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Disparate effects of antihypertensive drugs on large artery distensibility and compliance in hypertension
Disparate Effects of Antihypertensive on Large Artery Distensibility Compliance in Hypertension Luc M.A.B.
Van Bortel,
MD,
PhD, Mirian
J.F. Kool,
MD,
Drugs and
PhD, and Janneke
J. Spek,
MD
Distensibility and compliance are large artery properties, that may be important in cardiovascular disease. Distensibility is a determinant of the pulsatile stress on the vessel wall and is thought important in ageing and atherosclerotic disease. Compliance reflects the buffering capacity of the arteries and is a major determinant of the afterload on the heart. In hypertension large arteries are getting stiffer, resulting in a decreased distensibility and compliance. Decrease in blood pressure by itself can improve large artery properties. Despite a decrease in blood pressure, not all antihypertensive drugs improve large artery properties. Compliance is improved by firstline antihypertens’nre drugs such as angiotensin-converting enzyme (ACE) inhibitors,
calcium antagonists, R-blocken with vasodilating properties, selective RI-blockers and some diuretics. Recent data suggest that ACE inhibitors such as perindopril improve distensibility and compliance of large arteries more than diuretics such as amiloride/ hydrochlorothiazide. Apart from the indirect effect (decrease in blood pressure), this makes a direct effect of perindopril on large artery properties very likely. ACE inhibitors such as perindopril decrease the aftertoad on the heart more than diuretics such as amiloride/hydrochlorothiazide by both a more pronounced decrease in systemic vascular resistance and an increase in large artery compliance. (Am J Cardioll995; 76:46E-49E)
S
temporarily in order to obtain a more continuous tissue perfusion. Compliance-a measure of this buffering function-is defined as the change in volume per unit of pressure. Large artery compliance is a major determinant of the afterload on the heart (Table II). A decrease in compliance leads to an increased pulse pressure and a mechanical cardiac overload. Compliance of large arteries plays an important role in the onset and maintenance of cardiac hypertrophy in hypertension.2T3 Arterial distensibility is defined as the relative change in cross-sectional area of the vessel per unit of pressure. Distensibility is an important determinant of the pulsatile stress. Pulsatile stress in the vessel wall is a circumferential stress determined by a number of variables.5 It induces degeneration of the vascular media.6 Pulsatile stress is also thought a significant risk factor for endothelial lesions and plaque rupture, which are important features in atherosclerotic disease.’ In hypertensive* and ageing subjects9J0 arteries become less elastic, leading to a decrease in distensibility and compliance. Systolic blood pressure is more closely related to pulse pressure, while diastolic pressure better reflects mean arterial pressure. The Framingham study and also other epidemiologic studies have shown that the ill effects of hypertension (morbidity and mortality) are better correlated with the systolic than with the diastolic blood pressure,ll-l3 indicating an important role of the pulsatile stress (pulse pressure). In the literature, “compliance”
ystolic and diastolic blood pressure are determined by the mean arterial pressure and the pulse pressure oscillating around this mean arterial pressure. Determinants of blood pressure are shown in Table I.
DETERMINANTS
OF BLOOD
PRESSURE
Mean arterial pressure, the static component of blood pressure, depends on cardiac output and systemic vascular resistance. This vascular resistance is determined by blood viscosity and by the sustained tension in the resistance vessels, which are the small arteries, arterioles, and capillaries. Pulse pressure-the dynamic part of blood pressure-results from the amount of blood ejected from the heart (stroke volume) and the buffering capacity of the vessels. This buffering function is exerted by capacitance vessels, which are predominantly large arteries.’
LARGE ARTERY PROPERTIES AND ILL EFFECTS OF HYPERTENSION Large arteries have a particular function: they must store the blood flow jet from the heart From the Division of Clinical Pharmacology, Department of Pharmacology, Cardiovascular Research Institute Maastricht, University of Limburg, Maastricht, The Netherlands. A complete presentation of this study has been published in J h’ypertens 1995;13;839-848. Address for reprints: Luc Van Bortel, MD, Division of Clinical Pharmacology, Department of Pharmacology, University of Limburg, P.O. Box 616,620O MD Maastricht, The Netherlands.
46E
THE
AMERICAN
JOURNAL
OF
CARDIOLOGY
VOLUME
76
NOVEMBER
24,
1995
often This since bility
refers to compliance as well as distensibility. confusion remained until a few years ago, no means were available to measure distensias well as compliance accurately.
NONINVASIVE MEASUREMENT LARGE ARTERY PROPERTIES
OF
Recently, noninvasive measurement of wall properties of some large arteries became possible by the development of new echocardiographic Doppler techniques. One of these techniques is the vessel wall movement detector system, developed by Hoeks et al. l4 This system consists of a conventional B-mode echo-imager and a data acquisition system, connected to a personal computer. Arterial diameter (D) and change in diameter during the heart cycle (distension; AD) are measured accurately. From D, AD and pulse pressure (AP), distensibility and compliance can be calculated: DC = (AA/A)/AP CC = (AV/L)/AP
= 2(ADID)IAP = TD * AD/2AP
where DC = distensibility coefficient, CC = crosssectional compliance, AA/A = relative change in cross-sectional area of the vessel, and AV/L = change in volume per unit of length. Reproducibility of these measurements is fair: regarding the common carotid artery, coefficient of variation is <5% for diameter and about 8% for distension. Reproducibility of measurements of muscular arteries such as the common femoral and the brachial artery is slightly lower.15
EFFECT OF ANTIHYPERTENSIVE DRUGS ON LARGE ARTERY PROPERTIES The effect of different antihypertensive drugs on large artery compliance is shown in Table III. Large artery compliance can be increased by calcium antagonists, angiotensin-converting enzyme (ACE) inhibitors, B-blocking agents with vasodilating properties, and nitrates.5 Apart from metopro101, all pi blockers also improve compliance. At higher doses pi blockers lose selectivity. This might be an explanation for the difference between the effects of metoprolol (100 mg twice daily) and other selective pi blockers on large artery compliance. Since a higher blood pressure, by itself, may decrease arterial distensibility,16 the beneficial effect of some antihypertensive drugs on large artery compliance might, in part, be due to the decrease in blood pressure. Despite a marked fall in blood pressure, the nonselective P-blocker propranolol,
t
TABLE
I Determinants
of Blood
Pressure
I
Mean Arterial Pressure
Components
Pulse Pressure
Nature
Siotic
Dynamic
Main determinant vessels
Resistance vessels: Small arteries Arterioles Copillories
Capacitance vessels: Small arteries Large arteries
fl!
TABLE II Determinants
TABLE Ill
Effect
of Cardiac
Afterload
of Antihypertensive
Drugs
on Large
Artery
Compliance
I
Compliance
Compliance
Unchanged
ACE inhibitors
Nonselective
f3 blockers
Selective
Clonidine
f3 blockers Calcium
lncreosed
f3,-blockers with vasodilotory
action
antagonists
Direct vasodilators Urapidil
Some diuretics
Some diuretics
Ketanserin Nitrates
direct vasodilators of the hydralazine group, and the centrally acting oZ-adrenoceptor agonist clonidine do not increase arterial compliance. The effect of OLblocking agents is not clear. On the one hand ketanserin (a-adrenoceptor plus serotoninz [5-HTz] antagonist) improves arterial compliance, whereas urapidil (o-adrenoceptor antagonist plus central 5-HTiA agonist) does not. Some authors did find an increase in distensibility and/or compliance during treatment with diuretics,i7J8 whereas other authors did not.19 In general, diuretics containing thiazides improve compliance. Since most diuretics used in hypertension show some vasodilatory effect-which may improve large artery properties, but only after 4-g weeks-some studies might have been too short to depict this effect. It is clear that the effect of different antihypertensive drugs on large artery compliance is not uniform. More evidence for effect on large artery properties with the ACE inhibitor perindopril than with the combination diuretic amiloride/hydrochlorothiazide has been shown in a comparative study in hypertensive patients. l7 A placebo run-in period preceded a 6-month active-treatment phase in 41 patients with mild-to-moderate essential hypertension, according to a double-blind, randomized, parallel-group design. Patients started with either 4 mg perindopril or 2.5-25 mg amiloride plus A SYMPOSIUM:
ENDOTHELIAL
DYSFUNCTION
479
hydrochlorothiazide once a day. The following parameters were assessed after 3 and 6 months: blood pressure, heart rate, and vessel wall properties (D, AD, DC, and CC) of the right elastic common carotid artery, the right muscular common femoral artery and the brachial artery with a vessel wall movement detector system as previously described. Cardiac function was measured using an echocardiographic Doppler technique; cardiac index was defined as stroke index x heart rate; systemic vascular resistance index was defined as mean arterial pressure / cardiac index. After 6 months of treatment, blood pressure was reduced significantly by perindopril (supine systolic, - 11%; sitting systolic, -10%; supine diastolic, -8%; sitting diastolic, - 11%) and amiloride plus hydrochlorothiazide (supine systolic, -8%, sitting systolic, - 12%; supine diastolic, -4%; sitting diastolic, -9%). The distensibility of the common carotid artery was significantly enhanced by perindopril (+ 16%), but not changed by amiloride plus hydrochlorothiazide (+ 1%); the difference between perindopril and amiloride plus hydrochlorothiazide for carotid distensibility was statistically significant (p = 0.043). The compliance of the common carotid artery tended to be increased more by perindopril(+7%) than by amiloride plus hydrochlorothiazide (-5%; intergroup probability = 0.067). The distensibility of the femoral artery was significantly enhanced by perindopril (+39%) and by amiloride plus hydrochlorothiazide (+15%). The compliance of the femoral artery was increased by perindopril(+40%) and by amiloride plus hydrochlorothiazide (+ 13%). The distensibility of the brachial artery was significantly enhanced by perindopril (+49%) and by amiloride plus hydrochlorothiazide (+37%). The compliance of the brachial artery was increased by perindopril (+40%) and by amiloride plus hydrochlorothiazide (+32%). Both perindopril and amiloride plus hydrochlorothiazide decreased blood pressure and improved distensibility and compliance of large, arteries. Data during perindopril treatment are in accordance with those found by Asmar et a1.20A similar decrease in blood pressure is expected to induce a similar indirect increase in arterial distensibility and compliance. However, for a similar decrease in blood pressure during perindopril treatment, the increase in distensibility and compliance was (or tended to be) higher than during the diuretic combination. Therefore, this study suggests that there is a direct effect on large artery properties 48E
THE AMERICAN
JOURNAL
OF CARDIOLOGY
VOLUME
76
with perindopril, and this is larger than the effect with amiloride plus hydrochlorothiazide. In the same study, total peripheral resistance index was also decreased significantly more with perindopril (- 14%) than with amiloride $us hydrochlorothiazide (- 8%; intergroup probability = 0.023). Cardiac index increased with perindopril (+6%) because of an increased stroke index (+5%), but amiloride plus hydrochlorothiazide did not change cardiac function. This indicates a larger decrease of the afterload of the heart during treatment with perindopril than with the diuretic combination. This larger decrease in afterload is achieved by a more pronounced favorable effect on both large artery compliance and peripheral resistance, and this effect may-at least in partcontribute to the favorable effect of ACE inhibitors on mortality in patients with cardiac dysfunction.21-24
CONCLUSION Despite a decrease in blood pressure, not all antihypertensive drugs improve large.artery properties. Large artery properties can be improved by a direct action of a drug on the vessel wall and/or indirectly by the decrease in blood pressure. The data discussed herein suggest that ACE inhibitors such as perindopril improve distensibility and compliance of large arteries more than diuretics such as amiloride plus hydrochlorothiazide. In addition, it seems likely that the action of perindopril consists of an indirect, but also a direct effect, on large artery properties. In addition, it seems likely that the action of perindopril consists not only of an indirect, but also a direct, effect on large artery properties. 1. Safar ME. Pulse pressure in essential hypertension: clinical and therapeutical implications. J Hypertens 1989;7:769-776. 2. Safar ME, Toto-Moukouo JJ, Bouthier JA, Asmar RE, Levenson JA, Simon AC. Arterial dynamics, cardiac hypertrophy and antihypertensive treatment. Circulation 1987;75(supp11):156161. 3. Bouthier JD, De Luca N, &far ME, Simon AC. Cardiac hypertrophy and arterial distensibility in essential hypertension. Am Hean I 1985;109:134~1352. 4. Levy BI, Safar M. Ventricular afterload and aortic impedance. In: Swyngedauw 8, ed. Cardiac Hypettrophy and Failure. London, Paris: J Libbcyi INSERM; 1990:521-530. 5. LMAB Van Bortel, AP Hocks, MJ Kool, HA Struijker Boudier. Introduction to large artery properties as a target for risk reduction by antihypertensive therapy. .I Hypefew 1992;lO(suppl6):12>126. 6. O’Rourke MF. Basic concepts for the understanding of large arteries in hypertension. .I Cardiovasc Phammcol1985;7(suppl2):S14-S21. 7. Fuster V, Badimon L, Badimon JJ, Chesebro JH. The pathogenesis of coronary artery disease and the acute coronary syndromes. (first of two parts). N En@ J Med 1992;326:242-250. 8. Safar ME, Simon AC, Levenson JA. Structural changes of large arteries in sustained essential hypertension. H~emioon 1984,6(suppl III): 11 l-l 17. 9. Reneman RS, van Merode T, Hick P, Hocks APG. Flow velocity patterns in and distensibility of the carotid artery bulb in subjects of various ages. C&x/ulion 1985;71:5C%509.
NOVEMBER
24,
1995
10. Kawasaki T, Sasayama S, Yagi S, Asakawa T, Hirai T. Non-invasive assessment of the age-related changes in stiffness of major branches of human arteries. Cardiovasc Ret 1987;21:678-687. 11. Kannel WB, Castelli WP, McNamara PM, McKee PA, FeinIeib M. Role of blood pressure in the development of congestive heart failure. Framingham Study. N En& JMed 1972;287:781-787. 12. Kannel WB, Wolf PA, McGee DI., Dawber TR, McNamara P, CasteIIi WP. Systolic blood pressure, arterial rigidity and risk of stroke. The Framingham Study. Ji4&&4 1981;M5:1225-1229. 13. Rutan GH, KuIIer LH, Neaton JD, Wentworth DN, McDonald RH, McFate-Smith W. Mortality associated with diastolic hypertension and isolated systolic hypertension among men screened for Multiple Risk Factor Intervention Trial. Circulorion 1988,77z50&514. 14. Ho&s APG, Brands PJ, Smeets FAM, Reneman RS. Assessment of the distensibility of superticial arteries. UIrmFawrd Med Bio11990;16:121-128. 15. Kool MJF, van Merode T, Reneman RS, Ho&s APG, Struijker Boudier HAJ, Van Bortel LMAB. Evaluation of reproducibility of a vessel waII movement detector system for assessment of large artery properties. Cardiovasc Res 1994$X610-614 16. O’Rourke M. Arterial stitfness, systolic pressure, and logical treatment of arterial hypertension. Hyperrensn 1990;15:339-347. 17. MJF Kool, FAT Lustermans, JGS Breed, HAJ Struijker Boudier, APG Hoe&s, LMAB Van Bortel. Effect of perindopriI and amiIoride/hydmchlorothiazide on haemodynamics and vessel waII properties of large arteries. J @pem 1993;11(sup~l5):S362-363.
18. SmuIyan H, Vardan S, Grit%ths A, Gribbii B. Forearm arterial di.stensibiIity in systolic hypertension. JAm CoU Can&l 1984$387-393. 19. Laurent S, LacoIIey PM, Cuche JL, Safar ME. Influence of diuretics on bra&ii artery diameter and distensibility in hypertensive patients. Fwtdam Ch pharmacd 199Q468~93. 20. Asmar RG, Pannier B, Santoni JP, Laurent S, London GM, Levy BI, !&far ME. Reversion of cardiac hypertrophy and reduced arterial compliance after converting enzyme inhibition in essential hypertension. Circulation 1988;78:941950. 2 1. The CONSENSUS Trial Study Group. Effect of enalapd on mortality in severe congestive heart failure: results of the Cooperative North Scandiiavian EnaIapril Survival Study (CONSENSUS). N En@ J Med 1987;316:142%1435. 22. The SOLVD Investigators. Effect of enalapril on smvivaI in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med 1991;325:29%302. 23. Cohn JN, Archibald DG, Ziesche S, Franciosa JA, Harston WE, Tristani FE, Dunkman WB, Jacobs W, Francis GS, FIor KH, Goldman S, Cobb FR, Shah PM, Saunders R, Fletcher RD, Loeb HS, Hughes VC, Baker B. Effect of vasodiIator therapy on mortality in chronic congestive heart failure: results of a Veterans Administration Cooperative Study. N Engl JMed 1986;314:1547-1552. 24. Pfeffer MA, Braunwald E, Moy6 LA, Basta L, Brown EJ, Cuddy TE, Davis BR, Geltman EM, Goldman S, FIaker GC, Klein M, Lamas GA, Packer M, Rouleau J, Rouleau JL, Rutherford J, Wertheimer JH, Hawkins CM, The SAVE Investigators. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the Survival and Ventricular Enlargement Trial. N Engl JMed 1992;327&%677.
A SYMPOSIUM:
ENDOTHELIAL
DYSFUNCTION
49E
Van Bortel,
MD,
PhD, Mirian
J.F. Kool,
MD,
Drugs and
PhD, and Janneke
J. Spek,
MD
Distensibility and compliance are large artery properties, that may be important in cardiovascular disease. Distensibility is a determinant of the pulsatile stress on the vessel wall and is thought important in ageing and atherosclerotic disease. Compliance reflects the buffering capacity of the arteries and is a major determinant of the afterload on the heart. In hypertension large arteries are getting stiffer, resulting in a decreased distensibility and compliance. Decrease in blood pressure by itself can improve large artery properties. Despite a decrease in blood pressure, not all antihypertensive drugs improve large artery properties. Compliance is improved by firstline antihypertens’nre drugs such as angiotensin-converting enzyme (ACE) inhibitors,
calcium antagonists, R-blocken with vasodilating properties, selective RI-blockers and some diuretics. Recent data suggest that ACE inhibitors such as perindopril improve distensibility and compliance of large arteries more than diuretics such as amiloride/ hydrochlorothiazide. Apart from the indirect effect (decrease in blood pressure), this makes a direct effect of perindopril on large artery properties very likely. ACE inhibitors such as perindopril decrease the aftertoad on the heart more than diuretics such as amiloride/hydrochlorothiazide by both a more pronounced decrease in systemic vascular resistance and an increase in large artery compliance. (Am J Cardioll995; 76:46E-49E)
S
temporarily in order to obtain a more continuous tissue perfusion. Compliance-a measure of this buffering function-is defined as the change in volume per unit of pressure. Large artery compliance is a major determinant of the afterload on the heart (Table II). A decrease in compliance leads to an increased pulse pressure and a mechanical cardiac overload. Compliance of large arteries plays an important role in the onset and maintenance of cardiac hypertrophy in hypertension.2T3 Arterial distensibility is defined as the relative change in cross-sectional area of the vessel per unit of pressure. Distensibility is an important determinant of the pulsatile stress. Pulsatile stress in the vessel wall is a circumferential stress determined by a number of variables.5 It induces degeneration of the vascular media.6 Pulsatile stress is also thought a significant risk factor for endothelial lesions and plaque rupture, which are important features in atherosclerotic disease.’ In hypertensive* and ageing subjects9J0 arteries become less elastic, leading to a decrease in distensibility and compliance. Systolic blood pressure is more closely related to pulse pressure, while diastolic pressure better reflects mean arterial pressure. The Framingham study and also other epidemiologic studies have shown that the ill effects of hypertension (morbidity and mortality) are better correlated with the systolic than with the diastolic blood pressure,ll-l3 indicating an important role of the pulsatile stress (pulse pressure). In the literature, “compliance”
ystolic and diastolic blood pressure are determined by the mean arterial pressure and the pulse pressure oscillating around this mean arterial pressure. Determinants of blood pressure are shown in Table I.
DETERMINANTS
OF BLOOD
PRESSURE
Mean arterial pressure, the static component of blood pressure, depends on cardiac output and systemic vascular resistance. This vascular resistance is determined by blood viscosity and by the sustained tension in the resistance vessels, which are the small arteries, arterioles, and capillaries. Pulse pressure-the dynamic part of blood pressure-results from the amount of blood ejected from the heart (stroke volume) and the buffering capacity of the vessels. This buffering function is exerted by capacitance vessels, which are predominantly large arteries.’
LARGE ARTERY PROPERTIES AND ILL EFFECTS OF HYPERTENSION Large arteries have a particular function: they must store the blood flow jet from the heart From the Division of Clinical Pharmacology, Department of Pharmacology, Cardiovascular Research Institute Maastricht, University of Limburg, Maastricht, The Netherlands. A complete presentation of this study has been published in J h’ypertens 1995;13;839-848. Address for reprints: Luc Van Bortel, MD, Division of Clinical Pharmacology, Department of Pharmacology, University of Limburg, P.O. Box 616,620O MD Maastricht, The Netherlands.
46E
THE
AMERICAN
JOURNAL
OF
CARDIOLOGY
VOLUME
76
NOVEMBER
24,
1995
often This since bility
refers to compliance as well as distensibility. confusion remained until a few years ago, no means were available to measure distensias well as compliance accurately.
NONINVASIVE MEASUREMENT LARGE ARTERY PROPERTIES
OF
Recently, noninvasive measurement of wall properties of some large arteries became possible by the development of new echocardiographic Doppler techniques. One of these techniques is the vessel wall movement detector system, developed by Hoeks et al. l4 This system consists of a conventional B-mode echo-imager and a data acquisition system, connected to a personal computer. Arterial diameter (D) and change in diameter during the heart cycle (distension; AD) are measured accurately. From D, AD and pulse pressure (AP), distensibility and compliance can be calculated: DC = (AA/A)/AP CC = (AV/L)/AP
= 2(ADID)IAP = TD * AD/2AP
where DC = distensibility coefficient, CC = crosssectional compliance, AA/A = relative change in cross-sectional area of the vessel, and AV/L = change in volume per unit of length. Reproducibility of these measurements is fair: regarding the common carotid artery, coefficient of variation is <5% for diameter and about 8% for distension. Reproducibility of measurements of muscular arteries such as the common femoral and the brachial artery is slightly lower.15
EFFECT OF ANTIHYPERTENSIVE DRUGS ON LARGE ARTERY PROPERTIES The effect of different antihypertensive drugs on large artery compliance is shown in Table III. Large artery compliance can be increased by calcium antagonists, angiotensin-converting enzyme (ACE) inhibitors, B-blocking agents with vasodilating properties, and nitrates.5 Apart from metopro101, all pi blockers also improve compliance. At higher doses pi blockers lose selectivity. This might be an explanation for the difference between the effects of metoprolol (100 mg twice daily) and other selective pi blockers on large artery compliance. Since a higher blood pressure, by itself, may decrease arterial distensibility,16 the beneficial effect of some antihypertensive drugs on large artery compliance might, in part, be due to the decrease in blood pressure. Despite a marked fall in blood pressure, the nonselective P-blocker propranolol,
t
TABLE
I Determinants
of Blood
Pressure
I
Mean Arterial Pressure
Components
Pulse Pressure
Nature
Siotic
Dynamic
Main determinant vessels
Resistance vessels: Small arteries Arterioles Copillories
Capacitance vessels: Small arteries Large arteries
fl!
TABLE II Determinants
TABLE Ill
Effect
of Cardiac
Afterload
of Antihypertensive
Drugs
on Large
Artery
Compliance
I
Compliance
Compliance
Unchanged
ACE inhibitors
Nonselective
f3 blockers
Selective
Clonidine
f3 blockers Calcium
lncreosed
f3,-blockers with vasodilotory
action
antagonists
Direct vasodilators Urapidil
Some diuretics
Some diuretics
Ketanserin Nitrates
direct vasodilators of the hydralazine group, and the centrally acting oZ-adrenoceptor agonist clonidine do not increase arterial compliance. The effect of OLblocking agents is not clear. On the one hand ketanserin (a-adrenoceptor plus serotoninz [5-HTz] antagonist) improves arterial compliance, whereas urapidil (o-adrenoceptor antagonist plus central 5-HTiA agonist) does not. Some authors did find an increase in distensibility and/or compliance during treatment with diuretics,i7J8 whereas other authors did not.19 In general, diuretics containing thiazides improve compliance. Since most diuretics used in hypertension show some vasodilatory effect-which may improve large artery properties, but only after 4-g weeks-some studies might have been too short to depict this effect. It is clear that the effect of different antihypertensive drugs on large artery compliance is not uniform. More evidence for effect on large artery properties with the ACE inhibitor perindopril than with the combination diuretic amiloride/hydrochlorothiazide has been shown in a comparative study in hypertensive patients. l7 A placebo run-in period preceded a 6-month active-treatment phase in 41 patients with mild-to-moderate essential hypertension, according to a double-blind, randomized, parallel-group design. Patients started with either 4 mg perindopril or 2.5-25 mg amiloride plus A SYMPOSIUM:
ENDOTHELIAL
DYSFUNCTION
479
hydrochlorothiazide once a day. The following parameters were assessed after 3 and 6 months: blood pressure, heart rate, and vessel wall properties (D, AD, DC, and CC) of the right elastic common carotid artery, the right muscular common femoral artery and the brachial artery with a vessel wall movement detector system as previously described. Cardiac function was measured using an echocardiographic Doppler technique; cardiac index was defined as stroke index x heart rate; systemic vascular resistance index was defined as mean arterial pressure / cardiac index. After 6 months of treatment, blood pressure was reduced significantly by perindopril (supine systolic, - 11%; sitting systolic, -10%; supine diastolic, -8%; sitting diastolic, - 11%) and amiloride plus hydrochlorothiazide (supine systolic, -8%, sitting systolic, - 12%; supine diastolic, -4%; sitting diastolic, -9%). The distensibility of the common carotid artery was significantly enhanced by perindopril (+ 16%), but not changed by amiloride plus hydrochlorothiazide (+ 1%); the difference between perindopril and amiloride plus hydrochlorothiazide for carotid distensibility was statistically significant (p = 0.043). The compliance of the common carotid artery tended to be increased more by perindopril(+7%) than by amiloride plus hydrochlorothiazide (-5%; intergroup probability = 0.067). The distensibility of the femoral artery was significantly enhanced by perindopril (+39%) and by amiloride plus hydrochlorothiazide (+15%). The compliance of the femoral artery was increased by perindopril(+40%) and by amiloride plus hydrochlorothiazide (+ 13%). The distensibility of the brachial artery was significantly enhanced by perindopril (+49%) and by amiloride plus hydrochlorothiazide (+37%). The compliance of the brachial artery was increased by perindopril (+40%) and by amiloride plus hydrochlorothiazide (+32%). Both perindopril and amiloride plus hydrochlorothiazide decreased blood pressure and improved distensibility and compliance of large, arteries. Data during perindopril treatment are in accordance with those found by Asmar et a1.20A similar decrease in blood pressure is expected to induce a similar indirect increase in arterial distensibility and compliance. However, for a similar decrease in blood pressure during perindopril treatment, the increase in distensibility and compliance was (or tended to be) higher than during the diuretic combination. Therefore, this study suggests that there is a direct effect on large artery properties 48E
THE AMERICAN
JOURNAL
OF CARDIOLOGY
VOLUME
76
with perindopril, and this is larger than the effect with amiloride plus hydrochlorothiazide. In the same study, total peripheral resistance index was also decreased significantly more with perindopril (- 14%) than with amiloride $us hydrochlorothiazide (- 8%; intergroup probability = 0.023). Cardiac index increased with perindopril (+6%) because of an increased stroke index (+5%), but amiloride plus hydrochlorothiazide did not change cardiac function. This indicates a larger decrease of the afterload of the heart during treatment with perindopril than with the diuretic combination. This larger decrease in afterload is achieved by a more pronounced favorable effect on both large artery compliance and peripheral resistance, and this effect may-at least in partcontribute to the favorable effect of ACE inhibitors on mortality in patients with cardiac dysfunction.21-24
CONCLUSION Despite a decrease in blood pressure, not all antihypertensive drugs improve large.artery properties. Large artery properties can be improved by a direct action of a drug on the vessel wall and/or indirectly by the decrease in blood pressure. The data discussed herein suggest that ACE inhibitors such as perindopril improve distensibility and compliance of large arteries more than diuretics such as amiloride plus hydrochlorothiazide. In addition, it seems likely that the action of perindopril consists of an indirect, but also a direct effect, on large artery properties. In addition, it seems likely that the action of perindopril consists not only of an indirect, but also a direct, effect on large artery properties. 1. Safar ME. Pulse pressure in essential hypertension: clinical and therapeutical implications. J Hypertens 1989;7:769-776. 2. Safar ME, Toto-Moukouo JJ, Bouthier JA, Asmar RE, Levenson JA, Simon AC. Arterial dynamics, cardiac hypertrophy and antihypertensive treatment. Circulation 1987;75(supp11):156161. 3. Bouthier JD, De Luca N, &far ME, Simon AC. Cardiac hypertrophy and arterial distensibility in essential hypertension. Am Hean I 1985;109:134~1352. 4. Levy BI, Safar M. Ventricular afterload and aortic impedance. In: Swyngedauw 8, ed. Cardiac Hypettrophy and Failure. London, Paris: J Libbcyi INSERM; 1990:521-530. 5. LMAB Van Bortel, AP Hocks, MJ Kool, HA Struijker Boudier. Introduction to large artery properties as a target for risk reduction by antihypertensive therapy. .I Hypefew 1992;lO(suppl6):12>126. 6. O’Rourke MF. Basic concepts for the understanding of large arteries in hypertension. .I Cardiovasc Phammcol1985;7(suppl2):S14-S21. 7. Fuster V, Badimon L, Badimon JJ, Chesebro JH. The pathogenesis of coronary artery disease and the acute coronary syndromes. (first of two parts). N En@ J Med 1992;326:242-250. 8. Safar ME, Simon AC, Levenson JA. Structural changes of large arteries in sustained essential hypertension. H~emioon 1984,6(suppl III): 11 l-l 17. 9. Reneman RS, van Merode T, Hick P, Hocks APG. Flow velocity patterns in and distensibility of the carotid artery bulb in subjects of various ages. C&x/ulion 1985;71:5C%509.
NOVEMBER
24,
1995
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A SYMPOSIUM:
ENDOTHELIAL
DYSFUNCTION
49E