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(Hypertension. 1997;30:912-917.)
© 1997 American Heart Association, Inc.

Articles

Quinaprilat Induces Arterial Vasodilation Mediated by Nitric Oxide in Humans

Walter E. Haefeli; Lilly Linder; ; Thomas F. Lüscher

From the Division of Clinical Pharmacology, Department of Internal Medicine, University Hospital, CH-4031 Basel, Switzerland (W.E.H., L.L.); the Department of Pharmacy, University of Basel, CH-4051 Basel, Switzerland (W.E.H.); and the Division of Cardiology, University Hospital/CH-8091 Zürich, Switzerland (T.F.L.).

Correspondence to Walter E. Haefeli, MD, Division of Clinical Pharmacology, Department of Medicine, University Hospital, Petersgraben 4, CH-4031 Basel, Switzerland. E-mail haefeli{at}ubaclu.unibas.ch

	Abstract

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Abstract The beneficial therapeutic effects of angiotensin-converting enzyme (ACE) inhibitors are the result of reduced angiotensin II formation and possibly also of an accumulation of bradykinin that is inactivated by ACE. In particular, recently developed ACE inhibitors with tissue-penetrating properties, such as quinaprilat, may exert vascular effects via the bradykinin B₂-receptor. To test direct arterial effects of quinaprilat and enalaprilat and to study their effects on vasodilation induced by bradykinin, venous occlusion plethysmography was used during local intra-arterial drug administration into the brachial artery in healthy volunteers. The response to bradykinin was augmented by both ACE inhibitors, but the effect of quinaprilat (3.9 nmol/min) was exclusively attributable to its direct vasodilator action. Enalaprilat (13 nmol/min) did not change baseline blood flow in the human forearm circulation. In contrast, quinaprilat significantly increased arterial flow from 3.5±0.5 to 4.6±0.7 mL/100 mL tissue/min, which was inhibited by N^G-monomethyl-L-arginine (8 µmol/min IA). Moreover, the effect of sodium nitroprusside (0.023 to 22.9 nmol/min) was substantially attenuated during concomitant administration of quinaprilat. These results suggest that quinaprilat induces vascular effects beyond the inhibition of angiotensin II formation; it causes vasodilation by increasing vascular nitric oxide production and thereby attenuates the relaxing effect of the nitric oxide donor sodium nitroprusside.

Key Words: bradykinin • angiotensin-converting enzyme inhibition • nitric oxide • vasodilation • vascular resistance

	Introduction

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In recent years, inhibitors of angiotensin-converting enzyme (ACE) have gained substantial importance in the treatment of cardiovascular disease, and their beneficial effects on symptoms and mortality have been established in large clinical trials.^{1 2} ACE is a widely distributed enzyme that is present not only in the circulating blood and on the endothelial surface but also in large amounts in various parenchymatous tissues such as the kidney, heart, and vascular wall.³ Inhibition of ACE decreases the endogenous production of the vasopressor angiotensin II and thereby most likely the release of norepinephrine from peripheral sympathetic nerve endings.⁴ As a rather unspecific peptidase, ACE also cleaves other endogenous peptides such as bradykinin^{5 6 7 8} and substance P⁹ ; hence, in addition to the direct effects on the generation of the vasopressor angiotensin II and in turn on the release of norepinephrine, ACE inhibitors may increase the activity of vasodilator peptides, resulting in vascular relaxation.⁹ In particular bradykinin-mediated vasodilation is potentiated both in vitro^{10 11} and in vivo^{12 13 14} in the presence of ACE inhibitors. Indeed, for some of the beneficial clinical effects of tissue-penetrating ACE inhibitors, local accumulation of bradykinin with concomitant formation of nitric oxide (NO) and prostacyclin has been proposed as one of the crucial mechanisms of action.^{15 16 17 18}

Whereas older ACE inhibitors such as captopril or enalapril almost exclusively inhibit circulating ACE, the development of more lipophilic compounds such as quinaprilat provided drugs that potently inhibit vascular ACE at more distant sites that appear not to be readily accessible to ACE inhibitors of the first generation.¹⁹ With the use of venous occlusion plethysmography during intra-arterial drug administration, the effects of quinaprilat and enalaprilat on vascular responsiveness and on vasodilator responses induced by bradykinin were studied. The presented series of experiments revealed direct vasodilator effects of quinaprilat but not of enalaprilat in the arterial forearm circulation, which is mainly mediated via NO.

	Methods

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Subjects
Forty-four healthy subjects (32 men, 12 women, 2 smokers) with a mean age of 27 years (range, 19 to 43 years) were included into the study after giving written informed consent. They were not taking any medications other than oral contraceptives and had no history of significant medical disease. The protocol was reviewed and approved by the Ethics Committee of the University Hospital of Basel, Switzerland. Volunteers were admitted to the hospital in the morning. They were allowed a light breakfast and were asked to refrain from methylxanthine- and alcohol-containing beverages for at least 12 hours before the study. They remained semirecumbent in a quiet room with a constant temperature of approximately 23°C throughout the study. Each study design was performed in 8 volunteers; studies in the same volunteer were separated by at least 1 week.

Venous Occlusion Plethysmography
To measure drug-induced changes in forearm blood flow, venous occlusion plethysmography was performed bilaterally in a supine body position.²⁰ A mercury-in-silastic strain gauge was placed at the upper third of the forearm, which rested comfortably on a support slightly above heart level. The mercury strain gauge was coupled to an electronically calibrated plethysmograph (model EC3, Hokanson). Venous occlusion was achieved by a blood pressure cuff applied proximal to the elbow and inflated to 40 mm Hg by a rapid cuff inflator (model EC10, Hokanson). To eliminate unpredictable influences of arteriovenous shunts in the hand, it was excluded from the circulation by inflating a pediatric blood pressure cuff, which was placed around each wrist, to values well above systolic blood pressure 1 minute before and during blood flow measurements. Determinations of forearm blood flow were based on the analysis of at least 4 to 6 consecutive recordings. Only the mean values were taken for statistical evaluation. Forearm vascular resistance was calculated by dividing the mean blood pressure measured intra-arterially immediately after each series of recordings by forearm blood flow. To adjust drug doses to interindividual differences in forearm size, the forearm volume of each subject was measured by water displacement using the Archimedes principle. Drugs were administered into the brachial artery in which a cannula was inserted after local anesthesia with lidocaine.

At the beginning of each experiment the maximum dilator response of the forearm vasculature (reactive hyperemia) was tested after regional ischemia for 6 minutes without physical exercise. Once a stable baseline had been established, cumulative doses of bradykinin (0.14 to 470 pmol/min) were administered intra-arterially during 5 minutes at a constant flow using a Sage Instruments infusion pump. After a washout period of approximately 60 minutes, quinaprilat (3.9 nmol/min) or enalaprilat (13 nmol/min) was administered for 10 minutes alone and then together with the same bradykinin doses to construct the dose-response relationship during ACE inhibition. Only one ACE inhibitor was administered on each study day. The dose of quinaprilat that completely blocks the conversion of angiotensin I was established in n=4 pilot experiments, comparing angiotensin I (0.123 nmol/min) and angiotensin II (0.015 nmol/min). The same enalaprilat doses were used as previously reported to block angiotensin II formation in the human forearm circulation,¹² and the effectiveness of this dose in blocking angiotensin I effects was confirmed in four pilot experiments. As a control, the effect of quinaprilat on the dose-response relationship of the NO donor sodium nitroprusside (0.023 to 22.9 nmol/min IA) was studied.

To study the mechanism of vasodilator action of quinaprilat in the arterial bed, two series of experiments were performed. First, the effect of N^G-monomethyl-L-arginine (L-NMMA) on baseline flow was investigated, and then L-NMMA was reversed by excess administration of L-arginine (95 µmol/min for 15 minutes). After 60 minutes, quinaprilat (3.9 nmol/min) was administered for 20 minutes and the effect of L-NMMA was studied again during coadministration of the same dose of quinaprilat. The study was concluded by administration of a systemic dose of acetylsalicylic acid (500 mg IV) and the combined effect of L-NMMA, quinaprilat, and acetylsalicylic acid was recorded. The dose of L-NMMA was sufficiently high to completely block NO-induced vasodilation (8 µmol/min).²¹ In the second series of experiments the forearm vasculature was exposed to L-NMMA (8 µmol/min) for 10 minutes and while continuing administration of the NO synthase inhibitor quinaprilat (3.9 nmol/min) was coinfused for 10 minutes.

Drugs
All solutions were freshly prepared in normal saline and used within 3 hours. Enalaprilat (Renitec) was obtained from Merck, Sharp & Dohme-Chibret; quinaprilat was a generous gift from Gödecke Parke Davis (Freiburg, Germany). Angiotensin II (Hypertensin) was obtained from Ciba-Geigy. Bradykinin, angiotensin I, L-NMMA, and L-arginine were purchased from Clinalfa AG.

Data Analysis
Unless indicated otherwise, data are reported as mean±SEM. One-factor ANOVA was used to test for differences attributable to the different drugs. Dose-response curves were compared using two-way ANOVA for repeated measures with subsequent post-hoc analysis using the Bonferroni procedure. A value of P<.05 was considered to indicate a statistically significant difference; tests were two-tailed.

Adverse Effects
All drugs were well tolerated.

	Results

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Effect of ACE Inhibition on Bradykinin-Induced Vasodilation
The effect of quinaprilat on the dose-response relationship of intra-arterially administered bradykinin in the forearm circulation is shown in Fig 1. Bradykinin dose-dependently increased blood flow from 3.1±0.6 mL/100 mL tissue/min to 26.3±4 (P<.0005) and decreased forearm vascular resistance from 29.2±4.9 to 3.5±0.9 U (P<.001) in all eight volunteers studied. The two dose-response curves were significantly different from each other when absolute values for resistance were compared (P<.02). However, if changes in forearm flow or resistance were related to baseline values, ie, expressed in percent change from the baseline (which was set at 100%), there was no difference between the two bradykinin dose-response curves (Fig 1B), indicating that ACE inhibition did not significantly modify the overall response to the peptide but induced vasodilation on its own.

View larger version (17K): [in this window] [in a new window]   Figure 1. A, Effects of increasing intra-arterial dose rates of bradykinin on forearm vascular resistance in the absence () and presence () of quinaprilat (3.9 nmol/min) in eight healthy volunteers. The two curves are significantly different (P<.02). B, Change in forearm vascular resistance (expressed as percent change from baseline resistance) in the absence () and presence () of quinaprilat (3.9 nmol/min) in eight healthy volunteers.

The effect of enalaprilat on the bradykinin dose-response relationship was studied in eight healthy volunteers. In all of them bradykinin exerted a dose-dependent vasodilation, with a mean increase in blood flow from 2.6±0.4 to 20.8±4.7 mL/100 mL tissue/min (P<.005) and a decrease in arterial vascular resistance from 33.1±3.8 to 6.2±1.9 U (P<.0001). As a whole, the two dose-response curves were not significantly different from each other when absolute values for resistance were compared (Fig 2A). The same dose-response relationships expressed as percent change from baseline resistance are shown in Fig 2B. Similar to the effects of bradykinin administration during quinaprilat infusion, the two dose-response curves were not significantly different under these conditions.

View larger version (18K): [in this window] [in a new window]   Figure 2. A, Effect of increasing intra-arterial dose rates of bradykinin on forearm vascular resistance in the absence () and presence () of enalaprilat (13 nmol/min) in eight healthy volunteers. B, Change in forearm vascular resistance (expressed as percent change from baseline resistance) in the absence () and presence () of enalaprilat (13 nmol/min) in eight healthy volunteers.

Effect of ACE Inhibition on Baseline Arterial Flow
Immediately after infusion of quinaprilat there was a significant increase in forearm blood flow in all subjects (before the second administration of bradykinin); after 8 minutes of quinaprilat infusion, arterial blood flow increased from 4.1±0.5 to 4.9±0.6 mL/100 mL tissue/min (P<.004) and forearm vascular resistance decreased from 19±2.6 to 16.1±2.6 U (P<.001). In contrast, enalaprilat did not directly affect basal arterial flow (2.6±0.4 mL/100 mL tissue/min versus 2.8±0.4; NS) and neither did vascular resistance (32.9±4.1 versus 30.1±3.9 U; NS).

Mechanism of Quinaprilat-Induced Vasodilation
The effect of inhibition of NO synthase (L-NMMA) and cyclooxygenase (acetylsalicylic acid) on quinaprilat-induced vasodilation is shown in Fig 3. L-NMMA alone (8 µmol/min) significantly decreased forearm blood flow, from 3.2±0.5 to 2.2±0.4 mL/100 mL tissue/min (P<.0007), and increased resistance from 27.3±4.7 to 41.6±8.4 U (P<.02). L-arginine (95 µmol/min for 15 minutes) completely reversed the vasoconstriction induced by L-NMMA. Quinaprilat (3.9 nmol/min) alone increased forearm blood flow from 3.6±0.5 to 4.6±0.7 mL/100 mL tissue/min (P<.003) and decreased resistance from 25.1±4.4 to 17.9±2.5 U (P<.002). Coadministration of L-NMMA and quinaprilat resulted in changes in blood flow (2.3±0.4 mL/100 mL tissue/min) and vascular resistance (39.2±5.9 U) similar to those observed during infusion of L-NMMA alone (NS versus L-NMMA alone). The values were also not significantly different during the coadministration of L-NMMA and acetylsalicylic acid.

View larger version (30K): [in this window] [in a new window]   Figure 3. Effect of L-NMMA and acetylsalicylic acid (ASA) on vasodilation induced by intra-arterial quinaprilat (3.9 nmol/min) in eight healthy volunteers. The effect of quinaprilat alone was significantly different from both L-NMMA and quinaprilat+L-NMMA (P<.0001), whereas the change in forearm vascular resistance during coadministration of quinaprilat+L-NMMA was similar to those in L-NMMA alone and quinaprilat+L-NMMA+ASA.

Changes in forearm blood flow expressed as percent baseline flow (which was set at 100%) averaged -32±4% during the first L-NMMA administration, +34±7.7% during the infusion of quinaprilat alone, and -36±2.5% during the infusion of quinaprilat plus L-NMMA. Coadministration of L-NMMA and quinaprilat with acetylsalicylic acid did not further decrease blood flow (–41±3.7%, NS) (Fig 3).

In a second series of experiments in six volunteers, L-NMMA decreased blood flow from 4.0±0.5 to 2.4±0.2 mL/100 mL tissue/min (P<.01) and increased resistance from 17.8±2.8 to 29.1±3.5 U (P<.05). Coadministration of quinaprilat (3.9 nmol/min for 10 minutes) did not reverse the vasoconstriction induced by L-NMMA (forearm blood flow, 2.4±0.3 mL/100 mL tissue/min, P=.92; forearm vascular resistance, 28.0±3.6 U, P=.69).

Effect of Quinaprilat on Vasodilation Induced by Sodium Nitroprusside
As a control, the effect of quinaprilat on cGMP-mediated vasodilation induced by sodium nitroprusside (0.023 to 22.9 nmol/min, IA) was also studied. Sodium nitroprusside caused dose-dependent vasodilation in all eight volunteers studied, resulting in an increase in blood flow from 3.4±0.3 to 16.6±1.3 mL/100 mL tissue/min and a decrease in arterial vascular resistance from 21.3±1.7 to 4.1±0.4 U (P<.0001) (Fig 4A). Administration of sodium nitroprusside together with quinaprilat increased blood flow from 4.6±0.5 to 18.7±1.2 mL/100 mL tissue/min (peripheral vascular resistance: 15.9±1.2 to 3.7±0.3 U). Since baseline values again revealed significant direct vasodilator effects of quinaprilat (P<.005), the two dose-response relationships were again expressed as percent change from baseline (defined as forearm blood flow immediately before the administration of sodium nitroprusside). During coadministration of quinaprilat the vasodilator effect of sodium nitroprusside was significantly reduced (P<.005, Fig 4B).

View larger version (16K): [in this window] [in a new window]   Figure 4. A, Effect of increasing intra-arterial dose rates of sodium nitroprusside on forearm vascular resistance in the absence () and presence () of quinaprilat (3.9 nmol/min) in eight healthy volunteers. B, Change in forearm vascular resistance (expressed as percent change from baseline resistance) in the absence () and presence () of quinaprilat (3.9 nmol/min) in eight healthy volunteers. The two curves are significantly different (P<.005).

	Discussion

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The effect of the potent vasodilator bradykinin is controlled both by rapid enzymatic inactivation by proteases and by the occurrence of tolerance at the level of the B₂-receptor.²² Enzymes with relevant bradykinin-metabolizing capacity are membrane-bound enzymes such as neutral endopeptidase 24.11, prolyl endopeptidase, and ACE, the latter of which possesses the highest affinity for the peptide.²³ Inhibition of ACE by specific inhibitors might therefore result in the local accumulation of bradykinin and in potentiation of its vasorelaxant effects.

Bradykinin, which exerts vasodilation mainly through endothelial release of NO,^{24 25 26} dose-dependently increased arterial blood flow in the human forearm circulation in vivo. There was a slight shift of the dose-response curve to bradykinin during coadministration of enalaprilat and a substantial shift of this curve toward lower concentrations during quinaprilat administration. The results obtained with enalaprilat are in accordance with previous findings in the same vascular bed^{12 27} in which some potentiation of bradykinin-induced vasodilation by the ACE inhibitor has been reported. However, the findings observed with quinaprilat were entirely attributable to an increase in baseline flow induced by the ACE inhibitor that was abolished by specific inhibition of NO synthase by L-NMMA. The reason for this unexpected finding remains unknown; it could indicate accumulation of endogenous vasodilator substrates of ACE in the tissue and/or reduced activation of angiotensin I within the vessel wall. Direct relaxant effects of quinaprilat have not been reported thus far. In vitro, in endothelial cells in culture, inhibition of ACE stimulated the production of NO and prostacyclin and increased intracellular Ca²⁺ levels. These effects are most likely mediated via the bradykinin receptor, since they are abolished by coadministration of the B₂-bradykinin receptor antagonist icatibant (HOE 140).²⁸ The results obtained in isolated vessels and organs vary considerably depending on the origin of the tissue, the technique applied, and the nature of the ACE inhibitor. In certain vascular preparations the ACE inhibitors ramiprilat and moexiprilat have been shown to exert endothelium-dependent relaxation in preconstricted vessels¹⁶ and in isolated organs.²⁹ Moreover, ramiprilat exerts mild vasodilator effects in the human forearm in vivo that are related to the patients' plasma renin activity.³⁰ In contrast, in certain animal studies^{5 10 28} or in intact organs^{5 25} no direct vasodilator effect of ACE inhibitors has been observed, whereas in vivo in human hand veins, the results are conflicting.^{31 32}

Whenever quinaprilat was administered alone in our studies, arterial vasodilation occurred. Direct vasodilation induced by quinaprilat could be mediated by the following mechanisms: (1) A decrease in the local activation of pressor peptides such as angiotensin II could result in relaxation of the vascular bed. Angiotensin II is formed continuously and administration of angiotensin II antagonists has been shown to induce relaxation at least under certain conditions.³³ (2) Because quinaprilat-induced vasodilation was abolished by the NO inhibitor L-NMMA, an accumulation of bradykinin and/or other mediators with concomitant NO production appears likely. Whether this occurs via direct activation of the bradykinin receptor or via inhibition of enzymatic inactivation of bradykinin remains to be elucidated. (3) Finally, decreased angiotensin II formation within the vascular wall may offset the facilitating effects of the peptide on norepinephrine release from the sympathetic nerve endings. However, such an interpretation would be hard to reconcile with the inhibitory effects of L-NMMA. Similar to other circulatory beds,²⁹ it appears unlikely that vasodilator prostanoids play a significant role in quinaprilat-induced relaxation, since coadministration of the cyclooxygenase inhibitor acetylsalicylic acid during L-NMMA infusion did not result in further vasoconstriction and because the vasodilation induced by quinaprilat was prevented during blockade of NO synthase with L-NMMA.

Two dose-response curves to the NO donor sodium nitroprusside were constructed to study the activation of the guanylate cyclase–cGMP pathway in a receptor- and endothelium-independent manner. Compared with the first exposure to sodium nitroprusside, the vasodilator response of the second curve was substantially attenuated. Hence, it is likely that coadministration of quinaprilat reduced the arterial sensitivity to sodium nitroprusside, possibly through a NO-dependent mechanism. Indeed, experimental evidence strongly suggests that endothelium-derived NO may modulate the response of vascular smooth muscle to nitrovasodilators. Removal of the endothelium in vitro is associated with an increased sensitivity of the vessel to nitrates,^{34 35 36 37 38} and competitive inhibition of NO formation with L-arginine derivatives results in substantial potentiation of vasodilator effects of various exogenous NO donors both in vitro and in vivo.^{35 36} On the other hand, stimulation of NO release in vitro with acetylcholine markedly reduces sodium nitroprusside–induced relaxation of isolated arteries.³⁹ Hence, whereas withdrawal of endothelial NO results in a potentiation of the effects of nitrovasodilators, stimulation of endothelial NO release inhibits the action of exogenous nitrates. In the present studies, simultaneous administration of quinaprilat, which is likely to induce NO release, resulted in a substantial attenuation of vasodilator responses to sodium nitroprusside. The results of these in vivo studies, therefore, suggest that administration of quinaprilat at dosages sufficiently high to block vascular ACE evokes effects beyond ACE inhibition. The interactions of quinaprilat with sodium nitroprusside and with L-NMMA are in agreement with the concept that NO participates in the vasodilator effects of the ACE inhibitor in the human forearm circulation. Since NO is not only a potent vasodilator but also a powerful inhibitor of cellular growth and migration, some of the beneficial effects of quinaprilat might be attributed to its NO-liberating properties in addition to its inhibitor effects on angiotensin II formation in the vasculature.

	Acknowledgments

 
These studies were supported by grant 32-49825.96 from the Swiss National Research Foundation; by the Freiwillige Akademische Gesellschaft, Basel; and by a grant from Gödecke Parke Davis, Freiburg, Germany.

Received April 17, 1996; first decision May 17, 1996; accepted February 28, 1997.

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