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Assessment of the Acute Arterial Effects of Converting Enzyme Inhibition in Essential Hypertension: a Double-Blind, Comparative and Crossover Study

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Assessment of the Acute Arterial Effects of Converting Enzyme Inhibition in Essential Hypertension: a Double-Blind, Comparative and Crossover Study Journal of Human Hypertension (1998) 12, 181–187 1998 Stockton Press. All rights reserved 0950-9240/98 $12.00 ORIGINAL ARTICLE Assessment of the acute arterial effects of converting enzyme inhibition in essential hypertension: a double-blind, comparative and crossover study J Topouchian, AM Brisac, B Pannier, E Vicaut, M Safar and R Asmar Department of Internal Medicine and INSEM (U337) (U141), Broussais Hospital, Paris, France In subjects with essential hypertension, angiotensin- toward normal values. Carotid compliance and distens- converting enzyme (ACE) inhibition increases arterial ibility as well as aortic distensibility increased signifi- diameter, compliance and distensibility of peripheral cantly. Based on three-way analysis of variance, it was muscular arteries in association with blood pressure shown that, whereas the changes in carotid stiffness reduction. Whether pulse pressure amplification is were exclusively due to blood pressure reduction and modified by ACE inhibition and whether changes in not to a drug-induced relaxation of the arterial wall, the compliance and distensibility are due to a drug effect changes in aortic distensibility were due to the combi- on the arterial wall, to the blood pressure reduction or nation of both factors. Thus, using an atraumatic non- to a combination of both factors, is largely ignored. In invasive procedure, it was possible to show that: (i) ACE a randomised, double-blind crossover trial, we used the inhibition is able to maintain pulse pressure amplifi- ACE inhibitor quinapril as a marker to evaluate the cation, an important factor contributing to reduce the changes in: pulse pressure amplification (applanation afterload of the heart; and (ii) ACE inhibition alters the tonometry), carotid compliance and distensibility (echo- hypertensive arterial wall in a very heterogeneous man- tracking technique), and aortic distensibility (measured ner, with a maximal drug effect on muscular large from pulse wave velocity). Quinapril decreased in the arteries like the abdominal aorta, and not on elastic same extent carotid and brachial pulse pressure, thus arteries like the carotid artery and the thoracic aorta. causing a resetting of pulse pressure amplification Keywords: ACE inhibition; arterial compliance and distensibility; pulse wave velocity Introduction for myocardial infarction,4–6 it is of major impor- tance to also measure aortic pulse pressure, a major Both experimental and clinical studies indicate that component of cardiac after load. Indeed, increased large arteries respond actively to anti-hypertensive 1 aortic pulse pressure in old people is due both to an agents. However, in clinical situations, the evalu- increase in systolic pressure, which favours cardiac ation of the arterial response remains difficult to hypertrophy and to a decrease in diastolic blood elucidate, requiring either invasive investigations in 2 pressure (DBP), which alters coronary perfusion. a small number of subjects or atraumatic pro- Thus it is relevant, using the non-invasive method cedures with highly reproducible, but time consum- of applanation tonometry,7 to determine pulse press- ing, techniques. Thus it is important to develop ure in various arterial sites, and particularly at the methods which may be routinely performed for the site of the thoracic aorta. investigations of large arteries in cardiovascular Another point to consider in cardiovascular phar- pharmacology. macology is to determine whether the arterial effects Pulse pressure amplification is of major interest to 3 observed under treatment are a passive consequence evaluate the status of the arterial tree. Whereas of the pressure effect, or due to a direct drug effect mean arterial pressure is practically identical along on the arterial wall or to a combination of both fac- the arterial system, pulse pressure increases mark- tors.1 Studies in untreated subjects with essential edly from central to peripheral arteries, making that hypertension indicate that the decreased com- the degree of pulsatile stress differs markedly from pliance observed in hypertensive subjects may be one artery to another one. Because increased brach- the simple consequence of the elevated BP in some ial pulse pressure has been shown to be an inde- arterial segments, like the common carotid artery, or pendent predictor of cardiac mortality, principally may be strongly influenced by the structure of the arterial wall, as recently shown for the femoral 8,9 Correspondence: Professer Michel Safar, Medecine Interne 1, artery. This problem requires that, in cardiovascu- ˆ Hopital Broussais, 96 rue Didot, 75674, Paris Cedex 14, France lar clinical trials, sophisticated statistical analysis Received 21 June 1997; revised and accepted 4 November 1997 may be performed, enabling simultaneous evalu- Arterial effects of acute ACE inhibition J Topouchian et al 182 ation of the drug effect, of the pressure effect, and metric BP recorder (Dinamap type 845, Tampa, FL, finally also taking into account the large heterogen- USA). Measurements were taken every 3 min for 30 eity of the various segments of the arterial tree. Stat- min. For the individual evaluation of brachial and istical analysis, enabling the discrimination between ankle SBP, the two parameters were measured on such varieties of responses, have been widely the right and left sides using a pressure cuff of developed.10 appropriate diameter, a standard mercury sphygmo- The objective of the present study was, using the manometer, and a Doppler probe, according to the angiotensin-converting enzyme (ACE) inhibitor, qui- technique described by Yao et al.13 Brachial SBP napril,11 as a marker in subjects with essential was recorded as the appearance of an audible sound. hypertension, to develop accurate and simple Ankle SBP was determined by a pressure cuff methods enabling us to evaluate pulse pressure applied snugly above the malleolus. The cuff was amplification and changes in the stiffness of the inflated to a pressure exceeding the brachial SBP by aorta and the carotid artery following drug treat- about 40–50 mm Hg and the systolic pressure was ment. determined by the reappearance of the pulse (an audible Doppler sound). According to the require- ments of this technique, none of the limbs presented Patients and methods an incompressible arterial syndrome. Three Patients measurements were performed on each side, and the mean value was taken to calculate the ankle on Twenty patients (12 men and eight women) with brachial SBP ratio. No significant difference was essential hypertension completed this study. Mean observed between the right and the left sides. A ± ± age ( 1 s.d.) was 53 10 years (range 39 to 70). complete Doppler investigation, which involved all ± ± Mean weight was 73 11 kg and mean height 171 the leg arteries from the iliac to the ankle arteries, 7 cm. All subjects had mild to moderate hyperten- did not detect any significant stenosis of the lower sion according to World Health Organization cri- limbs. teria. All drugs treatment were stopped at least 1 month before the study. DBP measured by sphygmo- 14 manometer after a 2-week placebo period was above Pulse wave velocity measurements 95 mm Hg. Extensive clinical and biological investi- Carotid-femoral pulse wave velocity, a classic index gations were performed, according to previously of arterial stiffness, was determined according to the 12 described procedures, indicating that patients had foot-to-foot method. Transcutaneous Doppler flow essential hypertension without cardiac, neurologic velocity records were carried out simultaneously at or renal involvement, arteriosclerosis obliterans of the base of the neck over the common carotid artery the lower limbs, or diabetes mellitus. Written infor- and the right femoral artery in the groin with a non- med consent was obtained from patients. The study directional Doppler unit (Sega M842 8 Mhz, OR, was approved by the Ethical Committee of St Ger- USA) and a Gould 8188 recorder (Gould main en Laye (Ile de France). Patients participated Electronique, Ballainvillier, France) at 100 or in a randomised, double-blind, crossover study. 200 mm/sec. The foot of flow wave was identified After a 1-month wash-out and 2-week placebo per- as the point of the beginning at the sharp systolic iods, patients were randomised into two groups. upstroke or as the tangent drawn to the last part of Subjects in group A received a single acute oral dose the preceding flow wave and to the upstroke of the of quinapril (20 mg), whereas subjects in group B next wave, and the foot wave was taken as the inter- received identical tablets of placebo. Then all section point of these two lines. The time delay was patients received placebo for another 2-week period measured between the feet of the flow wave at the end of which the acute treatment was recorded at these different points from 10 consecu- changed, with patients in group A receiving placebo tive beats and designated as the pulse transit time and those in group B receiving quinapril. Haemo- (t). The distance travelled by the pulse wave was dynamic determinations were performed at the end measured over the body surface with a tape measure of each placebo period, before, and 2 h after each as the distance between the recording sites (D). acute single oral administration. Pulse wave velocity was calculated as PWV = D/t. For the measurements of PWV between the base of Brachial and ankle BP measurements the neck and the femoral artery, the distance from the suprasternal notch to the carotid was subtracted The haemodynamic study was performed during a from the total distance to take into account the pulse day hospitalisation, at a controlled room tempera- travelling in the opposite direction. A similar pro- ture of 20–23°C, and after a 30-min rest. Subjects cedure was used to measure carotid-radial pulse were recumbent during the investigation. First, wave velocity, as previously described.15 brachial BP was measured according to the WHO recommendation using a mercury sphygmoman- Evaluation of carotid wave reflections and pulse ometer and an oscillometric BP recorder.
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