(Hypertension. 1998;32:976-982.)
© 1998 American Heart Association, Inc.
Scientific Contributions |
Intracellular Angiotensin II Regulates the Inward Calcium Current in Cardiac Myocytes
From the Departments of Pharmacology and Anesthesiology, School of Medicine, University of Puerto Rico, San Juan.
Correspondence to Walmor C. De Mello, Professor and Chairman, Department of Pharmacology, School of Medicine, PO Box 5067, Medical Sciences Campus, UPR, San Juan, PR 00936-5067.
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Abstract |
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Abstract—The influence of intracellular administration of angiotensin II (Ang II) on the inward calcium current (ICa) was investigated in single myocytes isolated from adult rat ventricle. Comparative studies were also made in ventricular cells of Golden hamsters. The ICa was measured in single cells using the whole-cell voltage clamp configuration. The results indicated that Ang II (10-8 mmol/L) dialyzed into the rat myocytes reduced the peak ICa by 35±5.5% (n=20; P<0.05). Losartan (10-7 mmol/L) added to the bath did not suppress the effects of Ang II, indicating that the peptide is acting intracellularly. Moreover, the intracellular dialysis of losartan (10-6 mmol/L) or [Sar1Val5Ala8] Ang II (10-6 mmol/L) did not change the effect of Ang II. Stimulation of ICa by exogenous cAMP or inhibition of protein kinase C did not alter the effect of Ang II on ICa. Zaprinast (100 µmol/L), an inhibitor of cGMP phosphodiesterase, when added to the bath solution increased appreciably the effect of Ang II on ICa (P<0.05). In ventricular myocytes of Golden hamsters, in which Ang II has a positive inotropic action, the intracellular administration of Ang II (10-8 mmol/L) increased ICa by 36±2.4% (n=20; P>0.05). The effect of the peptide was not altered by the intracellular administration of losartan (10-6 mmol/L), by [Sar1Val5Ala8] Ang II (10-6 mmol/L), or by the inhibitor of protein kinase A. The inhibition of protein kinase C, however, prevented the effect of Ang II ICa in the hamster myocytes. The results particularly suggest that the activation of the cardiac renin-angiotensin system regulates ICa and myocardial contractility, an effect that varies with the species.
Key Words: angiotensin II, intracellular • calcium current • myocytes
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Introduction |
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There is increasing evidence that there is a local renin-angiotensin system in the heart.1 Indeed, genes of angiotensinogen and renin are coexpressed in isolated cardiac myocytes.2 3 4 5 Angiotensin I (Ang I), angiotensin II (Ang II), and the angiotensin-converting enzyme have been found around the nucleus of heart cells in culture,6 and Ang I is converted to Ang II in the isolated and perfused rat heart.7
In the last 5 years evidence has been accumulated that the plasma and the cardiac renin-angiotensin system contribute to the regulation of intercellular communication in heart muscle. For example, Ang II reduces whereas enalapril, an angiotensin-converting enzyme inhibitor, increases the gap junction conductance not only in cells of the adult rat ventricle8 but also in cardiomyopathic hamsters.9 Further studies showed that the intracellular administration of Ang I decreases cell communication, an effect suppressed by intracellular dialysis of enalaprilat,10 supporting the view that the decline in junctional conductance is related to the conversion of Ang I to Ang II inside the cardiac myocyte.
No information is available on whether the synthesis of Ang II inside the heart cells regulates other important membrane functions such as the inward calcium current (ICa). This is particularly important because Ang II has a positive inotropic action in different preparations,11 whereas in the rat heart the peptide reduces the action potential duration12 and has a negative inotropic action.13 Previous observations by Allen et al14 indicated that Ang II when added to the bath increases the L-type calcium current in cultured neonatal heart cells. Recently, Habuchi et al15 demonstrated that in the sinoatrial node of the rabbit, Ang II reduces ICa when added to the extracellular fluid.
In the present study, the possible effect of intracellular administration of Ang II on ICa was investigated in myocytes isolated from adult rat ventricle and also from the ventricle of Golden hamsters.
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Methods |
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Materials
Adult rats (Sprague-Dawley, Indianapolis, Ind) weighing 125 to 150 g were used. In some experiments adult Golden hamsters (Biobreeders, Watertown, Mass) of similar weight were used. The animals were kept in air-conditioned facilities on a normal laboratory animal diet and given tap water ad libitum. The animals were anesthetized with sodium pentobarbital (50 mg/kg IP), and the heart was removed with the animals under deep anesthesia.
Cells were obtained by enzymatic dispersion of the ventricle according to the methods of Powell and Twist16 and Tanigushi et al.17
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 collagenase (0.4%; Worthington Biochemical Corp) was recirculated through the heart for 1 hour. The collagenase solution was washed out with 100 mL of 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.
The ventricles were minced (1- to 2-mm-thick slices), and the resultant solution was agitated gently with a Pasteur pipette. The suspension was filtered through nylon gauze, and the filtrate was centrifuged for 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): potassium
aspartate 120, NaCl 10, MgCl2 3, EGTA 10,
tetraethylammonium chloride 20,
Na2ATP 5, and HEPES 5, with pH adjusted to 7.3.
In some experiments, cesium aspartate replaced potassium aspartate. The
resistance of the pipettes varied from 0.9 to 1.5 M
. Pipettes with
very similar resistances were used in the experiments in which Ang II
was dialyzed into the cells.
Drugs
Dibutyryl-cAMP, forskolin, the pseudosubstrate of protein
kinase C, staurosporine, Ang II,
[Sar1Val5Ala8]
Ang II, the inhibitor of protein kinase A, phorbol
12-myristate 13-acetate, and zaprinast were from Sigma Chemical
Co. PD 123,319 was from Fluka Laboratories, and losartan was a
gift from DuPont Merck (West Point, Pa).
Experimental Procedures
All experiments were performed in a small chamber mounted on the
stage of an inverted phase-contrast microscope (Diaphot; Nikon). A
video system (Diaphot; Nikon) made it possible to inspect the cells and
the pipettes throughout the experiments. The electrical measurements
were carried out in single ventricular myocytes using the
whole-cell configuration. Series resistance originated from the tips of
the micropipettes was compensated for electronically at the beginning
of the experiment. Current/voltage curves were obtained by applying
voltage steps in 8-mV increments (-40 to +36 mV) starting from a
holding potential of -40 mV. All current recordings were
obtained after ICa had been stabilized, which was
usually achieved approximately 5 minutes after the rupture of the cell
membrane. Data from experiments in which the stabilization was not
achieved within this time were discarded.
Data Analysis
The output of the preamplifier was filtered at 2 kHz, and data
acquisition and command potentials were controlled with PCLAMP software
(Axon Instruments). Voltage and current were displayed
simultaneously on an oscilloscope (Tektronix 5113;
Tektronix).
Statistical Analysis
Numerical data were expressed as mean±SEM. Student's
t test was used to estimate statistical significance,
defined as P<0.05.
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Results |
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To investigate the possible influence of intracellular Ang II on ICa in rat myocytes, the peptide was added to the pipette solution and then dialyzed into the cytosol using an electrode similar to that described by Irisawa and Kokubun.18 Figure 1
shows that Ang II at a concentration of
10-8 mmol/L reduced the peak
ICa generated by a test pulse from -40 to 0 mV
by 35±5.5% (n=20; P<0.05). The significance was estimated
by comparing values of ICa before and after the
administration of Ang II. The reaction to the peptide, which was dose
dependent (Figure 2), began within
seconds but reached a maximal and steady value 4 minutes later (Figure 1). Figure 1 (bottom) shows the effect of intracellular administration
of Ang II on the current-voltage relationship for
Ca2+ current (ICa). The
peptide reduced ICa for different values of
transmembrane voltage.
[Sar1Val5Ala8]
Ang II (10-6 mmol/L), an Ang II
antagonist, when dialyzed into the cell (n=7) had no effect
on ICa and did not influence the effect of Ang II
on ICa (P>0.05; not shown). Moreover,
the dialysis into the cell of PD 123,319
(10-6 mmol/L), an angiotensin
type 2 (AT2) receptor blocking agent, performed
in 6 myocytes did not alter the effect of the peptide on
ICa (n=6; P>0.05; not shown). Because
there is evidence that Ang II when added to the bath reduces
ICa in cardiac pacemaker
cells,15 it is reasonable to think that the
peptide dialyzed into the cytosol might leave the cell and interact
with AT1 receptors located at the surface cell
membrane.
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To investigate this possibility, losartan, a specific Ang II
AT1 receptor antagonist
(10-7 mmol/L), was added to the perfusion
fluid, and after 5 minutes of equilibration with this compound, Ang II
(10-8 mmol/L) was dialyzed into the cell
while the ICa was monitored. The results
indicated no influence of losartan on the effect of Ang II on
ICa (n=8; P>0.05; not shown). In 7
experiments, losartan (10-6 mmol/L)
was added to the pipette solution, the compound was dialyzed into the
cell for 4 minutes, and then Ang II (10-8
mmol/L) was administered intracellularly. The results indicated no
influence of losartan on the effect of Ang II on
ICa (P>0.05; Figure 2
). In other
experiments, the peptide (10-7 mmol/L) was
administered to the bath solution and its influence on
ICa was investigated. As seen in Figure 2, Ang II
caused a reduction in the ICa by 20±3.3%
(n=14), an effect that was abolished by losartan
(10-8 mmol/L; not shown).
These observations led to the idea that the effect of intracellular administration of Ang II on ICa is related to some intracellular action of the peptide.
Biochemical studies have shown previously that Ang II when added
extracellularly inhibits cAMP production in rat
myocardium (see Reference 1919 ). To investigate whether the
decline in ICa described above is related to the
inhibition of cAMP production, isolated cells were exposed to
dibutyryl-cAMP (10-5 mmol/L) for several
minutes, and as soon as the increase in
ICa elicited by dibutyryl-cAMP reached a maximal
and steady value, the peptide (10-8 mmol/L)
was dialyzed into the cell. Figure 3
demonstrates that despite the stimulation of ICa
by exogenous cAMP, the effect of Ang II on ICa
was not changed (P>0.05). In other experiments in which the
cells had been previously exposed to Krebs' solution containing
forskolin (10-6 mmol/L), an
activator of adenyl cyclase, the effect of internal
administration of Ang II (10-8 mmol/L) on
ICa was similar to that seen in the control cells
(P>0.05; not shown).
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The possibility that Ang II reduces ICa by
activating protein kinase C (PKC) was also investigated. The
pseudosubstrate of the kinase, an inhibitor of PKC (20
µg/mL), was dialyzed into the cell for 4 minutes before the addition
of Ang II (10-8 mmol/L) to the internal
solution. The results from 8 experiments indicated that the
pseudosubstrate of PKC did not alter the effect of Ang II on
ICa (Figure 3). Staurosporine
(50 µmol/L), a nonpeptide inhibitor of PKC, dialyzed
into the cell for 4 minutes was also unable to suppress the effect of
intracellular Ang II on ICa. Indeed, in 6
experiments with staurosporine, Ang II elicited a
decline of ICa of 34.2±4.9%, an effect not
significantly different from control (P>0.05). The
possibility that the activation of PKC per se influences
ICa was investigated by adding phorbol
12-myristate 13-acetate (300 nmol/L) to the bath and monitoring
ICa. Results from 4 experiments indicate a small
increase of ICa (13.8±3.9%; P<0.05)
at the end of 4 or 5 minutes (not shown; see References 14 and
2014 20 ).
Because evidence is available that cGMP protein kinase is involved in
the regulation of
ICa,21–23 the possibility
that the effect of Ang II on ICa is related to
the activation of this kinase was investigated. For this, myocytes were
perfused with Krebs' solution containing zaprinast (100
µmol/L), a selective inhibitor of cGMP phosphodiesterase,
and after 4 minutes of equilibration with this compound, Ang II
(10-8 mmol/L) was dialyzed into the cell.
As shown in Figure 4, the effect of Ang
II on ICa was significantly increased by
zaprinast (P<0.05), whereas zaprinast by itself at this
concentration did not change ICa
(P>0.05).
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The question of whether intracellular Ang II increases ICa in other species in which the peptide has a positive inotropic action was also investigated. For this, myocytes isolated from the ventricle of normal adult hamsters were used. Previous studies in these animals have indicated that Ang II added to the bath increases the strength of the heart beat (W.C. De M., unpublished observations, 1997).
Comparative experiments performed on myocytes isolated from the
ventricle of normal Golden hamsters indicated that intracellular
administration of Ang II (10-8 mmol/L)
increased ICa by 36±2.4% (n=20) as shown in
Figure 4. The effect of the peptide required 8 to 10 minutes to reach a
maximal and steady level, and in 4 experiments the increase in
ICa was transitory. Losartan
(10-6 mmol/L) added to the internal
solution did not influence the effect of the peptide on
ICa (Figure 5). In
5 experiments in which PD 123,319 (10-6
mmol/L) was dialyzed into the cell for 5 minutes, no change in the
effect of Ang II (10-8 mmol/L) was found
(P>0.05; not shown). Moreover, Ang II
(10-8 mmol/L) added to the bath increased
ICa by 18±1.9% (n=6; P<0.05), an
effect suppressed by losartan (10-7
mmol/L) added to the bath (not shown).
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To investigate the idea that the increase in ICa is related to the activation of cAMP cascade, experiments were performed on hamster myocytes previously dialyzed with an inhibitor of protein kinase A (20 µg/mL) for 4 minutes. The addition of Ang II (10-8 mmol/L) to the internal solution under these conditions elicited an effect on ICa similar to that of the controls (n=8; P>0.05; not shown).
Because evidence exists that activation of PKC increases
ICa in cardiac myocytes,14
it was important to investigate whether the increase in
ICa seen with intracellular administration of the
peptide was related to the activation of this kinase. For this
experiment, myocytes isolated from hamster ventricles were dialyzed
with the pseudosubstrate of PKC (20 µg/mL), an inhibitor
of the kinase, and ICa was monitored. As shown in
Figure 5, the inhibitor by itself caused a decline of
ICa of 15% within 3 minutes. As soon as the
effect of the inhibitor reached a steady level, Ang II
(10-8 mmol/L) was added to the internal
solution. Figure 5 shows that under these conditions Ang II was unable
to increase ICa. In other experiments
staurosporine (50 µmol/L) was dialyzed into the cell
before the addition of Ang II (10-8 mmol/L)
to the internal solution. The results from 5 experiments indicated that
Ang II under these conditions increased ICa by
only 1.89±0.97% (P>0.05; not shown). Moreover, the
activation of PKC per se elicited by the addition to the bath of
phorbol 12-myristate 13-acetate (300 nmol/L) increased
ICa by 9.8±3.8% (n=6; P<0.05; not
shown) within 6 minutes. Control measurements made with the same
concentration of DMSO used to dilute the phorbol ester showed no effect
on ICa. Experiments made with
[Sar1Val5Ala8]
Ang II (10-6 mmol/L) in the internal
solution showed no change in the effect of Ang II on
ICa (n=6; P>0.05; not shown).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The present results indicate that the administration of Ang II to the cytosol of ventricular myocytes of normal adult rats reduces ICa in an appreciable fashion. Conceivably, the synthesis of Ang II inside cardiac myocytes induced by activation of the cardiac renin-angiotensin system leads to similar decreases ICa and a decrease in rat heart contractility. Moreover, the addition of Ang II to the perfusion fluid also caused a decline in ICa, but the effect was smaller than that elicited by the intracellular administration of the peptide.
The possibility that Ang II diffuses out of the cell and activates AT1 receptors located at the surface cell membrane with a consequent decrease of ICa seems unlikely because losartan when added to the bath did not reduce the effect seen with the intracellular administration of Ang II. The plausible conclusion to be drawn from these experiments is that the peptide is acting intracellularly. Because losartan (10-6 mmol/L) when added to the internal solution did not change the effect of Ang II on ICa, it is possible to conclude that an intracellular Ang II receptor similar to AT1 is not involved in the effect of the peptide. This finding seems to explain why [Sar1Val5Ala8] Ang II (10-6 mmol/L) did not alter the effect of Ang II on ICa.
Previous work19 has indicated that Ang II administered to the extracellular fluid inhibits cAMP production in rat heart, an effect mediated by the inhibition of adenylate cyclase. Recently, it has been reported that Ang II inhibits the intracellular increase in cAMP produced by isoproterenol in heart cells.24 Our present studies in dialyzing Ang II into the cytosol show that the decrease in ICa produced by the peptide was not altered by the exogenous administration of cAMP (dBcAMP) or even forskolin. Furthermore, the inhibition of PKC did not change the effect of Ang II on ICa in rat myocytes.
It is known that the increase in intracellular Ca2+ decreases the amplitude of the inward calcium current.18 Although the concentration of EGTA used in the internal solution might preclude a change in free intracellular calcium, this possibility cannot be completely ruled out, and further studies are needed to clarify this point.
An alternative hypothesis to explain the decline in ICa is that Ang II activates the cGMP-dependent protein kinase. Evidence is available that Ca2+ current in mammalian heart cells is regulated by cGMP-dependent protein kinase.20 21 22 23 25 The finding that zaprinast, which is an inhibitor of cGMP phosphodiesterase, enhanced the effect of intracellular administration of Ang II on ICa supports the idea that the effect of the peptide is related at least in part to the increase in cGMP.
Of particular interest is the observation that the intracellular dialysis of Ang II increases ICa in myocytes of normal hamsters in which the peptide has a positive inotropic action. Previous findings have indicated that in the rat ventricle, Ang II when administered extracellularly reduces the action potential duration,12 an effect that is certainly related to the decrease in heart contractility,13 whereas in the normal hamster, the peptide increases the action potential duration and enhances the strength of heart beat (W.C. De M., unpublished observations, 1997). Therefore, the opposite effect of intracellular administration of Ang II on ICa in rat and hamster myocytes coincides with the effect of the peptide on heart contractility.
Concerning the mechanism of action of Ang II on ICa in hamster myocytes, the possible role of the cAMP cascade seems to be unlikely because neither the inhibition of protein kinase A nor the addition of forskolin could alter the effect of the peptide. However, the present results indicate that the activation of PKC is essential for the intracellular administration of Ang II to have an effect on ICa in normal hamsters. Furthermore, the lack of action of intracellular losartan on the effect of Ang II added to the cytosol supports the view that in Golden hamster myocytes, as in rat myocytes, the effect of Ang II on ICa is not related to the activation of an intracellular Ang II receptor similar to AT1. Further studies will be needed to identify all the factors involved in the effect of the peptide in other species.
In summary, the effect of intracellular administration of Ang II on ICa described above seems to be related to an intracellular mechanism and suggests that the activation of the cardiac renin-angiotensin system plays an important role on the regulation of heart contractility.
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Acknowledgments |
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This work was supported by grants from the American Heart Association and the National Institutes of Health (HL-34148, 532943, and RR03051).
Received February 2, 1998; first decision February 17, 1998; accepted July 14, 1998.
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P. Trongtorsak, T. O Morgan, and L. M. Delbridge Combined renin-angiotensin system blockade and dietary sodium restriction impairs cardiomyocyte contractility Journal of Renin-Angiotensin-Aldosterone System, December 1, 2003; 4(4): 213 - 219. [Abstract] [PDF]
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 A. N. Plotnikov, H. Yu, J. C. Geller, R. Z. Gainullin, P. Chandra, K. W. Patberg, S. Friezema, P. Danilo Jr, I. S. Cohen, S. J. Feinmark, et al. Role of L-Type Calcium Channels in Pacing-Induced Short-Term and Long-Term Cardiac Memory in Canine Heart Circulation, June 10, 2003; 107(22): 2844 - 2849. [Abstract] [Full Text] [PDF]
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S. Bartel, B. Hoch, D. Vetter, and E.-G. Krause Expression of Human Angiotensinogen-Renin in Rat: Effects on Transcription and Heart Function Hypertension, February 1, 2002; 39(2): 219 - 223. [Abstract] [Full Text] [PDF]
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K. Eto, Y. Ohya, Y. Nakamura, I. Abe, and M. Iida Intracellular Angiotensin II Stimulates Voltage-Operated Ca2+ Channels in Arterial Myocytes Hypertension, February 1, 2002; 39(2): 474 - 478. [Abstract] [Full Text] [PDF]
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C. M Filipeanu, R. H Henning, S A. Nelemans, and D. de Zeeuw Review: Intracellular angiotensin II: from myth to reality? Journal of Renin-Angiotensin-Aldosterone System, December 1, 2001; 2(4): 219 - 226. [PDF]
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 A. Charbonneau, M. Leclerc, and M. G. Brunette Effect of angiotensin II on calcium reabsorption by the luminal membranes of the nephron Am J Physiol Endocrinol Metab, June 1, 2001; 280(6): E928 - E936. [Abstract] [Full Text] [PDF]
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E. A. Aiello and H. E. Cingolani Angiotensin II stimulates cardiac L-type Ca2+ current by a Ca2+- and protein kinase C-dependent mechanism Am J Physiol Heart Circ Physiol, April 1, 2001; 280(4): H1528 - H1536. [Abstract] [Full Text] [PDF]
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W. C. De Mello and A. H. J. Danser Angiotensin II and the Heart : On the Intracrine Renin-Angiotensin System Hypertension, June 1, 2000; 35(6): 1183 - 1188. [Abstract] [Full Text] [PDF]
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R. Re The Nature of Intracrine Peptide Hormone Action Hypertension, October 1, 1999; 34(4): 534 - 538. [Abstract] [Full Text] [PDF]
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