness. Despite a similar effect on both parameters, for a given change in PMAP, the two drugs had divergent effects on peripheral pulse pressure and pulse pressure amplification. These data reveal that assessment of peripheral pulse pressure does not always reliably predict changes in central pulse pressure or arterial stiffness.

Arterial stiffness is an important, independent predictor of cardiovascular mortality (Blacher et al. 1999a,b) and can be assessed in a number of ways (Cockcroft & Wilkinson, 1998). Peripheral pulse pressure is a surrogate measure of arterial stiffness that can be easily assessed with conventional sphygmomanometry, and several studies have recently confirmed that it is a powerful predictor of cardiovascular risk in both normotensive (Benetos et al. 1997; Franklin et al. 1999) and hypertensive subjects (Benetos et al. 1998). However, whilst diastolic and mean arterial pressure are relatively constant throughout the arterial tree, systolic pressure and, therefore, pulse pressure varies considerably (Kroeker & Wood, 1955; Rowell et al. 1968). This is due, in part, to differences in vessel stiffness and the phenomenon of wave reflection within the arterial tree (Latham et al. 1985; Nichols & O'Rourke, 1998). Normally, there is considerable amplification of pulse pressure between the aorta and brachial artery (Kroeker & Wood, 1955). However, the degree of amplification is not fixed and is influenced by a number of factors including age (Nichols & O'Rourke, 1998), posture (Kroeker & Wood, 1955) and exercise (Rowell et al. 1968). Therefore, peripheral pulse pressure may not always provide a reliable estimate of central pulse pressure or indeed, arterial stiffness. Such differences may be clinically important because it is aortic, and not brachial, pressure that determines left ventricular workload (Westerhof & O'Rourke, 1995). Moreover, aortic pulse pressure has been shown to predict the rate of restenosis following coronary angioplasty, independently of peripheral pressure (Nakayama et al. 2000), and carotid, but not brachial, pulse pressure correlates with carotid intima-media thickness (Boutouyrie et al. 1999; Simons et al. 1999) - itself an independent predictor of cardiovascular risk (O'Leary et al. 1999).

The arterial pressure waveform contains valuable information concerning both aortic and systemic arterial stiffness, which may provide a better assessment of cardiovascular risk than central pulse pressure alone (Wilkinson et al. 1999). Indeed, the shape of the aortic pressure waveform is an independent predictor of left ventricular mass (Saba et al. 1993). Over 100 years ago (Mahomed, 1872), demonstrated that it was possible to record and analyse the peripheral pressure waveform, although mostly in a qualitative manner, but more recently, non-invasive assessment of the central arterial waveform has become possible (O'Rourke & Gallagher, 1996). Central pulse wave analysis (PWA), developed by O'Rourke and colleagues, employs applanation tonometry to record pressure waves from the radial artery accurately (Kelly et al. 1989), and a generalized transfer factor, which has been validated under resting conditions and during haemodynamic transients (Karamanoglu et al. 1993; Takazawa et al. 1996; Chen et al. 1997; Soderstrom et al. 1998; Fetics et al. 1999), can then be used to generate the corresponding central arterial waveform. From this, both aorticand systemic arterial stiffness can be assessed, non-invasively and reproducibly (Wilkinson et al. 1998), by calculating augmentation index (AIx) and the timing of the reflected pressure wave, respectively. In addition, unlike most other techniques for assessing arterial stiffness, central arterial pressure can also be determined.

Angiotensin II (Merillon et al. 1982) and noradrenaline (Gabe et al. 1964; O'Rourke & Taylor, 1966) both increase arterial stiffness and mean arterial pressure (Brod et al. 1969), but have different effects on peripheral pulse pressure. Indeed, while intravenous infusion of noradrenaline increases peripheral pulse pressure (Goldenberg et al. 1948), angiotensin II does not (Brown et al. 1988). We hypothesized that both drugs would produce similar changes in the shape of the central arterial pressure waveform and elevation of central pulse pressure, due to an increase in arterial stiffness, despite their different effects on peripheral pulse pressure. The aim of this study was to test this hypothesis in healthy men using stepped infusions of angiotensin II, noradrenaline and placebo, whilst determining central pressure waveforms non-invasively using the technique of PWA.

METHODS

Eight healthy male volunteers, mean age 30 years (range 21-42 years), were recruited from a community volunteer database held at the Western General Hospital, Edinburgh. Individuals with cardiovascular risk factors, including diabetes mellitus, hypercholesterolaemia (total cholesterol >6.5 mmol l−1), and brachial blood pressure >160/95 mmHg, or clinical evidence of cardiovascular disease, were excluded. All subjects were non-smokers and none were receiving any medication. Approval for the study was obtained from the local research ethics committee, and informed written consent obtained from each participant. The investigations conformed to the principles outlined in the Declaration of Helsinki.

Peripheral haemodynamics

Peripheral blood pressure was measured in duplicate, in the brachial artery of the dominant arm using the validated Omron HEM-705CP oscillometric sphygmomanometer (O'Brien et al. 1996). Peripheral mean arterial pressure (PMAP) was calculated from integration of the radial pressure waveform. Cardiac index (CI) was assessed non-invasively using a validated transthoracic electrical bioimpedance technique (Northridge et al. 1990) (BoMed; NCCOM3-R7; Irvine, CA, USA), and peripheral vascular resistance (PVR) was calculated as PMAP divided by CI (expressed in arbitrary units, a.u.).

Pulse wave analysis

Peripheral pressure waveforms were recorded from the radial artery of the dominant hand at the wrist using a high fidelity micromanometer (SPC-301; Millar Instruments, Texas, USA) and the SphygmoCor apparatus (SCOR; PWV Medical, Sydney, Australia), as previously described in detail (Wilkinson et al. 1998, 2000). After 20 sequential waveforms had been acquired, the technique of PWA (O'Rourke & Gallagher, 1996) was used to generate an averaged peripheral and corresponding central (ascending aortic), pressure waveform. The augmentation index and ascending aortic pressure were derived from the central pressure waveform. The augmentation index was defined as the difference between the second (P2) and first (P1) systolic peaks of the central arterial waveform, expressed as a percentage of the central pulse pressure. The aortic pulse wave velocity was estimated by calculating the time between the foot of the pressure wave and the inflection point as described previously (Murgo et al. 1980). The inflection point indicates the return of the reflected wave, which in turn provides a measure of the transit time between the ascending aorta and the main reflectance site (the aortic bifurcation) and thus aortic pulse wave velocity (Marchais et al. 1993).

Drugs

All drugs were prepared aseptically from freshly opened vials, using 0.9 % saline (Baxter; Norfolk, UK) as a diluent. Angiotensin II (Clinalfa; Laufelfingen; Switzerland) was infused intravenously at doses of 1, 3, 6 and 10 ng kg−1 min−1, and noradrenaline (Levophed; Winthrop, UK) at doses of 10, 30, 60 and 100 ng kg−1 min−1. These values were selected from the published literature to produce similar changes in PMAP (Brown et al. 1988; Tomlinson et al. 1990; Ramsay et al. 1992; Motwani & Struthers, 1992). Saline was used as a matching placebo and the infusion rate was kept constant at 60 ml min−1 throughout the study period.

Study protocol

The study was conducted in a double-blind, randomized manner, with three visits at weekly intervals. Subjects abstained from alcohol and caffeine for 24 h before each visit, and all studies were conducted after an overnight fast with subjects resting supine in a quiet, temperature-controlled room (22 ± 2°C). Saline was infused continuously via an 18G cannula sited in the antecubital fossa of the non-dominant arm and after 45 min, baseline values of peripheral blood pressure, CI and radial pressure waveforms were recorded in duplicate. Subjects then received a stepped infusion of either angiotensin II, noradrenaline or matching placebo. Each dose was infused for 15 min with peripheral blood pressure, CI and radial pressure waveforms being assessed during the last 5 min of each infusion period.

Data analysis

All data were analysed as changes from values at baseline, using analysis of variance (ANOVA). Comparisons between data were made using repeated measures ANOVA or Student's paired t tests, as appropriate. All values are reported as means ±s.e.m., unless otherwise stated and a P value < 0.05 was considered as statistically significant.

RESULTS

There was no significant difference in any of the measured parameters, at baseline, between the three infusion periods (Table 1), or during the placebo phase (data not shown). The effects of the stepped infusion of angiotensin II and noradrenaline on peripheral and central haemodynamics are presented in Table 2 and 3.

Table 1.

Baseline haemodynamic parameters

Placebo Angiotensin II Noradrenaline
Heart rate (beats min−1) 59 ± 2 61 ± 2 59 ± 3
Cardiac index (l min−1 m−2) 2.8 ± 0.2 3.1 ± 0.2 2.9 ± 0.2
PSBP (mmHg) 119 ± 2 120 ± 2 121 ± 3
PDBP (mmHg) 71 ± 2 70 ± 3 74 ± 2
PMAP (mmHg) 83 ± 3 83 ± 3 87 ± 2
PPP (mmHg) 48 ± 2 50 ± 2 47 ± 2
CMAP (mmHg) 83 ± 3 83 ± 3 87 ± 2
CPP (mmHg) 29 ± 1 30 ± 1 29 ± 1
AIx (%) −1 ± 4 −3 ± 4 3 ± 3
TR (ms) 160 ± 5 167 ± 5 161 ± 4
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Baseline haemodynamic parameters for each of the three visits (means ±s.e.m.). There was no significant difference in any parameter between visits. PSBP, peripheral systolic blood pressure; PDBP, peripheral diastolic blood pressure; PMAP, peripheral mean arterial pressure; PPP, peripheral pulse pressure; CMAP, central mean arterial pressure; CPP, central pulse pressure; AIx, augmentation index; TR, timing of the reflected pressure wave.

Table 2.

Absolute changes in haemodynamics during angiotensin II infusion

AngII (ng Kg−1 min−1) HR (beats min−1) PMAP (mmHg) PPP (mmHg) CI (l min−1 m−2) PVR (a.u.) CMAP (mmHg) CPP (mmHg) PPP:CPP ratio AIx (%) TR (ms) P1-CDBP (mmHg) ED (ms)
1 −3 ± 2 5 ± 2 −5 ± 2 −0.3 ± 0.1 4.6 ± 1.0 5 ± 2 0 ± 3 −0.1 ± 0.09 6 ± 4 −9 ± 4 −2 ± 1 −2 ± 2
3 −2 ± 1 15 ± 2 −4 ± 2 −0.5 ± 0.1 10.4 ± 0.9 15 ± 2 3 ± 2 −0.25 ± 0.08 17 ± 5 −11 ± 3 −2 ± 1 −2 ± 1
6 −2 ± 1 21 ± 2 −4 ± 3 −0.5 ± 0.1 12.3 ± 1.5 21 ± 2 6 ± 2 −0.38 ± 0.05 25 ± 4 −18 ± 7 −3 ± 1 2 ± 2
10 −7 ± 3 30 ± 3 −2 ± 3 −0.4 ± 0.1 15.1 ± 0.9 30 ± 3 11 ± 3 −0.47 ± 0.04 30 ± 4 −20 ± 5 −2 ± 1 4 ± 2
P < 0.001 < 0.001 0.1 < 0.001 < 0.001 < 0.001 0.002 < 0.001 < 0.001 < 0.001 0.3 0.1
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AngII, angiotensin II; HR, heart rate; PMAP, peripheral mean arterial pressure; PPP, peripheral pulse pressure; CI, cardiac index; PVR, peripheral vascular resistance; CMAP, central mean arterial pressure; CPP, central pulse pressure; AIx, augmentation index; TR, timing of the reflected pressure wave; P1, height of the first systolic peak; CDBP, central diastolic blood pressure; ED, ejection duration. Data are presented as changes from baseline (means ±s.e.m.). Significance was determined using ANOVA compared with the placebo phase, n = 8.

Table 3.

Absolute changes in haemodynamics during noradrenaline infusion

Norad (ng kg−1 min−1) HR (beats min−1) PMAP (mmHg) PPP (mmHg) CI (l min−1 m−2) PVR (a.u.) CMAP (mmHg) CPP (mmHg) PPP:CPP ratio AIx (%) TR (ms) P1-CDBP (mmHg) ED (ms)
10 −2 ± 2 −1 ± 1 1 ± 1 −0.1 ± 0.1 0.4 ± 0.7 −1 ± 1 1 ± 1 −0.01 ± 0.03 3 ± 2 −4 ± 4 1 ± 1 1 ± 1
30 −2 ± 2 5 ± 1 1 ± 2 −0.1 ± 0.1 3.2 ± 0.7 5 ± 1 3 ± 1 −0.09 ± 0.04 4 ± 2 −1 ± 4 1 ± 1 8 ± 2
60 −5 ± 2 13 ± 3 6 ± 2 −0.1 ± 0.1 6.9 ± 2.2 13 ± 3 8 ± 2 −0.19 ± 0.05 14 ± 2 −11 ± 4 2 ± 1 11 ± 2
100 −5 ± 4 19 ± 4 12 ± 3 −0.1 ± 0.2 8.2 ± 2.4 19 ± 4 15 ± 3 −0.27 ± 0.05 19 ± 1 −16 ± 4 6 ± 2 9 ± 3
P 0.002 < 0.001 < 0.001 0.4 < 0.001 < 0.001 < 0.001 < 0.001 < 0.001 0.001 0.029 0.1
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Norad, noradrenaline; for rest of abbreviations see legend to Table 2. Data are presented as changes from baseline (means ±s.e.m.). Significance was determined using ANOVA compared with the placebo phase, n = 8.

In the present study, infusion of angiotensin II resulted in a significantly greater increase in PMAP (P < 0.001, ANOVA) and PVR (P < 0.001), and fall in CI (P < 0.001) than did noradrenaline. The changes in central mean arterial pressure (P < 0.001), AIx (P = 0.001) and the timing of the reflected pressure wave (P = 0.043) were also significantly greater during infusion of angiotensin II than noradrenaline. There was no significant difference between drugs with regard to the observed changes in heart rate (P = 0.9), but ejection duration increased significantly more during infusion of noradrenaline (P < 0.001). However, the two drugs had significantly different effects on peripheral pulse pressure (P < 0.001), which tended to increase during infusion of noradrenaline and decrease with angiotensin II, but not central pulse pressure (P = 0.2). This resulted in a significantly smaller reduction in pressure amplification (the ratio of peripheral to central pulse pressure) during noradrenaline infusion compared with angiotensin II (P < 0.001). There was also a significant difference (P = 0.006) between the two drugs on non-augmented central pulse pressure (P1-central diastolic blood pressure), which was unaltered during infusion of angiotensin II, but which increased significantly with noradrenaline. Figure 1 illustrates the effects of the two drugs on the central arterial waveform in one representative subject.

Figure 1. Effect of angiotensin II and noradrenaline on the central arterial waveform.

Figure 1

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Representative central arterial pressure waveforms from one individual illustrating the changes in the shape of the waveform in response to incremental infusions of angiotensin II and noradrenaline.

Linear regression analysis was used to compare the effects of the two drugs on the various haemodynamic parameters with reference to PMAP - a key determinant of arterial stiffness, because angiotensin II resulted in a greater rise in PMAP. The slopes and intercepts of the regression lines for AIx, and the timing of the reflected wave on PMAP did not differ significantly indicating that, for a given change in PMAP, both drugs produced a similar change in the two measures of arterial stiffness (Fig. 2). There was a significant association between AIx and the timing of the reflected pressure wave, as shown in Fig. 3. With regard to the effect of the two drugs on pulse pressure, there was a significant difference in the slope of the regression lines for both peripheral and central pulse pressure (Fig. 4).

Figure 2. Relationship between arterial stiffness and mean arterial pressure.

Figure 2

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A, the relationship between augmentation index (AIx) and peripheral mean arterial pressure (PMAP) during infusion of angiotensin II (○) and noradrenaline (□). The linear regression lines are shown for angiotensin II (continuous line; r = 0.80; P < 0.001 ANOVA) and noradrenaline (dashed line; r = 0.89; P < 0.001), and did not differ significantly in slope (0.82 versus 0.80; P = 0.9). B, the relationship between the timing of the return of the reflected pressure wave to the ascending aorta (TR) and peripheral mean arterial pressure (PMAP). The linear regression lines for angiotensin II (r = -0.45; P = 0.007 ANOVA) and noradrenaline (r = -0.53; P = 0.001), did not differ significantly in slope (-0.38 versus -0.60; P = 0.3).

Figure 3. Relationship between augmentation index and aortic stiffness.

Figure 3

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The relationship between augmentation index (AIx) and the timing of the return of the reflected pressure wave to the ascending aorta (TR), which provides a measure of aortic stiffness, during infusion of angiotensin II (○) and noradrenaline (□). The linear regression lines for angiotensin II (continuous line, r = -0.50; P = 0.002 ANOVA) and noradrenaline (dashed line, r = -0.50; P = 0.002) did not differ significantly in slope (-0.56 versus -0.47; P = 0.5).

Figure 4. Relationship between pulse pressures and mean arterial pressure.

Figure 4

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DISCUSSION

The present study describes the effects of an incremental infusion of noradrenaline and angiotensin II, on peripheral arterial pressure, central arterial pressure and the ascending aortic waveform. The central waveform was derived from the radial artery waveform, recorded non-invasively with applanation tonometry, using the technique of central PWA (O'Rourke & Gallagher, 1996). Values of aortic and systemic arterial stiffness, and central arterial pressure were calculated from the central waveform. The main novel findings of the present study were that, despite similar increases in systemic and aortic arterial stiffness, intravenous infusion of angiotensin II widened central pulse pressure less than noradrenaline. The two drugs also differed in their effects on pulse pressure amplification between the aorta and brachial artery, as discussed later.

Peripheral haemodynamics

As expected, intravenous infusion of both angiotensin II and noradrenaline resulted in a significant increase in PMAP, PVR and reduction in heart rate (Goldenberg et al. 1948; Brod et al. 1969; Motwani & Struthers, 1992). These changes, which were greater with angiotensin II, are likely to reflect systemic vasoconstriction and a reflex bradycardia due to baroreceptor stimulation. In agreement with previous observations, peripheral pulse pressure increased during infusion of noradrenaline (Goldenberg et al. 1948; Ramsay et al. 1992), but did not change with administration of angiotensin II (Brown et al. 1988; Ramsay et al. 1992).

Pulse pressure is determined mainly by stroke volume, the peak rate of ventricular ejection and the distensibility of the arterial wall, and is often regarded as a surrogate measure of arterial stiffness (Rushmer, 1961). As discussed in more detail below, both drugs increased systemic and aortic stiffness and, therefore, it seems likely that their different effects on peripheral pulse pressure is due to a divergent effect on CI. In agreement with previous data, CI declined during angiotensin II infusion (Brod et al. 1969; Motwani & Struthers, 1992), probably due to baroreceptor stimulation and reflex cardio-inhibition, but was unaltered following infusion of noradrenaline (Goldenberg et al. 1948; Brod et al. 1969), which is likely to be due to the cardio-stimulatory effect of myocardial adrenoceptor activation by noradrenaline (Sarnoff et al. 1960) counteracting the reflex cardio-inhibition.

Central haemodynamics

Infusion of both angiotensin II and noradrenaline resulted in an increase in central mean arterial pressure and central pulse pressure. However, there was a significantly steeper, linear relationship between central pulse pressure and PMAP for noradrenaline than for angiotensin II, indicating that, for a given increment in PMAP, central pressure was elevated more by noradrenaline.

Assessment of the changes in central pulse pressure is complicated by the effects of wave reflection (Nichols & O'Rourke, 1998). Therefore, we examined the changes in non-augmented central pulse pressure (P1-CDBP), which remained static during angiotensin II infusion but increased significantly with noradrenaline. As with the changes in peripheral pulse pressure, this disparity is likely to be a consequence of the different effect of the two drugs on cardiac ejection - more vigorous ventricular ejection with noradrenaline than angiotensin II, which is likely to alter the flow pattern in the ascending aorta. These data indicate that the rise in central pulse pressure with angiotensin II was due mainly to enhanced augmentation of systolic pressure, due to increased wave reflection and earlier return of the reflected wave to the ascending aorta. However, during infusion of noradrenaline central pulse pressure increased due to enhanced wave reflection and an increase in non-augmented pulse pressure.

Normally, there is amplification of the pulse pressure moving from the aorta to the periphery, such that, brachial systolic pressure may exceed ascending aortic pressure by more than 20 mmHg (Kroeker & Wood, 1955). The degree of amplification varies, depending on a number of factors including age (Nichols & O'Rourke, 1998), posture (Kroeker & Wood, 1955) and exercise (Rowell et al. 1968). Amplification results from distortion of the pressure waveform during transmission to the upper limb and depends on the shape and harmonic content of the input (central) pressure waveform (Nichols & O'Rourke, 1998). However, the transfer function for the upper limb seems relatively constant (Karamanoglu et al. 1993), although as we did not directly assess aortic pressure invasively in this study, we cannot exclude the possibility of a change in the transfer function. Therefore, both changes in the pattern of left ventricular ejection and systolic augmentation, due to wave reflection, will influence the amplification ratio. Such mechanisms are likely to account for the different effects of angiotensin II and noradrenaline on pressure amplification in the present study, since non-augmented central pulse pressure increased significantly during infusion of noradrenaline but not angiotensin II, implying more vigorous left ventricular ejection with noradrenaline. Moreover, despite a similar reduction in heart rate, the increase in ejection duration was significantly less during infusion of angiotensin II compared with noradrenaline, indicating a relatively shorter ejection period. Such differences in amplification emphasize the fact that central and peripheral pulse pressures do not always change in parallel.

Central pressure waveforms and arterial stiffness

Previous studies have demonstrated significant changes in the shape of the peripheral pressure waveform in response to angiotensin II (Freis et al. 1966) and noradrenaline (Lax et al. 1956), indicative of increased arterial stiffness. However, this is the first time that the effect of these two drugs on central waveforms has been compared directly (Fig. 1). Aortic stiffness was assessed by calculating the timing of the return of the reflected pressure wave to the ascending aorta which provides an estimate of aortic pulse wave velocity as previously described (Murgo et al. 1980; Marchais et al. 1993). Augmentation index was used to quantify changes in systemic arterial stiffness.

Aortic, and systemic arterial, stiffness increased significantly during infusion of both angiotensin II and noradrenaline, confirming previous observations (Gabe et al. 1964; O'Rourke & Taylor, 1966; Merillon et al. 1982). Arterial stiffness is influenced by a number of factors including structural components of the vessel wall, distending pressure and vascular smooth muscle tone. Therefore, as PMAP increased more during infusion of angiotensin II than noradrenaline, we compared the slopes of the regression lines relating PMAP and the two measures of arterial stiffness to identify significant differences between the drugs. However, the slopes of the regression lines did not differ significantly (Fig. 2), indicating that for a given increment in PMAP, both drugs produced a similar increase in arterial stiffness. This suggests that either PMAP, rather than smooth muscle tone, is the most important determinant of arterial stiffness, or that both drugs induced a similar degree of smooth muscle constriction in the large arteries. However, from a practical point of view, these data demonstrate that when assessing arterial stiffness in vivo, changes in mean arterial pressure must be taken into consideration.

Augmentation index is a measure of the contribution of the reflected pressure wave to the central pressure waveform, and depends on the amplitude and velocity of the reflected wave. As noted above, both drugs resulted in an earlier return of the reflected wave to the aorta, indicating increased aortic pulse wave velocity and therefore, increased stiffness. Indeed, there was a linear relationship between AIx and estimated aortic pulse wave velocity (Fig. 3). In the present study, we did not assess pressure and flow simultaneously and could not therefore calculate vascular impedance or the amplitude of the pressure waveform directly. However, previous studies have demonstrated that the reflection coefficient is ∼0.85 under resting conditions (O'Rourke & Taylor, 1967; Nichols et al. 1977; Ting et al. 1991), implying a high degree of wave reflection within the arterial tree but this can be enhanced by infusion of angiotensin II (Merillon et al. 1982) or noradrenaline (O'Rourke & Taylor, 1966). The amplitude of wave reflection is thought to depend on the degree of impedance mismatch between the small arteries and the resistance vessels (Nichols & O'Rourke, 1998) and thus, on the stiffness of the small arteries and PVR. Therefore, it seems likely that both an increase in the amplitude of the reflected pressure waveform, and the speed of wave travel, accounts for the observed rise in AIx. Changes in heart rate can also influence AIx, as we have previously reported (Wilkinson et al. 2000). However, in the present study, infusion of both drugs resulted in a similar change in heart rate. Moreover, a 5 beats min−1 reduction in heart rate would only be expected to increase AIx by ∼4 percentage points, which would account for ∼13 % of the observed increase in AIx.

Summary

Angiotensin II and noradrenaline both increase aortic and systemic arterial stiffness to a similar degree, for a given increment in mean arterial pressure. However, angiotensin II had no effect on peripheral pulse pressure, which increased in response to noradrenaline. This differential effect is likely to be due to the reduction in CI during infusion of angiotensin II, which was not observed with noradrenaline. Both drugs increased central pulse pressure due, in part, to increased augmentation of systolic pressure by enhanced wave reflection, a consequence of increased arterial stiffness.

These observations indicate that mean arterial pressure is an important determinant of arterial stiffness in vivo and that changes in mean pressure cannot be ignored when interpreting changes in aortic pulse wave velocity or AIx. Moreover, although peripheral pulse pressure is an important predictor of cardiovascular risk and a useful surrogate measure of arterial stiffness under basal conditions, dynamic changes in peripheral pulse pressure, particularly in response to vasoactive drugs, need to be interpreted with caution, since they may not accurately reflect changes in central pulse pressure or arterial stiffness, particularly if cardiac output changes. This is likely to have important clinical implications since the available evidence would suggest that central pulse pressure (Boutouyrie et al. 1999; Nakayama et al. 2000) and the shape of the central pressure waveform (Saba et al. 1993; Covic et al. 2000) are important, independent predictors of cardiovascular risk.

Acknowledgments

This study was partly funded by the High Blood Pressure Foundation and a local Research and Development Grant (Lothian Universities NHS Hospital Trust). Dr I. B. Wilkinson, Dr J. R. Cockcroft and Professor D. J. Webb are supported by a Biomedical Research Collaboration Grant from the Wellcome Trust (056223). Professor D. J. Webb is currently in receipt of a Research Leave Fellowship from the Wellcome Trust (052633). We would like to thanks Mr D. Rooijmans for assistance with data collection.

References

  1. Benetos A, Rudnichi A, Safar M, Guize L. Pulse pressure and cardiovascular mortality in normotensive and hypertensive subjects. Hypertension. 1998;32:560–564. doi: 10.1161/01.hyp.32.3.560. [DOI] [PubMed] [Google Scholar]
  2. Benetos A, Safar M, Rudnichi A, Smulyan H, Richard J-L, Ducimetiere P, Guize L. Pulse pressure: a predictor of long-term cardiovascular mortality in a French male population. Hypertension. 1997;30:1410–1415. doi: 10.1161/01.hyp.30.6.1410. [DOI] [PubMed] [Google Scholar]
  3. Blacher J, Asmar R, Djane S, London GM, Safar ME. Aortic pulse wave velocity as a marker of cardiovascular risk in hypertensive patients. Hypertension. 1999a;33:1111–1117. doi: 10.1161/01.hyp.33.5.1111. [DOI] [PubMed] [Google Scholar]
  4. Blacher J, Guerin AP, Pannier B, Marchais SJ, Safar M, London G. Impact of aortic stiffness on survival in end-stage renal disease. Circulation. 1999b;99:2434–2439. doi: 10.1161/01.cir.99.18.2434. [DOI] [PubMed] [Google Scholar]
  5. Boutouyrie P, Bussy C, Lacolley P, Girerd X, Laloux B, Laurent S. Association between local pulse pressure, mean blood pressure, and large-artery remodeling. Circulation. 1999;100:1387–1393. doi: 10.1161/01.cir.100.13.1387. [DOI] [PubMed] [Google Scholar]
  6. Brod J, Hejl Z, Hornych A, Jirka J, Slechta V, Burianova B. Comparison of the haemodynamic effects of equipressor doses of intravenous angiotensin and noradrenaline in man. Clinical Science. 1969;36:161–172. [PubMed] [Google Scholar]
  7. Brown MA, Broughton PF, Symonds EM. The effects of intravenous angiotensin II upon blood pressure and sodium and urate excretion in human pregnancy. Journal of Hypertension. 1988;6:457–464. doi: 10.1097/00004872-198806000-00005. [DOI] [PubMed] [Google Scholar]
  8. Chen C-H, Nevo E, Fetics B, Pak PH, Yin FCP, Maughan WL, Kass DA. Estimation of central aortic pressure waveform by mathematical transformation of radial tonometry pressure. Circulation. 1997;95:1827–1836. doi: 10.1161/01.cir.95.7.1827. [DOI] [PubMed] [Google Scholar]
  9. Cockcroft JR, Wilkinson IB. Vessel wall properties and cardiovascular risk. Journal of Human Hypertension. 1998;12:343–344. doi: 10.1038/sj.jhh.1000605. [DOI] [PubMed] [Google Scholar]
  10. Covic A, Goldsmith DJA, Panaghiu L, Covic M, Sedor J. Analysis of the effect of haemodialysis on peripheral and central arterial pressure waveforms. Kidney International. 2000;57:2634–2643. doi: 10.1046/j.1523-1755.2000.00124.x. [DOI] [PubMed] [Google Scholar]
  11. Fetics B, Nevo E, Chen C-H, Kass DA. Parametric model derivation of transfer function for non-invasive estimation of aortic pressure by radial tonometry. IEEE Transactions on Biomedical Engineering. 1999;46:698–706. doi: 10.1109/10.764946. [DOI] [PubMed] [Google Scholar]
  12. Franklin SS, Khan SA, Wong ND, Larson MG, Levy D. Is pulse pressure useful in predicting risk for coronary heart disease? The Framingham Heart Study. Circulation. 1999;100:354–360. doi: 10.1161/01.cir.100.4.354. [DOI] [PubMed] [Google Scholar]
  13. Freis ED, Heath WC, Lushsimger PC, Snell RE. Changes in the carotid pulse which occur with age and hypertension. American Heart Journal. 1966;71:757–765. doi: 10.1016/0002-8703(66)90596-5. [DOI] [PubMed] [Google Scholar]
  14. Gabe IT, Karnell J, Porje IG, Rudewald B. The measurement of input impedance and apparent phase velocity in the human aorta. Acta Physiologica Scandinavica. 1964;61:73–84. doi: 10.1111/j.1748-1716.1964.tb02944.x. [DOI] [PubMed] [Google Scholar]
  15. Goldenberg M, Pines KL, Baldwin EF, Greene DG, Roh CE. The hemodynamic response of man to nor-epinephrine and epinephrine and its relation to the problem of hypertension. American Journal of Medicine. 1948;5:792–806. doi: 10.1016/0002-9343(48)90158-2. [DOI] [PubMed] [Google Scholar]
  16. Karamanoglu M, O'Rourke MF, Avolio AP, Kelly RP. An analysis of the relationship between central aortic and peripheral upper limb pressure waves in man. European Heart Journal. 1993;14:160–167. doi: 10.1093/eurheartj/14.2.160. [DOI] [PubMed] [Google Scholar]
  17. Kelly RP, Hayward CS, Ganis J, Daley JM, Avolio AP, O'Rourke MF. Non-invasive registration of the arterial pulse waveform using high fidelity applanation tonometry. Journal of Vascular and Medical Biology. 1989;1:142–149. [Google Scholar]
  18. Kroeker EJ, Wood EH. Comparison of simultaneously recorded central and peripheral arterial pressure pulses during rest, exercise and tilted position in man. Circulation Research. 1955;3:623–632. doi: 10.1161/01.res.3.6.623. [DOI] [PubMed] [Google Scholar]
  19. Latham RD, Westerhof N, Sipkema P, Rubal BJ, Reuderink P, Murgo J. Regional wave travel and reflections along the human aorta: a study with six simultaneous micromanometric pressures. Circulation. 1985;72:1257–1269. doi: 10.1161/01.cir.72.6.1257. [DOI] [PubMed] [Google Scholar]
  20. Lax H, Feinberg AW, Cohen BM. Studies of the arterial pulse wave. Journal of Chronic Diseases. 1956;3:618–631. doi: 10.1016/0021-9681(56)90158-8. [DOI] [PubMed] [Google Scholar]
  21. Mahomed FA. The physiological and clinical use of the sphygmograph. Medical Times Gazette. 1872;1:62–64. [Google Scholar]
  22. Marchais SJ, Guerin AP, Pannier BM, Levy BI, Safar M, London GM. Wave reflections and cardiac hypertrophy in chronic uremia. Hypertension. 1993;22:876–883. doi: 10.1161/01.hyp.22.6.876. [DOI] [PubMed] [Google Scholar]
  23. Merillon JP, Fontenier GJ, Lerallut JF. Aortic input impedance in normal man and arterial hypertension: its modification during changes in aortic pressure. Cardiovascular Research. 1982;16:646–656. doi: 10.1093/cvr/16.11.646. [DOI] [PubMed] [Google Scholar]
  24. Motwani JG, Struthers AD. Dose-response study of the redistribution of intravascular volume by angiotensin II in man. Clinical Science. 1992;82:397–405. doi: 10.1042/cs0820397. [DOI] [PubMed] [Google Scholar]
  25. Murgo JP, Westerhof N, Giolma JP, Altobelli SA. Aortic input impedance in normal man: relationship to pressure waveforms. Circulation. 1980;62:105–116. doi: 10.1161/01.cir.62.1.105. [DOI] [PubMed] [Google Scholar]
  26. Nakayama Y, Tsumura K, Yamashita N, Yoshimaru K, Hayashi T. Pulsatility of ascending aortic pressure waveform is a powerful predictor of restenosis after percutaneous transluminal coronary angioplasty. Circulation. 2000;101:470–472. doi: 10.1161/01.cir.101.5.470. [DOI] [PubMed] [Google Scholar]
  27. Nichols WW, Conti R, Walker WE, Milnor WR. Input impedance of the systemic circulation in man. Circulation Research. 1977;40:451–458. doi: 10.1161/01.res.40.5.451. [DOI] [PubMed] [Google Scholar]
  28. Nichols WW, O'Rourke MF. McDonald's Blood Flow in Arteries: Theoretical, Experimental and Clinical Principles. 4. London: Edward Arnold; 1998. [Google Scholar]
  29. Northridge DB, Findlay IN, Wilson J, Henderson E, Dargie HJ. Non-invasive determination of cardiac output by Doppler echocardiography and electrical bioimpedance. British Heart Journal. 1990;63:93–97. doi: 10.1136/hrt.63.2.93. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. O'Brien E, Mee F, Atkins N, Thomas M. Evaluation of three devices for self measurement of blood pressure according to the revised British Hypertension Society Protocol: the Omron HEM-705CP, Philips HP5332, and Nissei DS-175. Blood Pressure Monitoring. 1996;1:55–61. [PubMed] [Google Scholar]
  31. O'Leary DH, Polak JF, Kronmal RA, Manolio TA, Burke GL, Wolfson SK., Jr Carotid-artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults. New England Journal of Medicine. 1999;340:14–22. doi: 10.1056/NEJM199901073400103. [DOI] [PubMed] [Google Scholar]
  32. O'Rourke MF, Gallagher DE. Pulse wave analysis. Journal of Hypertension. 1996;14:147–157. [PubMed] [Google Scholar]
  33. O'Rourke MF, Taylor MG. Vascular impedance of the femoral bed. Circulation Research. 1966;18:126–139. [Google Scholar]
  34. O'Rourke MF, Taylor MG. Input impedance of the systemic circulation. Circulation Research. 1967;20:365–380. doi: 10.1161/01.res.20.4.365. [DOI] [PubMed] [Google Scholar]
  35. Ramsay M, Broughton PF, Rubin P. Comparative study of pressor and heart rate reponses to angiotensin II and noradrenaline in pregnant and non-pregnant women. Clinical Science. 1992;82:157–162. doi: 10.1042/cs0820157. [DOI] [PubMed] [Google Scholar]
  36. Rowell LB, Brengelmann GL, Blackmon JR, Bruce RA, Murray JA. Disparities between aortic and peripheral pulse pressures induced by upright exercise and vasomotor changes in man. Circulation. 1968;37:954–964. doi: 10.1161/01.cir.37.6.954. [DOI] [PubMed] [Google Scholar]
  37. Rushmer RF. Cardiovascular Dynamics. 2. London: W. B. Saunders; 1961. [Google Scholar]
  38. Saba PS, Roman MJ, Pini R, Spitzer M, Ganau A, Devereux RB. Relation of arterial pressure waveform to left ventricular and carotid anatomy in normotensive subjects. Journal of the American College of Cardiology. 1993;22:1873–1880. doi: 10.1016/0735-1097(93)90772-s. [DOI] [PubMed] [Google Scholar]
  39. Sarnoff SJ, Brockman SK, Gilmore JP, Linden RJ, Mitchell JH. Regulation of ventricular contraction: Influence of cardiac sympathetic and vagal nerve stimulation on atrial and ventricular dynamics. Circulation Research. 1960;8:1108–1122. doi: 10.1161/01.res.8.5.1108. [DOI] [PubMed] [Google Scholar]
  40. Simons PCG, Algra A, Bots ML, Grobbee DE, Van der Graaf Y. Common carotid intima-media thickness and arterial stiffness: Indicators of cardiovascular risk in high-risk patients: The SMART study (Second Manifestations of ARTerial disease) Circulation. 1999;100:951–957. doi: 10.1161/01.cir.100.9.951. [DOI] [PubMed] [Google Scholar]
  41. Soderstrom S, Nyberg G, Ponten J, Sellgren J, O'Rourke M. Substantial equivalence between ascending aortic pressure waveforms and waveforms derived from the radial pulse using a generalized transfer function. FASEB Journal. 1998;A712:4131. [Google Scholar]
  42. Takazawa K, O'Rourke M, Fujita M. Estimation of ascending aortic pressure from radial arterial pressure using a generalized transfer function. Zeitschrift fur Kardiologie. 1996;85:137–139. [PubMed] [Google Scholar]
  43. Ting CT, Chou CY, Chang MS, Wang SP, Chiang BN, Yin FCP. Arterial haemodynamic in human hypertension: effects of adrenergic blockade. Circulation. 1991;84:1049–1057. doi: 10.1161/01.cir.84.3.1049. [DOI] [PubMed] [Google Scholar]
  44. Tomlinson B, Ong ACM, Graham BR, Prichard BNC. Effects of noradrenaline infusion on cardiac output and systolic time intervals derived from electrical bioimpedance cardiography. British Journal of Clinical Pharmacology. 1990;29:639–640. [Google Scholar]
  45. Westerhof N, O'Rourke MF. Haemodynamic basis for the development of left ventricular failure in systolic hypertension and for its logical treatment. Journal of Hypertension. 1995;13:943–952. doi: 10.1097/00004872-199509000-00002. [DOI] [PubMed] [Google Scholar]
  46. Wilkinson IB, Cockcroft JR, Webb DJ. Pulse wave analysis and arterial stiffness. Journal of Cardiovascular Pharmacology. 1999;32:33–37. [PubMed] [Google Scholar]
  47. Wilkinson IB, Fuchs SA, Jansen IM, Spratt JC, Murray GD, Cockcroft JR, Webb DJ. The reproducibility of pulse wave velocity and augmentation index measured by pulse wave analysis. Journal of Hypertension. 1998;16:2079–2084. doi: 10.1097/00004872-199816121-00033. [DOI] [PubMed] [Google Scholar]
  48. Wilkinson IB, MacCallum H, Flint L, Cockcroft JR, Newby DE, Webb DJ. The influence of heart rate on augmentation index and central arterial pressure in humans. The Journal of Physiology. 2000;525:263–270. doi: 10.1111/j.1469-7793.2000.t01-1-00263.x. [DOI] [PMC free article] [PubMed] [Google Scholar]

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