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(Hypertension. 1997;30:1376-1381.)
© 1997 American Heart Association, Inc.
Articles |
Reduced Cardiac Contractile Responsiveness to Isoproterenol in Obese Rabbits
From the Department of Physiology and Biophysics, University of Mississippi Medical Center (Jackson).
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Abstract |
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Abstract Although obesity is characterized by increased sympathetic nervous system activity, there is often a paradoxical reduction in cardiovascular end-organ response to sympathetic stimulation. Mechanisms involved in reduced sympathetic responsiveness in obesity have not been well characterized. Therefore, we determined cardiac contractile responsiveness to ß-stimulation in the obese rabbit model using both isolated heart (IH) and isolated papillary muscle (IPM) preparations. Female New Zealand White rabbits were fed control (IH: n=9; IPM: n=6) or 10% fat diets (IH: n=9; IPM: n=7) for 12 weeks. Contractile responsiveness in the IH was determined using a modified Langendorff preparation to evaluate the dose-response relationship between isoproterenol and 1) peak developed pressure/g of left ventricular wet weight and 2) maximal rate of pressure development (+dP/dt/P). Contractile responsiveness in the IPM was determined using right ventricular papillary muscles to evaluate the dose-response relationship between isoproterenol and (1) peak developed tension (T)/mm2 cross-sectional area (CSA) and (2) maximal rate of tension development (dT/dt/CSA). In the IH, baseline and maximum developed pressure/g were reduced in obese rabbits by 37% and 31%, respectively (P
.05). In the IPM,
baseline and maximum T/CSA responses were reduced in obese rabbits by
59% and 33%, respectively (P.05). Potency of
isoproterenol as reflected by the EC50 did not differ
between lean and obese animals in either preparation. These results
demonstrate that left ventricular
contractility in obesity is reduced at baseline and in
response to stimulation with isoproterenol and suggest that decreased
responsiveness to ß-stimulation may be a factor in the
obesity-related systolic dysfunction.
Key Words: heart • obesity • isoproterenol • rabbits • dysfunction, systolic
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Introduction |
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The National Institutes of Health Consensus Development Panel on the Health Implications of Obesity concluded that morbidity and mortality increase significantly with increasing weight, primarily resulting from increased cardiovascular diseases such as stroke, coronary artery disease, and congestive heart failure.1 This represents a serious health problem in the United States because it is estimated that approximately 35% of Americans ages 20 to 74 years are overweight.2 Obesity is also associated with a hyperdynamic circulatory state characterized by hypertension, increased cardiac output, increased intravascular volume, and an increased tissue metabolic demand. These changes increase both preload and afterload on the heart. As a result, systolic function may become compromised and the risk for developing congestive heart failure increased.3 Decrements in systolic function in obesity include lower ejection fraction,4 peak ejection rate4 and fractional shortening,5 and higher end-systolic diameter.5 Paradoxically, this depressed cardiac function often occurs despite increased overall sympathetic activation.6,7 Unfortunately, little is known about the mechanisms whereby obesity may alter systolic function and lead to an increased risk for heart failure. In other models of reduced cardiac function, such as hypertension, coronary artery disease, and heart failure, alterations in the ß-receptor pathway have been implicated in reduced function.8–19 However, because of the unique cardiac structural alterations that take place in obesity as a result of the combined stresses of hypertension, hypertrophy, and increased blood volume, conclusions regarding mechanisms underlying reduced function in obesity cannot necessarily be made from other models. Therefore, the purpose of the present series of studies was to test the hypothesis that reduced responsiveness to ß-adrenergic stimulation contributes to left ventricular systolic dysfunction in obesity. This was accomplished by using the rabbit model of obesity20 to study (1) the dose-response relationship between isoproterenol and both peak developed pressure/g of LV weight and maximal rate of pressure development (+dP/dt/P) in the IH preparation and (2) the dose-response relationship between isoproterenol and both peak developed tension (T)/mm2 CSA and maximal rate of tension development (dT/dt/CSA) in the IPM preparation.
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Methods |
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Animals
The experimental protocols for this study were approved by the Institutional Animal Care and Use Committee of the University of Mississippi Medical Center. All animal care and use programs were carried out according to the Guide for the Care and Use of Laboratory Animals (NIH Publication 86 to 23, revised 1985) and the regulations of the Animal Welfare Act. Female New Zealand White rabbits were purchased when they were approximately 15 to 17 weeks old weighing 3.25 to 3.75 kg (Myrtle's Rabbitry, Thompson Station, Tenn). They were housed individually in a humidity- and temperature-controlled room with a 12-hour light cycle and fed 100 g/d standard rabbit chow (Laboratory Rabbit Chow 5321, Purina Mills). After a 2-week acclimation period they were randomly divided into two groups, one designated to remain lean (IH: n=9; IPM: n=6) and the other to become obese (IH: n=9; IPM: n=7). The lean groups continued with the same dietary regimen, which is an appropriate maintenance diet for a normal nonlactating adult rabbit.21 The obese groups were given a high fat diet, ad libitum, which consisted of the standard rabbit chow with 10% added fat. The excess fat in the diet consisted of two-thirds corn oil and one-third lard. Experiments were performed after the rabbits had been on their respective diets for 12 weeks.
Blood Pressure Measurement
On the day of the experiment the rabbit was restrained in a
Plexiglas holder (Plas Labs). The central auricular artery was
cannulated (PE-50 tubing) using 0.25% bupivacaine as a local
anesthetic. The rear and neck restraints were loosened, and the rabbit
was allowed to sit quietly for 60 to 90 minutes. Blood pressure was
recorded directly from the arterial catheter using a
disposable pressure transducer positioned at heart level. The signal
from the transducer was amplified and sent to an analog to digital
(A/D) converter in a personal computer. Data were collected using
customized software developed in our department.22 Briefly,
the signal to the A/D converter was sampled at 500 Hz for a burst
duration of 5 seconds and was immediately processed to detect
systolic, diastolic, and mean pressures as well as
heart rate for each burst. Five-second bursts were collected four times
each minute and saved to disks for later analysis. The reported
values of blood pressure were taken during the last half hour of
recording while the rabbit was in a quiet, resting state. At
the end of the pressure measurements and while the rabbit remained
quiet, a small arterial blood sample was withdrawn for the
measurement of hematocrit, plasma protein, and plasma sodium and
potassium values (IH experiment only).
IH Experiment
After blood sampling, general anesthesia was induced
in the rabbits with 4% to 5% isoflurane with an oxygen flow of 1
L/min administered with a face mask. Anesthesia was
maintained with 0.5% to 1% isoflurane. An endotracheal tube was
positioned in the trachea for subsequent mechanical ventilation using a
Harvard respiratory pump. A midline thoracotomy was performed, the
superior and inferior venae cavae were identified and
isolated, and silk sutures were placed around these vessels.
The heart was then subjected to cardioplegic arrest and prepared for the Langendorff preparation as described by Dzielak et al.23 First, 100 U of heparin-sodium was administered through the atrial appendage. Following heparin administration, the root of the aorta was dissected free from the pulmonary artery, and a silk suture was placed around the aorta. Venous return was stopped by tying the sutures around the superior and inferior venae cavae, and the heart was immediately arrested by infusing cold (4°C) Euro-Collins solution retrograde into the aortic root through an 18-gauge needle. Once the heart stopped, pressure on the suture around the aortic root occlusion was periodically relaxed to vent the cardioplegic solution and facilitate cardiac decompression. Iced Euro-Collins solution was also applied topically to the heart to accelerate cooling of the organ.
After flushing the coronary arteries with cardioplegic solution, the heart was dissected free and placed in iced Euro-Collins solution. The mitral valve was excised, and a latex balloon containing a high-fidelity micromanometer (Konigsberg Instruments) was positioned in the left ventricle. The heart was then placed in an organ bath and perfused with a modified Krebs-Henseleit solution in a retrograde fashion through a cannula in the aortic root. The perfusate consisted of (in mmol/L) NaCl 115.0; NaHCO3 20.0; KCl 4.0; K2HPO4 0.9; MgSO4 1.1; CaCl 2.5; and glucose 11.0, oxygenated with a 95% O2/5% CO2 mixture (pH 7.4) and maintained at a temperature of 37°C.
Contractile responsiveness in the heart was evaluated by determining the dose-response relationship between isoproterenol and both peak developed pressure/g of LV wet weight and peak +dP/dt/P using the Langendorff IH preparation. Signals from the high-fidelity micromanometer within the latex balloon were sampled at 250 Hz for a burst duration of 6 seconds and immediately processed to detect peak pressure, end-diastolic pressure, and +dP/dt for each burst. Developed pressure was calculated as peak pressure minus end-diastolic pressure. Bursts were collected six times each minute and saved to disks for later analysis. A Cobe transducer was positioned at the level of the aortic valve to measure perfusion pressure, which was maintained at approximately 70 mm Hg. Signals from both transducers were sent to an A/D converter and analyzed using customized software. Hearts were paced by an external pacemaker at a constant rate of 180 bpm, similar to the resting heart rate of lean rabbits.20 After initiating retrograde heart perfusion, heart function was allowed to stabilize for approximately 30 minutes. Volume was added to the balloon to achieve an end-diastolic pressure of approximately -5.0 mm Hg; control measurements of peak pressure, end-diastolic pressure, and +dP/dt were then recorded. Coronary flow was also determined by a timed measurement of coronary effluent. After stabilization, increasing concentrations of isoproterenol were infused in 5-minute intervals; isoproterenol concentrations were 10-9, 3x10-9, 10-8, 3x10-8, 10-7, and 3x10-7 mol/L. Reported values were the average of measurements taken during the final 40 seconds of each 5-minute period, when function had stabilized.
Isolated Papillary Muscle Experiment
After measurement of blood pressure, rabbits were
anesthetized with 4% to 5% isoflurane. The chest was opened,
and the heart was quickly removed and placed in cold modified
Krebs-Henseleit buffer solution (see "IH Experiment"). After the
right ventricular papillary muscles were excised, the base
of the muscle was anchored, platinum electrodes were attached, and the
tendinous end was connected to a force transducer (Grass Medical
Instruments, model FT03). Right papillary muscles were used because
their smaller cross-sectional area allowed maximal oxygen diffusion
into the muscle during the experiment.
Papillary muscles were studied in a temperature-controlled chamber containing modified Krebs-Henseleit solution bubbled with a 95% O2/5% CO2 mixture at a temperature of 37°C. Muscles were stimulated to contract isometrically with a square wave pulse (3-ms duration) at a frequency of 0.5 Hz and a voltage 10% above threshold (Grass Medical Instruments, model S44). Muscles were gradually stretched to the optimum length for maximum isometric tension development. Data from the force transducer were sent to an A/D converter in a personal computer, and a 5-second burst of data were collected at 500 Hz. Five-second bursts were collected four times each minute and saved to disks for later analysis. After contractile function had been constant for at least 30 minutes, baseline measurements of peak developed tension (T), and maximum rate of tension development (dT/dt) were made.
Contractile responsiveness in the papillary muscle was evaluated by determining the dose-response relationship between isoproterenol and peak developed tension (T) and peak rate of tension development (dT/dt), both normalized for CSA of the muscle. After baseline measurements had been determined, isoproterenol was added to the bath to yield progressively increasing concentrations of 10-10, 10-9, 3x10-9, 10-8, 3x10-8, 10-7, 3x10-7,10-6, and 3x10-6 mol/L. Contractile response stabilized approximately 3 to 5 minutes after adding each isoproterenol dose; data were then sampled and averaged over 1 minute.
Statistical Analyses
For the IH study, differences between lean and obese rabbits in
body weight, blood pressure, heart rate, and left and right
ventricular weights were analyzed using a MANOVA
(SAS, SAS Institute, Inc). A separate MANOVA was used to
analyze plasma hematocrit, protein, sodium, and potassium. For
the IPM experiment, a MANOVA was used to analyze the
variables body weight, blood pressure, heart rate, left
ventricular weight, and right ventricular
muscle CSA.
For data generated during both IH and IPM experiments, log dose-response data for each animal were fit to a sigmoidal function, using a four-parameter logistic equation (Microcal Origin 4.0, Microcal Software). The four parameters were the baseline, maximum, EC50, and slope; the slope factor describes the steepness of the curve around the EC50. Variables analyzed in the IH experiment included developed pressure/g of LV weight and dP/dt/P. Variables analyzed in the IPM experiment included peak developed tension/mm2 CSA and dT/dt/CSA. A MANOVA was used to analyze the average group values for the four parameters in each variable. For all MANOVA tests, significance was accepted at the P<.05 level. When a significant group effect was detected with the MANOVA test, ANOVA results were used to determine which variables differed between groups. Significance in the ANOVA tests was accepted at the P<.01 level. All data are expressed as mean±SEM.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Characteristics of Lean and Obese Rabbits
Rabbits in the IH experiment eating the high fat diet for 12 weeks developed significant obesity, hypertension, LV and RV hypertrophy, and resting tachycardia compared with their lean counterparts (Table 1
).
The MANOVA analysis indicated a significant group effect for
these variables (P=.0001). Subsequent ANOVA results
showed significant differences between lean and obese rabbits in all
variables (P.01). Body weight was higher by 44% in
the obese rabbits. Mean blood pressure was modestly but significantly
higher by 9% in obese rabbits while resting heart rate in the obese
rabbits was 28% higher. In addition, LV and RV wet weights were higher
in the obese rabbits by 36% and 42%, respectively.
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MANOVA analysis of hematocrit and plasma protein, sodium,
and potassium for rabbits in the IH experiment indicated a significant
group difference (P=.05). Subsequent ANOVA analyses
indicated that lean and obese rabbits differed only in hematocrit (0.36
±0.01 versus 0.41±0.01, respectively; P.01). Lean and
obese rabbits did not differ in plasma protein (143.5±1.5 versus
146.8±1.8 mmol/L, respectively), plasma sodium (136.1±1.3 versus
137.6±2.1 mmol/L, respectively), or plasma potassium values
(4.8±0.3 versus 5.3±0.4 mmol/L, respectively) (all
P>.01).
In the IPM experiment, MANOVA results indicated a significant group
effect when the variables of body weight, blood pressure, heart
rate, LV weight, and RV papillary muscle CSA were analyzed
(P=.0001). ANOVA results showed that the obese and lean
rabbits differed significantly in all variables (P.01)
except for heart rate (Table 1
). Body weights in the obese rabbits were
48% higher than in the lean rabbits, while mean blood pressures were
also significantly higher by 21%. In addition, LV wet weight was
higher in the obese rabbits by 41%, while RV papillary muscle CSA was
89% higher in the obese rabbits. Resting heart rate in the obese
rabbits was elevated by was 23%; however, this did not reach
significance (P=.03).
IH Experiment
The log dose-response relationship between isoproterenol
concentration and developed pressure/g of LV weight in lean and obese
rabbits is illustrated in Fig 1. One
heart from a lean rabbit was eliminated from these analyses
because of technical difficulties during the IH experiment. MANOVA
results indicated a significant group effect for the developed
pressure/g of LV weight (P=.0036). Subsequent ANOVA results
indicated that lean and obese rabbits differed in the baseline and
maximum responses (P.01). Baseline values were 37% lower
in obese rabbits, averaging 8.3±0.5 mm Hg/g compared with
13.2±1.0 mm Hg/g in lean rabbits. Maximum values were also lower
by 31% in obese rabbits compared with lean rabbits (12.7±1.3 versus
18.4±1.5 mm Hg/g). However, potency of isoproterenol as
reflected by the EC50 did not differ between lean and obese
(2.5x10-8 versus 1.1x10-8 mol/L); the slope
of the log dose-response curve also did not differ between lean and
obese (1.33±0.15 versus 1.31±0.17). Developed pressure/g was
consistently reduced at all isoproterenol concentrations by 31
to 39%. MANOVA results did not show a significant difference between
lean and obese rabbits in curve parameters for +dP/dt/P
(P>.05).
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IPM Experiment
The response of IPM to isoproterenol stimulation was also reduced
in obese rabbits. Fig 2 illustrates the
log dose-response relation between isoproterenol concentration and
developed tension/mm2 CSA. MANOVA results yielded a
significant group effect for developed tension/mm2 CSA
(P=.0023). ANOVA tests showed that that this difference was
due to reduced minimum and maximum responses in the obese rabbits.
Similar to the IH experiment, minimum values were lower by 59% in
obese rabbits (0.41±0.04 g/mm2) compared with lean rabbits
(1.00±0.12 g/mm2). Maximum values were also lower in obese
rabbits by 33% (1.99±0.21 g/mm2) compared with lean
rabbits (2.97±0.18 g/mm2). Also similar to the IH
experiment, the EC50 did not differ between lean and obese
(4.3x10-8 versus 7.2x10-8 mol/L,
respectively); the slope of the log dose-response curve also did not
differ between lean and obese (1.08±0.15 versus 1.41±0.17,
respectively).
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The maximum rate of tension development (dT/dt/CSA) in IPMs of lean and
obese rabbits is shown in Fig 3. MANOVA
results for this variable showed a significant group effect
(P=.02). This was due to 51% reduced baseline tension
development in obese rabbits (104±4 g/s/mm2) compared with
lean rabbits (211±27 g/s/mm2) (P.01).
However, while maximal tension development was 24% lower in obese
rabbits, this did not reach statistical significance (367±40 versus
483±35 g/s/mm,2 P=.08). The slope of the log
dose-response curve did not differ between lean and obese (1.37±0.11
versus 1.61±0.19, respectively). However, the EC50 tended
to be higher in obese rabbits compared to lean rabbits
(7.9x10-8 versus 3.7x10-8 mol/L,
respectively, P=.06).
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Discussion |
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This study demonstrates that rabbits fed an ad libitum high fat diet develop obesity, hypertension, resting tachycardia, LV and RV hypertrophy, and increased papillary muscle CSA. More importantly, we have shown that there is a reduction in cardiac contractile responsiveness to ß-adrenergic stimulation in the rabbit model of obesity. In the log dose-response relationships established in both the IH and IPM experiments, obese rabbits demonstrated reduced baseline and maximum responses to isoproterenol. This suggests that systolic dysfunction in obesity may be associated with defects in the ß-receptor system.
The present data regarding hypertension and hypertrophy are consistent with our previous work in the rabbit model.20,24,25 Despite the relatively mild hypertension in these acute experiments, we believe that the difference in blood pressure in free roaming lean and obese animals may be even greater. We have preliminary data indicating that differences in blood pressure and heart rate measured 18 hours per day using telemetry were more pronounced than those measured acutely, averaging 24% and 38% higher, respectively, in obese rabbits (n=4 each group). We have also shown that obesity in this model was associated with significant ventricular hypertrophy that was due mainly to myocyte hypertrophy and not fatty infiltration.20 Using echocardiography, we subsequently expanded those observations to show that obesity hypertension was accompanied by a combined concentric and eccentric hypertrophy. Functionally, obese rabbits showed increases in the peak atrial flow velocity and the peak atrial/peak early flow velocity (A/E) ratio25 similar to those seen in obese humans.26 Taken together, these data suggest that the obese rabbit provides a valuable model for the study of obesity-related cardiac abnormalities.
Although abnormal systolic cardiac function has been identified in pressure overload models of hypertrophy,8–11 there is limited information on contractile responses of the heart in obesity. Conclusions regarding the impact of obesity on heart function cannot necessarily be deduced from the body of literature developed from other models of heart disease because obesity is associated not only with hypertension but also with elevated intravascular volumes. This puts an unusual dual burden on the heart of both increased preload and increased afterload3 and may lead to the development of both concentric and eccentric hypertrophy.3,25,27 In addition, the metabolic and neurohumoral abnormalities that accompany obesity, such as hyperglycemia, hyperinsulinemia, and activation of the renin-angiotensin system,20 may differ from other hypertensive models. The functional sequelae of this unique constellation of outcomes have not been well characterized.
Most studies of contractile dysfunction in animal models of obesity suffer from the fact that the models do not adequately mimic the human condition because of the inconsistent association of obesity, hypertension, and LV hypertrophy.28–31 Nevertheless, these studies suggest potential mechanisms responsible for the reduced responsiveness to ß-adrenergic stimulation in obesity. In an early experiment using the genetically obese Zucker rat,32 the systolic pressure and +dP/dt responses to the sympathomimetic agent dobutamine were impaired, but in the absence of cardiac hypertrophy. In a later experiment, responsiveness to ß-adrenergic stimulation was impaired in heart tissue of the obese Zucker rat and was associated with both decreased ß-adrenergic receptor number and altered coupling between receptors and Gs.33 However, blood pressure and cardiac weights were not reported. In one of the few studies to use an obese, hypertensive animal model (the SHHP/Mcc-cp rat), decreases in ß-adrenergic receptor number and affinity were demonstrated34 in the absence of cardiac hypertrophy. In addition, the obese hypertensive rats exhibited decreased cAMP production and sarcoplasmic reticular calcium uptake. Therefore, despite the inconsistent association of hypertension and hypertrophy with obesity in these models, these data suggest that a defect in the one or more components of the ß-adrenergic receptor system may be associated with systolic dysfunction in obesity. The present data from the rabbit model of obesity extend these findings to an experimental model that more closely mimics many of the characteristics of human obesity, including hypertension, left ventricular hypertrophy, and neurohumoral activation.20
In limited work done in humans, it was demonstrated that obese hypertensive subjects demonstrate cardiac hypertrophy, a hyperkinetic circulation, and impaired left ventricular function. Using the circulating lymphocyte model of ß-receptors, these abnormalities were associated with decreased ß-adrenergic receptor density.16 While the circulating lymphocyte model is frequently used to study alterations in ß-adrenoceptors in humans, it is still uncertain whether lymphocyte ß-receptors can reflect the entire population of myocardial receptors since lymphocytes contain primarily ß2-adrenoceptors. Nevertheless, decreased response to ß-adrenergic stimulation may be a common mechanism of decreased function in many types of heart disease. Defects in the ß-receptor system have been identified in heart failure,17,18 and a reduced response to isoproterenol and an increased EC50 have been noted in the IPMs of human hearts with both idiopathic cardiomyopathy and ischemic coronary artery disease.19 The importance of hypertrophy in contributing to reduced responsiveness to ß-adrenergic stimulation in humans was suggested by the work of Yasuda et al,35 where the echocardiographically determined rate of change of ventricular dimension in response to isoproterenol was not related to mean blood pressure but was inversely related to ventricular hypertrophy.
Because obesity is associated with both concentric hypertrophy and hypertension, hypertrophy models12 or pressure overload models such as aortic banding, genetically associated hypertension, or renovascular hypertension8–11 may also provide clues as to mechanisms involved in obesity-related systolic dysfunction. In these models, reduced contractile responsiveness to ß-adrenergic stimulation has been demonstrated, both in the presence13,14 and absence11 of decreases in ß-receptor density and/or affinity. Alterations in one or more components of the ß-receptor–Gs protein–adenylate cyclase–cAMP pathway have been implicated in the reduced contractile response.8,13,10,15 In a nonhypertensive model of cardiac hypertrophy induced by chronic ß-adrenergic stimulation, cAMP production and isoproterenol-stimulated inotropic responses have also been shown to be reduced.12 It has been suggested that a reduced responsiveness to isoproterenol in hypertrophy is due to reduced coronary reserve secondary to increased intercapillary and diffusion distances.9 While it is possible that this might be a factor under some circumstances, it clearly cannot be the only factor. Gende et al11 demonstrated that IPMs from hypertrophied hearts had reduced ß-adrenergic responsiveness compared with papillary muscles from nonhypertrophied hearts despite having identical CSA.
While both the pressure overload and obesity studies cited offer clues as to the mechanisms responsible for a reduced responsivenss to ß-adrenergic stimulation in obesity, there are clear differences in the results regarding the contributions of the various components of the ß-receptor–cAMP pathway to systolic dysfunction. These discrepancies may arise from the presence or absence of hypertension, hypertrophy, and/or obesity in the model, from differences in nonhemodynamic factors such as activation of the renin-angiotensin system, sodium intake, or catecholamine levels, as well as from the age, strain, or species of the animal model used. Conclusive answers regarding the impact of obesity on systolic dysfunction will need to employ a model which consistently mimics many of the cardiac abnormalities of human obesity.
In summary, our data demonstrate that obesity in the rabbit model is characterized by a decreased responsiveness to ß-adrenergic stimulation by isoproterenol. This was demonstrated by consistent decreases in pressure and tension development in the IH and IPM preparations throughout the range of isoproterenol concentrations used. This suggests that the systolic dysfunction of obesity may be related to a defect in a component of the ß-receptor pathway.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was supported in part by National Heart, Lung, and Blood Institute grant HL-51971 and a Grant-in-Aid from the American Heart Association (No. 93-1485). The authors thank Dr Bruce Van Vliet for reviewing a version of this manuscript.
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Footnotes |
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Reprint requests to Joan F. Carroll, PhD, Department of Physiology and Biophysics, University of Mississippi Medical Center, 2500 North State St, Jackson, MS 39216-4505.
Received May 16, 1997; first decision June 11, 1997; accepted July 17, 1997.
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