(Hypertension. 1996;27:1267-1272.)
© 1996 American Heart Association, Inc.
Articles |
Renin-Angiotensin System and Cell Communication in the Failing Heart
From the Departments of Pharmacology and Anesthesiology, School of Medicine, University of Puerto Rico, San Juan.
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Abstract |
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Abstract The influence of heart failure on the process of cell communication was investigated in cell pairs isolated from the ventricle of cardiomyopathic hamsters (11 months old) and the results compared with age-matched normal hamsters. The gap junctional conductance (gj) was measured with two voltage-clamp amplifiers. The results showed two major populations of cell pairs with respect to gj values: one with very low values (0.8 to 2.5 nS) and the other with higher values (7 to 35 nS). In normal hamsters, the most frequent gj values were in the range of 40 to 100 nS. Angiotensin II (Ang II, 1 µg/mL) caused cell uncoupling in myopathic myocytes with low gj but reduced gj by 53±6.6% (±SE) in cell pairs with higher gj values (7 to 35 nS). The effect of Ang II on gj of myopathic cell pairs was suppressed by losartan (10-7 mol/L). In cardiomyopathic cell pairs with low gj (0.8 to 2.5 nS), enalapril (1 µg/mL) caused an appreciable increase in gj (219±20.3%), whereas in cell pairs with higher gj (7 to 35 nS), the gj increment was smaller (80±10.8%) but still larger than that seen in controls (33±5.4%). Intracellular dialysis of Ang I (10-8 mol/L) abolished cell communication in myopathic cell pairs with low gj (0.8 to 2.5 nS) and reduced gj by 66±1.7% in the other pairs (7 to 35 nS). The effect of Ang I on gj was greatly reduced by enalaprilat (10-9 mol/L) added to the cytosol. Dialysis of Ang II (10-8 mol/L) into the myopathic cell reduced gj by 48±4.2%, an effect abolished by losartan (10-8 mol/L). The results indicate that the decline in gj seen in the ventricle of cardiomyopathic hamsters is in part due to activation of the cardiac renin-angiotensin system.
Key Words: cell communication • heart failure, congestive • angiotensin II • enalapril
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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It is well known that a strain of hamsters, the Syrian TO-2 CM hamster (Biobreeders, Fitchburg, Mass), is characterized by several hereditary changes, including ventricular hypertrophy, which precedes ventricular dilation and death by congestive heart failure.1
There is increasing evidence that a local RAS exists in the heart.2 Indeed, renin and angiotensinogen genes are coexpressed in cardiac muscle3 4 5 6 7 ; Ang I is converted to Ang II in isolated and perfused rat heart8 ; and Ang II receptors have been identified in cultured heart myocytes.9 10 Recent studies by Dostal et al11 showed the presence of Ang I, Ang II, and ACE inside isolated heart cells. Studies by Schunkert et al12 in rats with abdominal aortic constriction showed that ACE activity is increased in the left ventricle and that the conversion rate of Ang I to Ang II is significantly enhanced in vitro.
In patients with congestive heart failure as well as in some animal models of heart failure,13 the activities of renin and ACE are not increased during the chronic compensated phase. However, evidence exists that cardiac RAS activity is enhanced in the compensated phase of heart failure when plasma RAS activity is normal.13 Hirsch et al14 described increased ACE activity in the rat model of heart failure as well as augmented expression of the gene coding for ACE in cardiac muscle (see also Reference 1515 ). As previously suggested,16 the induction of cardiac RAS activity during heart failure might have some beneficial effects by promoting local inotropic actions.
Hypertrophied myocytes show several abnormalities of ion pumps, calcium reuptake by the sarcoplasmic reticulum, hormone receptors, etc.17 In CM hamsters, a calcium overload of the heart cells has been considered an important etiologic factor. Indeed, calcium uptake is increased,18 19 and the duration of the action potential is augmented probably because of increased calcium conductance.20 As discussed by Weismand and Weinfeldt,21 the CM hamster represents an important model for cardiac myopathy and hypertrophy in humans.
It is known that hereditary cardiomyopathy is characterized by changes similar to a calcium-determined necrotic process, showing at the ultrastructural level myocytolysis with typical fibrillar disarray.22 Cardiac myocytes are communicated by hydrophilic channels (gap junctions) that permit the electrical synchronization and flow of chemical messages between cardiac cells.23 Previous studies24 indicated that the RAS plays an important role in the modulation of cell-to-cell communication in normal rat heart. Ang II reduces the gj in isolated cell pairs, whereas enalapril, an ACE inhibitor, increases gj appreciably.
No information is available about whether the process of cardiac failure alters gj or its regulation. In the present work, the role of the RAS on gj control was investigated in the ventricle of CM hamsters.
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Male Syrian TO-2 CM hamsters (11 months old) and age-matched healthy male F1B control hamsters were used. Both control and CM rats were kept at the animal house on a normal laboratory animal diet and tap water ad libitum.
Cell pairs were obtained by enzymatic dispersion of hamster ventricle following the method of Powell and Twist25 and Tanigushi et al.26 The heart was removed and immediately perfused with normal Krebs' solution containing (mmol/L) NaCl 136.5, KCl 5.4, CaCl2 1.8, MgCl2 0.53, NaH2PO4 0.3, NaHCO3 11.9, glucose 5.5, and HEPES 5, with pH adjusted to 7.3. After 20 minutes, a calcium-free solution containing 0.4% collagenase (Worthington Biochemical Corp) was recirculated through the heart for 1 hour. The collagenase solution was washed out with 100 mL recovery solution containing (mmol/L) taurine 10, oxalic acid 10, glutamic acid 70, KCl 25, KH2PO4 10, glucose 11, and EGTA 0.5, with pH adjusted to 7.4. All solutions were oxygenated with 100% O2.
Ventricles were minced (1 to 2 mm thick slices), and the resulting solution was agitated gently with a Pasteur pipette. The suspension was filtered through a nylon gauze and the filtrate centrifuged 4 minutes at 22g. The cell pellets were then resuspended in normal Krebs' solution. All experiments were conducted at 36°C.
Suction pipettes were pulled from microhematocrit tubing (Clark
Electromedical Instruments) by means of a controlled puller
(Narishige), and their tips were polished with a microforge
(Narishige). The pipettes, which were prepared immediately before the
experiment, were filled with the following solution (mmol/L): KCl 125,
NaCl 10, MgCl2 3, EGTA 5, and HEPES 10, with pH adjusted to
7.3. The resistance of the filled pipettes (about 2 µm in diameter)
varied from 0.5 to 1.5 M
.
Drugs
Ang I and II were from Sigma Chemical Co; enalapril was from
Merck Sharp & Dohme; and losartan was provided by DuPont
Laboratories.
Experimental Procedure
All experiments were performed in a small chamber mounted on the
stage of an inverted phase-contrast microscope (Diaphot, Nikon).
The junctional resistance was determined in cell pairs by two separated
voltage-clamp circuits. Gigaohm sealing was achieved in each cell,
and then the surface cell membrane of both cells was broken by
application of a stronger suction (-30 to -65 cm
H2O) and a whole-cell clamp configuration was produced.
Each pipette was connected to a separated voltage-clamp amplifier
(Dagan Corp) that made possible control of the nonjunctional membrane
potential in each cell as well as the voltage gradient across the
intercellular junction.
The experimental procedure consisted of holding the membrane potential of both cells at -40 mV. Cell 1 was then pulsed to 0 mV while the membrane potential of cell 2 was unchanged. A voltage was created across the junctional membrane (V1), and a compensating current of opposite polarity recorded from pipette 2 (I2) represented the current flowing through the gap junction. As I2=V1/rj, the junctional resistance (rj) was easily estimated.23 Data acquisition and command potentials were controlled with a software program (PCLAMP, Axon Instruments).
Series resistances (Rs1 and Rs2) located
between the input terminal of the head-stage of the amplifiers and
the preparation were compensated electronically before the experiment
and checked periodically during the experiment. When necessary, gj was
corrected, with the changes in series resistance taken into
consideration. For this, the following equation was used:
 | (1) |
Voltage and current signals were displayed simultaneously on an oscilloscope (Tektronix 5113) and chart recorder (Gould 2400).
Statistical Analysis
Data are mean±SE. Statistical significance was determined with
Student's t test and defined as a value of
P<.05.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Measurements of gj performed on cell pairs isolated from normal hamsters indicated values ranging from 8 to 200 nS, with most in the range of 40 to 100 nS (Fig 1
, top). These gj values were
much higher (P<.05) than those found in the ventricle of CM
hamsters, in which two clearly distinct groups of cells could be
identified: one with very low gj values (0.8 to 2.5 nS) and the other
with higher gj values (7 to 35 nS) (Fig 1, bottom).
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These two major populations of CM myocytes were characterized not only by their different gj values but also by some morphological characteristics. For instance, the group of cells with low gj values (0.8 to 2.5 nS) presented clear alterations in cross-striations, as previously described (see Reference 2727 ), and the cell pairs with higher gj values (7 to 35 nS) showed an increased cell length (see References 1, 27, and 281 27 28 ). No such morphological differences were found among the myocytes of normal hamsters.
For investigation of the role of the RAS on the control of cell communication in the ventricle of CM hamsters, gj was measured before and after administration of Ang II or enalapril to the bath. In most of these experiments, the gj values remained stable over periods of 20 to 30 minutes; in some experiments, contractures or changes in sealing resistance were found, and the experiment was discarded.
As shown in Fig 2, the effect of the peptide varied with
the control value of gj. In cell pairs showing low gj values (0.8 to
2.5 nS), Ang II (1 µg/mL) caused cell uncoupling within 2 minutes,
whereas in CM cell pairs with higher gj values (7 to 35 nS), the
average decline in gj elicited by Ang II was 53±6.6% (n=18) within 6
to 8 minutes (Fig 2). The effect of Ang II on this last group of cell
pairs was not statistically different from that seen in normal hamsters
(60±6.75%, n=14, P>.05) (Fig 2). The series resistance
measured at the beginning of the experiments was compensated
electronically, and gj values were corrected in two experiments for
changes in series resistance by use of Equation 1
above.
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The possible influence of changes in surface cell membrane resistance
on the interpretation of the results was also investigated. For this,
the tm was measured (Fig 3). Measurements of tm were
made in seven cells before and 7 minutes after administration of Ang II
(1 µg/mL) to the bath. The results indicated no significant change in
tm after Ang II administration (P>.05). The average value
of tm of CM cells at control conditions (20±4 milliseconds, n=8) was
not different from the values found after 7 minutes of administration
of Ang II (1 µg/mL) (17.8±3.9 milliseconds, n=7,
P>.05).
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For investigation of whether the effect of the peptide on gj was
related to the activation of type 1 (AT1) Ang II receptors,
cell pairs were exposed to Ang II (1 µg/mL), and then
losartan (10-7 mol/L) was added
to the bath containing Ang II. As shown in Fig 4,
losartan completely reversed the effect of the peptide.
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Further studies on the influence of the RAS on cell communication were made with enalapril, an ACE inhibitor. It was found that the effect of enalapril on gj in CM hamsters varied with the control value of gj. In cell pairs showing low gj values (0.8 to 2.5 nS), the ACE inhibitor increased gj appreciably (219±20.3%, n=18). The maximal effect of enalapril was seen within about 4 minutes after its administration to the bath, a time probably needed for its conversion to enalaprilat.24 However, in other cell pairs from the same CM preparation but showing higher gj values (7 to 35 nS), the increment of gj caused by the ACE inhibitor was smaller (80±10.8%, n=14). This effect of enalapril was greater than that seen in normal hamsters, in which an increment of gj by 33±5.4% (n=16) was seen. The change in cell coupling of CM cells caused by the ACE inhibitor was not influenced by variations in the surface cell membrane resistance because the tm values recorded at control conditions (18.9±3.8 milliseconds, n=7) and after 4 minutes of drug administration (20.2±4.6 milliseconds, n=5) were not different (P>.05). In addition, changes in series resistance were rare, and when they occurred (in one experiment), the gj values were corrected accordingly (see "Methods").
Is an Intracrine Cardiac RAS Involved in the Control of Cell
Coupling in the Failing Heart?
The question of whether the activation of a cardiac RAS in the
failing heart is partly responsible for the
electrophysiological abnormalities seen in
this condition merits serious consideration (see also Reference 2929 ).
For investigation of this problem, Ang I
(10-8 mol/L) was added to the pipette
solution, and the peptide was dialyzed into CM cell pairs. During these
experiments, no swelling or contraction of the cells was found. In a
few experiments, a slight contracture developed, and the experiment was
discarded. The results indicate that the effect of Ang I varies in
magnitude with the control value of gj. In cell pairs with low gj
values (0.8 to 2.5 nS), the effect of the peptide was quite strong and
cell uncoupling was seen within 2 to 4 minutes (Fig 5, left and
right), whereas in the group of cell pairs with greater
gj values (7 to 35 nS), the dialysis of the same amount of Ang I
(10-8 mol/L) caused a decrease in gj of
66±1.7% (n=12) within 9 minutes (Fig 5, right). The effect of the
peptide on this second group of CM cells was slightly greater than that
seen in normal hamster cells, in which gj was reduced by 50±3.2%
(n=5, P<.05). In these experiments, the possible influence
of variations in dialysis rate was minimized by performing all the
experiments with pipettes with the same tip diameter.
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Although in both normal and CM hamsters the effect of intracellular
dialysis of Ang I on gj was reduced by previous administration of
enalaprilat (10-9 mol/L) to the cytosol
(Fig 6, left), the effect of enalaprilat was greater in
CM cell pairs. In seven CM cell pairs in which enalaprilat
(10-9 mol/L) was previously dialyzed into
the cell for 4 minutes, the addition of Ang I
(10-8 mol/L) to the cytosol reduced gj by
only 10% to 15% in four experiments and by 8% to 10% in the other
three cell pairs (Fig 6, left); in normal cell pairs, enalaprilat
(10-9 mol/L) reduced the effect of Ang I
(10-8 mol/L) by 63±4.3% (n=8). In CM
cell pairs, the intracellular dialysis of Ang II
(10-8 mol/L) also caused a decline in gj
of 48±4.2% (n=8) within 2.5 minutes (Fig 6, right); in normal
hamsters, the reduction of gj was 40±5.6% (n=9) within 7 minutes.
Moreover, experiments made on six cell pairs from CM hamsters (gj=0.8
to 2.5 nS) indicated that losartan
(10-8 mol/L) administered to the cytosol
for 3 minutes before the introduction of Ang II
(10-8 mol/L) to the pipette solution
suppressed the effect of the peptide on gj (Fig 6, right). Similar
results were obtained in the controls (not shown).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The present results indicate that in the ventricle of the CM hamster, there are two major cell populations: one with low gj probably produced by the pathological process, and a second group characterized by higher gj values. The impairment in cell coupling is quite appreciable, particularly in some cell pairs in which extremely low gj values (0.8 to 2.5 nS) were found. Previous studies by Weingart and Maurer30 in rat ventricular cells indicated that these gj values are incompatible with the propagation of the action potential. This idea is supported by the finding that in some areas of the left ventricular wall, impulse propagation is greatly impaired.29 The low gj might be related to different factors: (1) A high cytosolic calcium concentration (477±10 nmol/L) was found in some areas of the CM hamster heart compared with controls (260±15 nmol/L).27 It is known that an increase in free calcium concentration decreases cell communication.31 The high intracellular free calcium concentration in CM myocytes might be related to alterations in calcium influx or efflux through the sarcolemma and to an impairment in calcium uptake by the sarcoplasmic reticulum. (2) Morphological abnormalities such as significant increases in cell length and width of the cardiocytes were described27 28 and indicate a drastic geometric alteration in the organization of the ventricular muscle, with possible impairment of intercellular communication. (3) Other alternatives include a change in the number or structure of gap junctions in the CM ventricle.
The evidence that ACE activity is enhanced in the myocardium of the CM hamster15 and the present observations that enalapril has an appreciable effect on increasing gj (219%) in the group of CM cells with low gj (compared with 33% in controls) seem to indicate that at least part of the impairment of cell coupling is related to the activation of the cardiac RAS. Although the mechanism by which enalapril increases gj remains to be determined, it is reasonable to think that the ACE inhibitor can enhance cell communication by suppressing Ang II synthesis inside the heart cells. Further support for this view is the great effect of intracellular dialysis of Ang I on gj in CM ventricular cells and its appreciable reduction by previous treatment with enalaprilat. Indeed, the addition of Ang I to the cytosol of cells showing a stronger ACE activity might generate more Ang II, with a consequent decline in gj.32 The fact that no complete suppression of the effect of Ang I was accomplished with enalaprilat is probably related to other pathways of conversion of Ang I to Ang II.33 Of particular interest was the observation that the effect of intracellular administration of Ang II in CM cell pairs was blocked by losartan, an AT1 receptor blocking agent. Because a similar finding was described in isolated cell pairs of rat ventricle,32 it is conceivable that there is a cytosolic "receptor" for Ang II in the heart cell that is similar to AT1 and that its activation is essential for the effect of the peptide on gj. The meaning of this observation, particularly in CM heart cells, is not known. Since Ang II increases the inward calcium current in heart cells,34 the question remains as to whether the excessive buildup of calcium in CM myocytes contributes to the enhanced effect of Ang II in some cell pairs. It is important to emphasize, however, that our present results preclude the influence of changes in intracellular free calcium or intracellular pH on the effect of Ang II on gj because of the concentrations of EGTA (5 mmol/L) or HEPES (10 mmol/L) used in the internal solution.
The improvement of cell-to-cell communication caused by enalapril is an important factor in the avoidance of slow conduction and reentry and consequently cardiac arrhythmias.35 Recent observations performed on isolated ventricular muscle of CM animals indicated that enalapril increases conduction velocity by 36% within 20 minutes.29 The reincorporation of these myocytes into the community of ventricular muscle elicited by enalapril might represent a major event in the improvement of heart function, particularly in the prevention of cardiac arrhythmias.36
Of particular interest is the possible role of an intracrine and paracrine RAS in the failing heart. For instance, an increased synthesis of Ang II inside the myocytes during the process of cardiac failure might be followed by its displacement to the nucleus with consequent increases in protein synthesis or its release into the extracellular space with activation of Ang II receptors located at the sarcolemma of neighboring cells. These events might result in hypertrophy and a decrease in electrical coupling of these cells.13 16 32 37 38 Enalapril would revert these events by suppressing the intracellular synthesis of Ang II.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was supported by grants from Merck Sharp & Dohme Laboratories, the American Heart Association, and the National Institutes of Health (HL-34148, RR03051, and 532943). I thank María González for technical help and Lagnny Jacobo for the preparation of this manuscript.
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Footnotes |
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Reprint requests to Dr Walmor C. De Mello, Department of Pharmacology, School of Medicine, University of Puerto Rico, PO Box 365067, San Juan, Puerto Rico 00936-5067.
Received December 1, 1995; first decision December 29, 1995; accepted February 7, 1996.
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W. H Litchenberg, L. W Norman, A. K Holwell, K. L Martin, K. W Hewett, and R. G Gourdie The rate and anisotropy of impulse propagation in the postnatal terminal crest are correlated with remodeling of Cx43 gap junction pattern Cardiovasc Res, January 14, 2000; 45(2): 379 - 387. [Abstract] [Full Text] [PDF]
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W. C. De Mello Gap Junctional Conductance in Cardiomyopathic Hamsters : The Role of c-Src Circ. Res., October 15, 1999; 85(8): 661 - 662. [Full Text] [PDF]
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T. Toyofuku, M. Yabuki, K. Otsu, T. Kuzuya, M. Tada, and M. Hori Functional Role of c-Src in Gap Junctions of the Cardiomyopathic Heart Circ. Res., October 15, 1999; 85(8): 672 - 681. [Abstract] [Full Text] [PDF]
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F. Gustafsson and N.-H. Holstein-Rathlou Angiotensin II modulates conducted vasoconstriction to norepinephrine and local electrical stimulation in rat mesenteric arterioles Cardiovasc Res, October 1, 1999; 44(1): 176 - 184. [Abstract] [Full Text] [PDF]
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 J. J. Lynch Jr., G. L. Stump, A. A. Wallace, C. A. Painter, J. M. Thomas, S. E. Kusma, R. J. Gould, and W. Grossman EXP3174, the AII antagonist human metabolite of losartan, but not losartan nor the angiotensin-converting enzyme inhibitor captopril, prevents the development of lethal ischemic ventricular arrhythmias in a canine model of recent myocardial infarction J. Am. Coll. Cardiol., September 1, 1999; 34(3): 876 - 884. [Abstract] [Full Text] [PDF]
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W. C. De Mello Intracellular Angiotensin II Regulates the Inward Calcium Current in Cardiac Myocytes Hypertension, December 1, 1998; 32(6): 976 - 982. [Abstract] [Full Text] [PDF]
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