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(Circulation. 1997;95:1115-1118.)
© 1997 American Heart Association, Inc.

Articles

Role of Bradykinin in Mediating Vascular Effects of Angiotensin-Converting Enzyme Inhibitors in Humans

Burkhard Hornig, MD; Christoph Kohler, BS; Helmut Drexler, MD

Abteilung Kardiologie, Medizinische Hochschule Hannover, Germany.

Correspondence to Helmut Drexler, MD, Medizinische Hochschule Hannover, Abteilung Kardiologie, Konstanty Gutschow Str 8, 30625 Hannover, Germany.

	Abstract

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Background The angiotensin-converting enzyme (ACE) not only generates angiotensin II but is also the main enzyme that destroys bradykinin. It has been hypothesized, therefore, that bradykinin is involved in the vascular effects of ACE inhibitors. However, its contribution has never been demonstrated in humans because of the lack of specific bradykinin receptor antagonists.

Methods and Results High-resolution ultrasound and Doppler were used to measure radial artery diameter and blood flow in 10 healthy volunteers. The vascular effects of the ACE inhibitor quinaprilat, the selective bradykinin B₂-receptor antagonist icatibant, and their combination were determined at rest, during reactive hyperemia (with increased flow causing endothelium-mediated, flow-dependent dilation), and during sodium nitroprusside, causing endothelium-independent dilation. Neither icatibant nor quinaprilat affected arterial diameter or blood flow at rest. However, icatibant reduced flow-dependent dilation by 33%, and quinaprilat increased flow-dependent dilation over baseline by 46%. After coinfusion of quinaprilat and icatibant, flow-dependent dilation was reduced to a similar extent as after infusion of icatibant alone.

Conclusions ACE inhibition enhances flow-dependent, endothelium-mediated dilation in humans by a bradykinin-dependent mechanism. This observation indicates that accumulation of endogenous bradykinin is involved in the vascular effects of ACE inhibitors in humans.

Key Words: endothelium • bradykinin

	Introduction

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Angiotensin-converting enzyme inhibitors are widely used in the treatment of heart failure and hypertension. ACE inhibition not only reduces the generation of angiotensin II but is also associated with increased levels of bradykinin¹ because ACE is identical to kininase II, which inactivates bradykinin. Although most effects of ACE inhibitors have been attributed to the reduced generation of angiotensin II, the contribution of kinins to the hypotensive effect of ACE inhibitors has been postulated² but has never been established in humans because of the lack of a bradykinin antagonist for application in humans. In this regard, the development of the bradykinin B₂-receptor antagonist icatibant provides a valuable tool because it has been shown to be highly specific³ and to inhibit the vasodilatory actions of bradykinin in humans.⁴

Bradykinin is a potent vasodilator peptide that exerts its vasodilatory action through stimulation of specific endothelial B₂ receptors, thereby causing the release of prostacyclin,⁵ NO,⁶ and EDHF.⁷ There is experimental evidence that ACE inhibitors stimulate the endothelial release of NO and prostacyclin by a bradykinin-mediated mechanism,⁸ thereby enhancing endothelium-dependent vasodilation.^{7 9} An important functional consequence of endothelial function is the ability to release endothelium-derived NO in response to physiological stimuli such as increases in flow,^{10 11 12} reflecting FDD. Experimental studies suggest the existence of a local kinin-generating system(s) that contributes to flow-dependent release of EDRFs.⁹

In the present study, we examined the effects of the ACE inhibitor quinaprilat, the selective bradykinin B₂–receptor antagonist icatibant, and their combination on resting tone and FDD of the radial artery in healthy volunteers.

	Methods

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The study, which had the approval of the local ethics committee, was performed in 10 healthy volunteers (5 men, 5 women; age, 28±2 years) who gave their informed consent. All subjects were nonsmokers, normotensive, and not taking any medication, and they had normal serum cholesterol levels. Radial artery diameters were measured by a recently developed high-resolution A-mode ultrasonic echo-tracking device (ASULAB) that allows measurements of arterial diameter with a precision of ±2.5 µm using a novel oversampling technique as established in our laboratory.¹² Recordings of arterial diameters were obtained with a 10-MHz transducer positioned perpendicular to the vessel. Radial artery blood flow velocity was measured continuously by an 8-MHz Doppler probe. Arterial blood flow (mL/min) at the mid-forearm level was calculated as the product of blood flow velocity and cross-sectional area. For each velocity value, 15 beats were averaged. To determine FDD, wrist arterial occlusion was performed by inflating an occlusion cuff to 40 mm Hg above systolic blood pressure for 8 minutes. After release of the arterial occlusion, arterial diameter was determined at 20-second intervals for 2 minutes, then every 30 seconds until the diameter returned to baseline. Arterial blood pressure and heart rate were measured on the contralateral arm by the cuff technique.

To inhibit bradykinin-induced prostaglandin release, 250 mg aspirin was given intravenously 30 minutes before measurements, a dose known to be effective in blocking vascular cyclooxygenase.¹³ After insertion of a polyethylene catheter into the left brachial artery (nondominant arm), saline was infused. Blood flow velocity was recorded continuously, and radial artery diameter was determined every 30 seconds until stable baseline conditions were obtained (30 minutes). Then a wrist arterial occlusion was performed to determine FDD in response to the reactive hyperemic blood flow response. Next, icatibant was infused (90 µg/min for 5 minutes; Hochst AG), followed by saline infusion during arterial occlusion and determination of FDD after release of arterial occlusion. The selection of the dose of icatibant was based on a recent report⁴ demonstrating that a similar dose of icatibant significantly inhibits forearm vasodilatory responses to exogenously administered bradykinin in humans. When diameter and blood flow returned to baseline values, FDD after wrist occlusion was repeated during infusion of saline, ie, during control conditions. Next, quinaprilat was infused (1.6 µg/min for 5 minutes). This dose of quinaprilat was chosen because pilot studies from our laboratory demonstrated that it improves FDD of the radial artery without affecting systemic hemodynamics. After obtaining baseline measurements again, coinfusion of icatibant and quinaprilat was performed with determination of FDD. In addition, this protocol was performed in four individuals with a placebo used instead of quinaprilat to document reproducibility and to identify the specific effects of ACE inhibition. Finally, all subjects received an intra-arterial infusion of SNP (10 µg/min for 5 minutes) to assess endothelium-independent vasodilatory capacity. Blood flow and diameter data, reported for icatibant, quinaprilat, coinfusion of both, and SNP, represent the measurements obtained during the last minute of each infusion.

Statistics
Data are expressed as mean±SE. ANOVA for repeated measures was used, followed by a Bonferroni test to evaluate statistical differences. A value of P<.05 was considered to be statistically significant.

	Results

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After wrist occlusion, a significant increase in radial arterial diameter was noted (Table), representing FDD, defined as percent increase in vessel diameter (Figure). Infusion of icatibant did not change radial artery diameter significantly (Table), but FDD after wrist occlusion was significantly reduced compared with baseline values (Figure). Infusion of quinaprilat did not change radial artery diameter at rest but significantly increased FDD. Administration of the placebo did not affect radial artery diameter at rest, and FDD was similar to that during control measurements 1 and 2 (Table). Coinfusion of icatibant and quinaprilat as well as coinfusion of icatibant and placebo did not affect arterial diameter at rest but reduced FDD to the same extent as FDD in the presence of icatibant alone (Table). These effects of icatibant, quinaprilat, and the combination thereof were observed to a similar extent in every subject studied. Intra-arterial SNP significantly increased radial artery diameter (from 2.73±0.09 to 3.18±0.18 mm; P<.01 versus before SNP).

View this table: [in this window] [in a new window]   Table 1. Effect of Icatibant, Quinaprilat, and Placebo on Radial Artery Diameter at Baseline and During Flow-Dependent Endothelium-Mediated Dilation

View larger version (17K): [in this window] [in a new window]   Figure 1. Percentage change in radial artery diameter during reactive hyperemia (FDD) at control measurements 1 and 2 (C1 and C2) and during icatibant (IC), quinaprilat (QUIN), and coinfusion of both icatibant and quinaprilat (IC + QUIN).

Radial artery blood flow at rest was not affected by infusion of icatibant, quinaprilat, or placebo or coinfusion of both drugs (data not shown). Maximal radial artery blood flow during reactive hyperemia after release of wrist occlusion was not affected by infusion of icatibant, quinaprilat, or both (control measurement 1, 91±16; icatibant, 91±13; control measurement 2, 94±15; quinapril, 96±13; icatibant plus quinapril, 95±12; placebo, 94±16; and icatibant plus placebo, 93±14 mL/min; P=NS). In addition, the area under the curve during reactive hyperemia, representing the total amount of reactive hyperemic blood flow, was similar at control and after infusion of icatibant, quinaprilat, or placebo or the coinfusion of both drugs (data not shown). Infusion of SNP increased radial artery blood flow (145±62%; P<.01). Systemic blood pressure and heart rate did not change during the experimental protocol.

	Discussion

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The present study shows that ACE inhibitors enhance flow-dependent, endothelium-mediated dilation in humans by a bradykinin-dependent mechanism. Thus, an important vascular effect of ACE inhibitors is related to accumulation of endogenous bradykinin rather than due to reduced generation of angiotensin II.

Icatibant attenuated FDD of the radial artery consistent with our previous observations in epicardial human coronary arteries.¹⁴ Similarly, experimental studies have shown that a bradykinin antagonist decreases the production (or release) of EDRFs in isolated perfused arteries.⁹ These observations suggest that an endothelial kinin-generating system(s) contributes to the flow-dependent release of EDRFs.⁹ On the other hand, quinaprilat but not placebo improved flow-dependent, endothelium-mediated dilation, an effect that was completely abolished during infusion of the bradykinin B₂–antagonist icatibant. Indeed, FDD during coinfusion of quinaprilat and icatibant as well as during coinfusion of placebo and icatibant was reduced to a similar extent as during infusion of icatibant alone. There is some experimental evidence suggesting that ACE inhibitors might influence endothelial function not only by inhibition of bradykinin-degradation but also in a manner that is secondary to accumulation of angiotensin I and its metabolite angiotensin-(1-7), which, in turn, may elicit receptor-linked release of kinins.¹⁵

The vasodilatory actions of bradykinin are largely mediated through stimulated release of endothelium-derived NO, prostacyclin, and EDHF.^{5 6 7} Because all subjects were pretreated with aspirin, bradykinin-mediated release of prostacyclin was probably not involved. Thus, it is most likely that the effects of the bradykinin antagonist icatibant were due to blockade of bradykinin-mediated release of NO, EDHF, or both. In contrast, our results suggest that ACE inhibition increased FDD by enhanced endothelial release of NO and/or EDHF secondary to the increased availability of endogenous bradykinin. This interpretation is supported by experimental studies¹⁰ demonstrating that ACE inhibition potentiates the bradykinin-induced endothelial release of NO due to potentiation of bradykinin. Thus, our data support the concept that ACE inhibitors exert endothelium-dependent vascular effects related to increased local concentrations of endogenous kinins.

Apparently, this beneficial effect of ACE inhibition did not play a major role under resting conditions because quinaprilat at the dose selected in our study had no effect on radial artery diameter and blood flow. However, during flow-stimulated conditions, ie, during physical activity, ACE inhibition may cause a marked improvement of FDD. Moreover, we have previously shown that endogenous bradykinin is involved in the regulation of basal tone at the level of coronary resistance and epicardial conduit arteries,¹⁴ suggesting that the role of endogenous bradykinin may differ throughout the vascular tree in humans. The present observations may explain some of the beneficial effects of ACE inhibitors, including those related to coronary artery disease.^{16 17} It is conceivable that an improved endothelial function, related to accumulation of bradykinin, might provide vascular protection during long-term treatment with ACE inhibitors.

The maximal reactive hyperemic blood flow response after wrist occlusion was not different under control, icatibant, quinapril, placebo, or coinfusion conditions. Therefore, the stimulus for endothelium-mediated dilation was similar during the different interventions. Previous studies have shown that oral captopril exerts a decrease in peripheral vascular resistance and an increase in forearm blood flow in normal subjects as determined by plethysmography.¹⁸ Therefore, the present finding may be surprising. However, our approach assessed forearm blood flow including the hand circulation, which may not respond to ACE inhibition in the same way. Notably, flow in the radial artery supplying both skeletal muscle resistance vessels and the cutaneous tissue of the hand is relevant for FDD in the radial artery. The present study was specifically designed to evaluate FDD. Thus, the fact that total forearm flow did not change after ACE inhibition in the present study does not exclude the possibility that flow to forearm skeletal muscle tissue was increased. In fact, the same dose of quinaprilat did increase forearm blood flow to skeletal muscle as determined by plethysmography.¹⁹

In conclusion, the present study has demonstrated that ACE inhibition enhances endothelial function in humans and supports the concept that endogenous bradykinin accumulation is involved in the vascular effects of ACE inhibition.

	Selected Abbreviations and Acronyms

 

EDHF = endothelium-derived hyperpolarizing factor EDRF = endothelium-derived relaxing factor FDD = flow-dependent dilation NO = nitric oxide SNP = sodium nitroprusside

	Acknowledgments

 
This study was supported in part by the Deutsche Forschungsgemeinschaft (Dr 148/7-2).

Received August 12, 1996; revision received January 9, 1997; accepted January 9, 1997.

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				B. Hornig, U. Landmesser, C. Kohler, D. Ahlersmann, S. Spiekermann, A. Christoph, H. Tatge, and H. Drexler Comparative Effect of ACE Inhibition and Angiotensin II Type 1 Receptor Antagonism on Bioavailability of Nitric Oxide in Patients With Coronary Artery Disease : Role of Superoxide Dismutase Circulation, February 13, 2001; 103(6): 799 - 805. [Abstract] [Full Text] [PDF]

J. M. A. van Ampting, M. L. Hijmering, J. J. Beutler, R. E. van Etten, H. A. Koomans, T. J. Rabelink, and E. S. G. Stroes Vascular Effects of ACE Inhibition Independent of the Renin-Angiotensin System in Hypertensive Renovascular Disease : A Randomized, Double-Blind, Crossover Trial Hypertension, January 1, 2001; 37(1): 40 - 45. [Abstract] [Full Text] [PDF]

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