(Hypertension. 1999;34:563-567.)
© 1999 American Heart Association, Inc.
Scientific Contributions |
Role of Nitric Oxide in the Control of Cardiac Oxygen Consumption in B2-Kinin Receptor Knockout Mice
From the Department of Physiology, New York Medical College, Valhalla, NY (K.E.L, C.M.L.C., E.J.M., S.K.L., T.H.H.), and the Division of Hypertension and Vascular Research, Henry Ford Hospital, Detroit, Mich (E.G.S., O.A.C.).
Correspondence to Thomas H. Hintze, PhD, Department of Physiology, New York Medical College, Valhalla, NY 10595. E-mail Thomas Hintze{at}NYMC.eduHintze@NYMC.edu
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Abstract |
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Abstract—The aim of this study was to determine whether bradykinin, the angiotensin-converting enzyme inhibitor ramiprilat, and the calcium-channel antagonist amlodipine reduce myocardial oxygen consumption (M
O2) via a B2-kinin
receptor/nitric oxide–dependent mechanism. Left
ventricular free wall and septum were isolated from normal
and B2-kinin receptor knockout (B2 -/-) mice.
Myocardial tissue oxygen consumption was measured in an airtight
chamber with a Clark-type oxygen electrode. Baseline
MO2 was not significantly different
between normal (239±13 nmol of O2 ·
min-1 · g-1) and B2 -/-
(263±24 nmol of O2 · min-1 ·
g-1) mice. S-nitroso-N-acetyl-penicillamine
(10-7 to 10-4 mol/L) reduced oxygen
consumption in a concentration-dependent manner in both normal
(maximum, 36±3%) and B2 -/- mice (28±3%). This was
also true for the endothelium-dependent vasodilator
substance P (10-10 to 10-7 mol/L; 22±7% in
normal mice and 20±4% in B2 -/- mice). Bradykinin
(10-7 to 10-4 mol/L), ramiprilat
(10-7 to 10-4 mol/L), and amlodipine
(10-7 to 10-5 mol/L) all caused
concentration-dependent decreases in MO2
in normal mice. At the highest concentration, tissue O2
consumption was decreased by 18±3%, 20±5%, and 28±3%,
respectively. The reduction in MO2 to
all 3 drugs was attenuated in the presence of
NG-nitro-L-arginine-methyl ester. However, in
the B2 -/- mice, bradykinin, ramiprilat, and
amlodipine had virtually no effect on
MO2. Therefore, nitric oxide, through a
bradykinin-receptor–dependent mechanism, regulates cardiac oxygen
consumption. This physiological mechanism is absent
in B2 -/- mice and may be evidence of an important
therapeutic mechanism of action of angiotensin-converting
enzyme inhibitors and amlodipine.
Key Words: heart • oxygen • angiotensin-converting enzyme inhibitors • amlodipine
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Introduction |
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Nitric oxide synthase (NOS) metabolizes L-arginine into nitric oxide (NO) and citrulline. NOS is a Ca2+/calmodulin-dependent enzyme present in endothelial cells that is inhibited by analogs of L-arginine such as NG-nitro-L-arginine-methyl ester (L-NAME).1 2 3 4 NO is involved in numerous physiological mechanisms, including the inhibition of platelet aggregation and neuronal communication and the regulation of vascular tone.1 2 We and others have shown that NO can modulate mitochondrial respiration in vivo5 6 and in vitro.7 NO attenuates mitochondrial respiration by inhibiting complexes I and II of the electron transport chain8 9 10 and by interactions with cytochrome oxidase.9
Bradykinin, an endogenous vasodilator, activates B2-kinin receptors, which are primarily on endothelial cells,11 12 to augment the release of NO.13 The angiotensin-converting enzyme (ACE) converts bradykinin into an inactive form; hence, ACE inhibitors, such as ramiprilat, are vasodilators, inhibit the inactivation of bradykinin, and augment the effects of bradykinin on NO release.14 15
Recent studies using the calcium-channel antagonist amlodipine, a dihydropyridine, have shown improvement in the morbidity and mortality of patients with severe, chronic, nonischemic heart failure.16 We have also shown that amlodipine decreases oxygen consumption in the normal and failing heart17 through a bradykinin-dependent mechanism subsequent to the release of NO in coronary microvessels.18 In the present study, we further elucidated the role of the B2-kinin receptor in the control of cardiac O2 consumption and its potential therapeutic mechanisms (ie, we determined if ACE inhibitors and amlodipine work through a kinin-dependent mechanism) by regulating oxygen consumption in hearts from mice deficient in the B2-kinin receptor.
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Methods |
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The use of mice was approved by the Institutional Animal Care and Use Committee of New York Medical College, and it conformed to the Guiding Principals for the Use and Care of Laboratory Animals, published by the National Institutes of Health. Female B2 -/- mice were acquired from the Henry Ford Hospital in Detroit, Mich. Female normal mice (+/+) were purchased from Jackson Laboratories (Bar Harbor, Me). We used all these methods previously.7 15 17 19
Experimental Preparations and Measurement of O2
Consumption
All animals were euthanized by cervical dislocation after
anesthesia. The heart was removed immediately, and the left ventricle
was bisected to give equal parts of left ventricular free
wall and septum in each piece of tissue. Myocardial tissues (20 to 40
mg) were then incubated in Krebs bicarbonate solution containing
(in mmol/L): NaCl 118, KCl 4.7, CaCl2 1.5,
NaHCO3 25,
KH2PO4 1.2,
MgSO4 1.1, and glucose 5.6 at 37°C; they were
then bubbled with a solution of 21% O2/5%
CO2/74% N2 (pH 7.4) to
equilibrate for 2 hours. After the incubation period, oxygen
consumption was measured polarographically with a YSI 5300 Biological
Oxygen Monitor with Clark-type oxygen electrodes (Yellow Springs
Instrument Co). Tissues were placed in a stirred bath containing
2.5 mL of Krebs buffer solution with 10 mmol/L HEPES at 37°C (pH
7.4), and the tissue bath was sealed with the oxygen electrode; hence,
the rate of oxygen consumed by the tissue was recorded on a strip
chart. Concentration response curves for the effect of different
agonists on cardiac oxygen consumption were examined. Only a single
drug was studied in each tissue slice, and the duration for each
concentration of the agonist was 
5 minutes. Succinate
(10-3 mol/L) and then sodium cyanide
(10-3 mol/L) were administered at the end of
each experiment to ensure changes in oxygen consumption originated from
mitochondria. The following experiments were performed in several mouse
hearts before and after the administration of L-NAME and in hearts from
B2 -/- mice.
Bradykinin and Substance P
Bradykinin at concentrations of 10-7 to
10-4 mol/L and substance P at concentrations of
10-10 to 10-7 mol/L were
added in a cumulative concentration-dependent manner. Bradykinin and
substance P were used to measure the effects of the stimulation of
endogenous NO production on tissue
O2 uptake. The response to these drugs was
examined after preincubation with L-NAME (10-4
mol/L) to determine the role of NO in the regulation of
MO2.
Ramiprilat and Amlodipine
The ACE inhibitor ramiprilat
(10-7 to 10-4 mol/L) and
the calcium-channel antagonist amlodipine
(10-7 to 10-5 mol/L) were
added in a cumulative concentration-dependent manner to assess the
potential role of the B2-kinin receptor as a
mediator of cardiac O2 uptake. The response to
these drugs was examined after preincubation with L-NAME
(10-4 mol/L).
NO Donor
S-nitroso-N-acetylpenicillamine (SNAP), at
concentrations of 10-7 to
10-4 mol/L, was added in a cumulative
concentration-dependent manner to assess the effects of exogenous NO on
cardiac O2 uptake. The response to SNAP was
examined after preincubation with L-NAME (10-4
mol/L).
Drugs
SNAP, bradykinin, substance P, L-NAME, and sodium cyanide were
purchased from Sigma. The ramiprilat was a gift from
Hoechst Marion Roussel (New Brunswick, NJ), and the amlodipine was a
gift from Pfizer (Groton, Conn).
Statistical Analysis
All data are expressed as mean±SEM. The rate of decrease in the
bath PO2 was used as an index of
tissue respiration, assuming an initial O2
concentration of 224 nmol/mL,20 and it was expressed as
nanomoles of O2 consumed per minute per gram
of tissue.7 15 17 19 The effect of drug treatment on
tissue O2 uptake is expressed as a percent change
in baseline O2 consumption. Statistical
analysis on baseline O2 consumption was
performed using ANOVA, and the changes in O2
consumption caused by various drug treatments were analyzed
using 2-way ANOVA followed by multiple comparisons between different
treatment groups using the Tukey test. Statistical significance was
achieved at P<0.05.
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Results |
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Baseline Cardiac O2 Consumption in Normal and B2 -/- Mice
Baseline M
O2 was not
different between normal and B2 -/- mice
(normal, 239±13 nmol of O2 ·
min-1 · g-1, n=52,
versus B2 -/- 263±24 nmol of
O2 · min-1 ·
g-1, n=40, respectively, P>0.05).
Inhibition of NOS with L-NAME had no effect on baseline tissue
O2 consumption in either normal (L-NAME–treated,
206±14 nmol of O2 ·
min-1 · g-1, n=50, P>0.05
versus normal) or B2 -/- mouse hearts
(L-NAME-treated, 203±29 nmol of O2 ·
min-1 · g-1, n=28,
P>0.05 versus B2 -/- alone).
Bradykinin and Substance P
Cumulative concentrations of bradykinin
(10-7 to 10-4 mol/L) in
tissues taken from normal mouse hearts caused concentration-dependent
decreases in MO2 (Figure 1A). In contrast, in myocardial tissues
taken from the B2 -/- mice or from the normal
+/+ mice treated with L-NAME, bradykinin caused virtually no change in
MO2 (Figure 1A).
Cumulative concentrations of substance P (10-10
to 10-7 mol/L) in tissues taken from normal mice
also caused concentration-dependent decreases in
MO2, with a maximum reduction
of 22±7% at 10-7 mol/L (Figure 1B).
Responses to substance P were attenuated in the presence of L-NAME
(10-7 mol/L: -10±5%). Substance P also caused
concentration-dependent decreases in
MO2 in
B2 -/- mice that were attenuated in the
presence of L-NAME (Figure 1B).
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significant
difference from B2 -/-; in both, P<0.05
using 2-way ANOVA followed by Tukey test. #Significant difference from
0; P<0.05 using 1-way ANOVA. Values are
mean±SEM.
Amlodipine and Ramiprilat
In normal mouse hearts, the ACE inhibitor ramiprilat
and the calcium channel antagonist amlodipine caused
concentration-dependent decreases in
MO2 (Figure 2). Responses to both
ramiprilat (at 10-5 and
10-4 mol/L, control: -23±4% and -20±5%
versus L-NAME: -1.1±6% and -8±6%; P<0.05) and
amlodipine (at 10-6 and
10-5 mol/L, control: -26±3% and -28±3%
versus L-NAME: -16±3% and -18±3%; P<0.05) were
attenuated in the presence of L-NAME. In addition, such
ramiprilat- or amlodipine-induced reductions in
MO2 were not observed in
cardiac tissues taken from B2 -/- mice (Figure 2).
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NO Donor SNAP
In both the normal and B2 -/- mouse
hearts, the NO donor SNAP caused concentration-dependent decreases in
MO2 (Figure 3). SNAP (10-4
mol/L) reduced O2 consumption by 36±3% in the
normal mice and by 28±3% in the B2 -/- mice.
These responses were not affected by L-NAME (normal mice, -32±4%;
B2 -/- mice, -35±5%).
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Discussion |
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The major findings of this study are as follows: (1) bradykinin and substance P can regulate cardiac oxygen consumption in the mouse heart, and this is, at least in part, NO-dependent; (2) the actions of bradykinin are mediated by the B2 kinin receptor; and (3) the ACE inhibitor ramiprilat and the calcium-channel blocker amlodipine stimulate a B2-kinin receptor–dependent mechanism and NO release to modulate oxygen consumption. These conclusions are supported by an earlier study from our laboratory in which icatibant (HOE 140) was used to block the B2-kinin receptor and to block the decrease in cardiac oxygen consumption in the canine left ventricle in vitro in response to 3 different ACE inhibitors.15 Bradykinin activates the B2-kinin receptor21 and stimulates the release of NO in cardiac tissue from normal mice to decrease oxygen consumption. This decrease in M
O2 was attenuated by L-NAME.
These results agree with previous work indicating that NOS
inhibitors block the effects of
bradykinin7 22 ; more recently, we demonstrated that the
bradykinin-induced reduction in
MO2 was mediated by
endothelial NOS-derived NO.19 The
present study also showed that the effects of bradykinin on
cardiac oxygen consumption were virtually absent in the
B2 -/- mice. Similar results have been shown
for vascular relaxation23 24 and the loss of the
cardioprotective effect of preconditioning by kinins on myocardial
ischemia and reperfusion injury.25 These
studies confirm the absence of the bradykinin B2
receptor in those mice and also suggest that the
B1 kinin receptor does not regulate
MO2 to any significant degree
in response to bradykinin.
Substance P is an endothelium-dependent
vasodilator26 27 28 29 30 31 that primarily activates the
neurokinin (NK)-1 receptor. Substance P does have a slight
affinity for the NK-2 and NK-3 receptors, both of which are present
on smooth muscle or endothelial cells.29
Furthermore, Tagawa et al28 showed that substance
P–induced coronary vasodilation is mediated by NO. Substance P
decreased MO2 in hearts from
both normal and B2-kinin receptor knockout mice.
L-NAME significantly attenuated the decrease in
O2 consumption in response to substance P in
cardiac tissue from both normal and B2-kinin
receptor knockout mice. These data indicate that the NK-1 receptor is
still able to release NO to modulate cardiac oxygen consumption in the
B2-kinin receptor knockout mouse heart,
indicating that there is no global defect in the ability of receptors
to stimulate NO production.
Our data indicate a concentration-dependent decrease in
MO2 in cardiac tissue from
normal mice after addition of the ACE inhibitor
ramiprilat. This is NO-dependent; the effects of
ramiprilat were attenuated by pretreatment of the tissue
with L-NAME. This NO-mediated decrease in
MO2 supports other studies
that show ACE inhibitors release NO to decrease cardiac
hypertrophy and afterload.32 33 In addition,
this property of ramiprilat may contribute to the efficacy
of the drug in the reduction of mortality in patients with clinical
symptoms of heart failure.34 In the present study,
ramiprilat had virtually no effect on oxygen consumption in
cardiac tissue from the B2 -/- mice. This
supports other studies from this laboratory suggesting that the effects
of ACE inhibitors on cardiac oxygen consumption in vitro
are dependent on activation of the B2-kinin
receptor and activation of NOS.22 This effect of ACE
inhibitors also supports the presence of a system
generating endogenous kinins,22 because no
exogenous bradykinin was added in these studies.
Amlodipine significantly reduced
MO2 in tissue from normal
mice. The decrease in MO2 was
significantly attenuated after treatment with L-NAME. These data
support our previous studies indicating that amlodipine modulates
MO2 via the release of
NO.17 18 Furthermore, the current study supports the
conclusion that the mechanism of action of amlodipine is through
activation of the B2-kinin receptor. Amlodipine
had no effect on oxygen consumption in cardiac tissue from
B2 -/- mice, suggesting that the
B2-kinin receptor has an important role in
controlling tissue oxygen consumption. In addition, because no kinins
were added, it seems that amlodipine modulates local kinin
production, which subsequently activates the
B2-kinin receptor in the mouse heart. One
discrepancy exists in our data: L-NAME was not entirely effective in
blocking NO-mediated reduction in O2
consumption. L-NAME partially but significantly attenuated the
response to amlodipine, whereas the response was abolished in the
B2 -/- mouse heart. In previous studies in the
canine heart, we found that only a portion of the response to
amlodipine was blocked by nitro-L-arginine, and we
concluded that the remaining portion of the reduction in
O2 consumption was dependent on the
calcium-channel blocking activity of amlodipine. Although unresolved,
the current study calls that conclusion into question and suggests that
(1) L-NAME blocked only a portion of the NO release induced by
amlodipine or (2) the B2 receptor may have an
additional action that involves calcium-channel activation.
Most likely, NO directly decreases mitochondrial tissue respiration via an interaction with cytochrome oxidase, and the addition of an NO donor such as SNAP would decrease oxygen consumption independent of endogenous NO synthesis and independent of the presence of the B2-kinin receptor. In this regard, SNAP caused a concentration-dependent decrease in oxygen consumption in cardiac tissue from both normal and B2-kinin receptor knockout mice. Pretreatment of the tissue with L-NAME had no effect on the reduction in tissue oxygen consumption caused by SNAP in the hearts from either normal mice or the B2-kinin receptor knockout mice because this is not dependent on local NO production.
In conclusion, bradykinin and substance P reduce oxygen consumption in
the mouse heart in vitro, and this reduction is NO-dependent. The
effects of bradykinin, but not substance P, are eliminated in hearts
from B2 -/- mice, indicating a potentially
important role for bradykinin and the B2 receptor
in the control of cardiac oxygen consumption. Finally, the
calcium-channel antagonist amlodipine and the ACE
inhibitor ramiprilat both activated a
B2-kinin/NO–dependent mechanism to modulate
MO2. This is due to
modification of the production of kinins locally in the mouse
heart; the control of tissue oxygen consumption by amlodipine and
ramiprilat is entirely absent in hearts from
B2 -/- mice. Furthermore, the control of tissue
oxygen consumption by kinins and NO may be part of the basis for the
therapeutic uses of amlodipine and ACE inhibitors in the
treatment of cardiovascular disease.
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Acknowledgments |
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Supported by grants PO1-HL43023, HL50142, and HL53053 from the National Heart, Lung, and Blood Institute. K.E.L. is the recipient of an American Heart Association Postdoctoral Fellowship (#9820046T). E.J.M. was a high school intern (from Pearl River High School, Pearl River, NY) from 1997 to 1998 and became an Intel semifinalist on the basis of a portion of the work.
Received April 14, 1999; first decision May 3, 1999; accepted May 24, 1999.
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W. Li, T. Jue, J. Edwards, X. Wang, and T. H. Hintze Changes in NO bioavailabilty regulate cardiac O2 consumption: control by intramitochondrial SOD2 and intracellular myoglobin Am J Physiol Heart Circ Physiol, January 1, 2004; 286(1): H47 - H54. [Abstract] [Full Text] [PDF]
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 R.P. Mason, P. Marche, and T.H. Hintze Novel Vascular Biology of Third-Generation L-Type Calcium Channel Antagonists: Ancillary Actions of Amlodipine Arterioscler Thromb Vasc Biol, December 1, 2003; 23(12): 2155 - 2163. [Abstract] [Full Text] [PDF]
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R. Tabrizchi Amlodipine and endothelial nitric oxide synthase activity Cardiovasc Res, October 1, 2003; 59(4): 807 - 809. [Full Text] [PDF]
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A. Linke, W. Li, H. Huang, Z. Wang, and T. H. Hintze Role of cardiac eNOS expression during pregnancy in the coupling of myocardial oxygen consumption to cardiac work Am J Physiol Heart Circ Physiol, September 1, 2002; 283(3): H1208 - H1214. [Abstract] [Full Text] [PDF]
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K. E Loke, E. J Messina, E. G Shesely, G. Kaley, and T. H Hintze Potential role of eNOS in the therapeutic control of myocardial oxygen consumption by ACE inhibitors and amlodipine Cardiovasc Res, January 1, 2001; 49(1): 86 - 93. [Abstract] [Full Text] [PDF]
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 X.-P. Yang, Y.-H. Liu, D. Mehta, M. A. Cavasin, E. Shesely, J. Xu, F. Liu, and O. A. Carretero Diminished Cardioprotective Response to Inhibition of Angiotensin-Converting Enzyme and Angiotensin II Type 1 Receptor in B2 Kinin Receptor Gene Knockout Mice Circ. Res., May 25, 2001; 88(10): 1072 - 1079. [Abstract] [Full Text] [PDF]
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