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© 1995 American Heart Association, Inc.
Articles |
Protective Role of Bradykinin in Cardiac Anaphylaxis
Coronary-Vasodilating and Antiarrhythmic Activities Mediated by Autocrine/Paracrine Mechanisms
From the Department of Pharmacology, Cornell University Medical College, New York, NY.
Correspondence to Roberto Levi, MD, Department of Pharmacology, Cornell University Medical College, 1300 York Ave, New York, NY 10021.
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Abstract |
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Abstract Cardiac anaphylaxis, an acute ischemic dysfunction comprising coronary vasoconstriction and arrhythmias, is a model of clinically recognized immediate hypersensitivity reactions affecting the heart. Bradykinin, a mediator of hypersensitivity, is also a potent coronary vasodilator, acting via nitric oxide and prostacyclin production. Because ischemia increases bradykinin outflow from the heart, we questioned whether bradykinin might mitigate anaphylactic coronary vasoconstriction. Antigen challenge of hearts isolated from presensitized guinea pigs was associated with an
30% increase in
bradykinin overflow. Furthermore, (1) when the half-life of bradykinin
was prolonged with the kininase II/angiotensin-converting enzyme
inhibitors captopril and enalaprilat, anaphylactic coronary
vasoconstriction was attenuated and reversed, and arrhythmias were
alleviated; (2) the bradykinin B2-receptor antagonist HOE
140 prevented these effects; and (3) HOE 140 exacerbated both
anaphylactic coronary vasoconstriction and arrhythmias. During cardiac
anaphylaxis, the coronary overflow of cGMP, a marker of nitric oxide
production, and 6-ketoprostaglandin F1
, a stable
prostacyclin metabolite, increased twofold and fourfold, respectively.
Because neither enalaprilat nor HOE 140 affected these changes, the
enhanced overflow of cGMP and 6-ketoprostaglandin F1 is
likely to reflect the actions of other hypersensitivity mediators (eg,
histamine and leukotrienes). We postulate that bradykinin plays a
protective role in cardiac anaphylaxis by accumulating at the luminal
surface of the coronary endothelium and promoting, in an autocrine
mode, a B2-receptor–mediated production of nitric oxide
and prostacyclin in concentrations sufficient to elicit a paracrine
effect on coronary vascular smooth muscle, thus opposing the
vasoconstricting effects of other anaphylactic mediators.
Key Words: bradykinin • cardiac anaphylaxis • myocardial ischemia • HOE 140 • nitric oxide
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Cardiac anaphylaxis is a laboratory model1 of clinically recognized2 immediate hypersensitivity reactions affecting the heart. In the isolated guinea pig heart model, anaphylaxis is an acute dysfunction characterized by tachycardia, arrhythmias, and coronary vasoconstriction.1 Tachyarrhythmias are provoked by the release of histamine from cardiac mast cells,3 whereas coronary vasoconstriction has been ascribed to the combined effects of leukotrienes, platelet-activating factor,4 and thromboxane.1 In contrast, atrioventricular nodal conduction disturbances are mediated by adenosine,1 5 which is released from the heart in response to ischemia.6
Bradykinin has long been known as a potent coronary vasodilator,7 and its action is mediated by endothelium-derived mediators, such as prostacyclin (PGI2) and nitric oxide.8 Local bradykinin production can occur in the heart by an independent kallikrein-kinin system present in the coronary vessels.9 Myocardial ischemia increases bradykinin outflow from the heart,10 11 an effect that is potentiated by kininase II/angiotensin-converting enzyme (ACE) inhibitors11 and is viewed as cardioprotective.11 12
Furthermore, bradykinin is a likely mediator of immediate hypersensitivity, because circulating levels of high molecular weight kininogen, a precursor of bradykinin, decrease during anaphylactic shock in humans.13 Because cardiac anaphylaxis is associated with marked ischemia caused by an array of coronary-vasoconstricting agents1 and ischemia increases bradykinin outflow from the heart,10 we questioned whether bradykinin production is increased during cardiac anaphylaxis and, if so, whether this nonapeptide may function as a mitigating factor against threatening vasoconstricting mediators.
In the present study, we report that cardiac bradykinin production is increased during anaphylaxis and that anaphylactic coronary vasoconstriction and ischemic arrhythmias, which are aggravated by bradykinin B2-receptor blockade, are in contrast alleviated by inhibitors of bradykinin breakdown. Accordingly, we postulate that bradykinin is a protective mediator of cardiac anaphylaxis.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Isolated Heart Perfusion
Male Hartley guinea pigs (Hilltop, Pa) weighing 250 to 300 g were killed by cervical dislocation under light anesthesia with CO2 vapor. After midline thoracotomy, the heart was rapidly excised and perfused retrogradely at a constant pressure of 45 cm H2O in a Langendorff apparatus with Ringer's solution at 37°C saturated with 100% O2.14 The composition of the Ringer's solution was (mmol/L) NaCl 154.0, KCl 5.61, NaHCO3 5.55, CaCl2 2.16, and dextrose 5.95. Sinoatrial and ventricular rates were continuously monitored from a bipolar surface electrogram recorded from the right atrium and left ventricle and calculated from the PP or RR intervals, respectively. Coronary flow rate was continuously monitored by measuring the volume of coronary flow collected during 1-minute periods. Variability in measurement between three consecutive 1-minute samples was never >0.2 mL/min (ie,
3%). Hearts were first perfused with oxygenated
Ringer's solution for 30 to 45 minutes until the sinoatrial rate and
coronary flow rate reached a steady state.
Isolated Heart Anaphylaxis
Male Hartley guinea pigs were passively sensitized by an
intravenous injection of 0.4 mg of homologous cytotropic
IgG1 (guinea pig anti–dinitrophenyl bovine
-globulin).15 Twelve to 14 hours later, the hearts of
the sensitized guinea pigs were isolated and perfused as indicated
above and eventually challenged intra-aortically with 1 mg of
dinitrophenyl bovine serum albumin in 0.4 mL of warm oxygenated
Ringer's solution.
Histamine Assay
Histamine was assayed by reverse-phase high-performance liquid
chromatography (HPLC) using an isocratic system.16 17 The
HPLC system included a Pharmacia LKB 2157 autoinjector and a 2150 pump
(Pharmacia LKB Biotechnology Inc) and an EM Science/Hitachi F-1000
fluorometer. Samples were first derivatized with
o-phthalaldehyde for 1 minute and then passed through a
Beckman Ultrasphere ODS (3 µm, 4.6 mmx7.5 cm) column containing
acetonitrile and 50 mmol/L KH2PO4 (pH 7.0) in a
30:70 proportion. Histamine peaks were detected by using excitation and
emission wavelengths of 358 and 446 nm, respectively, and recorded on a
strip-chart recorder. Histamine release was calculated by comparing
sample peak height with the peak height of a known standard. The
minimum level of detection was 20 pmol/mL.
cGMP Assay
Coronary effluents were assayed for cGMP with an enzyme
immunoassay kit (Cayman Chemical Co Inc). A 10-fold increase in
sensitivity (detection limit, 0.09 pmol/mL) was achieved by
acetylation of the samples and standards.
Prostacyclin Assay
Coronary effluents were assayed for 6-ketoprostaglandin
F1 (6-keto-PGF1), a stable
metabolite of PGI2, by using an enzyme immunoassay
kit (Cayman Chemical Co Inc). The detection limit for this assay was
17 fmol/mL.
Adenosine Assay
Adenosine and inosine were assayed by reverse-phase HPLC,
as previously described.14 The HPLC system included an
autoinjector (model 2157, Pharmacia-LKB), an LKB 2150 pump, and a
spectrophotometer (absorbance detector, model 160, Beckman
Instruments). The mobile phase was 0.05 mol/L phosphate buffer (pH 5.1)
containing 10% methanol. Samples of 10 to 50 µL were injected into a
reverse-phase column (ultrasphere ODS, 3 µm, 4.6x7.5 cm, Beckman
Instruments). The absorbance was measured at 254 nm. Adenosine overflow
was calculated by combining the concentration of adenosine with its
metabolic product, inosine.
Bradykinin Assay
Bradykinin was assayed using a 125I kit purchased
from Peninsula Laboratories, Inc. Coronary effluents were collected
into chilled polypropylene tubes containing several inhibitors of kinin
formation and degradation (ratio of sample to inhibitors, 9:1). Each
milliliter of the inhibitor mixture contained 10 000 KIU aprotinin,
800 µg soybean trypsin inhibitor, 4 mg hexadimethrine bromide
(Polybrene), 10 mg 1,10-phenanthroline, and 20 mg EDTA. Samples were
centrifuged at 4°C and then extracted in 70% ethanol. The ethanol
supernatants were evaporated to dryness under N2 at 70°C
and stored frozen at -70°C until they were assayed. Briefly, samples
were reconstituted with radioimmunoassay buffer and incubated with
rabbit anti-bradykinin serum in polypropylene tubes at 4°C overnight.
125I-bradykinin was added the following day, and samples
were incubated once again at 4°C overnight. On the third day, goat
anti-rabbit IgG serum and normal rabbit serum were added, and after a
90-minute incubation at room temperature, the tubes were centrifuged at
3000 rpm for 20 minutes at 4°C. The supernatants were then aspirated,
and the pellets were counted in a gamma counter. The minimum level of
kinin detection was 2 fmol/mL. The bradykinin antibody cross-reacted
with Met-Lys-bradykinin, Lys-bradykinin, and T-kinin but not with
des-Arg9-bradykinin, substance P, neurokinin A, or
neurokinin B.
Drugs
The nitric oxide synthase inhibitor
N
-methyl-L-arginine (NMA) was
synthesized and generously supplied by Dr O.W. Griffith, Medical
College of Wisconsin, Milwaukee. The B2-receptor antagonist
B6572 was synthesized and generously supplied by Dr John Stewart,
University of Colorado Medical School, Denver. The bradykinin receptor
antagonist HOE 140 was a gift from Hoechst AG. Captopril was a gift of
Bristol Myers Squibb Pharmaceutical Research Institute. Enalaprilat was
a gift from Merck Sharp & Dohme Research Laboratories. Losartan was a
gift of DuPont Merck Pharmaceutical Co. Bradykinin,
des-Arg9-bradykinin, angiotensin II, indomethacin,
arginine, adenosine, inosine, aprotinin, soybean trypsin inhibitor,
EDTA, Polybrene, and 1,10-phenanthroline were purchased from Sigma
Chemical Co.
DL-2-Mercaptomethyl-3-guanidinoethylthiopropanoic acid
(MERGETPA) was purchased from Calbiochem.
Data Analysis
All data are expressed as mean±SEM. Differences between mean
responses comparing two groups were determined by t test
with a level of significance of P<.05. Differences between
mean responses comparing more than two groups were determined by ANOVA,
with the Bonferroni t test used for post hoc
analysis.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Putative Role of Bradykinin in Cardiac Anaphylaxis
Antigen challenge of spontaneously beating presensitized guinea pig hearts resulted in histamine release into the coronary effluent (18.5±2.9 nmol/g, n=6), sinoatrial nodal tachycardia, coronary vasoconstriction, and atrioventricular nodal conduction block (Fig 1
). The decrease in coronary flow rate reached a maximum
of -20% in the first 2 minutes after antigen administration (Fig 1). As shown in Fig 2, bradykinin overflow into the
coronary effluent increased by 30% in the first minute following
antigen challenge. The B2-antagonist HOE 140 (30 nmol/L)
enhanced the coronary-vasoconstricting effects of anaphylaxis.
Histamine release was also increased (31.4±4.4 nmol/g histamine
released in the presence of HOE 140 versus 18.5±2.9 nmol/g in control
conditions). As shown in Fig 1C, the maximum effect of HOE 140 occurred
in the 1- to 2-minute interval after antigen injection, when coronary
flow decreased almost twice as much in the presence of HOE 140 than in
its absence. We also observed a significant enhancement of coronary
vasoconstriction when we elicited cardiac anaphylaxis in the presence
of another bradykinin B2-receptor antagonist, compound
B6572 (1 µmol/L; data not shown). B2-receptor blockade
also increased the severity of anaphylactic atrioventricular nodal
conduction arrhythmias. As shown in Fig 1, in the presence of HOE 140
the duration of atrioventricular conduction block increased by 20%,
ie, from 4.4±0.9 minutes in control conditions to 5.2±1.1 minutes
with HOE 140 (n=6; compare panels A and B).
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We next tested whether prolonging the half-life of bradykinin by
preventing its biotransformation lessens anaphylactic cardiac
dysfunction. For this, anaphylaxis was elicited in isolated hearts
perfused with captopril and enalaprilat, two inhibitors of kininase
II/ACE. We found that when hearts were perfused with captopril (10
µmol/L) or enalaprilat (3 µmol/L), anaphylactic histamine release
was unaffected (20.8±5.3 and 22.9±4.9 nmol/g for captopril and
enalaprilat, respectively, versus 18.5±2.9 nmol/g in control
conditions), but coronary vasoconstriction was alleviated. As shown in
Fig 3B, enalaprilat abolished the anaphylactic
vasoconstriction in the 1- to 2-minute interval following antigen
injection; furthermore, both captopril and enalaprilat each reversed
the vasoconstriction to a vasodilatation in the 3- to 5-minute interval
following antigen injection (see Fig 3A and 3B). These effects of
captopril and enalaprilat were completely prevented or reversed by HOE
140 (Fig 3C and 3D).
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Captopril (10 µmol/L) and enalaprilat (3 µmol/L) also
lessened the severity of atrioventricular nodal conduction block. As
shown in Fig 4, captopril and enalaprilat decreased the
duration of the conduction block by 50% (compare panels B and C
with panel A). Moreover, HOE 140 prevented the effects of captopril and
enalaprilat and increased the duration of atrioventricular conduction
block by 25% (see panels D and E).
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Because captopril and enalaprilat also inhibit the production of
angiotensin II, we questioned whether the protective effects of these
compounds in cardiac anaphylaxis might result from the elimination of
the coronary-vasoconstricting and arrhythmogenic effects of angiotensin
rather than from the potentiation of the coronary-vasodilating effects
of bradykinin. Accordingly, we used the specific angiotensin II
receptor antagonist losartan. The intra-aortic bolus administration of
0.9 nmol of angiotensin II into isolated guinea pig hearts caused an
immediate 50% decrease in coronary flow rate (ie, from 4.8±0.2 to
2.15±0.25 mL/min; n=18; P<.05), which was abolished in
hearts perfused with losartan (1 µmol/L, n=9). At this concentration,
however, losartan failed to affect the 22% fall in coronary flow
elicited by antigen challenge (n=12). Moreover, the duration of
atrioventricular nodal conduction block during anaphylaxis was as long
in control hearts as in hearts perfused with losartan (ie, 4.4±0.9
versus 5.0±1.3 minutes; n=6 for each set), and anaphylactic histamine
release was also unaffected (21.1±6.4 versus 18.5±2.9 nmol/g in
control conditions). This suggests that angiotensin II plays no role in
the coronary vasoconstriction and conduction arrhythmias of
anaphylaxis.
Mechanisms of the Protective Effects of Bradykinin in Cardiac
Anaphylaxis
In pilot experiments (n=15), we had found that the administration
of bradykinin (9 pmol to 0.9 nmol) into spontaneously beating isolated
guinea pig hearts elicits a dose-dependent increase (15% to 100%) in
coronary flow rate and coronary overflow of cGMP (a marker for nitric
oxide production) and 6-keto-PGF1 (a stable metabolite
of PGI2). HOE 140 (30 nmol/L) antagonized the
coronary-vasodilating effect of bradykinin as well as the increase in
cGMP and 6-keto-PGF1 overflow.
Thus, we questioned whether the protective role of bradykinin in
cardiac anaphylaxis is mediated by nitric oxide and PGI2.
As shown in Fig 5A, cGMP spillover into the coronary
effluent almost doubled in the first 5 minutes of cardiac anaphylaxis,
exceeding by 0.63±0.13 pmol/g the basal overflow of 0.83±0.19 pmol/g.
The nitric oxide synthase inhibitor NMA prevented this increase in cGMP
overflow, and the inhibitory action of NMA was overcome by an excess of
nitric oxide synthase substrate (L-arginine, 1 mmol/L;
Fig 5A). Notably, in the absence of NMA, L-arginine did
not modify cGMP overflow (Fig 5A). This suggests that the increased
cGMP spillover during anaphylaxis is due to an enhanced nitric oxide
production.
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As shown in Fig 5B
, when anaphylaxis was elicited in hearts perfused
with the kininase II/ACE inhibitor captopril, cGMP overflow increased
approximately sevenfold. In contrast, perfusion with the
non–thiol-containing kininase II/ACE inhibitor enalaprilat did not
modify cGMP spillover during anaphylaxis (Fig 5B), and the enhancing
effect of captopril was unaffected by the B2-receptor
antagonist HOE 140 (Fig 5B). Moreover, as shown in Fig 5C, neither HOE
140 nor B6572, another bradykinin B2-receptor antagonist,
modified cGMP spillover during cardiac anaphylaxis. The production
of 6-keto-PGF1 increased approximately fourfold during
cardiac anaphylaxis (ie, from 5.55±0.50 to 20.16±1.21 pmol/g for 5
minutes; n=12; P<.05), indicating an increased production
of PGI2. Neither HOE 140 (30 nmol/L) nor captopril (10
µmol/L) altered the overflow of 6-keto-PGF1,
which was 25.88±6.91 and 26.5±3.99 pmol/g for 5 minutes for HOE 140
and captopril, respectively (n=8, P=NS).
Because the protective effect of bradykinin in cardiac anaphylaxis appeared to be unrelated to the increased overflow of the markers for nitric oxide and PGI2, we questioned whether adenosine might be involved in the protective effect of bradykinin. Anaphylaxis caused an approximately fivefold increase in adenosine overflow (ie, from 10.05±2.55 to 48.54±6.27 nmol/g for 5 minutes; n=12; P<.05). This increase became twice as large in the presence of either HOE 140 (30 nmol/L) or NMA (300 µmol/L); ie, with HOE 140, anaphylactic adenosine overflow increased from 48.54±6.27 to 101.12±12.49 nmol/g for 5 minutes (n=12, P<.05); with NMA, from 48.54±6.27 to 115.36±26.41 nmol/g for 5 minutes (n=11, P<.05).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Our data indicate that bradykinin production is increased during cardiac anaphylaxis, a reaction characterized by the release of several coronary-vasoconstricting mediators. The following findings define the functional consequences of this increased bradykinin production: (1) HOE 140 potentiates anaphylactic coronary vasoconstriction and exacerbates arrhythmias. (2) When the half-life of bradykinin is prolonged with captopril and enalaprilat, anaphylactic coronary vasoconstriction is greatly diminished, or even reversed, and arrhythmias are alleviated. (3) HOE 140 prevents the effects of the kininase II/ACE inhibitors. Accordingly, we postulate that bradykinin functions as a mitigating factor in cardiac anaphylaxis by opposing the coronary-vasoconstricting effects of other mediators.
Given the potent coronary-vasodilating effects of bradykinin7 and the likelihood that this peptide is a mediator of immediate hypersensitivity,13 we questioned whether local bradykinin production is augmented during cardiac anaphylaxis and partially offsets the marked ischemia caused by the array of vasoconstricting mediators, such as thromboxane A2, leukotrienes, and platelet-activating factor, which are characteristically released during this reaction.1 Indeed, we found this to be the case. An increase in bradykinin overflow occurred within 1 minute after antigen challenge of presensitized guinea pig hearts in which bradykinin breakdown was reduced by perfusion with MERGETPA and captopril, inhibitors of kininase I/carboxypeptidase M18 and kininase II/ACE, respectively.19 20
This bradykinin spillover into the coronary effluent of anaphylactic hearts most likely reflects a functionally relevant increase in local nonapeptide concentrations at the luminal surface of the resistance coronary vessels. Indeed, local accumulation of bradykinin by inhibition of kininase II/ACE,21 an enzyme located at the endothelial luminal surface,22 mitigated, and even reversed, the characteristic coronary vasoconstriction of cardiac anaphylaxis. Moreover, this cardioprotective effect was abolished by HOE 140, a bradykinin B2-receptor blocker,23 which, in the absence of kininase II/ACE inhibitors, actually intensified anaphylactic coronary vasoconstriction.
Clearly, the action of captopril and enalaprilat was not due to prevention of angiotensin II formation and abolition of its powerful vasoconstricting effects. In fact, we found that at a concentration that completely abolished the coronary-vasoconstricting effect of exogenous angiotensin II, losartan24 failed to modify anaphylactic vasoconstriction and conduction arrhythmias, demonstrating a lack of angiotensin II involvement in cardiac anaphylaxis.
The protective effect of bradykinin in cardiac anaphylaxis is further revealed by the antiarrhythmic effects of captopril and enalaprilat and their abolition by HOE 140. Atrioventricular nodal conduction block consistently occurs during cardiac anaphylaxis as a result of the reduced atrioventricular node perfusion and the negative dromotropic effect of enhanced adenosine release.1 Therefore, it is plausible that prolongation of the half-life of bradykinin by kininase II inhibition improves coronary flow and nodal perfusion, thus decreasing adenosine production and abbreviating the duration of atrioventricular nodal conduction block, an action that was clearly prevented by B2-receptor blockade.
Circulating levels of high molecular weight kininogen have been found to decrease during anaphylactic shock in humans,13 whereas plasma kinin levels have long been known to increase in experimental animals after anaphylactic challenge.25 26 Yet our findings are the first demonstration of an increased overflow of bradykinin into the effluent of a buffer-perfused organ undergoing anaphylaxis in vitro, such as the heart.
Production of bradykinin in these conditions can be ascribed to the presence of an independent vascular kallikrein-kinin system.9 Indeed, vascular endothelial cells contain large amounts of high molecular weight kininogen,27 and the vascular wall expresses and releases kallikreins that can yield enough kinin to elicit the formation of endothelium-derived relaxing factors in an autocrine mode.9 28 Notably, coronary vasoconstriction in cardiac anaphylaxis would be expected to generate shear stress on the walls of the coronary vessels29 and thus activate the local kallikrein-kinin system.9 28 Moreover, decreases in luminal flow have been shown to activate both basal and bradykinin-induced Ca2+ entry in the plasma membrane of endothelial cells,30 thus stimulating nitric oxide and PGI2 production.8 Indeed, bradykinin is known to induce endothelium-dependent hyperpolarization in coronary arteries,31 thus promoting Ca2+ entry into endothelial cells through small-conductance Ca2+-activated K+ channels32 and nitric oxide synthase activation.
Synthesis of PGI2 and nitric oxide is stimulated during cardiac anaphylaxis.1 33 Indeed, most mediators of cardiac anaphylaxis, such as histamine,34 35 leukotrienes,36 thromboxane A2,34 and platelet-activating factor,37 all stimulate nitric oxide release from the vascular endothelium. Furthermore, shear stress on the coronary vessel wall and hypoxia, both of which are associated with cardiac anaphylaxis, increase nitric oxide production and cGMP overflow from the heart.14 29
The increase in nitric oxide and PGI2 synthesis, as
inferred from the overflow of cGMP and 6-keto-PGF1 into
the coronary sinus during cardiac anaphylaxis, appears to be unrelated
to the increase in bradykinin production or to the effects and
half-life of this peptide. Thus, although one can observe ample
increases in cGMP and PGF1 overflow in response to the
administration of large doses of exogenous bradykinin in the isolated
guinea pig heart, in the context of cardiac anaphylaxis, bradykinin is
formed in small, yet pathophysiologically significant, amounts from the
endothelial cells of coronary vessels. At the endothelial surface,
then, bradykinin functions in an autocrine fashion to stimulate the
production of nitric oxide and PGI2 in amounts sufficient
to induce paracrine cyclic nucleotide changes in smooth muscle cells
and vascular relaxation.21 Thus, we envision that
bradykinin functions as an effective local modulator of coronary
vascular resistance in cardiac anaphylaxis. Accordingly, discrete
changes in its local concentration, or blockade of its endothelial cell
receptors, would result in functionally relevant changes in coronary
flow without affecting cGMP and PGF1 overflow, which
depends instead on the action of many other anaphylactic mediators.
As a further demonstration of the pathophysiological relevance of a local bradykinin action, we found that blockade of B2-receptors in hearts undergoing anaphylaxis was met by a large increase in adenosine spillover into the coronary effluent. In fact, a similar increase in adenosine production occurred when anaphylactic coronary vasoconstriction was enhanced by NMA, a specific inhibitor of nitric oxide synthase.38
Curiously, unlike the nonsulfhydryl kininase II/ACE inhibitor
enalaprilat, captopril caused a large increase in cGMP overflow during
cardiac anaphylaxis; this action, however, was insensitive to HOE 140
(see Fig 5B). Hence, this change is clearly unrelated to the cardiac
kallikrein-kinin system. One possible explanation for this phenomenon
is that the sulfhydryl moiety of captopril scavenges superoxide anions,
thereby protecting nitric oxide.39 Another possibility is
that sulfhydryl groups combine with nitric oxide to form a stable R-SNO
adduct.39
Our view that bradykinin functions as an autocrine/paracrine mediator in cardiac anaphylaxis is supported by experimental evidence from other laboratories indicating that ACE inhibitors promote local vasodilatation by enhancing the effects of subthreshold amounts of bradykinin generated by the endothelium. Thus, it was found that ACE inhibitors stimulate the formation of nitric oxide and PGI2 by endothelial cells by inhibiting the breakdown of endothelium-derived kinins.21 Furthermore, ACE inhibitors selectively potentiate endothelium-dependent relaxations to submaximal concentrations of bradykinin in coronary arteries by a local action.40 Finally, ACE inhibitors may interact with the B2-receptor, or its signaling pathway, potentiating the effects of bradykinin by a novel mechanism, distinct from the accumulation of the peptide at the luminal endothelial surface of the vessel wall.41
In conclusion, we have found that bradykinin is generated in the guinea pig heart undergoing anaphylaxis in vitro. We postulate that bradykinin accumulates at the luminal surface of the coronary endothelium, where it stimulates in an autocrine mode the production of nitric oxide and PGI2. These autacoids then act in a paracrine fashion on smooth muscle cells to oppose the coronary-vasoconstricting and arrhythmogenic effects of other mediators. Thus, bradykinin is likely to play a protective role in cardiac anaphylaxis.
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Acknowledgments |
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This study was supported by National Institutes of Health grants HL-34215 and HL-46403. Dr Rubin was a predoctoral fellow of the Pharmaceutical Research and Manufacturers of America Foundation. We wish to thank our colleague Dr Harry M. Lander for his helpful suggestions and criticism.
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Footnotes |
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Preliminary data were presented at the FASEB 1992 meeting in Anaheim, Calif, and published in abstract form (FASEB J. 1992;6:A2018).
Received July 5, 1994; accepted November 7, 1994.
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