(Hypertension. 1997;30:1105-1111.)
© 1997 American Heart Association, Inc.
Articles |
Role of Endothelial Kinins in Control of Coronary Nitric Oxide Production
From the Departments of Physiology (X.Z., X.X., T.H.H.) and Pharmacology (A.N.), New York Medical College, Valhalla, NY, and Henry Ford Hospital (G.A.S.), Detroit, Mich.
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Abstract |
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Abstract The purpose of the present study was to determine whether interventions that promote kinin production or decrease kinin inactivation affect nitric oxide production in isolated canine coronary microvessels. Accordingly, bradykinin (10-8 to 10-5 mol/L), ramiprilat (10-10 to 10-8 mol/L), A23187 (10-8 to 10-6 mol/L), kallikrein (1 to 20 U/mL), and kininogen (0.5 to 10 µg/mL) were used to stimulate endothelium-dependent nitric oxide production. Receptor antagonists, serine protease inhibitors, and a kinin antibody were used to inactivate local kallikrein-kinin activity. Nitrite, the metabolite of nitric oxide in aqueous solution, was measured using the Griess reaction. All the agonists significantly increased nitrite release. For instance, the highest dose of bradykinin, ramiprilat, A23187, kallikrein, and kininogen markedly increased nitrite production, from 60±10 to 156±12, 153±11, 161±15, 176±15, and 168±16 pmol/mg (all P<.05), respectively. The increased nitrite production caused by these agents was not only blocked by N
-nitro-L-arginine methyl ester
(L-NAME) and HOE 140 (which blocks B2 kinin receptor) but
by the kinin antibody also. For instance, nitrite production
elicited by bradykinin, ramiprilat, A23187, and kininogen
was reduced to 95±8, 87±8, 94±11, and 85±11 pmol/mg (all
P<.05), respectively, by the kinin antibody.
Carbachol-induced nitrite production (from 66±8 to 144±13)
was blocked by L-NAME but not by HOE 140 or the kinin antibody. These
results suggest that either increasing kininogen to promote
endogenous kinin formation or inhibiting
angiotensin-converting enzyme to decrease kinin breakdown,
increases nitric oxide production in isolated coronary
microvessels. These data indicate that a microvessel kallikrein-kinin
system has an important role in the control of nitric oxide
production in coronary microvessels.
Key Words: nitric oxide synthase • serine protease inhibitors • kallikrein-kinin system • kininogen
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Introduction |
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The endothelium plays a fundamental and obligatory role in the regulation of vascular tone throughout the circulation by producing a variety of substances that modulate the contractile behavior of underlying vascular smooth muscle cells.1 Various components of the kallikrein-kinin system are present in vascular tissue, and kinins of vascular origin stimulate the production of endothelial mediators, including NO and prostaglandins.2 3 Since the discovery of endothelium-derived relaxing factor,4 a number of studies5 6 have found that BK can cause substantial and endothelium-dependent blood vessel relaxation. These effects can be substantially reduced by inhibitors of NO synthase.7 8 9 10 11 Therefore, it has been proposed that kinins cause vasodilation mainly through the release of NO from endothelial cells.12 NO, a vasodilator, is the major endothelial mediator formed from the metabolism of L-arginine by NO synthase, a constitutively expressed enzyme in vascular endothelial cells, and elicits vascular smooth muscle relaxation in vitro and blood vessel dilation in vivo via activation of soluble guanylate cyclase.1 12 13
Kinins are vasodilatory peptides liberated from the protein precursor, kininogen, by plasma or tissue kallikreins.2 3 Studies from Nolly et al14 15 and others12 16 17 18 19 have found that there is a local kinin-forming system in mammalian vascular tissues and that endothelial cells are capable of producing kinins.17 18 Recently, a study from our laboratory19 demonstrated that stimulation of angiotensin receptors in isolated coronary microvessels caused kinin-dependent NO production. We showed also that three different ACE inhibitors (captopril, enalaprilat, and ramiprilat) increase NO production from canine coronary microvessels, most likely by inhibiting kinin breakdown.20 Furthermore, local kinins also appear to promote NO production in human coronary microvessels.21 Accordingly, we hypothesize that vascular kinin formation plays an important role in the control of coronary microvascular NO production. The goal of this study was to determine (1) whether stimulation of local kinin formation or inhibition of kinin breakdown can increase NO production and (2) whether inactivation of kinins using a specific kinin antibody or blockade of the B2 kinin receptor using HOE 140 can reduce NO generation from isolated canine coronary microvessels.
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Methods |
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Sixteen male mongrel dogs (body weight 23 to 34 kg) were used. Hearts were obtained quickly from pentobarbital-anesthetized dogs and kept in ice-cold PBS containing 0.1% bovine serum albumin at pH 7.4. All of the studies in dogs were approved by the Institutional Animal Care and Use Committee of New York Medical College and conformed with National Institutes of Health's and the American Physiological Society's current Guidelines for the Use and Care of Laboratory Animals.
Isolation of Coronary Microvessels
The isolation of coronary microvessels from the left
ventricle of the dog heart was performed using the method originally
developed by Gerritsen and Printz.22 Coronary
microvessels were obtained free of both large arteries and veins and
also of myocytes by a series of steps involving sequential dissection,
homogenization, sieving, and glass bead
purification. These methods have also been previously used by
us.19 20 21
Incubation of Coronary Microvessels
Microvessels were placed in a small package of 80-µm nylon
mesh, transferred into a tissue bath containing PBS, and
oxygenated with 95% O2 and 5% CO2
for 30 minutes. About 20 mg (wet weight) of tissue was placed in 5 mL
plastic tubes that contained 500 µL of PBS as control or 450 µL PBS
and 50 µL of drugs (eg, ramiprilat and kininogen) used to
stimulate or inhibit (eg, L-NAME) NO formation. All tissues were
incubated with the drugs for 20 minutes. At the end of the incubation
time, the tubes were removed from the tissue bath, and then
sulfanilamide (450 µL of 1%) and N-(1-naphthyl)
ethylene diamine (50 µL of 0.2%) were added to each tube for
diazotization of sulfanilic acid by NO, resulting in a pink color.
After 5 to 10 minutes' incubation at room temperature, the supernatant
was removed from each tube. Formation of NO was measured as nitrite,
which is the major metabolite of NO in aqueous solution. Nitrite was
measured using a spectrophotometer (Uvikon 930 Spectrophotometer,
Kontron Instruments Inc) as the increase in absorbance at 540 nm and
compared with known concentrations of nitrite. We have used these
methods previously.19 20 21
BK and Ricin Antibodies
Monoclonal antibodies against BK were obtained using a hybridoma
cell line (SBK-1) kindly provided by M. Web (Sandoz, Sandwich, UK).
Monoclonal antibodies were purified from ascites fluid of BALB/B mice
treated with the hybridoma. Briefly, after clarification by
centrifugation at 9000 rpm for 10 minutes, the ascites
fluid was diluted 1:1 with 20 mmol/L phosphate buffer, pH
7.0. The IgG fraction was obtained by adsorption to and elution from a
Fast Flow Protein G column (Pharmacia). The IgG fraction was
equilibrated against PBS, pH 7.4, and concentrated by
pressure-filtration using an Amicon Cell Concentrator (Amicon). Final
protein concentration was 19 mg/mL. In a kinin
radioimmunoassay15 a dilution of 1 000 000 of the
antibody bound approximately 90% of 125I-Ttr8-bradykinin.
The purified IgG fraction monoclonal antibodies against ricin (a plant
structural component) were used as controls to account for possible
nonspecific actions of the monoclonal antibodies. Ricin monoclonal
antibodies were produced as previously described.16
Effect of BK on the NO Production From Coronary
Microvessels
A 10-7 to 10-5
mol/L aliquot of BK was incubated 20 minutes with 20 mg isolated
coronary microvessels, and nitrite was measured. Fifty
microliters of 10-4 mol/L of HOE 140 (a
specific B2 kinin receptor antagonist) or 50
µL of 10-3 mol/L of L-NAME (an NO
synthase inhibitor) was incubated with vessels 20 minutes
before the addition of the highest dose of BK. The highest dose of BK
was incubated with vessels in the presence of kinin and ricin
antibodies (80 µg/mL).
Effect of Carbachol on NO Production From Coronary
Microvessels
Fifty microliters of 10-3 mol/L
of L-NAME, 10-4 mol/L of HOE 140, or 80
µg/mL of kinin or ricin antibodies was incubated with 20 mg
coronary microvessels for 20 minutes before the addition of
10-5 mol/L of carbachol, and then
nitrite was measured.
Effects of Ramiprilat and A23187 on NO
Production From Coronary Microvessels
Ramiprilat (10-10 to
10-8 mol/mL) or A23187
(10-8 to 10-6
mol/mL) was added to PBS that contained coronary
microvessels. After incubation for 20 minutes, nitrite was measured.
Vessels were also incubated with HOE 140 (10-4
mol/L), L-NAME (10-3 mol/L), and
kinin or ricin antibodies (80 µg/mL) 20 minutes before the
addition of the highest doses of ramaprilat or A23187. DCIC (a serine
protease inhibitor of 10-5
mol/mL) also was incubated with vessels 20 minutes before the
addition of the highest doses of ramaprilat or A23187, and then nitrite
production was measured.
Effects of Kininogen and Kallikrein on NO Production From
Coronary Microvessels
Kininogen (0.5 to 10 µg/mL) or pancreatic kallikrein (1
to 20 units/mL) was added to 450 µL of PBS that contained 20 mg of
coronary microvessels after 20 minutes, and then nitrite was
measured. The highest concentration of kininogen or kallikrein was
incubated with vessels in the presence or absence of L-NAME
(10-3 mol/L) and HOE 140
(10-4 mol/L). Kinin or ricin antibodies
(80 µg/mL) were also incubated with vessels 20 minutes before
the addition of the highest dose of kininogen. To block kallikrein,
DCIC (10-5 mol/L) was incubated with
vessels before the addition of the highest dose of kininogen or
kallikrein, and then nitrite production was measured.
Drugs and Chemicals
Ramiprilat and HOE 140 was generously supplied
byHoechst-Roussel Inc (Somerville, NJ). Bovine kininogen was purchased
from Seikagaku Kogyo Co, Ltd. Porcine pancreatic kallikrein and other
drugs or chemicals were purchased from Sigma Chemical Co. One unit of
porcine kallikrein will hydrolyse 1 µmol of benzoyl-arginine ethyl
ester per minute at pH 8.7 at 25°C.
Statistical Analysis
To construct a standard curve for nitrite, a stock solution of
NaNO2 (10-5 mol/L) was
prepared and diluted each day. Sulfanilamide (450 µL of 1%) and
N-(1-naphthyl) ethylene diamine (50 µL of 0.2%) were
added to each tube and mixed well. The tubes were allowed to stand at
room temperature for 5 to 10 minutes for full color (pink) development,
and absorbance of nitrite was measured at 540 nm. Absorbance was
computed and converted to a straight line using a regression
analysis (y=a+bx, r>.99).
Nitrite absorbance produced by microvessels from dog heart was measured
using the linear regression formula, and resulting values were
computed. Data were expressed as mean±SEM. Differences of nitrite
production from control were determined using ANOVA. A value of
P<.05 was considered statistically significant. Statistical
analysis and graphs were produced on a 486 computer (Everex)
using commercially available software (Lotus 1-2-3; GBSTAT; Slide
Write).
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Results |
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Effect of BK on the NO Production From Coronary Microvessels
BK increased nitrite production in a concentration-related manner. The actual changes in nitrite production are shown in Fig 1
. Relative to control, BK
(10-7 to 10-5
mol/L) markedly increased nitrite production, by 53%,
169%, and 245% (all P<.05), respectively. Compared with
the formation of nitrite elicited by the highest dose of BK, the kinin
antibody, L-NAME, and HOE 140 decreased nitrite production by
71%, 94%, and 72% (all P<.05, Fig 2), respectively. There was no
inhibitory effect of the ricin antibody (not shown).
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Effect of Carbachol on the NO Production From Coronary
Microvessels
As shown in Fig 2
, carbachol (10-5
mol/L) significantly increased nitrite production from
coronary microvessels. In comparison with control conditions,
carbachol increased nitrite production by 132%
(P<.05). Carbachol-stimulated nitrite production
was decreased by 75% (P<.05) by L-NAME but not by either
the kinin or ricin antibodies or by HOE 140 (not shown).
Effects of Ramiprilat and A23187 on NO
Production From Coronary Microvessels
Ramiprilat and A23187 significantly increased nitrite
production from coronary microvessels in a
concentration-related manner (Fig 3). In
comparison with control conditions, ramiprilat
(10-8 mol/L) and A23187
(10-6 mol/L) increased nitrite
production by 167% and 131%, respectively. These effects were
blocked not only by L-NAME, HOE-140, and DCIC but also by the kinin
antibody (Fig 4). The ricin antibody had
no effect (not shown). The production of nitrite caused by the
highest concentrations of ramiprilat or A23187 was
decreased, by 64% and 60%, respectively, by the kinin antibody; by
79% and 67%, respectively, by L-NAME; by 69% and 60%, respectively,
by HOE 140; and by 78% and 78%, respectively, by DCIC (all
P<.05, Fig 4).
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Effects of Kininogen and Kallikrein on NO Production From
Coronary Microvessels
The production of nitrite increased in a
concentration-dependent manner in response to kininogen and kallikrein.
In comparison with control conditions, kininogen (10 µg/mL)
and kallikrein (20 U/mL) increased nitrite production by
189% and 144% (P<.05), respectively. Nitrite
production induced by the highest doses of kininogen and
kallikrein was reduced by 86% and 70%, respectively, by L-NAME; by
72% and 80%, respectively, by HOE 140; by 88% and 81%,
respectively, by DCIC (all P<.05). Nitrite
production induced by the highest concentration of kininogen
was attenuated to 80% by the kinin antibody (P<.05). The
actual changes in nitrite production in response to kininogen
and kallikrein are shown in Figs 4 and 5,
respectively.
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Discussion |
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In this study, we found that BK, carbachol, ramiprilat, A23187, kininogen, and kallikrein significantly increased nitrite release from isolated canine coronary microvessels. These effects were dramatically reduced by L-NAME, an NO synthase inhibitor, indicating that the release of nitrite by all these agents is dependent upon NO release. NO production caused by ramiprilat, A23187, kininogen, and kallikrein was substantially reduced not only by B2 kinin receptor antagonist, HOE 140 but also by both DCIC and the monoclonal antibody against BK, suggesting that the release of nitrite by all these agents is dependent upon activation of the B2 kinin receptor by endogenous kinins. A kinin antibody, but not a ricin antibody, significantly reduced NO production caused by BK, ramiprilat, A23187, and kininogen but not that by carbachol, clearly supporting the notion that endogenous kinins participate in the control of NO production. These results demonstrate that vascular kinin formation plays an essential role as a mediator in the control of NO production by coronary microvessels. Interestingly, the kinin antibody, a large-molecular-weight kinin antibody that cannot cross the cell membrane, significantly reduced nitrite release evoked by agents presumed to increase endogenous kinin formation or to decrease kinin degradation, indicating that inactivation of kinins caused by the kinin antibody most likely occurs on the outside of cells. These results and the ability of HOE 140 to block NO production suggest that extracellular kinins are the major stimulus for B2 kinin receptor–mediated nitrite release in coronary microvessels.
Mammalian blood vessels contain a local kinin-forming
system.12 14 15 16 17 18 19 23 24 The endothelium can
constitutively produce and release kinins,12 and this may
mediate basal NO production. Under
physiological conditions, endogenous
kinins are degraded into inactive peptides by the activity of
membrane-bound kininase II (ACE).8 Since ACE is largely
responsible for the local breakdown of kinins,2 inhibition
of ACE prolongs the half-life of kinins and increases local kinin
concentration. In the present study, the ACE inhibitor,
ramiprilat, caused increased NO formation, probably by
enhancing the accumulation of endogenously released kinins.
This has been also suggested by Wiemer et al25 who found
that ramiprilat concentration- and time-dependently
increased the formation of NO (as assessed by measurement of
intracellular cGMP accumulation) in cultured human and bovine capillary
endothelial cells. Preincubation of the detector cells
with the B2 kinin receptor antagonist HOE 140
or the stereospecific NO synthase inhibitor
N-nitro-L-arginine, totally
suppressed the enhanced cGMP production that was induced by ACE
inhibition. To further substantiate increased kinin generation, kinins
were measured in the supernatant of cultured bovine aortic
endothelial cells. After 30 minutes of incubation with
ramiprilat (10-8 mol/L),
the kinin concentration in the supernatant was increased
fourfold.26 Grafe et al27 also found that the
half-life of exogenously added BK was significantly prolonged during
ACE inhibition in endothelial cells. Although
stimulation of NO production by ACE inhibitors is
attributable to the protection of endogenously produced
kinins from inactivation, one cannot neglect the possibility that ACE
inhibitors interact "directly" with the
B2 kinin receptor at the surface of
endothelium.8 Alternatively and more
likely, ramiprilat may sensitize the B2 kinin receptor
rather than act as a ligand. This would be consistent with the
action of HOE 140 and the kinin antibody but is only speculation since
this was not the goal of the current investigation. Characteristically,
ramiprilat is the most potent ACE inhibitor to
release NO in this preparation, as previously shown by
us.20 The exact mechanism responsible for this difference
remains to be determined. In the present study, we found that HOE
140 blocked the increase in NO production induced by
ramiprilat, clearly indicating the participation of the
B2 kinin receptor. It is important to note that a kinin
antibody, but not a ricin antibody, significantly reduced NO
production in response to ramiprilat, strongly
suggesting that ramiprilat-stimulated NO production
depends on the effect of kinin rather than an interaction between the
ACE inhibitor and the B2 kinin receptor.
Plasma and tissue kallikreins are the principal enzymes involved in the formation of kinin from kininogen.2 High- and low-molecular weight kininogens (HK and LK, respectively), the precursors of BK and kallidin, may undergo processing by kallikreins to generate kinins.12 HK is the preferred substrate for plasma kallikrein. Tissue kallikrein, which can be synthesized by endothelium, also preferentially cleaves LK to a kallidin.2 12 HK and LK both can bind to the surface of endothelium where they may be cleaved to produce kinins.28 Vanhoutte et al10 demonstrated that porcine tissue kallikrein elicits endothelium-dependent relaxation in isolated canine coronary artery. This effect was antagonized by both HOE 140 and an inhibitor of tissue kallikrein, aprotinin. In the present study, porcine tissue kallikrein and bovine kininogen both markedly stimulated NO production from isolated coronary microvessels. These effects are kinin-mediated since L-NAME, HOE 140, DCIC, and a kinin antibody dramatically attenuated the production of nitrite in response to kininogen and kallikrein. These results indicate that a vascular kininogen can be converted by exogenous kallikrein and that conversely there is a sufficient amount of kininogen in coronary microvessels for conversion by a vascular kallikrein and production of kinins.
A23187 is a calcium ionophore that can increase intracellular free calcium by promoting calcium influx. It is well known that relaxation of isolated blood vessels by A23187 is entirely endothelium-dependent.5 A23187-stimulated vasodilation is linked to an increased NO synthase activity and is secondary to NO production from endothelium, because constitutive NO synthase is primarily regulated by calcium/calmodulin.1 Surprisingly, data from the present study show that the increase in NO production in response to A23187 was substantially reduced by HOE 140, DCIC, and kinin antibody, indicating that local kinin formation and B2 kinin receptor activation were involved during this process. Our study is consistent with a previous study29 that demonstrated that formation of NO from coronary microvessels in pig heart in response to A23187 is due to the activation of local kinin production following calcium influx. These results indicate that A23187-induced calcium influx promotes local kinin formation in coronary microvessels.
A very interesting finding in the present study is that kinin antibody, which cannot easily cross the cell membrane, significantly reduced NO production to a number of agonists, suggesting that extracellular kinin is most likely responsible for the stimulation of endothelial NO production. Both the B2 kinin receptor and ACE, the major kinin metabolic enzyme, are located on the luminal surface of the plasma membrane of endothelial cells.8 12 30 31 HK and LK can bind to the surface of endothelium and act as a storage pool for kinin that is accessible to kallikreins or other related serine proteases.32 It is probable that kinins are produced outsideof endothelial cells. However, increasing evidence also supports intracellular kininogen synthesis and release from endothelial cells. Schmaier et al33 reported that there were measurable amounts of HK inside cultured endothelial cells. This observation may reflect either intracellular kinin synthesis or uptake and storage from the outside. Current opinions34 favor the latter possibility, because endothelium can express HK and LK binding sites on the cell surface and mediate attachment and internalization of kininogen from plasma.35 36 Stimulation of endothelial cells by BK enhances the expression of such putative kininogen receptors on endothelial cells and increases the binding of kininogen.37 38 Graf et al18 found that there was a considerable amount of intracellular tissue kallikrein and kinins in cultured human pulmonary arterial endothelial cells. Intracellular kinin concentrations measured immediately after homogenization were within the range of concentrations that cause physiological responses such as vasodilation and were 8- to 10-fold higher than the kinin concentrations found in the supernatant. During the 30 minutes after homogenization, there was an additional increase in kinin generation in endothelial cells, indicating cleavage of kininogen by cellular kallikreins. The addition of exogenous kallikrein (5 mU) to these homogenized cells led to a 5-fold increase of kinin concentrations after 5 minutes, indicating the presence of a large pool of kininogen. All these effects can be abolished by an inhibitor of tissue kallikrein, aprotinin. These data18 35 36 37 38 strongly suggest the presence of a kinin-forming enzyme that can access endothelial kininogen in cultured human endothelial cells, leading to kinin formation and release from these cells. The results from the current study and previous work by Seyedi et al29 suggest that kinins produced extracellularly or intracellularly and then released can lead to stimulation of NO production.
In summary, nitrite production by isolated canine coronary microvessels was increased by BK, kallikrein, kininogen, A23187, and ramiprilat. These data indicate that endothelial kinin formation plays an important role in the control of endogenous NO production. The fact that blockade of B2 kinin receptor and inactivation of kinins with an antibody or inhibition of serine protease markedly reduced nitrite production induced by ramiprilat, A23187, HK, or tissue kallikrein, but not by carbachol, clearly demonstrates the role of the local kinin-forming system in NO generation in coronary microvessels.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was supported by grants PO-1-43023 and RO-1-50142, 53053, and HL-18579 (Dr Nasjletti) from the National Heart, Lung, and Blood Institutes, and a Fellowship Award (96-103 to Dr Zhang) from the New York State Affiliate of the American Heart Association. We would like to thank Hoechst-Roussel Inc for the generous supply of HOE 140 and ramiprilat.
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Footnotes |
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Reprint requests to Thomas H. Hintze PhD, Professor, Department of Physiology, New York Medical College, Valhalla, NY 10595.
Received October 18, 1996; first decision November 26, 1996; accepted May 8, 1997.
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