(Hypertension. 1995;26:78-82.)
© 1995 American Heart Association, Inc.
Articles |
Modulation of Left and Right Ventricular ß-Adrenergic Receptors From Spontaneously Hypertensive Rats With Left Ventricular Hypertrophy and Failure
From the Department of Veterans Affairs Medical Center; Department of Medicine, Boston University School of Medicine; Department of Medicine (Cardiovascular Division), Lemuel Shattuck Hospital; and Tufts University School of Medicine, Boston, Mass.
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Abstract |
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Abstract Inotropic responsiveness to ß-adrenergic stimulation is generally found to be depressed in cardiac hypertrophy and failure. To investigate whether inotropic responsiveness is associated with alterations in ß-adrenergic receptors in spontaneously hypertensive rats (SHR), we studied left ventricular myocardial contractile responses to isoproterenol and ß-adrenergic receptor density and affinity in age-matched rats (18 to 24 months), including SHR without heart failure, SHR with evidence of heart failure, and normotensive control Wistar-Kyoto rats (WKY). In the baseline state, papillary muscles from failing SHR demonstrated decreased isometric tension development and a reduction in maximal rate of tension development relative to normotensive WKY and compensated SHR. Compared with WKY, ß-adrenergic receptor density of the left ventricle was unchanged in nonfailing SHR and increased in failing SHR (P<.05 versus WKY and nonfailing SHR), and ß-adrenergic receptor affinity did not differ among groups. In the right ventricle, ß-adrenergic receptor density was decreased in failing SHR relative to WKY and nonfailing SHR, and ß-adrenergic receptor affinity was not different among groups. Muscle preparations did not exhibit a positive inotropic response to 10-8 to 10-5 mol/L isoproterenol or 6.3 µmol/L forskolin in either failing or nonfailing SHR, whereas a positive inotropic response to both drugs was observed in the normotensive WKY. The lusitropic response to isoproterenol and forskolin was intact and similar in both SHR groups and WKY. The findings suggest that in the SHR model of heart failure, impaired intrinsic left ventricular myocardial function and depressed inotropic responsiveness to ß-adrenergic stimulation are not associated with downregulation of the ß-adrenergic receptor. Impaired inotropic responses, with intact lusitropic responses, to both isoproterenol and forskolin are consistent with the concept that "downstream" events are responsible for impaired inotropy in response to ß-adrenergic stimulation in the SHR with chronic left ventricular hypertrophy and failure.
Key Words: receptors, adrenergic • ventricular hypertrophy, left • heart failure, congestive
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Introduction |
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Altered contractile function and decreased responsiveness to adrenergic stimulation are among the earliest reported changes with myocardial hypertrophy1 2 3 and failure.4 5 6 7 Some investigators have correlated the depressed inotropic responsiveness to ß-adrenergic stimulation of hypertrophied left ventricular (LV) myocardium with decreases in ß-adrenergic receptor density.8 Several abnormalities in the adenyl cyclase cascade have been documented in the spontaneously hypertensive rat (SHR) with stable hypertrophy9 10 11 12 and the pacing-induced model of heart failure in dogs.7 13 14 15 There are few studies of inotropic responsiveness in models of chronic pressure overload, in which stable hypertrophy persists throughout life and then progresses to failure. The SHR is a laboratory model of naturally developing hypertension and heart failure that appears similar in many respects to essential hypertension in humans.16 17 The purpose of the present study was to examine the relationship between ß-adrenergic receptor density, affinity, and inotropic responsiveness to ß-adrenergic stimulation of LV myocardium from the SHR. In addition, ß-adrenergic receptor characteristics of left and right ventricles from the same heart were examined. We evaluated ß-adrenergic receptor activation by isoproterenol and direct stimulation of adenyl cyclase by forskolin by determining inotropic and lusitropic responses in isolated LV papillary muscles from SHR with compensated hypertrophy and failure and age-matched normotensive Wistar-Kyoto rats (WKY).
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Methods |
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Animal Model
Seventeen male SHR and 10 WKY were purchased as retired breeders at 6 to 9 months of age (Taconic Farms, Germantown, NY) and were studied between 18 and 24 months of age. All rats were housed in the animal facility at the Boston VA Medical Center under identical conditions, maintained on a 12-hour light/dark cycle, and had free access to food and water until the time of study. All experiments were conducted in accordance with institutional guidelines and the Guide for the Care and Use of Laboratory Animals (US Department of Health and Human Services, NIH Publication 86-23). Peak systolic arterial pressure was measured with the indirect tail-cuff technique.18 Nine of the SHR demonstrated clinical and pathophysiological evidence consistent with heart failure (SHR-F). These features included tachypnea, pleural and/or pericardial effusions, left atrial thrombi, and right ventricular (RV) hypertrophy (defined as a ratio of RV weight to body weight >0.80 mg/g).19 20 21
Experimental Preparation
After rats were killed, hearts were quickly removed and placed
in oxygenated Krebs-Henseleit solution at 28°C as previously
described.19 21 LV papillary muscles were dissected free,
mounted between two spring clips, and placed vertically in a 100-mL
acrylic chamber containing Krebs-Henseleit solution. The solution was
bubbled with a gas mixture of 95% O2 and 5%
CO2 and equilibrated to pH 7.4 at 28°C. The muscle
preparation was stimulated at a rate of 12/minute by parallel platinum
electrodes delivering 5-millisecond pulses at voltages 10% above the
minimum necessary to produce a maximal mechanical response. The spring
clip on the upper end of the muscle was attached to a low-inertia DC
pen motor (G100-PD, General Scanning) and the lower clip to a
semiconductor strain-gauge tension transducer (DSC-3, Kistler-Morse). A
digital computer with an analog-to-digital interface allowed control of
either tension or length of the preparation. Tension and length data
were sampled at a rate of 1 kHz and stored on disk for later
analysis.
After removal of the papillary muscles, the left and right ventricles were dissected free. Tissues were gently blotted and weighed. Samples of left and right ventricle were then immediately frozen in liquid nitrogen. LV and RV wet weights were normalized by body weight (LV/BW and RV/BW).19 20
After mounting, muscles were equilibrated by isotonic contraction at a light load (on the order of 0.4 g/mm2) for 30 minutes. Muscles then were gradually stretched to the peak of the active tension versus length curve (Lmax, defined as the muscle length resulting in the peak active tension). Baseline isometric contraction parameters were recorded after a 30-minute equilibration period. Parameters of five twitches were determined and averaged; these were resting tension (grams per millimeter squared); active tension (grams per millimeter squared), defined as peak isometric tension minus resting tension; peak rate of isometric tension development (peak +dT/dt, grams per millimeter squared per second); time to peak tension (milliseconds), defined as the time from the onset of tension development to the time of peak tension; and time from peak tension to 50% relaxation (milliseconds).
Protocol
Concentration-response relationships to isoproterenol
(10-8 to 10-5 mol/L) were studied in 6 to 10
papillary muscles per group and to forskolin (6.3 µmol/L) in 5 to 7
additional papillary muscles per group. Isometric contraction and
relaxation parameters were obtained approximately 10 minutes after each
increment in isoproterenol concentration. Forskolin was added to the
bath at a single concentration of 6.3 µmol/L, and mechanical
parameters were measured at 2, 5, 10, 20, and 30 minutes.
Biochemical Determinations
ß-Adrenergic receptors were measured by a modification of the
method of Alexander et al22 as previously
described.23 Briefly, for determination of ß-adrenergic
receptor density and affinity, the frozen tissue samples were thawed
and homogenized in cold buffer (0.25 mol/L sucrose, 5 mmol/L Tris-HCl,
pH 7.4, and 1 mmol/L MgCl2) with two 15-second bursts on a
Polytron homogenizer (Brinkmann Instruments). The resultant
homogenate was then centrifuged at 50 000g for
10 minutes at 4°C. The pellet was resuspended in cold buffer (50
mmol/L Tris-HCl, pH 7.4, and 10 mmol/L MgCl2). A 100-µL
aliquot containing 0.2 to 0.4 mg protein and 10 to 400 pmol/L
(+)-125I-iodocyanopindolol to a total volume of 150 µL
was incubated for 60 minutes at 37°C. Incubations were terminated by
the addition of 2 mL buffer at 37°C followed by rapid vacuum
filtration through 24-mm GF/C glass fiber filters (Whatman). The
filters were then washed with 10 mL buffer at 37°C, dried, and
counted in a gamma counter.23 Nonspecific binding was
determined in the presence of 1 µmol/L (±)-propranolol.
Scatchard analysis was applied to linearize the data and gather
information about the total number of binding sites and their
affinities.24 Protein concentration in the membrane
fractions was measured by the method of Lowry et al.25
Statistical Analysis
Data from the SHR-F, SHR without heart failure (SHR-NF), and WKY
groups were compared using one-way ANOVA with replications. The
Newman-Keuls multiple-sample comparison test was used to localize
differences where appropriate.26 Data are expressed as
mean±SD or ±SEM where indicated.
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Results |
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Clinical and Pathological Data
Table 1 presents blood pressure, body weight, and chamber weight data. Nine SHR between 18 and 24 months of age were noted to have rapid, labored respirations. At the time of death, these rats were found to have left atrial thrombi, pleural and/or pericardial effusions, and RV hypertrophy (RV/BW, 1.15±0.18 mg/g; Table 1). In WKY and SHR-NF, RV/BW was 0.48±0.04 and 0.67±0.08 mg/g, respectively.
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Systolic pressure, measured immediately before study, was most elevated in SHR-NF and to a lesser extent in SHR-F compared with normotensive WKY (Table 1). LV weight was greater in SHR than WKY despite smaller body weights (P<.01). Increases in LV weight and LV/BW ratio indicated the presence of significant LV hypertrophy in both SHR groups (SHR-NF and SHR-F) relative to the WKY group (P<.05). However, RV hypertrophy was present in SHR-F compared with SHR-NF and WKY, as indicated by the RV/BW ratio (P<.05).
Baseline Isometric Contraction Parameters
Fig 1 presents mean data for isometric
contraction parameters for the LV papillary muscles from WKY, SHR-NF,
and SHR-F hearts. Active isometric tension and peak +dT/dt at
Lmax were depressed in SHR-F compared with both
WKY and SHR-NF (P<.01). Time to peak tension was prolonged
in both SHR-NF and SHR-F compared with WKY (P<.01). The
relaxation time index was reduced in SHR-F compared with both SHR-NF
and WKY (P<.01).
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ß-Adrenergic Receptors
Table 2 compares ß-adrenergic receptor
density (Bmax) and affinity
(Kd) of LV and RV myocardium from WKY, SHR-NF,
and SHR-F (mean±SEM). LV Bmax was significantly
increased in SHR-F versus both SHR-NF and WKY (P<.05).
However, no differences in ß-adrenergic receptor affinity were
present among WKY, SHR-NF, and SHR-F. In contrast to the left
ventricle, RV Bmax was decreased in SHR-F versus
both SHR-NF and WKY (P<.05); no difference in
Kd among groups was found.
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Effect of Isoproterenol and Forskolin
Fig 2 compares the effects of isoproterenol and
forskolin addition on +dT/dt of LV papillary muscles from WKY, SHR-NF,
and SHR-F hearts (mean±SEM). In WKY, isoproterenol and forskolin
resulted in a small but statistically significant increase in dT/dt. In
SHR-NF and SHR-F, no significant increase in dT/dt was in evidence with
either agent.
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), spontaneously hypertensive rats
without heart failure (SHR-NF, 
), and spontaneously hypertensive
rats with failure (SHR-F, 
). Values are mean±SEM.
*P<.05 vs baseline control (C) before drug
administration.Fig 3 compares time to 50% relaxation in WKY, SHR-NF, and SHR-F after isoproterenol and forskolin administration. Isoproterenol and forskolin administration reduced the time to 50% relaxation in a dose-dependent manner in all groups (P<.01); there was no significant effect of failure or rat strain on these responses.
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Discussion |
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The present findings demonstrate that in the compensated SHR, impaired inotropic responsiveness of LV myocardium to isoproterenol is observed, which is not associated with alterations in the density or affinity of ß-adrenergic receptors relative to control (WKY) myocardium. Moreover, with the development of heart failure, despite a reduction in baseline inotropic state and lack of inotropic responsiveness to isoproterenol, ß-adrenergic receptor density was found to increase in the left ventricle.
In previous studies with the SHR model,27 28 29 ß-adrenergic receptor density was found to be normal27 29 or decreased,28 with no change in affinity in relatively young rats (9 weeks old).29 The mechanism for the increase in LV ß-adrenergic receptors observed in the present study is unclear and may represent a finding specific to SHR-F myocardium. On the other hand, these findings are similar to those in the guinea pig with chronic heart failure.30 ß-Adrenergic receptor density was also found to be increased in the left ventricle of dogs with chronic hypertension.31 Other researchers have noted an increase in ß2-adrenergic receptors from the left ventricle in an experimental model of cardiac transplantation.32
It is interesting that experimental coronary artery occlusion in the dog has been shown to be associated with an increase in ß-adrenergic receptor density in ischemic tissue.33 The ischemia-induced increase in ß-adrenergic receptor density has been attributed to a cycling of intracellular receptors to the cell surface34 35 thought to be triggered by a reduction in tissue high-energy phosphate levels.36 37 In SHR myocardium, there is evidence for an increase in the oxygen cost of stress development20 during the transition to failure that may increase the susceptibility of SHR myocardium to ischemia. Thus, the presence of in vivo ischemia might explain the increase in ß-adrenergic receptor density observed in the left ventricle of SHR-F. The absence of an increase in ß-receptor density in the right ventricle may be consistent with the presence of ischemia in the left ventricle but not the right ventricle. Differences in ß-adrenergic receptor density between the two ventricles also suggest that circulating factors such as circulating catecholamines do not play a role. Therefore, local factors such as LV ischemia or tissue concentration of catecholamines may be important. It will be necessary to measure tissue catecholamines as well as markers of ischemia, such as tissue lactate concentration, to further elucidate the mechanism for the increase in Bmax in the failing left ventricle and the differences between chambers. Although adult rat ventricular myocytes have only ß1-receptors,38 it is possible that an increase in ß2-receptors of nonmyocytes (eg, fibroblasts), which appear to be increased in SHR-F left ventricle,39 could explain the increase in ß-receptor density observed in the failing left ventricle in the present study. However, it will be necessary to carry out studies of ß1- and ß2-receptor subtypes in these hypertrophied and failing hearts to further examine this possibility.
The fact that LV papillary muscles from hypertrophied and failing rats did not demonstrate a positive inotropic response to forskolin (6.3 µmol/L) would suggest that impaired inotropy does not involve the ß-adrenergic receptor because forskolin acts directly on adenyl cyclase distal to the ß-receptor complex. Moreover, the presence of an intact lusitropic response to both isoproterenol and forskolin and an undiminished intracellular calcium transient in response to isoproterenol21 suggest an intact response of the sarcoplasmic reticulum and the calcium channel to intracellular formation of cAMP. That is, there is no evidence for impaired cAMP generation by ß-adrenergic stimulation. Findings provide no evidence for downregulation of the ß-adrenergic receptor complex; in fact, the number of ß-adrenergic receptors appears to increase with the development of failure.
Cellular defects distal to cAMP production (ie, downstream defects) may be involved in the decreased inotropic responsiveness to ß-adrenergic stimulation. These abnormalities may involve a change in calcium handling or sensitivity of the contractile proteins. In studies of rested-state contractions and rest potentiation in papillary muscles of 6-month-old SHR, it was deduced that fractional calcium release from the sarcoplasmic reticulum was reduced in SHR relative to WKY.40 In studies of the rat myocardial infarction model, the peak of the calcium transient was found to increase in hypertrophied papillary muscles in response to isoproterenol but to a lesser extent than in normotensive controls.41 Therefore, diminished calcium release from the sarcoplasmic reticulum could contribute to the depressed inotropic responsiveness to isoproterenol. However, in a study of calcium transients in compensated and failing myocardium from SHR, a blunted inotropic response to isoproterenol was found despite an increase in the intracellular calcium transient which was equivalent to that seen in the WKY, suggesting that impaired calcium release is not the mechanism for depressed inotropy in response to catecholamine stimulation in the SHR.21 It is of interest that with an equivalent increase in [Ca2+]i with added isoproterenol or [Ca2+]o, inotropic responses were reduced or absent with isoproterenol and intact with calcium.21
Changes in myofilament sensitivity to calcium must also be considered to possibly play a role in the reduced inotropy with isoproterenol; however, in studies of skinned muscle preparations, no baseline differences in force-pCa2+ curves among WKY, SHR-NF, and SHR-F were found.42 It is possible, however, that baseline myofilament calcium responsiveness may be intact while myofilament calcium responsiveness is impaired in the presence of cAMP. This may be mediated by an effect of cAMP on V1 and V3 myosin. A shift in the myosin isozyme distribution toward predominantly V3 has been observed in hypertrophied and failing papillary muscles from the SHR.21 cAMP has been shown not to increase myosin ATPase activity in myocardium containing V3 myosin.43 Epinephrine has been shown to increase crossbridge cycling in V1 relative to V3 myosin.44 Indeed, the addition of dibutyryl cAMP, which exerts a positive inotropic effect without stimulation of the ß-receptor, has been shown to have a smaller inotropic response in isolated papillary muscles from aortic constricted Wistar rats with higher V3 levels relative to age-matched normotensive controls.45 A reduced inotropic response to dibutyryl cAMP has also been observed in hypertrophied noninfarcted papillary muscles from rats with large myocardial infarctions relative to control preparations.46 Therefore, the shift to V3 myosin generally observed in hypertrophied and failing SHR myocardium21 may result in an inability to increase crossbridge cycling rate and a blunted inotropic response to ß-adrenergic stimulation.
Conclusions
The present study demonstrates that inotropic responsiveness
to ß-adrenergic stimulation and forskolin administration is depressed
in chronically hypertrophied but compensated LV myocardium from the
aged SHR, whereas ß-adrenergic receptor density and affinity are
unaltered. In the failing heart, despite baseline depression of
contractile function and absent inotropic responses to isoproterenol,
ß-adrenergic receptor density is increased and RV ß-adrenergic
receptor density is decreased, while receptor affinity remains
unaltered. Inotropy is impaired despite intact lusitropic responses
with both isoproterenol and forskolin, suggesting intact intracellular
cAMP formation. The results suggest that depressed contractile function
and impaired inotropic responsiveness in SHR-F myocardium cannot be
accounted for by ß-adrenergic receptor downregulation. Impaired
inotropy to ß-adrenergic stimulation in chronically hypertrophied and
failing SHR myocardium appears to involve a "downstream"
mechanism.
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Acknowledgments |
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This work was supported by Medical Research Funds from the Veterans Administration. This work was done during the tenure of a Clinician-Scientist Award from the American Heart Association (C.H. Conrad).
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Footnotes |
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Reprint requests to Wesley W. Brooks, DSc, Research Service (151), Boston VA Medical Center, 150 S Huntington Ave, Boston, MA 02130.
Received October 26, 1994; first decision December 16, 1994; accepted March 23, 1995.
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W. W. Brooks, O. H. L. Bing, M. O. Boluyt, A. Malhotra, J. P. Morgan, N. Satoh, W. S. Colucci, and C. H. Conrad Altered Inotropic Responsiveness and Gene Expression of Hypertrophied Myocardium With Captopril Hypertension, June 1, 2000; 35(6): 1203 - 1209. [Abstract] [Full Text] [PDF]
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J. F. Carroll, A. E. Jones, R. L. Hester, G. A. Reinhart, K. Cockrell, and H. L. Mizelle Reduced Cardiac Contractile Responsiveness to Isoproterenol in Obese Rabbits Hypertension, December 1, 1997; 30(6): 1376 - 1381. [Abstract] [Full Text]
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