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J Am Coll Cardiol, 2003; 41:1373-1379, doi:10.1016/S0735-1097(03)00162-1
© 2003 by the American College of Cardiology Foundation
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CLINICAL STUDY: SYSTEMIC AND PULMONARY HYPERTENSION

Angiotensin-converting enzyme inhibition but not angiotensin II type 1 receptor antagonism augments coronary release of tissue plasminogen activator in hypertensive patients

Tetsuya Matsumoto, MD*,*, Kazuo Minai, MD*, Hajime Horie, MD*, Naoto Ohira, MD*, Hiroyuki Takashima, MD*, Yasuhiro Tarutani, MD*, Y. o Yasuda, MD*, Tomoya Ozawa, MD*, Shinro Matsuo, MD*, Masahiko Kinoshita, MD* and Minoru Horie, MD*

* First Department of Internal Medicine, Shiga University of Medical Science, Seta Tsukinowa, Otsu, Shiga, Japan

Manuscript received March 5, 2002; revised manuscript received December 27, 2002, accepted January 16, 2003.

* Reprint requests and correspondence: Dr. Tetsuya Matsumoto, First Department of Internal Medicine, Shiga University of Medical Science, Seta Tsukinowa, Otsu, Shiga 520-2192, Japan.
tetsuyam{at}belle.shiga-med.ac.jp


   Abstract
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 Abstract
Methods
 Results
 Discussion
 References
 
OBJECTIVES: We compared the effects of perindopril and losartan on endothelium-dependent coronary vasomotor and fibrinolytic function.

BACKGROUND: The renin-angiotensin system regulates the vascular fibrinolytic balance. However, the effects of angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor antagonists on coronary fibrinolytic function have not been compared in hypertensive patients.

METHODS: Forty-five patients with hypertension were randomly assigned to three groups: 16 patients were treated with perindopril (4 mg/day) for four weeks; 15 were treated with losartan (50 mg/day) for four weeks; and 14 were not treated with either perindopril or losartan (control group). Graded doses of bradykinin (BK) (0.2, 0.6, and 2.0 µg/min) were administered into the left coronary artery. Coronary blood flow (CBF) was evaluated by Doppler flow velocity measurement.

RESULTS: Bradykinin induced dose-dependent increases in CBF in all groups. The increases in CBF induced by BK in the perindopril and losartan groups were significantly greater than those in the control group. Net coronary tissue-type plasminogen activator (t-PA) release was enhanced by BK in all groups, and the increase in the perindopril group was greater than that in the losartan and control groups. Bradykinin did not alter plasminogen activator inhibitor type 1 levels in any of the groups.

CONCLUSIONS: Perindopril and losartan similarly augment BK-induced coronary vasodilation. Perindopril may have a greater potential to enhance the BK-induced coronary release of t-PA than losartan.

Abbreviations and Acronyms
  ACE
  angiotensin-converting enzyme
  Ao
  aorta
  AT1
  angiotensin II type 1
  BK
  bradykinin
  CBF
  coronary blood flow
  CS
  coronary sinus
  CVR
  coronary vascular resistance
  HF
  heart failure
  MAP
  mean arterial pressure
  NO
  nitric oxide
  t-PA
  tissue-type plasminogen activator
  PAI-1
  plasminogen activator inhibitor type 1

Impairment of fibrinolysis is an established risk factor for thrombotic events such as stroke and myocardial infarction (1,2). Thus, it is important to evaluate the role of fibrinolysis in the pathophysiology of cardiovascular disease. Fibrinolytic activity is primarily determined by the balance between the levels of tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor type 1 (PAI-1) (3,4).

The fibrinolytic system and the renin-angiotensin system are linked through angiotensin-converting enzyme (ACE) (5–7). The ACE inhibitors are thought to favorably alter the fibrinolytic balance by increasing bradykinin (BK)-induced t-PA release, by decreasing angiotensin II–mediated PAI-1 release, or by both (6,7). We recently demonstrated that ACE inhibitors augment BK-induced t-PA release in human coronary circulation (8).

There is a growing body of evidence that ACE inhibitors and angiotensin II type 1 (AT1) receptor antagonists improve peripheral and coronary vascular endothelial dysfunction (9–11). Based on the results of animal experiments, they can improve endothelial dysfunction by reducing angiotensin II–induced NADH-oxidase–mediated superoxide formation (12). In addition, unlike AT1 receptor antagonists, ACE inhibitors inhibit BK breakdown, thus enhancing plasma levels of BK and the subsequent release of nitric oxide (NO), prostacyclin, and endothelium-derived hyperpolarizing factor from the vascular endothelium. Previous comparative studies have shown that ACE inhibitors and AT1 receptor antagonists differ in their effects on fibrinolysis in the peripheral circulation (13–16). However, the effects of AT1 receptor antagonists on endothelium-dependent vasomotion and fibrinolysis in the human coronary circulation, as compared with the effects of ACE inhibitors, have not yet been assessed.

The aim of the present study was to compare the effects of an ACE inhibitor, perindopril, and an AT1 receptor antagonist, losartan, on BK-induced fibrinolytic and vasomotor responses in the human coronary circulation.


   Methods
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Results
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Study patients.   The study population consisted of 45 patients with atypical chest pain and hypertension (systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg at the time of recruitment into the study) who underwent diagnostic cardiac catheterization and were shown to have angiographically normal coronary arteries. Secondary hypertension was excluded on the basis of a history, physical examination, and appropriate laboratory tests (including a renal arteriogram, if indicated). Patients with diabetes mellitus, myocardial infarction, congestive heart failure (HF), cardiomyopathy, or valvular heart disease were also excluded. Forty-five patients were randomly assigned to three groups: 16 patients were treated with the ACE inhibitor perindopril (4 mg/day) for four weeks; 15 were treated with the AT1 antagonist losartan (50 mg/day) for four weeks; and 14 were not treated with ACE inhibitors or AT1 antagonists (control group). All cardiac medications except for ACE inhibitors and AT1 antagonists were discontinued for at least 72 h before the study. For at least seven days before the study, the subjects received a low-sodium diet (NaCl 5 g/day). The Ethical Committee on Human Research of our institution approved the study protocols, and written, informed consent was obtained from all patients.

Protocol.   All patients received the last dose of perindopril or losartan at 7 AM, and cardiac catheterization was performed between 9 and 11 AM in the fasting state. A 0.014-in. Doppler-tipped guide wire (FloWire, Cardiometrics Inc., Mountain View, California) was advanced to the area between the proximal and middle segments of the left anterior descending coronary artery to measure blood flow velocity, as previously described (8). All drugs were infused directly into the left main coronary artery via the guide catheter at infusion rates ranging from 0.5 to 1 ml/min. A 6F multipurpose catheter (GCS6, Goodtec, Gifu, Japan) was inserted via the right femoral vein into the coronary sinus (CS) for blood sampling. Baseline coronary blood flow (CBF) velocity measurement, blood sampling, and coronary angiography were performed. The following studies were then performed. 1) Bradykinin was started at 0.2 µg/min and then increased to 0.6 and 2.0 µg/min for 2 min. During BK infusion, CBF velocity reached a peak at about 60 s and maintained a plateau by 60 s. 2) After completing the protocol with the intracoronary injection of BK, we waited for at least 10 min before beginning the infusion of papaverine, by which time the coronary diameter and CBF velocity had returned to their baseline values. 3) Finally, papaverine (an endothelium-independent vasodilator) was administered into the left coronary artery at 12 mg over 20 s. Coronary angiography was performed after each infusion.

Quantitative coronary angiography and measurement of CBF.   Coronary cineangiograms were recorded using a Philips cineangiographic system (Philips Medical Systems, Tokyo, Japan). The change in the diameter of the left anterior descending coronary artery was measured in a vessel segment 5 mm beyond the tip of the Doppler wire. Coronary angiography was performed using the Judkins technique with contrast material (Omnipaque, Dai-ichi Pharmaceutical Co., Tokyo, Japan). Coronary angiograms were analyzed by quantitative coronary angiography, using the Cardiovascular Measurement System (CMS-MEDIS Medical Imaging Systems, Leiden, The Netherlands). Peak CBF velocity was continuously monitored using a fast Fourier transform–based spectral analyzer (FloMap, Cardiometrics Inc.). Coronary blood flow was derived from the CBF velocity, and measurements of the diameter were derived by the formula: (17). Coronary vascular resistance (CVR) was calculated as the mean arterial pressure (MAP) divided by CBF.

Phasic pressure and MAP, heart rate, and 12-lead electrocardiograms were continuously monitored using a polygraph system (Nihon-Kohden Kogyo Co., Tokyo, Japan) and recorded on a multichannel recorder.

Blood sampling and biochemical assays.   Paired blood samples in the aorta (Ao) and CS were taken simultaneously before infusion of BK and after infusion of BK and papaverine for the measurement of t-PA antigen and antibody and PAI-1 antigen, as previously described (8).

Blood samples were collected on ice and centrifuged immediately, and plasma was stored at –70°C until the time of assay. Blood for the measurement of t-PA and PAI-1 was collected in tubes containing citrate and acidified buffered citrate. Antigen levels were determined using two-site ELISA (Biopool, AB, Umea, Sweden) (8). In samples obtained from seven patients in the control group, eight patients in the perindopril group, and eight patients in the losartan group in a randomized manner, plasma levels of t-PA activity were determined by a photometric method (Chromolize t-PA, Biopool, AB). Blood for the measurement of plasma levels of the plasma-active renin concentration, aldosterone, epinephrine, norepinephrine, angiotensin I, and angiotensin II was collected in tubes containing EDTA (1 mg/ml). The plasma-active renin concentration and aldosterone levels were measured using commercial radioimmunoassay kits. Plasma epinephrine and norepinephrine concentrations were measured by high-performance liquid chromatography. Plasma angiotensin I and angiotensin II levels were measured by radioimmunoassay, using a specific antibody (Special Research Laboratory, Tokyo, Japan).

Arteriovenous concentration gradients were calculated by subtracting the plasma level measured in simultaneously collected arterial and CS venous blood. Thus, the net release or uptake rates at each time point were calculated as: .

Statistics.   Data are expressed as the mean value ± SEM. Discrete variables were expressed as counts or percentages and compared using the chi-squared test. Continuous variables were compared using the unpaired Student t test or one-way analysis of variance (ANOVA). When serial changes in systemic and coronary hemodynamic variables and fibrinolytic parameters in response to graded doses of BK were compared, we used two-way ANOVA for repeated measures, followed by the Bonferroni multiple comparisons test, between groups; and we used one-way ANOVA within each group (StatView version 5.0). A value of p < 0.05 was considered statistically significant.


   Results
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 Methods
 Results
Discussion
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Baseline characteristics and neurohormonal factors.   There were no significant differences in baseline characteristics among the control, perindopril, and losartan groups (Table 1).


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  		Table 1 Baseline Characteristics

 
There were no significant differences in aldosterone, epinephrine, or norepinephrine among the control, perindopril, and losartan groups after one month of treatment. Plasma-active renin concentration levels in the perindopril and losartan groups were higher than those in the control group. The level of ACE in the perindopril group was lower than that in the control and losartan groups. Levels of angiotensin I and II in the losartan group were higher than those in the control and perindopril groups (Table 2).


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  		Table 2 Neurohormonal Values

 
Systemic and coronary hemodynamics.   As shown in Figure 1, intracoronary infusion of BK resulted in a significant decrease in MAP in the perindopril group, and this effect was dose-dependent. However, BK did not alter MAP in the control or losartan group. After infusion of each of three graded doses of BK, MAP was significantly lower in the perindopril and losartan groups than in the control group. With increasing doses of BK, the heart rate did not change in either group (Fig. 1). The addition of 12 mg papaverine did not affect MAP or heart rate in either group. Intracoronary infusion of BK increased CBF and decreased CVR in a dose-dependent manner in all three groups (Fig. 2). The increases in CBF and decreases in CVR induced by the three doses of BK in both the perindopril and losartan groups were significantly greater than those in the control group. No significant differences were observed in the CBF and CVR responses to BK between the perindopril and losartan groups. Intracoronary infusion of papaverine caused similar increases in CBF and decreases in CVR in the three groups (Fig. 2).



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  		Figure 1 The effects of bradykinin (0.2, 0.6, and 2.0 µg/min) and papaverine (PA) (12 mg) on mean arterial pressure (upper panel) and heart rate (lower panel) in the control group (solid circles), perindopril group (solid triangles), and losartan group (open squares). *p < 0.05 versus baseline.

 


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  		Figure 2 The effects of bradykinin (0.2, 0.6, and 2.0 µg/min) and papaverine (PA) (12 mg) on percent changes in coronary blood flow and vascular resistance in the control group (solid circles), perindopril group (solid triangles), and losartan group (open squares).

 
Fibrinolytic parameters.   The basal levels of t-PA antigen at either the Ao or CS did not differ among the three groups (control group: Ao 6.3 ± 0.8 ng/ml, CS 6.3 ± 0.7 ng/ml; perindopril group: Ao 6.3 ± 0.7 ng/ml, CS 6.9 ± 0.9 ng/ml; losartan group: Ao 5.1 ± 0.8 ng/ml, CS 5.2 ± 0.9 ng/ml). The level of t-PA in the Ao was not changed by the infusion of BK in any of the three groups (Fig. 3, left). The levels of t-PA in the CS in all three groups were significantly increased in a dose-dependent manner by the infusion of graded doses of BK (Fig. 3, right). The level of t-PA in response to BK in the CS in the perindopril group was significantly higher than that in the control and losartan groups. The net t-PA release induced by the intracoronary infusion of BK was increased in all three groups, and the increase in the perindopril group was markedly greater than that in the control and losartan groups (Fig. 4). Baseline levels of plasma t-PA activity in the Ao and CS were <0.5 IU/ml in the three groups (control group: n = 7; perindopril group: n = 8; losartan group: n = 8). Bradykinin at doses of 0.2, 0.6, and 2.0 µg/min did not significantly increase plasma levels of t-PA activity in the control and losartan groups. Increases in t-PA activity across the coronary circulation were observed only after infusion of BK at doses of 0.6 and 2.0 µg/min in the perindopril group (0.6 µg/min BK: Ao <0.5 IU/ml, CS 2.2 ± 0.8 IU/ml; 2.0 µg/min BK: Ao <0.5 IU/ml, CS 4.9 ± 1.6 IU/ml). Intracoronary infusion of papaverine did not alter the level of t-PA in either the Ao or CS in any of the three groups.



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  		Figure 3 The effects of bradykinin (0.2, 0.6, and 2.0 µg/min) and papaverine (PA) (12 mg) on tissue-type plasminogen activator (t-PA) antigen in the aorta (Ao) and coronary sinus (CS) in the control group (solid circles), perindopril group (solid triangles), and losartan group (open squares). *p < 0.05 versus baseline.

 


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  		Figure 4 The effects of bradykinin (0.2, 0.6, and 2.0 µg/min) and papaverine (PA) (12 mg) on net tissue-type plasminogen activator (t-PA) release in the control group (solid circles), perindopril group (solid triangles), and losartan group (open squares). *p < 0.05 versus baseline.

 
The basal levels of PAI-1 in both the Ao and CS in the control group tended to be higher than respective levels in the other two groups, but these differences were not significant (control group: Ao 6.2 ± 0.8 ng/ml, CS 6.8 ± 1.2 ng/ml; perindopril group: Ao 5.1 ± 0.8 ng/ml, CS 5.5 ± 1.0 ng/ml; losartan group: Ao 4.7 ± 0.9 ng/ml, CS 5.1 ± 1.2 ng/ml) (Fig. 5). With an increase in the dosage of BK, the level of PAI-1 in the CS tended to decrease, compared with that in the Ao, in all three groups. However, there were no significant differences among the three groups. Papaverine also had no significant effects on the level of PAI-1 in either the Ao or CS in any group (Fig. 5).



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  		Figure 5 The effects of bradykinin (0.2, 0.6, and 2.0 µg/min) and papaverine (PA) (12 mg) on plasminogen activator inhibitor type 1 (PAI-1) antigen in the aorta (Ao) and coronary sinus (CS) in the control group (solid circles), perindopril group (solid triangles), and losartan group (open squares).

 

   Discussion
Top
 Abstract
 Methods
 Results
 Discussion
References
 
Principal findings.   The major findings of the present study are as follows: AT1 receptor antagonism and ACE inhibition augmented endothelium-mediated vasodilation induced by BK in human coronary circulation. Also, ACE inhibition potentiated the ability of BK to stimulate the release of t-PA in the human coronary circulation, which is not observed with AT1 receptor antagonism.

Endothelial vasomotor function.   Four weeks of therapy with the ACE inhibitor perindopril or the AT1 receptor antagonist losartan augmented the BK-induced CBF and CVR responses to a similar extent. Although many clinical studies have found that ACE inhibitors improve endothelial function under various conditions (9,10,18), it is not clear whether AT1 receptor antagonists have beneficial effects comparable to those of ACE inhibitors. Treatment with perindopril for three months improved the forearm blood flow response induced by acetylcholine in patients with congestive HF who improved clinically (9). The Trial on Reversing ENdothelial Dysfunction (TREND) study showed that quinapril improved acetylcholine-induced coronary vasomotor function in normotensive patients with coronary artery disease (10). Recently, Prasad et al. (11,19) showed that losartan improved flow-mediated brachial and coronary artery dilation in patients with atherosclerosis.

The ACE inhibitors may act on kininase II and increase tissue concentrations of BK, which would augment vasodilation through the release of NO, prostacyclin, and endothelium-derived hyperpolarizing factor. In addition, angiotensin II strongly stimulates NADH/NADPH-oxidase-dependent vascular superoxide anion generation (20,21). Thus, ACE inhibitors and AT1 receptor antagonists may enhance BK-induced coronary vasodilation partly through increased NO bioavailability by reducing vascular angiotensin II production (22).

Tissue-type plasminogen activator.   This is a serine protease released from endothelial cells through translocation of a dynamic intracellular storage pool. The effectiveness of plasminogen activation and fibrin degradation is regulated by the relative balance between the local release of t-PA and its subsequent inhibition via the formation of complexes with PAI-1.

In the present study, baseline t-PA antigens in both the Ao and CS were similar among the three groups. There have been only a few direct comparison studies on the effects of ACE inhibitors and AT1 receptor antagonists on fibrinolysis. In one study, the administration of losartan, but not quinapril, for three weeks reduced the plasma t-PA antigen concentration in normotensive subjects under activation of the renin-angiotensin-aldosterone system (13). Similarly, immediate administration of losartan, but not enalapril, reduced the plasma t-PA antigen concentration in patients with HF (14). Other comparative studies showed that plasma t-PA antigen concentrations were unchanged in patients with hypertension using two therapeutic regimens (15).

In the present study, the CBF and CVR responses and net t-PA release induced by BK were significantly increased in the perindopril group compared with the control group. AT1 receptor antagonism did not influence the effect of BK on t-PA release, despite the augmented BK-induced CBF response. On the contrary, Labinjoh et al. (23) reported that seven days of treatment with losartan (50 mg/day) did not change the blood flow response and t-PA release induced by BK in the forearm circulation. In the present study, plasma concentrations of angiotensin II in the losartan group were higher than those in the perindopril and control groups. There have been some reports that blockade of AT1 receptors may cause the generation of NO mediated by BK from the endothelium through an increase in plasma angiotensin II and stimulation of AT2 receptors (24,25). Our data suggest that AT2 receptor stimulation may have little, if any, effect on coronary net t-PA release in response to BK.

Tranquille and Emeis (26) reported that blockade of NO did not affect BK-stimulated t-PA release. Brown et al. (27) reported that BK stimulates t-PA release from the forearm vascular endothelium through a B2 receptor–dependent, NO synthase–independent, and cyclooxygenase-independent pathway. They suggested that endothelium-derived hyperpolarizing factor may contribute to BK-stimulated t-PA release. Interestingly, Node et al. (28) suggested that epoxyeicosatrienoic acids, which share many of the properties of endothelium-derived hyperpolarizing factor (29), possess fibrinolytic properties through the induction of t-PA expression without affecting PAI-1 in vascular endothelial cells. Further studies are needed to examine whether endothelium-derived hyperpolarizing factor could contribute to coronary t-PA release in response to BK and, if so, to determine the mechanism.

As far as the human coronary circulation is concerned, ACE inhibition may have greater beneficial effects than AT1 receptor antagonism by increasing BK-induced t-PA release, even if ACE inhibition and AT1 receptor antagonism may have similar beneficial effects on BK-induced coronary vasodilation. The present results may be associated with the beneficial effects of ACE inhibitors on the observed incidence of coronary thrombotic events in several previous randomized clinical trials.

Plasminogen activator inhibitor-1.   Our study demonstrates that the basal levels of PAI-1 in both the Ao and CS did not significantly differ among the three groups. Goodfield et al. (14) recently reported that ACE inhibition with enalapril and AT1 receptor antagonism with losartan lowered PAI-1 antigen in chronic HF patients. Another recent report showed that levels of PAI-1 antigen were reduced after treatment with either an ACE inhibitor (perindopril) or AT1 receptor antagonist (losartan) among patients with hypertension (15). In contrast, trandolapril decreased PAI-1 levels, whereas losartan did not, in hypertensive postmenopausal women (16). Similar results were found in a comparison of quinapril and losartan in normotensive subjects under activation of the renin-angiotensin system (13).

In the present study, PAI-1 levels at the CS, but not the Ao, tended to decrease with increasing doses of BK in all three groups. Nagata et al. (30) showed that ACE inhibition, but not AT1 receptor antagonism, decreased PAI-1 synthesis in human cultured monocytes, suggesting that BK may be involved in PAI-1 synthesis. Many factors influence the production of PAI-1 (e.g., glucose, insulin, estrogen, angiotensin II). Further studies are needed to determine whether t-PA release induced by BK is associated with PAI-1 synthesis and clearance in human coronary circulation.

Conclusions.   AT1 receptor antagonism and ACE inhibition augment endothelium-mediated vasodilation induced by BK in human coronary circulation. Angiotensin-converting enzyme inhibition potentiates the ability of BK to stimulate the release of t-PA in the human coronary circulation, which is not seen with AT1 receptor antagonism. The present study raised the possibility that ACE inhibitors may have a greater potential to induce coronary fibrinolytic activity, and thus reduce the prevalence of thrombotic cardiovascular events, than AT1 receptor antagonists.


   References
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 Discussion
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