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(Hypertension. 2004;43:488.)
© 2004 American Heart Association, Inc.

Scientific Contribution

Mediators of Bradykinin-Induced Vasorelaxation in Human Coronary Microarteries

Wendy W. Batenburg; Ingrid M. Garrelds; Jorge P. van Kats; Pramod R. Saxena; A. H. Jan Danser

From the Departments of Pharmacology (W.W.B., I.M.G., P.R.S., A.H.J.D.) and Thoracic Surgery and Heart Valve Bank (J.P.v.K.), Erasmus Medical Center, Rotterdam, The Netherlands.

Correspondence to Prof Dr A.H.J. Danser, Department of Pharmacology, Room EE1418b, Erasmus MC, Dr Molewaterplein 50, 3015 GE Rotterdam, Netherlands. E-mail a.danser{at}erasmusmc.nl

	Abstract

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To investigate the mediators of bradykinin-induced vasorelaxation in human coronary microarteries (HCMAs), HCMAs (diameter 300 µm) obtained from 42 heart valve donors (20 men and 22 women; age range, 3 to 65 years; mean age, 46 years) were mounted in Mulvany myographs. In the presence of the cyclooxygenase inhibitor indomethacin, bradykinin relaxed preconstricted HCMAs in a concentration-dependent manner. N^G-nitro-L-arginine methyl ester and ODQ (inhibitors of nitric oxide [NO] synthase and guanylyl cyclase, respectively) and the NO scavenger hydroxocobalamin, either alone or in combination, shifted the bradykinin concentration-response curve to the right. Removal of H₂O₂ (with catalase), inhibition of cytochrome P450 epoxygenase (with sulfaphenazole or clotrimazole) or gap junctions (with 18-glycyrrhetinic acid or carbenoxolone), and blockade of large- (BK_Ca) and small- (SK_Ca) conductance Ca²⁺-dependent K⁺ channels (with iberiotoxin and apamin), either alone or in addition to hydroxocobalamin, did not affect bradykinin. In contrast, complete blockade of bradykinin-induced relaxation was obtained when we combined the nonselective BK_Ca and intermediate-conductance (IK_Ca) Ca²⁺-dependent K⁺ channel blocker charybdotoxin and apamin with hydroxocobalamin. Charybdotoxin plus apamin alone were without effect. Inhibition of inwardly rectifying K⁺ channels (K_IR) and Na⁺/K⁺-ATPase (with BaCl₂ and ouabain, respectively) shifted the bradykinin concentration-response curve 10-fold to the right but did not exert an additional effect in the presence of hydroxocobalamin. In conclusion, bradykinin-induced relaxation in HCMAs depends on (1) the activation of guanylyl cyclase, K_IR, and Na⁺/K⁺-ATPase by NO and (2) IK_Ca and SK_Ca channels. The latter are activated by a factor other than NO. This factor is not a cytochrome P450 epoxygenase product or H₂O₂, nor does it depend on gap junctions or BK_Ca channels.

Key Words: bradykinin • arteries • endothelium-derived factors • nitric oxide

	Introduction

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Endothelium-dependent relaxation induced by bradykinin cannot fully be attributed to the release of nitric oxide (NO). In resistance-size vessels, a large proportion of endothelium-derived relaxation involves the release of endothelium-derived hyperpolarizing factors (EDHFs).¹ Putative EDHF candidates are prostacyclin, S-nitrosothiols, K⁺, cytochrome P450 products of arachidonic acid (epoxyeicosatrienoic acids [EETs]), and H₂O₂,^2–8 and EDHF-dependent responses have been reported to involve large-, intermediate-, and/or small-conductance Ca²⁺-activated K⁺ channels (BK_Ca, IK_Ca, and SK_Ca, respectively), inwardly rectifying K⁺ (K_IR) channels, Na⁺/K⁺-ATPase, and gap junctions.^4,5,8–10

Busse et al⁹ recently summarized all currently available data on EDHF and proposed that EDHF-mediated relaxation (ie, relaxation observed in the absence of NO) depends on the activation of endothelial IK_Ca and SK_Ca channels.⁴ Such activation results in the release of K⁺ into the myoendothelial space, which subsequently induces smooth muscle hyperpolarization by activating K_IR channels and/or Na⁺/K⁺-ATPase.⁴ According to this concept, EETs regulate endothelial hyperpolarization as well as the spread of this hyperpolarization to the adjacent smooth muscle cells through myoendothelial gap junctions. In addition, EETs might directly activate BK_Ca channels on smooth muscle cells.⁸

In the present study, we set out to verify the aforementioned concept in human coronary microarteries (HCMAs). Bradykinin has already been reported to hyperpolarize smooth muscle cells in human coronary arteries,¹¹ and this hyperpolarization could not be attributed to NO.^12,13

	Methods

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Human Tissue Collection
HCMAs were obtained from 42 heart-beating organ donors (20 men and 22 women; age range, 3 to 65 years; mean age, 46 years) who had died of noncardiac causes (3 cerebrovascular accident, 11 head trauma, 18 subarachnoid bleeding, 3 postanoxic encephalopathy, 7 intracranial bleeding) <24 hours before the heart was taken to the laboratory. Hearts were provided by the Rotterdam Heart Valve Bank after removal of the heart valves for transplantation purposes. The study was approved by the Ethics Committee of the Erasmus Medical Center. The hearts were stored in an ice-cold, sterile, organ-protecting solution after circulatory arrest. After arrival at the laboratory, a tertiary branch of the left anterior descending coronary artery (diameter range, 160 to 600 µm; mean diameter, 380 µm) was removed and stored overnight in a cold (4°C), oxygenated, Krebs bicarbonate solution of the following composition (in mmol/L): NaCl 118, KCl 4.7, CaCl₂ 2.5, MgSO₄ 1.2, KH₂PO₄ 1.2, NaHCO₃ 25, and glucose 8.3, pH 7.4.

Myograph Studies
After overnight storage, HCMAs were cut into segments 2 mm long and mounted in a Mulvany myograph (J.P. Trading) with separate 6-mL organ baths containing Krebs bicarbonate solution aerated with 95% O₂ and 5% CO₂ and maintained at 37°C. Tissue responses were measured as changes in isometric force by using a Harvard isometric transducer. After a 30-minute stabilization period, the optimal internal diameter was set to a tension equivalent to 0.9 times the estimated diameter at 100 mm Hg effective transmural pressure, as described by Mulvany and Halpern.¹⁴ Endothelial integrity was verified by observing relaxation to 10 nmol/L substance P after preconstriction with 10 nmol/L of the thromboxane A₂ analogue U46619. Subsequently, to determine the maximum contractile response, the tissue was exposed to 100 mmol/L KCl. The segments were then allowed to equilibrate in fresh organ bath fluid for 30 minutes in the absence or presence of 1 or more of the following inhibitors: the bradykinin type 2 (B₂) receptor antagonist Hoe140 (1 µmol/L), the NO synthase inhibitor N^G-nitro-L-arginine methyl ester (L-NAME, 100 µmol/L), the NO scavenger hydroxocobalamin (200 µmol/L), the guanylyl cyclase inhibitor ODQ (10 µmol/L), the IK_Ca and BK_Ca channel inhibitor charybdotoxin (100 nmol/L), the SK_Ca channel inhibitor apamin (100 nmol/L), the BK_Ca channel inhibitor iberiotoxin (100 nmol/L), the K_IR channel inhibitor BaCl₂ (30 µmol/L), the Na⁺/K⁺-ATPase inhibitor ouabain (1 mmol/L), the H₂O₂ inhibitor catalase (1000 U/mL), the cytochrome P450 epoxygenase inhibitors sulfaphenazole (10 µmol/L) and clotrimazole (50 µmol/L), or the gap junction inhibitors 18-glycyrrhetinic acid (10 µmol/L) and carbenoxolone (100 µmol/L). Vessels were then preconstricted with U46619 (3 to 30 nmol/L), and concentration-response curves (CRCs) were constructed to bradykinin. The cyclooxygenase inhibitor indomethacin (5 µmol/L) was present during all experiments to suppress spontaneously occurring contractions and relaxations.

cGMP Measurements
To study bradykinin-induced cGMP production, vessel segments (5 to 10 mg) were exposed to 1 µmol/L bradykinin in 10 mL oxygenated Krebs bicarbonate solution for 1 minute at 37°C in the presence of the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (100 µmol/L) after a 30-minute preincubation in the absence (control) or presence of ODQ or L-NAME at the aforementioned concentrations. Tissues were then frozen in LN₂ and stored at -80°C. To determine cGMP content, frozen tissues were homogenized in 0.5 mL of 0.1 mol/L HCl in a stainless steel Ultraturrax (Polytron). Homogenates were centrifuged at 3300g, and cGMP was measured in 300 µL of supernatant by ELISA, after acetylation (R&D Systems). Results are expressed as picomoles per milligram protein. The lower limit of detection was 0.1 pmol/mg protein.

Data Analysis
Data are given as mean±SEM, or median and range. Relaxant responses are expressed as a percentage of the contraction to U46619. CRCs were analyzed as described¹⁵ to obtain pEC₅₀ (ie, the negative logarithm of the bradykinin concentration that caused 50% of the maximum effect) values. In experiments in which no clear maximum effect (E_max) was reached, E_max was defined as the relaxation obtained at the highest bradykinin concentration tested (1 µmol/L). pEC₅₀ values were not calculated when E_max was <50%, and in such cases, statistical analysis was performed under the assumption that pEC₅₀ equaled 6. The addition of L-NAME, ODQ, hydroxocobalamin, charybdotoxin plus apamin, iberiotoxin plus apamin, or ouabain plus BaCl₂ increased basal tone by 20% to 80%. In such cases, the concentration of U46619 was adjusted to obtain a preconstriction corresponding to 95% of the maximal contractile response. Statistical analysis of the relaxant responses (pEC₅₀ and E_max) was by t test, after 1-way ANOVA (followed by Dunnett post hoc evaluation) had revealed that differences existed between groups. Statistical analysis of the cGMP data was done by the Mann-Whitney U test because of the nonnormal distribution of cGMP values. P<0.05 was considered significant.

	Results

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Role of NO and H₂O₂
Bradykinin relaxed preconstricted vessel segments in a concentration-dependent manner (pEC₅₀, 8.2±0.1; E_max, 94±2%; n=32; Figure 1). Relaxation was fully prevented by Hoe140 (n=3, data not shown), confirming that it is mediated by B₂ receptors.¹⁶ L-NAME (n=8), ODQ (n=5), and hydroxocobalamin (n=14) shifted the bradykinin CRC to the right (pEC₅₀, 7.4±0.4, 7.8±0.1, and 7.1±0.3, respectively), although significance was reached for L-NAME (P<0.05) and hydroxocobalamin (P<0.01) only. When given in addition to hydroxocobalamin, L-NAME did not induce a further rightward shift (pEC₅₀, 7.2±0.3; n=7). Both L-NAME and hydroxocobalamin reduced E_max (from 95±2% to 69±9% and 60±9%, respectively; P<0.02), and a similar reduction (E_max, 73±11%; P<0.01) was observed when the 2 drugs were combined. ODQ did not affect E_max (85±8%). Catalase, either alone (pEC₅₀, 7.7±0.5; E_max, 73±13%; n=5) or combined with hydroxocobalamin (pEC₅₀, 6.9±0.3; E_max, 50±12%; n=7), did not affect the bradykinin CRC.

View larger version (25K): [in this window] [in a new window]   Figure 1. Relaxations of HCMAs, preconstricted with U46619, to bradykinin in the absence (control) or presence of 1 or more of the following inhibitors: 10 µmol/L ODQ, 100 µmol/L L-NAME, 200 µmol/L hydroxocobalamin (HC), or 1000 U/mL catalase. Data (mean±SEM; n=5 to 32) are expressed as a percentage of the contraction induced by U46619.

Role of K⁺ Channels
Charybdotoxin plus apamin tended to decrease E_max (to 73±15%; P=NS versus control, n=8; Figure 2) without affecting potency (pEC₅₀, 7.7±0.5). When given in addition to hydroxocobalamin, charybdotoxin plus apamin completely abolished the bradykinin-induced relaxations in 6 experiments, whereas a >10-fold rightward shift was observed in 2 experiments (difference versus hydroxocobalamin for all 8 experiments at P<0.05). Iberiotoxin plus apamin did not affect the bradykinin CRC (pEC₅₀, 8.0±0.4; E_max, 101±1%; n=5), nor did these drugs exert additional effects in the presence of hydroxocobalamin (pEC₅₀, 7.1±0.4; E_max, 62±15%; n=6). Moreover, in no experiment did these drugs in combination with hydroxocobalamin fully block the effects of bradykinin. Ouabain plus BaCl₂ decreased E_max to 53±14% (n=5, P<0.05) and shifted the bradykinin CRC 10-fold to the right (pEC₅₀, 7.1±0.5; P<0.05) but did not exert additional effects in the presence of hydroxocobalamin (pEC₅₀, 6.4±0.4; E_max, 26±13%; n=5).

View larger version (26K): [in this window] [in a new window]   Figure 2. Relaxations of HCMAs, preconstricted with U46619, to bradykinin in the absence (control) or presence of 200 µmol/L hydroxocobalamin (HC) with 1 or more of the following inhibitors: 100 nmol/L charybdotoxin (char), 100 nmol/L apamin (apa), 100 nmol/L iberiotoxin (iber), or 1 mmol/L ouabain + 30 µmol/L BaCl2. Data (mean±SEM; n=5 to 32) are expressed as a percentage of the contraction induced by U46619.

Role of EETs and Gap Junctions
Clotrimazole (n=5) and sulfaphenazole (n=7) did not affect the bradykinin CRC (pEC₅₀, 7.9±0.3 and 8.3±0.2, respectively, and E_max, 89±6% and 85±10%, respectively; Figure 3), nor did clotrimazole exert effects in the presence of hydroxocobalamin (pEC₅₀, 6.7±0.6; E_max, 63±8%; n=5). Similarly, carbenoxolone (n=5) and 18-glycyrrhetinic acid (n=5) did not affect bradykinin-induced relaxation when given either alone (pEC₅₀, 8.2±0.3 and 8.3±0.1, respectively, and E_max, 81±9% and 85±11%, respectively) or in the presence of hydroxocobalamin (pEC₅₀, 6.6±0.5 and 6.7±0.4, respectively, and E_max, 58±13% and 47±17%, respectively; n=5 for each).

View larger version (28K): [in this window] [in a new window]   Figure 3. Relaxations of HCMAs, preconstricted with U46619, to bradykinin in the absence (control) or presence of 200 µmol/L hydroxocobalamin (HC) with 1 or more of the following inhibitors: 50 µmol/L clotrimazole, 10 µmol/L sulfaphenazole, 18-glycyrrhetinic acid (18-GA), or 100 µmol/L carbenoxolone. Data (mean±SEM; n=5 to 32) are expressed as a percentage of the contraction induced by U46619.

cGMP Levels
Bradykinin increased microvascular cGMP from 3.9 (range, 0.1 to 12.6) to 9.1 (0.7 to 43) pmol/mg protein (n=11, P<0.01). ODQ and L-NAME reduced cGMP levels after bradykinin stimulation to 0.1 (0.1 to 0.5; n=5) and 0.1 (0.1 to 1.7; n=4) pmol/mg protein, respectively (P<0.001 for both).

	Discussion

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Bradykinin-induced, B₂ receptor–mediated relaxation of HCMAs in the presence of indomethacin depends on NO and an EDHF that is not de novo synthesized NO. Both pathways appear to be interchangeable, because inhibiting the EDHF pathway only (with the K_Ca channel inhibitors charybdotoxin + apamin) did not significantly shift the bradykinin CRC, whereas combined inhibition of the NO and EDHF pathways (with the NO scavenger hydroxocobalamin and charybdotoxin + apamin) resulted in full blockade of the bradykinin-induced effects in 6 of 8 experiments. In the 2 remaining experiments, a >10-fold rightward shift of the bradykinin CRC occurred without an alteration in the maximum effect of bradykinin. The most likely explanation of this latter finding is incomplete scavenging of NO at the hydroxocobalamin concentration that was used in the present study. Its solubility did not allow us to use higher concentrations,² and thus, in vessels that release large amounts of NO in response to bradykinin, a rightward shift of the bradykinin CRC rather than complete inhibition of the bradykinin-induced effects will occur at this concentration of hydroxocobalamin. Heterogeneity in bradykinin-induced NO release, as well as the possibility that EDHF replaces NO in vessels where endothelial B₂ receptor stimulation no longer results in sufficient NO release, were already predicted in an earlier study that investigated the effects of intracoronary Hoe140 application in humans.¹⁶

In agreement with previous studies in porcine coronary arteries,² the rightward shift of the bradykinin CRC in the presence of hydroxocobalamin was larger than the rightward shift in the presence of L-NAME. Similar data were obtained in HCMAs with the NO scavenger HbO and the NO synthase inhibitor N^G-nitro-L-arginine.¹² Taken together, these data suggest the release of NO from a source other than L-arginine, eg, from NO-containing factors such as S-nitrosothiols. Such sources become depleted only on repeated exposure to bradykinin or after prolonged NO synthase inhibition.^2,17,18 Interestingly, the guanylyl cyclase inhibitor ODQ did not significantly affect the bradykinin CRC, despite the fact that ODQ fully prevented the 2- to 3-fold rise in cGMP levels after exposure of the HCMAs to 1 µmol/L bradykinin. This suggests that NO is capable of inducing relaxation through mechanisms other than the guanylyl cyclase–cGMP pathway. Because the blocking effects of BaCl₂ and ouabain toward bradykinin were comparable to the effect of hydroxocobalamin, whereas these drugs did not exert significant additional effects in the presence of hydroxocobalamin, one possibility is that NO activates K_IR channels and/or Na⁺/K⁺-ATPase directly. Evidence to support the latter concept is available.^19,20 Direct activation of K_Ca channels by NO^21,22 seems unlikely, because neither charybdotoxin plus apamin nor iberiotoxin plus apamin affected the bradykinin CRC in the absence of hydroxocobalamin.

With regard to the identity of EDHF, our data confirm the blocking effects of charybdotoxin plus apamin, as reported by Miura et al,¹³ toward bradykinin in HCMAs in the absence of NO. However, because no significant effects were observed with the selective BK_Ca channel inhibitor iberiotoxin in addition to hydroxocobalamin, the present results suggest that the effects of the nonselective IK_Ca and BK_Ca channel inhibitor charybdotoxin are caused by blockade of IK_Ca channels rather than blockade of BK_Ca channels. Thus, the EDHF component of the bradykinin-induced relaxation in HCMAs involves the activation of both IK_Ca and SK_Ca channels. In endothelial cells, such activation results in the release of K⁺ in the myoendothelial space.⁴ This K⁺ subsequently relaxes smooth muscle cells through activation of K_IR channels and Na⁺/K⁺-ATPase.²³ Although our data are in agreement with this concept, we cannot exclude the possibility that the IK_Ca and SK_Ca channels are located on smooth muscle cells.

Finally, our data do not support a role for H₂O₂, EETs, or gap junctions in the bradykinin-induced relaxations of HCMAs, despite previous studies in other human vessels that have demonstrated such a role.^10,24 Apparently, the nature of EDHF differs among vessels from different organs, in the same way it varies between vessels from different species and even between vessels of different sizes. The lack of effect of the cytochrome P450 epoxygenase inhibitors is in agreement with the nonsignificant effect of iberiotoxin, because EETs have been reported to exert their effects through activation of BK_Ca channels on smooth muscle cells.⁸

In conclusion, bradykinin-induced relaxation in HCMAs depends on (1) the activation of guanylyl cyclase, K_IR, and Na⁺/K⁺-ATPase by NO and (2) IK_Ca and SK_Ca channels. The latter are activated by a factor other than NO. This factor is not a cytochrome P450 epoxygenase product or H₂O₂, nor does it depend on gap junctions or BK_Ca channels.

Perspectives
Our data are the first to show that the unifying EDHF concept proposed by Busse et al⁹ also applies to human coronary arteries. As such, they form a basis for further investigations on the identity of EDHF, as well as on ways to interfere with EDHF in humans. This is of particular importance in patients with endothelial dysfunction, where B₂ receptor–mediated vasorelaxation depends largely on EDHF.¹⁶

Received September 29, 2003; first decision November 15, 2003; accepted November 25, 2003.

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