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Cardiology Section, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157-1045
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The diastolic dysfunction present
at rest in congestive heart failure (CHF) is exacerbated during
exercise (Ex). Increases in circulating ANG II and endothelin-1 (ET-1)
during Ex may contribute to this response. We assessed the effect of Ex
on circulating plasma levels of ANG II and ET-1 and left ventricular
(LV) dynamics before and after pacing-induced CHF at rest and during Ex
in nine conscious, instrumented dogs. Before CHF, there were modest
increases in circulating levels of ANG II (but not ET-1) during Ex. LV
diastolic performance was enhanced during Ex with decreases in the time constant of LV relaxation (
), LV end-systolic volume
(VES), and LV minimum pressure with a downward shift of the
LV early diastolic portion of the pressure-volume (P-V) loop. This
produced an increase in peak LV filling rate without an increase in
mean left atrial (LA) pressure. After CHF, the resting values of ANG II
and ET-1 were elevated and increased to very high levels during Ex.
After CHF, mean LA pressure, , and LV minimum pressure were elevated at rest and increased further during Ex. Treatment with L-754,142, a
potent ET-1 antagonist, or losartan, an ANG II AT1-receptor blocker, decreased these abnormal Ex responses in CHF more effectively than an equally vasodilatory dose of sodium nitroprusside. Combined treatment with both ANG II- and ET-1-receptor blockers was more effective than either agent alone. We conclude that in CHF, circulating ANG II and ET-1 increase to very high levels during Ex and exacerbate the diastolic dysfunction present at rest.
relaxation; left ventricle filling; nitroprusside; congestive heart failure; angiotensin II
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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THE TACHYCARDIA that
accompanies exercise (Ex) decreases the duration of diastole. For the
cardiac output to increase during Ex, the left ventricle (LV) must fill
more rapidly without requiring an excessive increase in left atrial
(LA) pressure. During normal Ex, the peak filling rate markedly
increases in response to an increased early diastolic mitral valve
pressure gradient produced by a fall in early diastolic LV pressure
without change in LA pressure. The fall in early diastolic LV pressure
during normal Ex is associated with a faster rate of LV relaxation
() and decreases in LV minimum pressure. This results from the
combined effects of tachycardia, sympathetic stimulation, and/or
enhanced elastic recoil due to contraction to lower volumes
(5). The normal Ex response is lost after the development
of congestive heart failure (CHF) both in experimental animals
(6) and in patients (29). During CHF Ex, LV
relaxation slows and both LV end-systolic volume (VES) and
minimum pressure increase. The early diastolic portion of the LV
pressure-volume (P-V) loop shifts upward and rightward during Ex after
CHF. Thus any diastolic dysfunction present at rest in CHF is
exacerbated during Ex. The contribution of neurohormonal activation to
this abnormal response is not known.
Plasma levels of ANG II and endothelin-1 (ET-1) are increased at rest in CHF (12). Strenuous Ex normally produces up to fourfold increases in circulating levels of ANG II (35). It is possible that circulating levels of ANG II and ET-1 may reach even higher levels during CHF Ex than at rest. Both hormones are potent vasoconstrictors and may contribute to increased LV pressure. The increase in LV systolic pressure during Ex contributes to the slowing of relaxation and the higher diastolic LV pressure in CHF (6). In addition, the direct effects of ANG II and ET-1 on myocardial contraction and relaxation may be altered by CHF (7, 26, 33). In normal myocardium these are mildly positive inotropic effects, but in animal models of CHF the response is converted to a reduction in LV contraction and slowed LV relaxation (7, 33). Furthermore, infusion of ANG II increases LV diastolic stiffness in animals subjected to rapid pacing (30). Similarly, ET-1 contributes to myocardial depression in pacing-induced CHF (26, 32). Thus if ANG II and ET-1 increase to high levels during CHF Ex, LV diastolic performance could be impaired by both the production of arterial vasoconstriction and direct myocardial effects.
From these considerations, we hypothesized that both ANG II and ET-1 may play an important role in producing the abnormal response to Ex in CHF that exacerbates the diastolic dysfunction present at rest. This study was undertaken to test this hypothesis. Our results provide insight into a mechanism of Ex intolerance in CHF and suggest a therapeutic strategy to enhance Ex performance in patients with CHF.
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METHODS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Instrumentation
This investigation was approved by the Institutional Animal Care and Use Committee. The pericardium was opened via a left thoracotomy and dogs (13 healthy adult heartworm-negative mongrel dogs, weight 26-33 kg) were instrumented to measure LV and LA pressures with micromanometers and three orthogonal LV dimensions using sonomicrometers as we have previously described (4-7). Two ultrasonic transit-time flow probes (model 2R or 3R, Transonic Systems) were placed around the proximal left circumflex and left anterior descending coronary arteries. One 54-cm sutureless myocardial lead (model 4312, Cardiac Pacemakers) was implanted within the myocardium of the right ventricle (RV), and the lead was attached to unipolar multiprogrammable pacemakers (model 8329, Medtronics, Minneapolis, MN) positioned under the skin of the chest. The wires and tubing were tunneled subcutaneously and brought out through the skin of the neck.Data Collection
Studies were performed after full recovery from instrumentation (10 days after the original surgery) with the dogs standing and then running on a motorized treadmill (model 1849C, Quinton, Seattle, WA) as we have previously described (6).Experimental Protocol
Studies before CHF: effect of normal Ex. Steady-state measurements were obtained, and blood was collected from the LA catheter at rest while the animals stood on a motorized treadmill. The animals then ran on the treadmill. The treadmill speed was gradually increased over 1-2 min from 2.5 miles/h to the maximum tolerated level of steady-state Ex (5.5-8.5 miles/h). The animals then exercised at this level until they no longer kept up with the treadmill. At submaximal levels of Ex, blood was collected. Data were acquired during 15-s periods throughout the Ex protocol. We analyzed the data recorded during the last minute of Ex. The total Ex time ranged from 8 to 15 min. We have previously observed that there is no difference in the response to Ex repeated after a 30-min rest period (6). The values of resting controls were also similar before Ex and with a 30-min resting period after Ex.
Induction of CHF. After completion of the baseline Ex studies, rapid RV pacing was initiated. The pacing rate was adjusted using an external magnetic control unit to 180-200 beats/min. After 3 days the pacing rate was readjusted to 220-240 beats/min. Three times per week the pacemaker was inactivated, the animal was allowed to stabilize for 30 min, and then data were collected. At the end of data collections the pacing rate was returned to 220-240 beats/min. After pacing for 3 weeks, when the LV end-diastolic pressure during the nonpaced period had increased by >15 mmHg over the prepacing control level, the pacing rate was changed to 190 beats/min and held at this rate for 3 additional weeks. This pacing protocol produced a stable degree of CHF that was maintained for 3 weeks of pacing at 190 beats/min. The measurements were made after week 4.
Study after CHF. During the stable CHF period, hemodynamic data and blood samples were obtained at rest and during submaximal Ex as described. After 30 min of recovery, rest and Ex measurements were performed after one of the interventions described below. After each study, pacing was resumed. The animals equilibrated for 2 days between studies.
The following interventions were studied in random order: 1) infusion of the ANG II receptor blocker losartan (LOS) (1 mg/kg plus 50 µg · kg
1 · min1 iv),
which completely blocks the pressure and contractile responses to ANG
II (7); 2) infusion of L-754,142 (3 mg/kg plus
3 mg · kg1 · h1 iv), a
potent mixed ET-1 antagonist (ET-ANT) (38) that completely blocks the response to infused ET-1 (26); 3)
administration of both LOS and ET-ANT; and 4) administration
of sodium nitroprusside (SNP) (0.5-2.0
µg · kg1 · min1) titrated
to obtain a similar decline in net vascular loading estimated by
arterial elastance (Ea) as produced by LOS or
ET-ANT.
Data Processing and Analysis
As previously described (7), the LV volume was calculated as a modified general ellipsoid. We analyzed by
determining the exponential time constant of the isovolumic fall of LV
pressure by the nonzero asymptote method as well as via the Weiss
method (monoexponential decay model to zero asymptote)
(37). In addition, half-maximal time
(t1/2) was computed as the time
from peak 
dP/dt until LV pressure fell to one-half of its
value at peak dP/dt. Ea was
calculated as end-systolic pressure divided by stroke volume.
Plasma ANG II and ET-1 Determinations
Plasma renin activity, ANG II, and ET-1 concentrations were determined as we have previously described (7, 33).Statistical Analysis
Group data were summarized as means ± SD. Multiple comparisons were performed using ANOVA. When a significant overall effect was present, intergroup comparisons were performed using paired t-tests and a Bonferroni correction for multiple comparisons. The level of significance was P < 0.05.| |
RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Effect of Pacing-Induced CHF
A total of 13 animals were instrumented and underwent induction of CHF with the modified pacing protocol. Of these, 11 animals had data collected for hemodynamic and neurohormonal changes at rest and during Ex before and after CHF, and 4 of the 13 were eliminated from the data analysis because of transducer failures (2 animals) or an inability to Ex (2 animals). Thus data are reported for nine animals that had data recorded during Ex after CHF with the three drug treatments (LOS, ET-ANT, or LOS + ET-ANT). Data are reported only for the six animals that had data collected during Ex after CHF with SNP treatment.Effects of Ex on Hemodynamic Response, Renin-Angiotensin System, and ET-1 Before and After CHF
Consistent with our previous observations (5, 6), normal Ex caused an improvement of LV diastolic performance with a decreased, lower minimal LV pressure, and an increase in LV filling rate (dV/dtmax) without an increase in
LA pressure. The early diastolic portion of the LV P-V loop was shifted
downward so that LV pressure was lower throughout early and
mid-diastole during Ex than at rest (Fig.
1). In contrast to the findings during Ex
before CHF, , LV end-diastolic pressure, minimum LV pressure, and
mean LA pressure all increased during Ex after CHF. As shown in Fig. 1,
these changes were accompanied by a consistent rightward and upward
shift of the early diastolic portion of the LV P-V loop during Ex after
CHF. Thus during early diastole at an equivalent LV volume, the LV
pressure was significantly higher during Ex than at rest.
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During normal Ex (before CHF) there were modest increases in plasma
renin activity (PRA) and plasma ANG II. The plasma levels of ET-1 were
not changed during normal Ex (Fig. 2).
PRA, ANG II, and ET-1 increased at rest with the development of
CHF and further increased to very high levels during Ex (Fig. 2). After
CHF, the duration of Ex was reduced from 12.3 ± 1.8 to 5.5 ± 1.8 min and the speed of Ex was decreased from 5.5-8.0 to
3.5-5.0 mph.
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Effects of SNP, LOS, L-754,142 Alone, and Combined LOS + L-754,142 During Ex After CHF
Compared with CHF at rest, SNP, LOS, and ET-ANT reduced resting LV end-systolic pressure, Ea, mean LA pressure, and (Tables 1-3).
Although SNP, LOS, and ET-ANT caused similar declines in net vascular loading (estimated by Ea), only LOS
and ET-ANT significantly reduced resting minimum LV pressure (Fig.
3). During CHF Ex, all agents blunted the
Ex-induced increase in LV systolic pressure. SNP blunted but LOS and
ET-ANT prevented Ex-induced abnormal increases in minimum LV pressure
and (Fig. 3 and Tables 1-3). The duration of Ex was not
significantly altered with these agents (SNP, 5.9 ± 2.1; LOS,
6.4 ± 2.0; and ET-ANT, 6.2 ± 1.9 min; P = not significant). Compared with the CHF control, there were no
significant changes in cardiac output (CO) with infusion of SNP at rest
and during Ex. Both LOS and ET-ANT caused a significant increase in CO;
however, the combination of LOS + ET-ANT dramatically increased CO
both at rest and during Ex (Table 4). The
combination of LOS + ET-ANT was more effective than either
agent alone, producing decreases in minimum LV pressure,
VES, and during CHF Ex. Ex duration in CHF was
increased only by the combination of LOS + ET-ANT from 5.5 ± 1.8 to 7.8 ± 1.0 min (P < 0.05).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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We investigated the roles of ANG II and ET-1 on the response of LV diastolic function to Ex in an animal model of CHF that mimics many of the functional and neurohormonal changes of clinical CHF (7, 8, 22, 32, 36). We found that the elevated circulating ANG II and ET-1 levels in CHF contributed to diastolic LV dysfunction at rest because blocking the receptors responsible for the corresponding cardiovascular actions resulted in lower LV diastolic pressure, reduced LA pressure, and enhanced LV relaxation at rest (7, 26). Importantly, the circulating levels of ANG II and ET-1 increased to even higher levels during CHF Ex and contributed to an exacerbation of the resting diastolic dysfunction during Ex.
During normal Ex sympathetic stimulation and tachycardia speed LV relaxation and contribute to a downward shift of the early diastolic portion of the LV P-V relation (5). The enhanced elastic recoil caused by contraction to a smaller VES may also importantly contribute to the enhanced LV relaxation during normal Ex. The fall in early diastolic LV pressure during normal Ex allows for more rapid LV filling without an increase in LA pressure (14, 24). This compensates for the decreased diastolic filling time that results from the tachycardia that accompanies Ex. After CHF the response of LV diastolic performance to Ex is altered: instead of augmented LV relaxation, there is slowing of LV relaxation and an upward shift of the early diastolic portion of the LV P-V relation during Ex (6, 29). Thus after CHF the increase in the dV/dtmax during Ex results entirely from an elevation of LA pressure as minimum LV pressure increases.
Why are the effects of Ex on and early diastolic LV pressure
altered after CHF? During normal Ex there is an increase in peak LV
systolic pressure. This effect alone would tend to slow . Normally,
any slowing of LV relaxation produced by increased systolic load is
overcome by sympathetic stimulation, and the increased heart rate that
enhances the rate of LV isovolumic pressure falls. After CHF, the
Ex-induced increase in peak LV pressure persists, but the effects of
increased heart rate and 
-adrenergic stimulation to speed relaxation
are reduced (6).
The abnormal response of LV relaxation and early diastolic LV pressure
to Ex after CHF may be attributable to an enhanced sensitivity of LV
relaxation to the increased systolic load during Ex (6, 10,
21). Previous observations in dogs (17) and in
humans (21) suggests that in CHF both VES and
may be more sensitive to the increase in systolic load. Komamura
and colleagues (18) demonstrated that resting LV diastolic
dysfunction early in pacing-induced CHF is due to increased systolic
load. Because LV VES is greater, the wall stress at a
similar systolic LV pressure is higher after CHF than during normal Ex.
Consistent with this concept we found that preventing the increase in
systolic LV pressure during CHF Ex with SNP blunted but did not prevent
the slowing of LV relaxation and the increase in minimum LV pressure as
we have previously observed (6).
Consistent with previous reports in normal patients (35) and in patients with mild CHF (9), we found that circulating levels of PRA and ANG II increased somewhat during normal submaximal Ex although ET-1 levels were relatively unchanged. After CHF the resting values of both ANG II and ET-1 were elevated and increased severalfold further to very high levels during Ex. It is possible that during Ex after CHF the ANG II and ET-1 levels in the myocardium may be even higher than circulating levels due to myocardial production of ANG II and ET-1. It is also possible that tissue levels may be more important and that the circulating levels may represent a spillover.
Our study demonstrated that elevated ANG II and ET-1 exacerbate LV diastolic dysfunction during CHF Ex. Both ANG II and ET-1 are potent vasoconstrictors and contribute to an increase in systolic LV pressure during Ex and thus slow LV relaxation. However, AT1- or ETA-receptor blockade was more effective in preventing the abnormal response to Ex than an equally hypotensive dose of SNP. Thus in CHF it appears that ET-1 and ANG II exacerbate diastolic dysfunction through both their vasoconstrictive and direct myocardial effects.
CHF alters the myocardial response to ANG II and ET-1. After CHF both ANG II (7) and ET-1 (26, 33) directly depress LV contraction and relaxation. In this study we found that blocking the actions of both ANG II and ET-1 was more effective than blocking either alone. Only after blocking the actions of both hormones was there a normal enhancement of LV relaxation and a fall in early LV diastolic pressure that occur during Ex.
ANG II and ET-1 have similar actions and intracellular signaling pathways (11, 16) and thus may potentially provide a pathway for escape from the effects of blocking the actions of either one. Our results demonstrate the synergistic interaction of the high circulating levels of ANG II and ET-1 in producing the slowed relaxation and elevated diastolic LV pressure at rest and during Ex.
The upward shift in the early diastolic portion of the LV P-V loop that we observed during CHF Ex is similar to that reported by Miyazaki and colleagues (24) in exercising dogs with coronary stenosis as well as that found in clinical studies of Ex-induced ischemia (23, 34). In these studies the decrease in LV distensibility during Ex was due to the effect of myocardial ischemia. Although our animals did not have coronary stenosis, Ex-induced ischemia may have contributed to our findings. The significantly increased coronary blood flow after we blocked the effects of ET-1 may have contributed to the improved LV relaxation and LV filling during Ex after CHF.
An upward shift of the diastolic P-V curve can be due to pericardial
effects (1). This would be expected to produce a parallel upward shift and should not alter relaxation. In contrast, we also
observed an increase in during CHF Ex that was blunted by blocking
ET-1 or ANG II and reversed by blocking both.
Potential Limitations of Methods
Several methodological issues should be considered in interpreting our data. First, our study was performed after opening the pericardium. It is clear that at higher cardiac volumes the pericardium substantially restrains LV filling (3). In addition, Hoit and co-workers (15) observed that pericardiotomy altered the pattern of RV but not LV filling. Because LV volumes increased during Ex after CHF, it is possible that if the pericardium had been intact there would have been greater restraint of cardiac filling and even more marked increases in LV diastolic pressure during Ex.Second, the use of a simple exponential to characterize relaxation is an approximation, because LV isovolumic pressure does not decay exactly exponentially. However, the calculation of the time constant of LV relaxation, based on the assumption of monoexponential decay, is a reasonable approximation to characterize the time course of pressure fall. Furthermore, the Ex-induced changes in the rate of LV pressure fall were also apparent in the changes in t1/2, which is not model dependent.
Third, SNP was used as a "control" vasodilator. It may have some direct effects on the myocardium.
Clinical Implications
The limitation of Ex tolerance in CHF results from both cardiac and peripheral factors (28). The exacerbation of diastolic dysfunction during CHF Ex and the resulting increase in LA pressure may contribute to exertional dyspnea. For example, Ex tolerance in patients with CHF varies more closely with resting LA pressure than LV systolic ejection fraction (27). Our study suggests that interfering with the formation of ANG II or blocking its actions may improve Ex tolerance in CHF. Angiotensin converting enzyme (ACE)-inhibitor therapy improves survival in patients with CHF but does not always enhance Ex tolerance (25). However, ANG II formation may escape from ACE inhibition during Ex (2). Thus AT1-receptor blockade (as used in our study) may be a more effective means of preventing the effects of ANG II during Ex. Consistent with this hypothesis is the observation that the addition of LOS to ACE-I improved Ex tolerance in patients with CHF (13).Our study found that in addition to ANG II, ET-1 also contributes to worsened LV diastolic function during Ex. Consistent with this finding, Krum and colleagues (20) found that in CHF patients taking an ACE inhibitor, Ex tolerance was worst in patients with the highest ET-1 levels during Ex. Our study suggests that blocking the effects of both ANG II and ET-1 may be more effective than blocking the action of either hormone alone in improving Ex tolerance in CHF.
Our observations have been obtained from a pacing-induced CHF canine model. Although rapid pacing produces an animal model of CHF that closely mimics the clinical spectrum of a congestive cardiomyopathy (7, 8, 18, 20, 22, 31, 36), we cannot be certain that our results apply to CHF that is due to other causes.
In conclusion, elevated ANG II and ET-1 contribute to the diastolic dysfunction present at rest in pacing-induced CHF, and a further increase in these neurohormonal levels during Ex exacerbates the diastolic dysfunction. These adverse functional effects of both ANG II and ET-1 may contribute to the Ex intolerance of CHF.
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ACKNOWLEDGEMENTS |
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The authors acknowledge the computer programming of Ping Tan (SPECTRUM), the technical assistance of Mack Williams and Ellen Tommasi, and the secretarial assistance of Amanda Burnette.
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FOOTNOTES |
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This work is supported in part by National Heart, Lung, and Blood Institute Grants HL-45258 and HL-53541, American Heart Association Grant 9640189N, and by the Alcohol Beverage Medical Research Foundation. C. P. Cheng is an Established Investigator of the American Heart Association.
The abstract for this work was presented at the American Heart Association Meeting in 1998.
Address for reprint requests and other correspondence: C.-P. Cheng, Section of Cardiology, Wake Forest Univ. School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157-1045 (E-mail: ccheng{at}wfubmc.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 8 August 2000; accepted in final form 7 November 2000.
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REFERENCES |
|---|
|
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
1.
Alderman, EL,
and
Glantz SA.
Acute hemodynamic interventions shift the diastolic pressure-volume curve in man.
Circulation
54:
662-671,
1976
2.
Aldigier, JC,
Huang H,
Dalmay F,
Lartigue M,
Baussant T,
Chassain AP,
Leroux-Robert C,
and
Galen FX.
Angiotensin-converting enzyme inhibition does not suppress plasma angiotensin II increase during exercise in humans.
J Cardiovasc Pharmacol
21:
289-295,
1993[ISI][Medline].
3.
Applegate, RJ,
Johnston WE,
Vinten-Johansen J,
Klopfenstein HS,
and
Little WC.
Restraining effect of intact pericardium during acute volume leading.
Am J Physiol Heart Circ Physiol
262:
H1725-H1733,
1992
4.
Cheng, CP,
Freeman GL,
Santamore WP,
Constantinescu MS,
and
Little WC.
Effect of loading conditions, contractile state, and heart rate on early diastolic left ventricular filling in conscious dogs.
Circ Res
66:
814-823,
1990
5.
Cheng, CP,
Igarashi Y,
and
Little WC.
Mechanism of augmented rate of left ventricular filling during exercise.
Circ Res
70:
9-19,
1992
6.
Cheng, CP,
Noda T,
Nozawa T,
and
Little WC.
Effect of heart failure on the mechanism of exercise-induced augmentation of mitral valve flow.
Circ Res
72:
795-806,
1993
7.
Cheng, CP,
Suzuki M,
Ohte N,
Ohno M,
Wang ZM,
and
Little WC.
Altered ventricular and myocyte response to angiotensin II in pacing-induced heart failure.
Circ Res
78:
880-892,
1996
8.
Cody, RJ.
Angiotensin II-mediated vasoconstriction in chronic congestive heart failure and response to converting enzyme inhibition.
Am J Med
77:
71-77,
1984[ISI][Medline].
9.
De Groote, P,
Millaire A,
Racadot A,
and
Decoulx E.
Plasma levels of endothelin-1 at rest and after exercise in patients with moderate congestive heart failure.
Int J Cardiol
51:
267-272,
1995[ISI][Medline].
10.
Eichhorn, EJ,
Willard JE,
Alvarez L,
Kim AS,
Glamann DB,
Risser RC,
and
Grayburn PA.
Are contraction and relaxation coupled in patients with and without congestive heart failure?
Circulation
85:
2132-2139,
1992
11.
Fareh, JF,
Touyz RM,
Schiffrin EL,
and
Thibault G.
Endothelin-1 and angiotensin II receptors in cells from rat hypertrophied heart: receptor regulation and intracellular Ca2+ modulation.
Circ Res
78:
302-311,
1996
12.
Goldsmith, SR,
Francis GS,
Cowley AW,
Levine TB,
and
Cohn JN.
Increased plasma arginine vasopressin levels in congestive heart failure.
J Am Coll Cardiol
1:
1385-1390,
1983[ISI][Medline].
13.
Hamroff, G,
Katz SD,
Mancini D,
Blaufarb I,
Bijou R,
Patel R,
Jondeau G,
Guillaume P,
Olivari MT,
and
Thomas S.
Addition of angiotensin II receptor blockade to maximal angiotensin-converting enzyme inhibition improves exercise capacity in patients with severe congestive heart failure.
Circulation
99:
990-992,
1999
14.
Higginbotham, MB,
Morris KG,
Williams RS,
McHale PA,
Colemen RE,
and
Cobb FR.
Regulation of stroke volume during submaximal and maximal upright exercise in normal man.
Circ Res
58:
281-291,
1986
15.
Hoit, BD,
Dalton N,
Bhargava V,
and
Shabetai R.
Pericardial influences on right and left ventricular filling dynamics.
Circ Res
68:
197-208,
1991
16.
Hoque, AN,
Haist JV,
and
Karmazyn M.
Na+-H+ exchange inhibition protects against mechanical, ultrastructural, and biochemical impairment induced by low concentrations of lysophosphatidylcholine in isolated rat hearts.
Circ Res
80:
95-102,
1997
17.
Ishizaka, S,
Asanoi H,
Wada O,
Kameyama T,
and
Inoue H.
Loading sequence plays an important role in enhanced load sensitivity of left ventricular relaxation in conscious dogs with tachycardia-induced cardiomyopathy.
Circulation
92:
3560-3567,
1995
18.
Komamura, K,
Shannon RP,
Pasipoularides A,
Ihara T,
Lader AS,
Patrick TA,
Bishop SP,
and
Vatner SF.
Alterations in left ventricular diastolic function in conscious dogs with pacing-induced heart failure.
J Clin Invest
89:
1825-1838,
1992.
20.
Krum, H,
Goldsmith R,
Wilshire-Clement M,
Miller M,
and
Packer M.
Role of endothelin in the exercise intolerance of chronic heart failure.
Am J Cardiol
75:
1282-1283,
1995[ISI][Medline].
21.
Little, WC.
Enhanced load dependence of relaxation in heart failure: clinical implications.
Circulation
85:
2326-2328,
1992
22.
McMurray, JJ,
Ray SG,
Abdullah I,
Dargie HJ,
and
Morton JJ.
Plasma endothelin in chronic heart failure.
Circulation
85:
1374-1379,
1992
23.
Mirsky, I,
Corin WJ,
Murakami T,
Grimm J,
Hess OM,
and
Krayenbuehl HP.
Correction for preload in assessment of myocardial contractility in aortic and mitral valve disease. Application of the concept of systolic myocardial stiffness.
Circulation
78:
68-80,
1988
24.
Miyazaki, S,
Guth BD,
Miura T,
Indolfi C,
Schulz R,
and
Ross J, Jr.
Changes of left ventricular diastolic function in exercising dogs without and with ischemia.
Circulation
81:
1058-1070,
1990
25.
Narang, R,
Swedberg K,
and
Cleland JGF
What is the ideal study design for evaluation of treatment for heart failure?
Eur Heart J
17:
120-134,
1996
26.
Onishi, K,
Ohno M,
Little WC,
and
Cheng CP.
Endogenous endothelin-1 depresses left ventricular systolic and diastolic performance in congestive heart failure.
J Pharmacol Exp Ther
288:
1214-1222,
1999
27.
Packer, M.
Abnormalities of diastolic function as a potential cause of exercise intolerance in chronic heart failure.
Circulation
81:
78-86,
1990
28.
Pouleur, H,
Hanet C,
Rousseau MF,
and
Van Eyll C.
Relation of diastolic function and exercise capacity in ischemic left ventricular dysfunction. Role of beta-agonists and beta-antagonists.
Circulation
82:
89-96,
1990.
29.
Sato, H,
Hori M,
Ozaki H,
Yokoyama H,
Imai K,
Morikawa M,
Takeda H,
Inoue M,
and
Kamada T.
Exercise-induced upward shift of diastolic left ventricular pressure-volume relation in patients with dilated cardiomyopathy. Effects of beta-adrenoceptor blockade.
Circulation
88:
2215-2223,
1993
30.
Senzaki, H,
Gluzband YA,
Pak PH,
Crow MT,
Janicki JS,
and
Kass DA.
Synergistic exacerbation of diastolic stiffness from short-term tachycardia-induced cardiodepression and angiotensin II.
Circ Res
82:
503-512,
1998
31.
Spinale, FG,
Holzgrefe HH,
Mukherjee R,
Hird RB,
Walker JD,
Arnim-Barker A,
Powell JR,
and
Koster WH.
Angiotensin-converting enzyme inhibition and the progression of congestive cardiomyopathy: effects on left ventricular and myocyte structure and function.
Circulation
92:
562-578,
1995
32.
Spinale, FG,
Walker JD,
Mukherjee R,
Iannini JP,
Keever AT,
and
Gallagher KP.
Concomitant endothelin receptor subtype-A blockade during the progression of pacing-induced congestive heart failure in rabbits. Beneficial effects on left ventricular and myocyte function.
Circulation
95:
1918-1929,
1997
33.
Suzuki, M,
Ohte N,
Wang ZM,
Williams DL, Jr,
Little WC,
and
Cheng CP.
Altered inotropic response of endothelin-1 in cardiomyocytes from rats with isoproterenol-induced cardiomyopathy.
Cardiovasc Res
39:
589-599,
1998
34.
Tebbe, U,
Scholz H,
Kreuzer H,
and
Neuhaus KL.
Changes in left ventricular diastolic function during exercise in patients with coronary artery disease.
Eur Heart J
8:
21-28,
1987.
35.
Tidgren, B,
Hjemdahl P,
Theodorsson E,
and
Nussberger J.
Renal neurohormonal and vascular responses to dynamic exercise in humans.
J Appl Physiol
70:
2279-2286,
1991
36.
Wei, CM,
Lerman A,
Rodeheffer RJ,
McGregor CG,
Brandt RR,
Wright S,
Heublein DM,
Kao PC,
Edwards WD,
and
Burnett JC, Jr.
Endothelin in human congestive heart failure.
Circulation
89:
1580-1586,
1994
37.
Weiss, JL,
Frederiksen JW,
and
Weisfeldt ML.
Hemodynamic determinants of the time-course of fall in canine left ventricular pressure.
J Clin Invest
58:
751-760,
1976.
38.
Williams, DL, Jr,
Murphy KL,
Nolan NA,
O'Brien JA,
Pettibone DJ,
Kivlighn SD,
Krause SM,
Lis EV, Jr,
Zingaro GL,
Gabel RA,
Clayton FC,
Siegl PKS,
Zhang K,
Naue J,
Vyas K,
Walsh TF,
Fitch KJ,
Chakravarty PK,
Greenlee WJ,
and
Clineschmidt BV.
Pharmacology of L-754,142, a highly potent, orally active, nonpeptidyl endothelin antagonist.
J Pharmacol Exp Ther
275:
1518-1526,
1995
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