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(Circulation. 1996;93:1734-1739.)
© 1996 American Heart Association, Inc.

Articles

Coronary Vasodilation Induced by Angiotensin-Converting Enzyme Inhibition In Vivo

Differential Contribution of Nitric Oxide and Bradykinin in Conductance and Resistance Arteries

Krishnankutty Sudhir, MD, PhD; Tony M. Chou, MD; Stuart J. Hutchison, MD; Kanu Chatterjee, MD

From the Cardiovascular Research Institute and Division of Cardiology, University of California at San Francisco.

Correspondence to K. Sudhir, MD, PhD, Box 0124, University of California at San Francisco, 505 Parnassus Ave, San Francisco, CA 94143-0124. E-mail sudhir@cardio.ucsf.edu.

	Abstract

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Background We studied in coronary conductance and resistance arteries the coronary vasodilator effects of the angiotensin-converting enzyme inhibitor ramiprilat and the contribution of nitric oxide, bradykinin, and prostaglandins to this vasodilation.

Methods and Results In seven anesthetized dogs, a Doppler guidewire was placed in the circumflex coronary artery to measure coronary flow velocity, and an ultrasound imaging catheter was introduced over the Doppler wire to measure coronary cross-sectional area. Drugs were infused directly into the left main coronary artery to minimize systemic effects. Ramiprilat increased both epicardial cross-sectional area and coronary blood flow velocity, resulting in an increase in absolute coronary blood flow. Pretreatment with N-nitro-L-arginine methyl ester (100 µmol/L intracoronary) to block nitric oxide synthase attenuated ramiprilat-induced increase in epicardial coronary cross-sectional area (P<.05) but not in coronary flow velocity or coronary blood flow. In contrast, pretreatment with the selective bradykinin antagonist HOE 140 (10 µmol/L) attenuated ramiprilat-induced increase in flow velocity (P<.025) and coronary blood flow (P<.05) but not epicardial coronary cross-sectional area. Pretreatment with indomethacin (5 mg/kg body wt IV) did not alter ramiprilat-induced increase in epicardial cross-sectional area, nor did it significantly influence coronary blood flow.

Conclusions Other than decreasing angiotensin II production, acute ramiprilat-induced vasodilation in canine coronary conductance arteries is mediated in part by nitric oxide. Ramiprilat-induced vasodilation in resistance arteries is in part mediated by the action of bradykinin.

Key Words: angiotensin • blood flow • bradykinin • endothelium-derived factors

	Introduction

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Among the various potential mechanisms by which ACE inhibitors may be cardioprotective, a direct effect on coronary hemodynamics is likely. ACE inhibitors have been shown to decrease myocardial oxygen consumption.¹ In addition, studies in animals² and humans³ have demonstrated that intracoronary administration of ACE inhibitors increases coronary blood flow. After intravenous administration of enalaprilat in patients with heart failure, absolute coronary blood flow does not increase, yet flow remains in excess of metabolic demand despite decreased perfusion pressure, suggesting ACE inhibition–induced primary coronary vasodilation.⁴ In subjects without coronary artery disease, captopril is reported to increase coronary blood flow,⁵ whereas in patients with angina, captopril either did not influence⁶ or decreased⁷ coronary blood flow, findings that probably reflect interaction between ventricular unloading and a variable reduction in coronary vasomotor tone. The mechanisms by which ACE inhibitors induce coronary vasodilation are unclear and may in part result from attenuation of the direct vasoconstrictor effect of angiotensin II. However, in addition to mediating the conversion of angiotensin I to angiotensin II, ACE is structurally identical to the kinase II enzyme responsible for the degradation of bradykinin.⁸ Therefore, an additional mechanism of ACE inhibition–induced coronary vasodilation is an increase in circulating or local concentrations of bradykinin. In addition, the vasodilator effects of kinins are mediated in part by stimulation of prostaglandin and NO release^{9 10} : thus, coronary vasodilation induced by ACE inhibition may be mediated via one or more of these mechanisms.

Vasodilator agents in the coronary circulation may predominantly influence either conductance or resistance arteries.¹¹ The relative contributions of NO and prostaglandin release and of increased bradykinin levels to ACE inhibition–induced vasodilation in large and small coronary arteries have not been adequately defined in vivo. In the present study, we examined the acute vasodilating properties of the ACE inhibitor ramiprilat in coronary conductance and resistance arteries in vivo by using simultaneous intravascular 2D and Doppler ultrasound. Using inhibitors of NO and prostaglandin synthesis and an antagonist to the bradykinin receptor, we examined the mechanism of its action in both large and small coronary arteries.

	Methods

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Seven mongrel dogs (mean weight, 27±0.9 kg) were anesthetized with Innovar (0.04 mg/kg SQ) and sodium pentobarbital (15 mg/kg IV), with additional doses of sodium pentobarbital as needed to maintain the level of anesthesia. They were mechanically ventilated with room air. Heart rate was monitored with an ECG, and blood pressure was monitored with a cannula placed in the right internal carotid artery. All studies conformed to the "Position of the American Heart Association on Research Animal Use" adopted November 11, 1984, by the AHA.

Catheterization Procedures
Under fluoroscopic guidance, the left main coronary artery was cannulated via the transfemoral approach with an 8F canine guiding catheter (Advanced Cardiovascular Systems). As previously described,^{11 12} a 0.014-in Doppler wire (Cardiometrics Inc) was first introduced through the 8F guiding catheter, after which a 4.3F ultrasound imaging catheter (Cardiovascular Imaging Systems) was introduced directly over the Doppler wire into the circumflex coronary artery. The Doppler transducer was positioned 2 cm distal to the tip of the imaging catheter.¹²

Experimental Protocols
Unless otherwise indicated, pharmacological agents were administered directly into the coronary circulation through the guiding catheter in the ostium of the left main coronary artery. Measurements of coronary artery cross-sectional area and flow velocity were made at 30-second intervals after each administration. Intracoronary drug infusions were made over a 1-minute period unless otherwise specified; final concentrations in the coronary artery are indicated, assuming a flow rate of 80 mL/min, as previously described.^{2 11} Ramiprilat and HOE 140 were obtained from Hoechst-Roussel Pharmaceuticals, and other drugs were obtained from Sigma Chemical Co.

Ramiprilat was infused at concentrations increasing from 10^-10 to 10^-5 mol/L. With each concentration, sufficient time (range, 5 to 9 minutes) was allowed for epicardial coronary dimensions and flow velocity to return to baseline before the next dose was administered. The effect of ramiprilat (10^-6 mol/L) was then assessed after the following pharmacological interventions, the order of which was randomized: (1) inhibition of NO synthesis by intracoronary administration of L-NAME to obtain a final concentration of 10^-4 mol/L in the coronary artery¹³ ; (2) inhibition of prostaglandin synthesis by intravenous infusion of indomethacin (5 mg/kg IV over 5 minutes; Du Pont-Merck Pharmaceuticals) previous studies have suggested that this dose is sufficient to block prostaglandin synthesis¹⁴ ; and (3) inhibition of the bradykinin (B₂) receptor by intracoronary administration of HOE 140 (10^-5 mol/L).¹⁵ A washout period of at least 45 minutes was allowed between the administration of antagonists. Transvenous atrial pacing at a rate of 130 bpm was used during the entire study to prevent changes in heart rate.

2D Ultrasound System Description and Image Analysis
The ultrasound catheter (4.3F) has a fixed 30-MHz transducer and a rotating mirror assembly. Images are displayed on a video monitor; axial resolution was 150 µm, and lateral resolution was 250 µm. Gain, contrast, and reject settings were adjusted by the operator to yield a well-balanced gray-scale appearance on the video display. Real-time images were stored on high-quality super VHS videotape for subsequent off-line analysis. As previously described,^{11 12} selected portions of the videotape were digitized (12 bits; model 324, Rasterops) in real time (30 frames per second) and stored on a computer disk for off-line determination of luminal area.

Doppler Ultrasound System Description
Doppler-derived blood flow velocities were measured with use of a 0.014-in steerable Doppler guidewire (FloWire; Cardiometrics Inc). This guidewire system has a miniature Doppler ultrasound crystal that transmits signals at a carrier frequency of 15 MHz and receives pulsed wave ultrasound signals, sampled at a distance of 5 mm from the guidewire tip. The Doppler signals are analyzed with a FloMap instrument (Cardiometrics Inc) in which dedicated digital signal processing chips perform the fast Fourier transformation required for the spectral display. The signals are transformed into a gray scale, and the resultant spectrum is displayed on a monitor. In our study, the ECG and arterial pressure waveform were displayed simultaneously on the monitor; also displayed were quantitative measurements of average peak velocity throughout the cardiac cycle. The monitor display was continuously recorded on VHS videotape for further off-line analysis and comparison with corresponding cross-sectional ultrasound images.

Calculations and Statistical Analysis
Luminal cross-sectional areas at baseline and after administration of drugs were determined with computer-assisted planimetry. Volumetric coronary blood flow was calculated with the following equation: CBF=CSAxAPVx0.5, as previously validated,¹² where CBF is coronary blood flow, CSA is cross-sectional area, and APV is average peak velocity. Dose-response relations with ramiprilat were examined with the use of ANOVA for repeated measures, followed by a post hoc Student-Newman-Keuls test. The effects of L-NAME, indomethacin, and HOE 140 on ramiprilat-induced vasodilation were analyzed with Student's t test for paired observations. Values are expressed as mean±SEM.

	Results

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Resting Coronary Dimensions and Flow
Mean resting heart rate and mean arterial pressure are shown in the Table. Mean resting coronary cross-sectional area was 8.6±0.9 mm², mean average peak velocity was 25.5±3.6 cm/s, and mean volumetric coronary blood flow was 65.2±10.7 mL/min.

View this table: [in this window] [in a new window]   Table 1. Mean Arterial Pressure and Heart Rate Changes Induced by Ramiprilat Before and After Pharmacological Antagonism of Prostaglandins, NO Synthase, and the Bradykinin Receptor

Effect of Ramiprilat on Coronary Artery Dimensions and Flow
At concentrations of 10^-7 and higher, ramiprilat caused a significant increase in coronary cross-sectional area, average peak velocity, and volumetric coronary blood flow, as shown in Fig 1. The peak effect on coronary blood flow was seen between 90 and 120 seconds, and the mean duration of the vasodilator response was 10±3.5 minutes. No significant changes in systemic arterial pressure or heart rate were observed with any dose.

View larger version (14K): [in this window] [in a new window]   Figure 1. Effect of increasing concentrations of intracoronary ramiprilat on coronary cross-sectional area (CSA), Doppler-derived average peak velocity (APV) and calculated coronary blood flow (CBF). *Significant difference from baseline at P<.05.

Effect of L-NAME on Ramiprilat-Induced Coronary Vasodilation
There was a tendency for L-NAME to cause reduction in baseline cross-sectional area (to 8.17±1.0 mm²; P=.07), but average peak velocity remained unchanged (25±4.3 cm/s). Blood pressure and heart rate remained unchanged with L-NAME (Table). The magnitude of ramiprilat-induced increase in cross-sectional area was significantly attenuated by L-NAME (P<.05), but the increases in average peak velocity and coronary blood flow were unchanged by L-NAME (Fig 2).

View larger version (19K): [in this window] [in a new window]   Figure 2. Ramiprilat-induced increase in cross-sectional area (CSA), average peak velocity (APV), and calculated coronary blood flow (CBF) before and after administration of L-NAME (100 µmol/L), showing an attenuation of ramiprilat-induced increase in epicardial coronary artery CSA but no change in ramiprilat-induced increase in APV or CBF by L-NAME. *Significant difference at P<.05.

Effect of Indomethacin on Ramiprilat-Induced Coronary Vasodilation
Baseline cross-sectional area and average peak velocity remained unchanged with indomethacin (9.0±1.1 mm² and 25.5±3.3 cm/s, respectively). Blood pressure and heart rate remained unchanged with indomethacin (Table). The magnitude of ramiprilat-induced increase in cross-sectional area was unchanged by indomethacin; however, there was a tendency for the increase in average peak velocity to be attenuated by indomethacin (P=.06) (Fig 3). Ramiprilat-induced increase in coronary blood flow was not significantly attenuated by indomethacin.

View larger version (20K): [in this window] [in a new window]   Figure 3. Ramiprilat-induced increase in cross-sectional area (CSA), average peak velocity (APV), and calculated coronary blood flow (CBF) before and after administration of indomethacin (5 mg/kg IV), showing no significant change in ramiprilat-induced coronary vasodilation after indomethacin. *Significant difference at P<.05.

Effect of HOE 140 on Coronary Vasodilation Induced by ACE Inhibition
After infusion of HOE 140, coronary artery cross-sectional area (8.5±1.0 mm²) and coronary blood flow velocity (26.2±3.8 cm/s) did not change significantly. Blood pressure and heart rate remained unchanged with HOE 140 (Table). The magnitude of the increase in epicardial coronary cross-sectional area did not change after HOE 140, but ramiprilat-induced increases in blood flow velocity (P<.025) and volumetric blood flow (P<.05) were significantly attenuated by HOE 140 (Fig 4).

View larger version (20K): [in this window] [in a new window]   Figure 4. Ramiprilat-induced increase in cross-sectional area (CSA), average peak velocity (APV), and calculated coronary blood flow (CBF) before and after administration of HOE 140 (10 µmol/L), showing an attenuation in ramiprilat-induced increase in APV and CBF but no change in ramiprilat-induced increase in CSA after HOE 140. *Significant difference at P<.05.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
Results of the present study confirm that ACE inhibitors exert direct vasodilatory effects on coronary conductance and resistance arteries in vivo. At the highest dose of ramiprilat, there was a 50% increase in coronary blood flow in the absence of any significant change in determinants of myocardial oxygen demand, ie, blood pressure or heart rate. We did not measure changes in contractility or left ventricular wall tension. However, because angiotensin II has positive inotropic effects,¹⁶ ACE inhibitors would be expected to decrease contractility³ and wall tension, which should result in a decrease in coronary blood flow. Thus, the increase in coronary blood flow in response to intracoronary administration of ramiprilat observed in the present study must be directly related to a decrease in coronary vascular resistance. Mechanisms other than inhibition of angiotensin II may play a role in vasorelaxation induced by ACE inhibition: release of NO appears to contribute to this effect in conductance arteries, whereas in resistance arteries, it appears to be mediated in part via increase in local bradykinin levels and stimulation of the bradykinin (B₂) receptor.

Recent studies have suggested that some vascular effects of ACE inhibitors may be mediated by mechanisms other than a decrease in local production of angiotensin II, such as decreased bradykinin breakdown, release of NO, and increased prostacyclin levels.^{17 18 19} The relative contribution of each of these mechanisms to vasodilation in conductance and resistance coronary arteries is unclear. Furthermore, the majority of published studies have been performed in vitro, either in cultured endothelial cells or in vascular ring preparations, and few studies have addressed the mechanisms of ACE inhibition in an in vivo model.

Previous studies have shown that although ACE inhibitors cause vasorelaxation in superfused vessels in large arteries, there appears to be little effect of these agents in bovine or canine coronary artery rings under no-flow conditions in organ chambers.²⁰ Thus, flow may sensitize blood vessels to ACE inhibitor—induced vasodilation: our in vivo data are consistent with these observations. Studies in the superfused bovine coronary artery preparation showed that vasodilation induced by ACE inhibition was attenuated to a similar degree by a NO synthase inhibitor and a bradykinin (B₂) receptor antagonist.²¹ However, in our in vivo study, only L-NAME inhibited ramiprilat-induced vasodilation in the epicardial coronary arteries; neither HOE 140 nor indomethacin attenuated ACE inhibitor–induced vasorelaxation in the conductance vessels. Our results suggest that the NO release induced by ramiprilat in the conductance arteries is not secondary to increased local bradykinin concentrations and subsequent bradykinin-induced NO release. NO has been reported to mediate the vasodepressor effect of ACE inhibitors in an animal model of hypertension.²² The selective angiotensin subtype 1 receptor antagonist losartan has also been shown to induce epicardial coronary arterial vasodilation that is attenuated in part by pretreatment with L-NAME.² NO has also been shown to contribute to the renal vasodilator effect of both the ACE inhibitor lisinopril and the angiotensin subtype 1 receptor antagonist losartan.²³ Angiotensin subtype 1 receptors occur on the endothelium: decreased local concentrations of angiotensin II may result in increased NO release. Our data with indomethacin further suggest that at the level of the epicardial coronary arteries, vasodilator prostaglandins do not play a significant role in ACE inhibitor–induced vasodilation.

In the coronary microcirculation, evidence from isolated perfused rabbit hearts suggests that ACE inhibitors potentiate local effects of bradykinin and thus induce vasorelaxation.²¹ In the isolated rat heart, the effects of ramipril were shown to be abolished by a bradykinin antagonist.²⁴ Zanzinger et al²⁵ demonstrated that in the microcirculation of conscious dogs, ACE inhibitors enhance vasomotor responses to endothelium-dependent agents by facilitating the release of both NO and prostaglandins through a mechanism coupled to endogenously formed bradykinin. Our in vivo study lends support to a bradykinin-dependent mechanism of ramiprilat-induced vasodilation in coronary resistance arteries. The mechanism of bradykinin-induced vasodilation in these arteries is, however, not entirely clear. NO release appears not to be involved because L-NAME had no influence on the response. With indomethacin, there was a trend to a decrease in ramiprilat-induced increase in flow velocity; however, the magnitude of this decrease was substantially less than the attenuation induced by HOE 140. Thus, we cannot exclude the possibility that increases in local bradykinin concentrations in response to ACE inhibition induce vasodilation in part via bradykinin-stimulated release of prostaglandins; however, it is likely that this occurs largely through a direct effect of B₂ receptor stimulation. Our findings in coronary resistance arteries are similar to those of Ehring et al,²⁶ who recently demonstrated in dogs that attenuation of myocardial stunning by the ACE inhibitor ramiprilat involves a signal cascade of bradykinin and prostaglandins but not NO.

Study Limitations
We did not explore other potential mechanisms of ACE inhibition–induced vasodilation. The vasoconstrictor effect of angiotensin II may, in part, be sympathetically mediated,^{27 28} and a sympatholytic effect may contribute to vasodilation induced by ACE inhibition.²⁹ Furthermore, the measurement of absolute coronary blood flow with combined 2D and Doppler ultrasound may have some inaccuracy inherent in the technique.¹² However, all of our inferences are based on within-animal comparisons and paired data, and the final emphasis is on change from baseline rather than on absolute values. So, it is unlikely that the interpretation of our data was influenced by the measurement technique.

Potential Clinical Applications
Two recent studies—the Survival and Ventricular Enlargement study³⁰ and the Acute Infarction Ramipril Efficacy (AIRE) study³¹ —have shown survival beneficial effects of captopril and ramipril, respectively, in patients after an acute myocardial infarction. It is possible that some of the benefits of ACE inhibition may be mediated via an increase in myocardial blood flow. The beneficial effect of ramipril in the AIRE study was observed within the first 30 days of treatment. During this period, improvement in myocardial blood flow may accelerate recovery of reversibly injured myocardium, as suggested by the study of Ehring et al.²⁶ The contribution of NO and bradykinin in large and small coronary arteries to ACE inhibitor–induced vasorelaxation suggests that mechanisms other than inhibition of angiotensin II may play a role in its vasoprotective effects. However, the present study was performed in anesthetized dogs with a normal coronary circulation, and the effects of ACE inhibition in diseased human coronary arteries may be different.

In conclusion, ramiprilat induces direct vasodilation in coronary conductance and resistance arteries, possibly via mechanisms in addition to decreases in local or circulating angiotensin II. In large arteries, the vasorelaxation is largely NO dependent, whereas in small arteries, bradykinin appears to play a major role. Further studies are required to elucidate the clinical relevance of these findings.

	Selected Abbreviations and Acronyms

 

ACE = angiotensin-converting enzyme 2D = two-dimensional L-NAME = N-nitro-L-arginine methyl ester NO = nitric oxide

	Acknowledgments

 
This study was supported by grants from the Cardiac Research Foundation, University of California at San Francisco. Dr Sudhir was funded as a C.J. Martin Fellow by the National Health and Medical Research Council of Australia, Canberra, Australia. Dr Chou was partially funded by a grant from Devices for Vascular Intervention, Redwood City, Calif. Dr Hutchison was partially funded by a traveling fellowship from the R.S. McLaughlin Foundation, Toronto, Ontario, Canada.

	Footnotes

 
Reprint requests to Kanu Chatterjee, MD, FRCP, Box 0124, University of California at San Francisco, 505 Parnassus Ave, San Francisco, CA 94143-0124.

Received July 12, 1995; revision received November 9, 1995; accepted November 15, 1995.

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