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Captopril, but Not Nifedipine, Improves Endothelium-Dependent Vasodilation in Hypertensive Patients

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Captopril, but Not Nifedipine, Improves Endothelium-Dependent Vasodilation in Hypertensive Patients Journal of Human Hypertension (1998) 12, 511–516 1998 Stockton Press. All rights reserved 0950-9240/98 $12.00 http://www.stockton-press.co.uk/jhh ORIGINAL ARTICLE Captopril, but not nifedipine, improves endothelium-dependent vasodilation in hypertensive patients J Millga˚rd, A Ha¨gg, M Sarabi and L Lind Department of Internal Medicine, University Hospital of Uppsala, Sweden The present study aimed to investigate the influence of decline in blood pressure (BP) 1 h after administration -the angiotensin-converting enzyme (ACE)-inhibitor cap- (؊11 to 10 mm Hg/؊8 to 7 mm Hg), captopril signifi topril and the Ca-antagonist nifedipine on endothelium- cantly potentiated the vasodilator response to MCh dependent vasodilation (EDV) in the forearm of hyper- (؉32 ؎ 13%, MCh 4 ␮g/min, P Ͻ 0.01) but not SNP, while tensive patients. Twenty-three middle-aged untreated nifedipine did not significantly alter the response to hypertensive patients underwent evaluation of EDV and either MCh or SNP. The improvement in vasodilator endothelium-independent vasodilation (EIDV) in the response to MCh induced by captopril was closely .(P Ͻ 0.01 ,0.72 ؍ forearm, by means of local intra-arterial infusions of related to the reduction in BP (r methacholine (MCh, evaluating EDV) and sodium- Third, in the pilot study, 3 months of captopril treat- nitroprusside (SNP, evaluating EIDV), before and 1 h ment induced a significant potentiation of the vaso- ,after intake of either captopril (25 mg) or nifedipine dilator response to MCh (؉34 ؎ 17%, MCh 4 ␮g/min (10 mg) in a randomised, double-blind fashion. A P Ͻ 0.05) in parallel with a significant BP reduction matched normotensive control group was investigated (؊22 ؎ 24/13 ؎ 13 mm Hg, P Ͻ 0.05), while the response at baseline conditions only. Five of the hypertensives to SNP was unchanged. were also evaluated after 3 months of treatment with In conclusion, the present study confirmed that captopril 25 mg twice daily in an open pilot study. essential hypertension is associated with a defect in First, the vasodilation induced by methacholine EDV. Furthermore, an improvement in EDV was seen in (MCh), but not SNP, was significantly attenuated in the hypertensive patients shortly after administration of hypertensive patients compared to the normotensive captopril, but not nifedipine. In addition, a significant controls (P Ͻ 0.001 at MCh 4 ␮g/min). beneficial effect on EDV was seen in a small pilot study Second, although the two drugs induced a similar during long-term treatment with captopril. Keywords: hypertension; blood pressure; endothelium; vasodilation; ACE-inhibitors; calcium-antagonists Introduction tension,10 as well as promote vascular compli- cations,11 improving EDV in this patient group may By elaboration of several vasoactive factors such as be beneficial in several ways. nitric oxide (NO), endothelin-1 (ET-1), prosta- Previous investigations of the endothelial effects glandins and yet unidentified endothelium-derived of anti-hypertensive medications have produced hyperpolarising factor (EDHF), the vascular endo- disappointing results,8 even if there are some indi- thelium plays a crucial role in the regulation of cations of a positive effect of angiotensin-converting blood flow, peripheral resistance and thereby blood 4,12 1 enzyme (ACE)-inhibition. pressure (BP). The present study aimed to investigate if the ACE- Several investigators have found an impaired inhibitor captopril or the Ca-antagonist nifedipine endothelium-dependent vasodilation (EDV) in the could improve EDV in the forearm vascular bed in forearm circulation in patients with primary hyper- untreated hypertensive patients. The acute effects 2–9 tension, a defect that has been proposed to com- induced by a single dose of captopril or nifedipine prise a dysfunctional NO-system or an over-pro- were investigated in a randomised, double-blind duction of an endothelium derived contracting study, while the effects of long-term treatment with factor. Whether this endothelial dysfunction is a pri- captopril was studied in a small, open pilot study. mary or secondary phenomenon of the hypertensive disease is so far not known. However, as a defect in endothelial function might be of pathogenetic Materials and methods importance in the development of primary hyper- Subjects The study population (Table 1) consisted of 23 Correspondence: Dr Lars Lind, Dept of Internal Medicine, Univer- patients (22 men and one woman) with essential sity Hospital of Uppsala, S-751 85 Uppsala, Sweden hypertension defined as diastolic BP (DBP) Ͼ95 Received 10 October 1997; revised and accepted 8 May 1998 mm Hg without treatment confirmed by BP re- Anti-hypertensive treatment and endothelial function J Millga˚rd et al 512 Table 1 Basic characteristics in the study sample undertaken in one of the arms while the contra- lateral arm served as a control. Evaluations of FBF Normotensive Hypertensive were made by calculations of the mean of five con- controls patients secutive recordings. The reproducibility of this test of EDV and endothelium-independent vasodilation n 25 23 (EIDV) was evaluated in 10 healthy young volun- ± ± Age (years) 54 11 55 11 teers in whom the investigation was performed Body mass index (kg/m2)26± 2.7 27 ± 3.0 before and after 2 h of intravenous saline infusion, Systolic BP (mm Hg) 124 ± 13 162 ± 23*** as well as repeated after 2–3 weeks. Baseline resting Diastolic BP (mm Hg) 81 ± 7.7 100 ± 8.1*** FBF showed a variation less than 10%, while FBF ± ± during vasodilation induced by either MCh or SNP Serum cholesterol (mmol/l) 5.3 0.8 5.5 0.9 showed a variation of less than 5%, in the short- Baseline forearm vascular resistance 19 ± 6.1 22 ± 8.6 term (2 h) as well as the long-term (2–3 weeks) per- (mm Hg/ml/min/100 ml tissue) spective. Forearm circumference (mm) 294 ± 14 294 ± 18 In the present study, the measurements of EDV and EIDV were undertaken at baseline conditions, ***Denotes P Ͻ 0.001 vs normotensive controls. ± 1 h after intake of either captopril or nifedipine Values are expressed as means standard deviation (s.d.). (n = 21). Evaluations of the vasodilation in normot- ensive subjects were only undertaken at baseline cordings at different locations. The presence of sec- conditions and no oral drugs were given in this ondary hypertension was excluded by laboratory group. BP measurements were made with a mercury tests and physical examination. Another two sub- sphygmomanometer in parallel with the FBF re- jects entered the trial, but were later excluded as sec- cordings. ondary hypertension was discovered. The study protocol was approved by the Hospital Ten of the patients were previously untreated and ethics committee and informed consent was the remaining 13 had been without anti-hyperten- obtained from all participants. sive treatment for at least 3 weeks at the time of the investigation. Anti-hypertensive drugs An age- and sex-matched normotensive (BP below Captopril (25 mg, n = 12) or nifedipine (10 mg, n = 9) 140/90 mm Hg) control population (n = 25, Table 1) was administered orally in a randomised, double- was randomly recruited from the general population blind manner for the evaluation of the acute effects in the city of Uppsala. All controls were without his- of these drugs. tory of cardiovascular disorders and were free from Furthermore, five patients received 25 mg of cap- any medications. topril twice a day for 3–6 months in an open fashion in a pilot study. The follow-up measurements in Measurements of forearm blood flow (FBF) these five patients were performed at least 8 h after intake of the last dose. The patients included in the During the blood flow measurements, the subjects long-term study were similar in demographies and were supine in a quiet room maintained at a con- BP distribution as the hypertensive sample as a stant temperature (21–23°C). An arterial cannula whole. was inserted into the brachial artery of one arm for regional infusions of MCh (muscarinic agonist) and SNP (nitric oxide donor). Muscarinic agonists have Calculations previously been shown to induce EDV13 while NO Mean artery pressure (MAP) was calculated as one- donors act as direct smooth muscle relaxants, third of the pulse pressure (systolic BP (SBP) minus inducing vasodilation independent of the endo- DBP) added to DBP. thelium. Forearm vascular resistance (FVR) was given by The vasodilative drug-infusions were given dur- MAP divided by FBF. In the present study vaso- ing 5 min for each dose with a 20 min wash-out per- dilation was evaluated by the reduction in FVR iod between the two drugs. The infused dosages achieved by MCh or SNP-infusion in relation to ␮ ␮ − were 2 and 4 g/min for MCh and 5 and 10 g/min baseline FVR, (FVRdrug FVRbaseline)/FVRbaseline. for SNP. These drugs were given in a random order at a rate of 1 ml/min. Statistical analysis Before and at the end of the different dosages of Treatment effects were evaluated by two-way the two drugs, FBF was measured in both forearms ANOVA in the short-term study and with the Wil- by venous occlusion plethysmography according to coxon signed rank sum test (two-tailed) in the long- the following. A mercury in-silastic strain gauge, term pilot study. Differences between groups were connected to a calibrated plethysmograph, was calculated by means of one-way ANOVA; P Ͻ 0.05 placed on the upper third of the forearm, which was regarded as significant. rested comfortably slightly above the level of the heart. Venous occlusion was achieved by a BP cuff applied proximal to the elbow and inflated to 40 Results mm Hg by a rapid cuff inflator; approximately four Baseline characteristics for the hypertensive sub- inflations per minute, each of about 7 sec duration jects and the normotensive controls are given in were performed.
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