(Circulation. 1995;92:2660-2665.)
© 1995 American Heart Association, Inc.
Articles |
Enhancement of Left Ventricular Relaxation in the Isolated Heart by an Angiotensin-Converting Enzyme Inhibitor
From the Cardiovascular Sciences Research Group, Departments of Pharmacology and Therapeutics (P.B.A., M.J.L.) and Cardiology (R.M.G.-M., A.M.S.), University of Wales College of Medicine, Cardiff, UK.
Correspondence to Dr A.M. Shah, Department of Cardiology, University of Wales College of Medicine, Heath Park, Cardiff CF4 4XN, UK.
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Abstract |
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Background ACE inhibitors exert both acute and chronic beneficial effects on cardiac function (eg, remodeling, diastolic dysfunction) in experimental studies and in patients. They inhibit the formation of angiotensin II as well as the degradation of endogenous bradykinin. We recently reported that bradykinin induces selective left ventricular (LV) relaxant effects in isolated hearts via the release of nitric oxide. The present study examined the direct effects of interaction between the ACE inhibitor captopril and endogenous bradykinin on cardiac contractile function.
Methods and Results Isolated ejecting guinea pig hearts were studied under conditions of constant loading and heart rate. LV pressure was monitored by a 2F micromanometer-tipped catheter. Captopril (1 µmol/L, n=9) caused a progressive acceleration of LV relaxation without significantly affecting early systolic parameters (eg, LV dP/dtmax) or coronary flow. These effects were inhibited by the nitric oxide scavenger hemoglobin (1 µmol/L, n=5) or by the B2-kinin receptor antagonist HOE140 (10 nmol/L, n=5). In the presence of captopril, bradykinin (0.1 nmol/L, n=6) markedly accelerated LV relaxation (significantly more than captopril alone), whereas bradykinin alone (0.1 nmol/L, n=6) had no effect.
Conclusions These data indicate that the ACE inhibitor captopril causes an acute and selective enhancement of LV relaxation independent of changes in coronary flow, probably via an endogenous bradykinin/nitric oxide pathway.
Key Words: angiotensin • bradykinin • ventricles
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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ACE inhibitors are widely used in the treatment of essential hypertension and congestive cardiac failure. Clinical studies have shown that chronic treatment with ACE inhibitors may reduce mortality and have beneficial effects on ventricular remodeling and diastolic dysfunction in congestive cardiac failure and after acute myocardial infarction.1 2 ACE inhibitors also may exert acute beneficial effects on cardiac contractile function. In an experimental model of acute ischemia in isolated hypertrophied rat hearts, the ACE inhibitor enalaprilat attenuated the ischemia-induced increase in left ventricular (LV) end-diastolic pressure.3 In patients with LV hypertrophy secondary to hypertension, acute infusion of enalaprilat into the left coronary artery improved isovolumic relaxation in those with severe hypertrophy.4 In another study in patients with LV hypertrophy, intracoronary infusion of enalaprilat improved LV diastolic chamber distensibility and regional relaxation.5 Foult et al6 reported that intracoronary infusion of enalaprilat in patients with dilated cardiomyopathy resulted in a reduction in cardiac index and end-systolic stress/volume ratio, indicative of a negative inotropic effect. However, changes in LV relaxation were not assessed in this study. The underlying mechanisms of the above acute and chronic effects are not clear but could include systemic effects (eg, changes in cardiac loading) as well as local cardiac effects.
As well as increasing the local and systemic formation of angiotensin II from angiotensin I, ACE or kininase II catalyses the degradation of endogenous kinins, eg, the potent vasoactive peptide bradykinin.7 Bradykinin induces the release of endothelium-derived relaxing factor (or nitric oxide),8 prostaglandins9 and other vasoactive factors such as endothelium-derived hyperpolarizing factor 10 11 and ATP,12 via activation of B2-kinin receptors on endothelial cells. The peptide may be released by endothelial cells themselves, probably from H-kininogen via a local kallikrein-kinin system.13 14 Since both ACE and B2-kinin receptors are located on the luminal membrane of the endothelium, it seems likely that the activity of the enzyme may influence the local concentration of bradykinin in the vicinity of the receptor.15 Indeed, inhibition of ACE by ACE inhibitors has recently been shown to increase endogenous levels of bradykinin.16 Besides increasing the accumulation of local kinins, ACE inhibitors also may enhance the action of bradykinin at the level of the receptor.15 Although ACE inhibitor–induced changes in levels of endogenous bradykinin have been shown to contribute to changes in coronary flow,17 to be cardioprotective in ischemia-reperfusion18 19 and to be antiarrhythmic,20 their possible acute effects on cardiac contractile function remain largely unexplored.
We have recently reported the effects of exogenous bradykinin and substance P on left ventricular function in the isolated ejecting (working) guinea pig heart, in which cardiac function may be studied relatively independent of changes in loading or heart rate.21 Both agents selectively enhance LV relaxation in this preparation without altering LV early systolic performance, eg, the peak rate of LV pressure rise (dP/dtmax) or peak LV systolic pressure. These effects are attributable to the release of nitric oxide, probably from coronary microvascular endothelial cells, and its direct cGMP-mediated action on cardiac myocytes. Similar LV relaxant effects are observed with the exogenous nitric oxide–donor sodium nitroprusside but not with cGMP-independent vasodilators, eg, the Ca2+-antagonist nicardipine.22 Enhancement of myocardial relaxation has been observed similarly in isolated papillary muscle preparations after the release of nitric oxide from endocardial endothelium by substance P23 or with lipid-soluble cGMP analogues.24 These experimental data regarding endothelium-derived nitric oxide substantiate the initial suggestions by Brutsaert and coworkers25 that cardiac endothelial agents might modulate myocardial relaxation. Recently, we have extended these findings to human subjects, demonstrating that low-dose bicoronary infusion of sodium nitroprusside26 or of substance P27 induces acute LV relaxation–hastening effects together with improved LV end-diastolic distensibility.
The aim of the present study was to investigate the possible direct effects of interaction between ACE and endogenous bradykinin on ventricular contractile performance in the isolated ejecting guinea pig heart.
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Methods |
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TopAbstractIntroductionMethods Results Discussion References |
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Ejecting Heart Preparation
Hearts were excised from anticoagulated, anesthetized guinea pigs of either sex (weight, 350 to 450 g; heparin 300 U IV and pentobarbital 60 mg/kg IP) and immersed in ice-cold Krebs-Henseleit solution. The composition of the buffer was (in mmol/L): 118 NaCl, 4.7 KCl, 1.2 MgSO4 · 7 H2O, 24 NaHCO3, 1.1 KH2PO4, 10 glucose, and 2.5 CaCl2 · 2H2O, with added acebutolol (0.1 µmol/L) and indomethacin (1 µmol/L) to inhibit ß-adrenergic and prostanoid effects, respectively, constantly gassed with 95% O2–5% CO2. The aorta was canulated rapidly, and hearts were initially perfused retrogradely in the Langendorff mode at a constant pressure of 80 cm H2O with Krebs-Henseleit solution at 37°C. After canulation of the left atrium via the largest pulmonary vein and ligature of all other pulmonary veins, hearts were switched to the ejecting mode as described previously.22 Loading conditions were constant (left atrial filling pressure, 10 cm H2O; aortic afterload, 70 cm H2O), and the heart was paced about 10% above its intrinsic rate by an external electrode that was placed on the right atrium. The pulmonary artery was vented to ensure free drainage of coronary effluent. Timed collection of this allowed measurement of coronary flow. Aortic flow was measured with a flotation flowmeter (KDG Flowmeters), and stroke volume was calculated by adding aortic flow to coronary flow and dividing by the heart rate. High-fidelity LV pressure was recorded with a 2F Millar micromanometer-tipped catheter-transducer inserted directly into the LV cavity via the apex. This was calibrated with the use of a transducer control unit (TC-510, Millar Instruments) and zeroed to atmospheric pressure at the level of the left ventricle. Great care was taken to avoid any leakage of fluid around the catheter. The LV pressure signal was sampled at 4 kHz and fed via a bridge amplifier into an Apple Macintosh personal computer connected to a Maclab 4 recording and analysis system (Analog Digital Instruments). LV dP/dtmax was obtained from the first derivative of the LV pressure signal. LV end-diastolic pressure was measured as the pressure at the time of the initial upward deflection on the dP/dt trace.
We have previously described in detail the characteristics of LV pressure fall in this preparation.21 22 LV pressure fall is biphasic, with an early slower phase commencing immediately after peak LV pressure and a later faster phase commencing around the time of LV dP/dtmin, which approximately corresponds to the phase of isovolumic relaxation. For the purposes of description and quantification, each phase may be characterized by a monoexponential time constant, TE corresponding to the early slower phase and TL to the later faster phase, respectively, calculated as described previously.22
Protocol
Baseline LV pressure and aortic and coronary flows
were
monitored for an equilibration period of 12 minutes, and if these
parameters were not stable, then the heart was excluded
from study. After this period the study drug (0.15 mL volume) was
introduced via a fine canula into the gassing chamber, and repeat
measurements were taken over the next 16 minutes. Hearts were studied
in 10 groups: group 1, control hearts, which were treated with 0.15 mL
of distilled water; groups 2 through 4, hearts treated with captopril 1
µmol/L alone or in the presence of hemoglobin 1 µmol/L, which
inactivates nitric oxide, or in the presence of HOE140 10
nmol/L, a specific inhibitor of B2-kinin
receptors28 ; groups 5 and 6, hearts treated with
bradykinin 0.1 and 1.0 nmol/L, respectively; group 7, hearts in which
captopril 1 µmol/L was added from the onset of the experiment (ie,
present in the Langendorff mode) as a time control for groups 8 and
9; groups 8 and 9, hearts treated with bradykinin 0.1 and 1.0 nmol/L,
respectively, in the presence of captopril; and group 10, hearts
treated with bradykinin 0.1 nmol/L in the presence of both captopril
and hemoglobin. The baseline characteristics of these hearts before
addition of the study drug are given in the Table
. There
were minor differences in peak LV pressure in groups 5 and 6, in LV
end-diastolic pressure in group 9, and peak LV pressure
and stroke volume in group 10 that were likely to have occurred by
chance. In experiments involving hemoglobin and HOE140, these were
added at least 8 minutes before the addition of the study drug. In the
experiments with hemoglobin, one drop of an antifoaming agent (antifoam
A) was added to prevent excessive frothing. Neither hemoglobin, HOE140,
or antifoam A had any effect on basal cardiac function.
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Drugs and Chemicals
Bradykinin, captopril, antifoam A,
acebutolol, and
indomethacin were obtained from Sigma Chemicals. HOE140
was a gift from Hoechst. All drugs were dissolved in distilled water
with the exception of indomethacin, which was dissolved
in 100% ethanol. The final concentration of ethanol in the
recirculating buffer was 0.1%, which was without effect on the hearts.
Hemoglobin was prepared from human blood as described
previously.23 All other chemicals were of the purest
reagent grade available.
Statistics
For all LV pressure data, measurements from at
least four
consecutive beats were averaged, and the percentage change from
baseline was calculated. Within-group comparisons were performed on
the absolute values using the Student's paired t test
followed by Dunnett's correction for multiple tests. Between-group
comparisons were performed by a repeated-measures ANOVA followed by
a post hoc Student-Newman-Keuls test to isolate differences.
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Results |
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TopAbstractIntroductionMethods Results Discussion References |
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Effect of Captopril on Basal Cardiac Function (Groups 1 Through 4)
Captopril 1 µmol/L caused a selective enhancement of LV relaxation without significantly altering LV early systolic pressure development (Fig 1
). The time
constant of early LV relaxation, TE, was
significantly reduced at all time points recorded, but there was no
change in TL, peak LV pressure, or
dP/dtmax (Fig 2).
LVEDP was unaltered (+9.8±3.5% at 12 minutes;
P=NS).
Stroke volume was also unchanged (data not shown), as was
coronary flow (maximal change, +0.3±0.3%; P=NS).
All parameters remained stable in the control group of
hearts, with no significant changes during the time course of the
experiments (Fig 2).
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)
or captopril in the presence of either hemoglobin (1 µmol/L, 
)
or HOE140 (10 nmol/L, 
) on peak left ventricular
systolic pressure (LVP), peak rate of pressure rise (dP/dt),
time constant of early relaxation (TE), and time
constant of late relaxation (TL).
*P<.05 compared with control group (
);
P<.05 compared with captopril alone (
In the presence of HOE140 10
nmol/L, the effects of captopril
were significantly attenuated (Fig 2
), suggesting that
at least part of the response to captopril may be due to activation of
B2-kinin receptors. There was a small but statistically
significant fall in peak LV pressure during exposure to captopril in
the presence of HOE140 (Fig 2).
In the presence of
hemoglobin 1 µmol/L, the captopril-induced
fall in TE was completely blocked at all time points
recorded, suggesting that the response is mediated through nitric
oxide (Fig 2). The time constant of late LV relaxation,
TL, was initially significantly decreased in the
presence of hemoglobin, but values tended to return to control levels
toward the end of the experiment.
Effect of Exogenous Bradykinin (Groups 5 and 6)
We have
previously described in detail the effects of exogenous
bradykinin (1 to 100 nmol/L, ie, higher doses than those used in the
present study) in the isolated ejecting guinea pig
heart.21 The bradykinin concentrations used in the
present study (0.1 to 1 nmol/L) were just within the threshold for
activity in this preparation, allowing easier interpretation of any
possible potentiation by captopril of the bradykinin response.
Bradykinin 0.1 nmol/L had no significant effect on LV relaxation, ie,
the time constants TE and TL were unchanged
(maximal change, -7.3±2.4% and -2.7±1.8%,
respectively;
both P=NS). There were no significant changes in other
parameters (data not shown). Bradykinin 1 nmol/L caused a
significant progressive enhancement of early LV relaxation, with
TE being reduced by -8.7±1.8% at 16 minutes
(P<.05, Fig 3). Small and transient but
nevertheless significant changes also were seen in TL
(-4.2±2.0% at 8 minutes; P<.05). Bradykinin 1
nmol/L caused a small, transient increase in coronary flow at 2
minutes (15.5±3.0%; P<.05) accompanied by a transient
increase also in peak LV pressure, dP/dtmax,
and stroke volume.
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) on LVP, dP/dt, TE, TL,
coronary flow (CF), and stroke volume (SV).
*P<.05 compared with control group (
Effect of Captopril on Responses to Exogenous Bradykinin (Groups 7
Through 10)
In captopril-pretreated hearts, the effects of bradykinin
0.1
nmol/L were more marked than those observed in the absence of the ACE
inhibitor (Fig 4). Thus, the
reduction in TE at 12 and 16 minutes was significantly
augmented compared with either bradykinin alone or with captopril alone
from the onset of the experiment. However, in the presence of
hemoglobin together with captopril, these relaxant effects of
bradykinin were inhibited (Fig 4). There was a prolonged
significant increase in coronary flow in the group treated with
bradykinin and captopril; this increase was not abolished in the
presence of hemoglobin. Neither peak LV pressure nor
dP/dtmax were altered in any group.
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) on
TE, TL, CF, and SV.
*P<.05 compared with both captopril pretreatment
group and BK-alone group at equivalent time points. Abbreviations as in
Figs 2
Addition of bradykinin 1
nmol/L to captopril-pretreated hearts had
similar but greater effects on coronary flow but not on
TE compared with the group treated with 0.1 nmol/L
bradykinin (Fig 5). Coronary flow
increased by 65.8±8.8% within 2 minutes (P<.05). In this
group, the large increase in coronary flow was accompanied by
small but significant increases in peak LV pressure (+5.1±2.4% at
2
minutes), dP/dtmax (+15.9±4.9% at 2 minutes), and
stroke volume (+13.5±4.2% at 2 minutes; all P<.05).
Early
LV relaxation (TE) was unaltered compared with bradykinin
alone, whereas late LV relaxation was significantly delayed (ie,
TL was increased) at two time points.
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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The main finding of this study is that the ACE inhibitor captopril enhanced LV relaxation in the isolated ejecting guinea pig heart without significantly altering early systolic parameters such as LV dP/dtmax or peak LV pressure. These effects were similar in pattern to those of exogenous bradykinin, which we have previously reported are attributable to nitric oxide.21 The inhibition of the captopril effects by the B2-kinin receptor antagonist HOE140 suggests that the accelerated decline in LV relaxation was due at least in part to increased B2-kinin receptor activation. Furthermore, in the presence of the nitric oxide scavenger hemoglobin, the effects of captopril were almost totally inhibited, indicating an involvement of nitric oxide in the response. Our previous studies also have shown similar myocardial relaxant effects of nitric oxide or of cGMP analogues in the isolated ejecting heart,21 22 in isolated papillary muscles,23 24 and in isolated cardiac myocytes.29 In captopril-pretreated hearts, the addition of exogenous bradykinin 0.1 nmol/L resulted in greater LV relaxant effects than observed either with captopril alone or with bradykinin alone. In the presence of hemoglobin, these enhanced effects of bradykinin were inhibited. The simplest explanation of these data would be an increase in levels of endogenous bradykinin after ACE inhibition, resulting in increased B2-kinin receptor activation and increased release of nitric oxide. Although no measurements of bradykinin levels were performed, this postulate is supported by previous data showing that ACE inhibitors increase levels of endogenous bradykinin in isolated hearts.16 An alternative possibility is that the enhanced relaxation with captopril and bradykinin represents the addition of two separate effects, both of which presumably involve nitric oxide, since they are inhibited by hemoglobin. In the hearts treated with hemoglobin and captopril, a transient decrease in TL was observed for which we have no obvious explanation.
Of note, captopril had no effect on coronary flow, as perhaps would be expected if it was acting via increased coronary vascular concentrations of bradykinin. The absence of a rise in coronary flow with ACE inhibitors also was reported by Baumgarten and colleagues16 in their studies with ramiprilat in the isolated rat heart. One explanation for this finding could be that nitric oxide release or its actions were selectively enhanced at the level of the capillary endothelium and not at the level of the more proximal resistance vasculature, perhaps via interaction of captopril with B2-kinin receptors at this site.15 In this case, the nitric oxide would have little effect on coronary flow but a large effect on adjacent cardiac myocytes, which are only a few microns away from capillary endothelial cells.30 Alternatively, the data could be consistent with release of nitric oxide at an extravascular site. In the experiments in which both captopril and bradykinin were administered, the bradykinin-induced rise in coronary flow was augmented. However, hemoglobin did not inhibit this increase in coronary flow even though it abolished the effects on LV relaxation. This finding suggests that the bradykinin-induced rise in coronary flow in this preparation is not mediated by nitric oxide, consistent with our previous findings21 and those of others.31 These divergent effects on LV relaxation and on coronary flow are in keeping with a direct action of nitric oxide on cardiac myocytes independent of any changes in coronary flow. We have also reported previously that elevation of coronary flow with a non-cGMP–dependent vasodilator, nicardipine, is not associated with enhancement of LV relaxation.22
When a larger dose of bradykinin (1 nmol/L) was studied in captopril-pretreated hearts, no change in early LV relaxation was observed. Instead, there was a large rise in coronary flow accompanied by significant increases in peak LV pressure, LV dP/dtmax, and stroke volume, and a slight delay in late LV relaxation. At first sight, the lack of a dose-response relationship to bradykinin seems puzzling. However, the results with higher-dose bradykinin may be explained on the basis of the Gregg phenomenon,32 ie, an augmentation of LV performance secondary to a large increase in coronary flow. The observed increases in peak LV pressure, dP/dtmax, and stroke volume are compatible with the occurrence of a "Gregg" effect. LV relaxation is recognized to be sensitive to systolic load,33 34 and the increases in peak LV pressure and LV dP/dtmax may have obscured any intrinsic change resulting from the direct effects of bradykinin or nitric oxide. The rise in LV pressure also may account for the prolongation of late relaxation observed in this group.33 34
The changes in LV relaxation induced by captopril were selective for early pressure decline, whereas late ("isovolumic") pressure fall was generally unaltered, as we have previously reported with sodium nitroprusside and substance P in the isolated ejecting guinea pig heart.21 22 The data are also in keeping with recent clinical studies in which bicoronary infusion of sodium nitroprusside or substance P in normal human subjects induced LV relaxation–hastening effects (reduced the time to peak LV dP/dtmin) but had no effect on isovolumic relaxation.26 27 LV relaxation is a complex event comprising at least two phases34 and is determined by the interaction of several different mechanisms including inactivation of contractile proteins (influenced by sarcoplasmic reticulum function and contractile protein properties), loading conditions, chamber properties, and temporal and spatial heterogeneities.33 Different interventions may have varying effects on the different phases of LV pressure fall.34 In the isolated ejecting heart, in which loading is kept relatively constant, Ca2+-myofilament interaction may have a particularly important influence on the early phase of relaxation, whereas factors such as sarcoplasmic reticulum Ca2+ uptake may be more important during late relaxation.22 33 We have previously reported that cGMP (the likely intracellular mediator of nitric oxide activity) enhances myocardial relaxation in isolated cardiac myocytes by reducing the myofilament response to Ca2+ independent of changes in Ca2+ transient kinetics.29 A similar action of cGMP on myofilament response has been reported previously in experiments in skinned cardiac fibers.35 Thus, the selective effects of captopril/nitric oxide on early relaxation may be explained by a cGMP-mediated reduction in myofilament response to Ca2+ with minimal effects on sarcoplasmic reticulum function.
In our clinical studies, the LV relaxation–hastening effects of exogenous nitric oxide were accompanied by a reduction in peak LV pressure and an increase in LV end-diastolic distensibility.26 27 In the present study, captopril did not cause significant changes in peak LV pressure. This is likely to be a feature of the isolated ejecting heart preparation in which peak LV pressure occurs much earlier than in vivo because of the absence of significant pressure wave reflections from the periphery. Changes in diastolic distensibility could not be assessed in the present study because no measurements of LV volume were available. However, it is of interest to note that a recent clinical study in patients with LV hypertrophy reported an increase in LV diastolic distensibility after acute intracoronary infusion of an ACE inhibitor.5 In patients with dilated cardiomyopathy, bicoronary infusion of enalaprilat was reported to reduce peak LV pressure, but detailed assessment of LV relaxation or diastolic properties were not reported.6 These authors speculated that these changes might have resulted from inhibition of angiotensin II effects, but in view of our current findings an augmentation of bradykinin activity is an additional possibility.
The physiological and pathophysiological relevance of the present findings remain speculative at this stage. Our data indicate that an intracardiac bradykinin–nitric oxide pathway may modulate LV relaxation acutely and that this may in turn be potentiated by inhibition of intracardiac ACE activity. With chronic administration of ACE inhibitors, LV relaxation and diastolic function also may be favorably influenced through changes in cardiac loading and by ventricular remodeling.1 2 Both the acute and chronic effects may be particularly relevant in disease states, eg, LV hypertrophy or heart failure, in which LV relaxation and diastolic function are abnormal and local ACE activity is altered.36 37 38 The present acute in vitro study raises the possibility that bradykinin- and nitric oxide–mediated myocardial actions of ACE inhibitors may contribute to their beneficial effects in the chronic treatment of cardiac disease states.
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Acknowledgments |
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This work was supported by the British Heart Foundation and the UK Medical Research Council. P.B.A. is the recipient of a BHF PhD Studentship, R.M.G.-M. of a BHF Junior Research Fellowship, and A.M.S. of an MRC Senior Clinical Fellowship.
Received February 9, 1995; revision received April 26, 1995; accepted June 8, 1995.
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