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(Circulation. 1996;94:3115-3122.)
© 1996 American Heart Association, Inc.
Articles |
Angiotensin-Converting Enzyme Inhibition Restores Flow-Dependent and Cold Pressor Test–Induced Dilations in Coronary Arteries of Hypertensive Patients
the Service d'Explorations Fonctionnelles et Institut National de la Sante et de la Recherche Medicale Unite 426, Centre Hospitalier et Universitaire Xavier Bichat, Paris, France.
Correspondence to Isabelle Antony, MD, Hopital Louis Mourier, CHU Xavier-Bichat, INSERM U. 426, 178 rue des Renouillers, F-92700 Colombes, France.
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Abstract |
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Background Cold pressor test (CPT)–induced and flow-dependent epicardial coronary artery dilations are impaired in patients with hypertension. ACE inhibition can attenuate sympathetic coronary constriction and potentiate or restore endothelium-dependent relaxations. This study was designed to determine whether the ACE inhibitor perindoprilat can restore normal coronary dilative responses in hypertensive patients.
Methods and Results Coronary vasomotor responses to CPT and to maximal increase of blood flow induced by papaverine were studied in 10 untreated patients with essential hypertension, no other risk factors, and angiographically normal coronary arteries before and after intravenous ACE inhibition by perindoprilat. Diameters of proximal and distal left anterior descending (LAD) and circumflex coronary arteries were measured by quantitative angiography. Estimates of coronary blood flow and resistance index were calculated with an intracoronary Doppler catheter in the distal LAD. Perindoprilat did not modify the hemodynamic responses to CPT and papaverine. In response to CPT, perindoprilat changed the epicardial coronary constriction (-8.4±5.8%, P<.001) into a significant dilation (+12.0±6.4%, P<.001). Perindoprilat significantly increased the coronary blood flow (from 33.7±10.0 to 57.9±20.5 mL/min, P<.01) and enhanced the decrease in coronary resistance (from 4.28±1.27 to 2.96±0.84 mm Hg·mL-1·min-1, P<.001) caused by CPT. Flow-dependent dilation of the proximal LAD was abolished in the control condition and was restored after perindoprilat (12.6±4.7%, P<.001).
Conclusions ACE inhibition restored CPT-induced and flow-mediated coronary artery dilations in patients with essential hypertension. These results indicate that impaired coronary vasomotor responses may be reversible in recently diagnosed hypertension.
Key Words: hypertension • arteries • endothelium • tests • enzymes
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Introduction |
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The endothelium, by releasing relaxing and constricting factors,1 2 3 4 and the sympathetic nervous system play a fundamental role in the regulation of vascular tone. Structural5 and functional6 7 changes of the endothelium are present in rats with chronic hypertension. In human hypertension, endothelium-dependent dilation (assessed by the response to acetylcholine) is impaired in coronary epicardial and resistance vessels.8 9 We have shown previously that flow-dependent dilation, which is substantial in normal coronary arteries of humans,10 is abolished in epicardial coronary arteries of patients with hypertension.11 We have also shown that epicardial coronary arteries constrict in response to sympathetic stimulation by the CPT,12 whereas the normal response is dilation.13
ACE inhibitors are potent antihypertensive drugs that block the conversion of angiotensin I into angiotensin II and act on the endothelium. They have a protective effect against the breakdown of locally produced bradykinin,14 which is a releaser of EDRF15 and EDHF.16 ACE inhibitors potentiate the endothelium-dependent relaxation to bradykinin in isolated canine coronary arteries.17 In addition, in hypertensive humans, ACE inhibition attenuates the forearm vasoconstriction induced by sympathetic stimulation.18 ACE inhibitors may modulate sympathetic activation by removing the facilitation of angiotensin II19 and/or because the endothelium has a modulator influence on sympathetic stimulation.20
The present study was designed to investigate whether or not the ACE inhibitor perindoprilat improves the impaired flow-dependent and CPT-induced responses of epicardial coronary arteries in patients with hypertension and no other risk factors.
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Methods |
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Patient Selection
Ten patients with essential hypertension undergoing diagnostic coronary angiography for evaluation of chest pain were studied. No patient had a history suggestive of variant angina. All patients had a well-established history of elevated blood pressure >140/90 mm Hg on the basis of four or more separate office visits at 1-week intervals (each blood pressure value was the mean of three readings). Hypertension was recently diagnosed in all patients who had never been treated. To perform the present study on patients with hypertension while avoiding atherosclerosis, patients were included only if coronary arteries were angiographically normal and completely smooth without luminal irregularities by consensus of two experienced investigators on immediate review of the angiograms. Furthermore, patients who had diabetes mellitus, patients with hypercholesterolemia (total cholesterol serum level >5.70 mmol/L [>220 mg/dL] or LDL cholesterol >3.70 mmol/L [>143 mg/dL]), smokers, and patients >65 years were excluded. None of the patients had a family history of premature coronary artery disease (defined as a first-degree relative <60 years old with clinical evidence of coronary atherosclerosis). By selection, the total number of coronary atherosclerosis risk factors was calculated by use of total cholesterol level >5.42 mmol/L (>210 mg/dL), age >40 years, and male sex. Left ventricular systolic function assessed by two-dimensional and M-mode echocardiography was normal in all patients. The left ventricular mass index was calculated at end diastole by use of the Penn convention.21 The study protocol was approved by the institutional review Committee of the University of Kremlin-Bicetre. All patients gave written informed consent before cardiac catheterization.
Catheterization Protocol
Patients were studied in the fasting state. Nitrate therapy, when given, was discontinued 24 hours before catheterization. No premedication was administered, 1% lidocaine was used for local anesthesia, and 5000 U heparin IV was administered. Coronary arteriography was performed by percutaneous femoral approach with 6F catheters. After documentation of normal coronary arteries, an additional 5000 U heparin IV was given, and an 8F guiding catheter was positioned in the ostium of the left coronary artery. Each patient then underwent the following study protocol. A 3F, 20-MHz coronary Doppler catheter (Monorail Doppler 3, Schneider Europe AG) connected to a single-channel 20-MHz pulsed Doppler velocimeter (model MDV, 20 Single Channel Velocimeter, Millar Instruments) was placed in the LAD. The proximal lumen of the Doppler catheter was placed in the midportion of the LAD by injection of contrast medium, and catheter position was adjusted to obtain an optimal audio signal and phasic tracing of coronary blood flow velocity. The use of this device to assess intracoronary blood flow velocity has been discussed in detail.11 12
The protocol design is presented in Fig 1
. Thirty minutes after the diagnostic coronary arteriography, the first hemodynamic measurements and left coronary arteriography (Base1) were realized. Five minutes later, the CPT1 was performed. The patient's hands were immersed in ice water for 120 seconds. Then, after blood pressure and heart rate had returned to baseline values (Base2), flow-dependent coronary dilation was assessed as previously described.11 Briefly, a bolus of 10 mg papaverine (PAP1) was injected into the midportion of the LAD through the proximal lumen of the Doppler catheter, and the diameter of the proximal LAD (LAD1) was measured. Papaverine reflux that should have caused direct dilation of the LAD1 was excluded by verification that injection of a bolus of 2 mL contrast through the Doppler catheter did not cause dye reflux to the LAD1. The proximal Cx segment served as control. Coronary angiograms were performed with an injection of 8 mL low-osmolarity contrast medium (meglumine ioxaglate) in the left coronary artery at Base1, at the peak of the CPT1 (immediately before removal of the hands from ice water), at Base2, and 60 seconds after the peak blood flow velocity induced by PAP1. Serial injections of the left coronary artery were performed at intervals of at least 5 minutes to exclude contrast-induced coronary dilation. Intracoronary blood flow velocity was measured in the distal LAD (LAD2), near the tip of the Doppler catheter, just before each angiogram to avoid the hyperemic effect of the contrast material. Heart rate, aortic pressure (through the guiding catheter), mean and phasic blood flow velocities (kilohertz shift), and ECG were continuously monitored throughout the protocol.
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Measurements of the diameters of the LAD1, LAD2, and Cx were made on each angiogram. Estimates of blood flow (F) in LAD2 were calculated from measurements of mean coronary flow velocity in LAD2 (v) and LAD2 cross-sectional area (CSA), F=vxCSA. Cross-sectional area was calculated from measurements of LAD2 diameter (d) assuming a circumferential model: CSA=
d2/4. An index of coronary vascular resistance was calculated by the ratio of the mean aortic pressure divided by the estimate of coronary blood flow.
In all patients, the above-described procedure was repeated (Base3, CPT2, Base4, PAP2) after intravenous infusion over a period of 10 minutes of 1 mg perindoprilat, the active deesterified form of the oral ACE inhibitor perindopril (Servier). This dosage was chosen because it has been safely prescribed, without significant effect on blood pressure, for patients with acute myocardial infarction and caused an immediate inhibition of plasma ACE activity of >90% during >6 hours (unpublished data from Servier, 1992). Left coronary angiograms, hemodynamic recordings, and measurements of blood flow velocity in LAD2 were thus performed at Base3, at the peak of the CPT2, at Base4, and 60 seconds after the peak blood flow velocity induced by papaverine (PAP2).
Last, measurements were repeated 4 minutes after intracoronary infusion of 2 mg ISDN through the guiding catheter. Five minutes after intracoronary injection of ISDN, coronary flow reserve was evaluated by injection of 10 mg papaverine hydrochloride through the proximal lumen of the coronary Doppler catheter (8 mg papaverine/mL 0.9% saline solution).22 Coronary flow reserve was calculated as the ratio of peak blood flow velocity to resting blood flow velocity.22
Quantitative Coronary Arteriography
Left coronary arteriograms were obtained by ECG-triggered digital subtraction at a rate of six frames per second on a 512-pixel matrix (General Electric CGR DG 300). The angiographic system was set up in the right anterior oblique position with adequate cranial or caudal angulation allowing optimal view of the LAD1, LAD2, and Cx segments on end-diastolic frames without overlap by side branches. Relations between focal spot, patient, and height of image tube were kept constant throughout the procedure. Analysis of coronary angiograms was performed by a previously validated technique.11 12 The reliability and accuracy of the method have been previously established on seven empty catheters ranging from 3F to 9F whose outer diameters were accurately measured with a 0.01-mm micrometer and on nine calibrated contrast medium–filled catheters ranging from 1 to 5 mm in inner diameter. A calibrated catheter filled with saline and positioned close to the center of the image was used as a scaling device for calibration. The accuracy of the technique was 3.6±0.5% (mean±SD) and the precision, 2.4±0.9%. The maximum error between the actual and the calculated diameters was ±5.7% (R2=.994).
In this study, a segment of the guiding catheter positioned in the left main coronary artery and filled with saline was placed close to the center of the image and used as a scaling device for calibration before the procedure was begun. Segments 6 to 10 mm long of the LAD1, LAD2, and Cx were analyzed as described above, and the mean diameter was calculated for each coronary segment from a series of diameter measurements (18 to 30). Each segment was defined with two anatomic references to reproducibly measure the same segment after each injection. All diameter measurements were corrected by a magnification factor taking into account the distance of the segment from the center of the image. A change in vessel diameter was defined as a minimum 6% variation, which corresponded to the highest error reported with the quantitative angiography validation technique (5.7%). Each angiogram was analyzed at random without knowledge of the sequence of the procedure (Base1, CPT1, Base2, PAP1, Base3, CPT2, Base4, PAP2, and ISDN).
Statistical Analysis
All data are expressed as mean±SD. Statistical comparisons of hemodynamic parameters; coronary vessel diameters; and coronary velocity, flow, and resistance under base, CPT, and papaverine; before and after the administration of the ACE inhibitor perindoprilat; and under post-ISDN conditions were made by two-way ANOVA with repeated measures for experimental condition factor, followed by the Fisher protected least significant difference test. Relations between changes in rate-pressure product and coronary blood flow before and after perindoprilat administration were determined by linear regression analysis using the least-squares method. Statistical significance was assumed if the null hypothesis could be rejected at the .05 probability level.
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Clinical Data
The characteristics of the patients are listed in the Table
. Two patients were >60 years (one man 62 years old and one woman 64 years old who had postmenopausal estrogen replacement). On the basis of selection, the number of coronary risk factors per patient (excluding hypertension) was low (1.6±0.5). The mean arterial pressure at the time of catheterization was elevated (130±7 mm Hg). Left ventricular end-diastolic diameter and fractional shortening were normal in all patients, and left ventricular mass index was slightly elevated in two.
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Effects of the Cold Pressor Test Before and After Administration of Perindoprilat
Hemodynamics
As shown in Fig 2, baseline heart rate was slightly but significantly reduced after perindoprilat administration compared with the control condition, from 72±10 bpm (Base1) to 68±9 bpm (Base3) (P<.05). Baseline mean arterial pressure and rate-pressure product were not significantly altered by perindoprilat. The CPT before (CPT1) and after (CPT2) perindoprilat caused no significant change in heart rate, whereas it caused a comparable increase in mean arterial pressure from 130±7 to 151±11 mm Hg and from 126±5 to 148±11 mm Hg, respectively (P<.001 for both). During CPT1 and CPT2, the rate-pressure product (bpmxmm Hg) increased similarly from 12 110±1884 to 15 036±3100 and from 11 229±1671 to 14 147±2930, respectively (P<.001 for both).
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Epicardial Coronary Artery Dimensions
Thirty coronary artery segments were analyzed. Before perindoprilat, the CPT1 caused a significant decrease in vessel diameters of LAD1, LAD2, and Cx (Fig 3), resulting in a mean reduction of epicardial artery diameter (-8.4±5.8%, P<.001) (no segment dilated, 22 segments constricted, and 8 segments did not change according to the change in vessel diameter defined in "Methods") (Fig 3), whereas the normal response to CPT is dilation.12 After perindoprilat administration, the constriction of LAD1, LAD2, and Cx was changed into a significant dilation (Fig 3), resulting in a mean diameter increase of 12.0±6.4% (P<.001) (no segment constricted, 25 segments dilated, and 5 segments did not change). After perindoprilat administration, mean epicardial artery cross-sectional area increased by 23.6±8.3% (P<.001).
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Coronary Blood Flow
The baseline (Base3) estimate of LAD2 blood flow was not significantly altered by perindoprilat compared with the control condition (Base1) (Fig 4). Before administration of perindoprilat, the CPT1 caused no significant change in the estimate of LAD2 blood flow (+33.6±11.9%), whereas it increased significantly during the CPT2 after administration of perindoprilat (from 33.7±10.0 to 57.9±20.5 mL/min, P<.01) (Fig 4). Before perindoprilat administration, there was no relation between the increase in rate-pressure product and the changes in coronary blood flow, whereas a significant positive correlation was observed after perindoprilat (P<.01, r=.75) (Fig 5). At baseline (Base1 and Base3), the coronary resistance index was comparable before and after the administration of perindoprilat (Fig 6). Given the comparable CPT-induced increases in mean aortic pressure before and after perindoprilat, the mean decrease in total coronary vascular resistance index observed before perindoprilat was significantly enhanced after perindoprilat, from 4.28±1.27 to 2.96±0.84 mm Hg·mL-1·min-1 (P<.001) (Fig 6).
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Flow-Dependent Coronary Artery Dilation Before and After Perindoprilat
As shown in Fig 7, baseline (Base4) heart rate and mean arterial pressure were not significantly altered by perindoprilat compared with the control condition (Base2). Before and after perindoprilat, papaverine caused no significant change in heart rate, whereas it decreased mean arterial pressure similarly, from 130±9 to 118±10 mm Hg and from 128±7 to 118±8 mm Hg, respectively (P<.001 for both). Before and after perindoprilat, papaverine caused a comparable increase in mean LAD2 diameter (the coronary segment exposed directly to papaverine) (P<.001 for both) (Fig 3
) and LAD2 blood flow velocity from 10.20±2.90 to 42.16±15.35 cm/s and from 10.34±2.06 to 43.68±15.48 cm/s, respectively (P<.001 for both). This resulted in a significant increase in the estimate of LAD2 coronary blood flow both before and after perindoprilat (421±94% and 469±116%, respectively, P<.001 for both) (Fig 7).
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As shown in Fig 3, at baseline (Base2 and Base4), the mean diameters of LAD1 (the coronary segment not exposed to papaverine) were comparable before and after perindoprilat. Before perindoprilat administration, no LAD1 segment dilated in response to increased flow in any patient, indicating the abolition of flow-dependent coronary dilation (Fig 3). In all patients, perindoprilat administration strikingly changed the flow-dependent coronary response into a substantial flow-dependent dilation. The mean LAD1 diameter increased 12.6±4.7% (P<.001) (Fig 3), and epicardial artery cross-sectional area increased by 27.2±12.1% (P<.001).
Vasomotor Response of Epicardial Coronary Arteries to Intracoronary ISDN Infusion
ISDN infusion caused a 26.6±11.1% increase in mean LAD1, LAD2, and Cx diameters compared with Base4 (P<.001).
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Discussion |
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The present study shows that acute intravenous administration of the ACE inhibitor perindoprilat restores two main vasomotor responses of epicardial coronary arteries in patients with hypertension: the normal response to sympathetic activation caused by the cold pressor test and the endothelium-mediated flow-dependent dilation. The ACE inhibitor also restores coronary blood flow regulation during cold pressor testing.
Cold Pressor Test
Cold pressor stimulation induces sympathetic release of norepinephrine and epinephrine23 and increases myocardial oxygen demand.13 The increase in myocardial metabolic demand has been shown to increase coronary blood flow and to dilate epicardial coronary arteries,24 despite the 
-adrenergic coronary constriction induced by sympathetic nervous system stimulation. The endothelium plays a major role in coronary vasomotion, mediating flow-dependent dilation of large and resistance vessels.25 26 In control subjects, the CPT dilates the epicardial coronary arteries in the absence of stenosis or luminal irregularities.12 13 27 The abnormal constriction of epicardial coronary arteries observed in hypertensive patients in response to CPT may be due to abnormal endothelium-mediated flow-dependent dilation and/or to an exaggerated response to sympathetic -adrenergic stimulation. The present study is the first one showing that acute administration of an ACE inhibitor restores the normal response to CPT in patients with hypertension. The magnitude of coronary dilation observed after administration of perindoprilat was comparable to that reported in control subjects in the literature.12 13 27 The favorable effect of the ACE inhibitor perindoprilat may be due first to attenuation of sympathetic nervous system–mediated vasomotor response. Indeed, a sympathetic modulating effect of angiotensin II and attenuation of sympathetic nervous system–mediated responses by ACE inhibitors have been evidenced in coronary and peripheral vasculature of animals.28 29 In humans with hypertension, it has been shown that ACE inhibition reduces sympathetic forearm vasoconstriction.18 ACE inhibition also attenuates sympathetic coronary constriction due to CPT in patients with coronary artery disease.30 The mechanism likely to account for this effect is a reduction of the facilitation of sympathetic function by angiotensin II.19 The hypothesis that the ACE inhibitor may have reduced a direct coronary constrictor effect of circulating angiotensin II seems unlikely, because this effect has been shown when the renin-angiotensin system is stimulated, as in patients with renovascular hypertension or those treated with diuretics.31 32 Second, taking into account that the coronary vasomotion induced by CPT is related to the integrity of endothelial function, the favorable effect of perindoprilat may also be due to the restoration of normal flow-dependent dilation we have observed (see below).
Moreover, before the administration of perindoprilat, the coronary blood flow did not increase significantly in response to CPT (whereas it has been demonstrated to increase in control subjects12 ), and no relation was observed between changes in rate-pressure product and changes in coronary blood flow. The administration of perindoprilat caused a significant increase in coronary blood flow during CPT, with a magnitude comparable to that reported in control subjects,12 and restored a relation between changes in rate-pressure product and changes in blood flow. The decrease in coronary vascular resistance observed during CPT was also enhanced after the administration of perindoprilat. The impaired coronary blood flow regulation suggests an abnormal coupling between myocardial metabolic demand and dilator capacity of the coronary microcirculation. In the present study, impairment of coronary reserve does not play a primary role, because coronary flow reserve was normal in 8 patients and near the lower limit of normal value reported in the literature in 2 (mean, 4.6; range, 3.4 to 6.1). The impaired dilator capacity of the microcirculation might be due to endothelial dysfunction of the coronary microcirculation. Indeed, Zeiher et al33 showed that an abnormal coronary blood flow response to cold pressor testing occurring in patients with early atherosclerosis was associated with impaired endothelium-dependent dilation of the coronary microvasculature. Endothelial dysfunction of the coronary microcirculation has been shown in patients with hypertension9 and might be due to an impaired endothelium-derived NO system (NO has been reported to participate in coronary blood flow regulation during an increase in myocardial oxygen consumption34 ) and/or to the release of endothelium-dependent constricting factors. However, the mechanism by which perindoprilat restores coronary blood flow regulation is not explained by the present study.
Endothelium-Mediated Flow-Dependent Dilation
In the majority of studies realized in patients with hypertension, endothelium-dependent vasodilation (in response to acetylcholine) was impaired in forearm35 36 37 38 and coronary8 9 39 circulation, whereas it was preserved in another study.40 Several groups of investigators reported that chronic antihypertensive therapy (with or without ACE inhibitors) improved endothelium-mediated relaxations in experimental models of hypertension.41 42 43 Blood pressure lowering by itself has been discussed as a possible determinant of this improvement.41 42 43 Indeed, Shultz and Raij44 showed that certain antihypertensive drugs, at doses that do not alter blood pressure, improve endothelium-dependent relaxations in normotensive rats. In patients with hypertension, discrepancies in the effects of antihypertensive therapy on endothelial function have been reported. Some authors reported that normalization of blood pressure by conventional antihypertensive therapy or by ACE inhibitors did not improve the endothelium-mediated forearm vascular relaxation.45 46 These findings conflict with those of Hirooka et al,47 who demonstrated that acute oral administration of captopril but not nifedipine augmented endothelium-dependent forearm vasodilation in patients with hypertension, whereas the two drugs lowered blood pressure similarly.
We demonstrated in a previous study11 and in the present one that epicardial coronary flow-dependent dilation is abolished in patients with essential hypertension. This study is the first one that evidences the restoration of epicardial coronary flow-dependent dilation by acute administration of an ACE inhibitor in patients with hypertension. Moreover, the magnitude of dilation was comparable to that reported in control subjects in the literature10 11 and was observed despite the absence of a blood pressure–lowering effect. Flow-dependent dilation is mediated by the endothelium.25 48 In isolated arteries, it is mediated through the release of EDRF,25 identified as NO.49 Endogenous NO is also responsible for flow-dependent dilation in human forearm arteries.50 However, a recent study done in normal subjects reported that coronary flow-mediated dilation was not mediated by NO.51 EDHF may also contribute to coronary flow-dependent vasodilation.2 Conversely, prostacyclin is unlikely to regulate flow-mediated vasodilation,48 and an impaired responsiveness of the vascular smooth muscle cells to nitrovasodilators has been excluded.11
The mechanism by which perindoprilat restores flow-dependent vasodilation is not explained by the present study. The magnitude of dilation induced by ISDN after perindoprilat administration was comparable to that reported in control subjects,11 12 and ACE inhibitors have no direct effects on vascular smooth muscle52 or on its responsiveness to nitrovasodilators.42 46 It is thus suggested that perindoprilat acts through endothelial function. The alteration in endothelial function may be related to bradykinin bioactivity. It has been shown recently that endogenous bradykinin has a role in mediating flow-dependent dilation in the human epicardial coronary vessels.53 Bradykinin is a potent releaser of NO15 52 and EDHF.16 Angiotensin I–converting enzyme cleaves bradykinin into inactive peptides.54 Perindoprilat, by preventing the breakdown of bradykinin in canine coronary arteries,55 has a potentiating effect on endothelium-dependent relaxations to bradykinin that is related to greater production of NO and EDHF.55
We did not observe any effects of perindoprilat on baseline coronary blood flow and epicardial diameter, unlike other studies using intracoronary administration of ACE inhibitors.56 57 This may be related to the intravenous administration and to the dose of perindoprilat used in our study. Furthermore, the measurement of absolute coronary blood flow with combined quantitative coronary angiography and Doppler ultrasound may have some limitation in detection of small changes. Conversely, the dose of perindoprilat used in our study may be sufficient to sensitize coronary vessels to ACE inhibitor–induced vasodilation only when coronary flow increases.
Last, ACE inhibition does not seem to attenuate endothelium-dependent contraction via a cyclooxygenase product, because indomethacin had no effect on endothelium-dependent relaxations in rats treated with ACE inhibitors,42 44 and perindoprilat is not a scavenger of superoxide anions and does not alter the contractions of isolated arteries evoked by endothelin.52
In summary, the present study shows that the intravenous administration of the ACE inhibitor perindoprilat restored normal flow-dependent and CPT-induced dilative responses of epicardial coronary arteries in patients with hypertension. Perindoprilat also improved the abnormal coronary blood flow regulation during CPT. These results indicate that such impaired coronary vasomotor responses may be reversible in recently diagnosed hypertension. Perindoprilat, in addition to its antihypertensive effect, might have a clinical interest during physiological conditions of increase in coronary blood flow and sympathetic activation by improving myocardial perfusion.
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Presented in part at the 67th Scientific Sessions of the American Heart Association, Dallas, Tex, November 14-17, 1994 and published in abstract form (Circulation. 1994;90[pt 2]:I-506).
Received April 17, 1996; revision received July 29, 1996; accepted August 7, 1996.
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