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induces systolic cardiac failure marked by exhausted inotropic reserve and intact Frank-Starling mechanism
Center for Cardiovascular Research, 1Department of Medicine, Section of Cardiology, and 2Department of Physiology and Biophysics, College of Medicine, University of Illinois at Chicago, Chicago, Illinois
Submitted 5 May 2005 ; accepted in final form 8 June 2005
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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initially depresses myofilament activity and then leads to a progression of changes characteristic of human heart failure. Here, we examined the effects of PKC on contractile reserve, Starling mechanism, and myofilament activation in this model of end-stage dilated cardiomyopathy. Pressure-volume loop analysis and echocardiography showed that the PKC mice have markedly compromised systolic function and increased end-diastolic volumes. Dobutamine challenge resulted in a small increase in contractility in PKC mice but failed to enhance cardiac output. The PKC mice showed a normal length-dependent tension development in skinned cardiac muscle preparations, although Frank-Starling mechanism appeared to be compromised in the intact animal. Simultaneous measurement of tension and ATPase demonstrated that the maximum tension and ATPase were markedly lower in the PKC mice at any length or Ca2+ concentration. However, the tension cost was also lower indicating less energy expenditure. We conclude 1) that prolonged overexpression of PKC ultimately leads to a dilated cardiomyopathy marked by exhausted contractile reserve, 2) that PKC does not compromise the Frank-Starling mechanism at the myofilament level, and 3) that the Starling curve excursion is limited by the inotropic state of the heart. These results reflect the significance of the primary myofilament contractilopathy induced by phosphorylation and imply a role for PKC-mediated phosphorylation in myofilament physiology and the pathophysiology of decompensated cardiac failure.
pressure-volume loops; cardiac myofilaments
and ) affect contractile function directly through myofilament phosphorylation (11, 13, 16, 17). We recently showed in a murine model that PKC-mediated phosphorylation, when upregulated or unchecked, first results in altered myofilament calcium sensitivity and then subsequently leads to a series of molecular, cellular, and morphological alterations that mimic the progression of human failure (8). Evaluating the energetic features of the myofilament contractilopathy inherent in the PKC mice could provide insight into the characteristics of dilated cardiomyopathy (DCM) in general.
The two principal ways by which the heart augments CO from beat-to-beat are increases in activation of the 
-adrenergic system and changes in end-diastolic volume (EDV), the so-called Frank-Starling (F-S) mechanism (25). Both mechanisms employ cellular effectors that converge on the myofilaments. For that reason, the state of myofilament activity could reasonably affect both mechanisms. There is a general consensus that there are important changes in the adrenergic signaling during failure, including membrane-associated changes in the -adrenoceptor and intracellular signaling cascades (7). On the other hand, the role of the F-S mechanism during the progression to failure is debated. Some investigators report normal Starling function in human heart failure (24), whereas others show substantial compromise in this intrinsic function of the heart (10). The impact that a primary myofilament contractilopathy would have on the effects of inotropic stimulation and the intrinsic F-S mechanism in this model of end-stage dilated cardiac failure was examined here. How PKC-mediated phosphorylation of myofilament proteins also affects the efficiency of contraction was also examined here and may provide insight into its physiological role.
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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cDNA was driven by a mouse 
-myosin heavy chain (MHC) promoter on an FVB/N background and as previously described (8). Mice were genotyped using PCR with primers specific for the rabbit sequence (forward) 5'-GATACCCTTACGACGTCC and (reverse) 5'-CACATCAGTGACGAATTCGTCG. Crosses were established to produce homozygous offspring with respect to the transgene, of which 12-mo-old males were used.
Pressure-volume loop analysis.
All experiments were carried out according to the guidelines proscribed by the Animal Care Committee at the University of Illinois (Chicago). Anesthesia was induced by inhalation with methoxyflurane in a closed chamber. Animals were then intubated. An appropriate plane of anesthesia was maintained with 0.75–1.25% isoflurane through a vaporizer with 100% oxygen connected to a ventilator as previously described (8). A 1.4-Fr pressure-conductance catheter (Millar Instruments, Houston, TX) was then retrogradely inserted into the left ventricle (LV) across the aortic valve and steady-state pressure-volume loops and hemodynamics were recorded (ARIA-Millar Instruments). After stabilization, the end-systolic pressure-volume relationship and its slope (Emax) were derived by varying EDVs. The EDV was selectively altered by intermittent occlusion of the inferior vena cava (IVC) to avoid reduction in thoracic pressure, as previously described. Briefly, a midline incision through the linea alba exposed the falciform ligament, which was dissected to expose the subdiaphragmatic IVC. Intermittent occlusion of the IVC was accomplished using suture ligature and a short segment (
4 mm) of PE-50 tubing. On average, 10–20 loops were analyzed using the customized software from PVAN (Millar Instruments). Pressure-volume loops were also recorded during an inotropic challenge using intraperitoneal bolus injection of dobutamine (Dob; 250–300 µl of 2.5 µM). Acute saturation of the receptors was inferred by lack of further hemodynamic response to additional Dob injection. Representative loops are shown.
Economy of tension and the Ca2+-tension relationship.
Simultaneous tension-ATPase activity at short (1.95 µm) and long (2.15 µm) sarcomere length (SL) was measured, as previously detailed (5, 22). The normalized Ca2+-tension and Ca2+-ATPase relations at both SLs were obtained as previously described (15). Briefly, mice were anesthetized with pentobarbital sodium (50 mg/kg body wt), and the hearts were rapidly excised and placed into ice-cold high-relaxing (HR) solution containing (in mM) 20 EGTA, 10 creatine phosphate, 100 BES, 5.93 ATP, 6.6 magnesium chloride, 20.7 potassium proprionate, at pH 7.0, 10 IU/ml creatine kinase (bovine heart, Sigma) and 0.5 mM DTT. The total ionic strength of HR was 200 mM. A cocktail of protease inhibitors, containing 10 µM leupeptin, 1 µM pepstatin, and 100 µM phenylmethylsulfonyl fluoride (PMSF), was included in the buffer. Left ventricular papillary muscles were isolated from the heart and dissected into thin fiber bundles 150–200 x 1.5–2.0 µm in width and length, respectively. Fiber bundles were detergent-skinned overnight in HR solution containing 1% Triton X-100 and the phosphatase inhibitors, calyculin A (0.1 µg/ml) and okadaic acid (0.2 µg/ml). The experimental procedures for measuring force and ATPase activity were as described previously (5, 15). A computer program (6) was used to calculate the composition of the activating and relaxing solutions. Activating solution contained (in mM) 20 Ca-EGTA, 1.55 potassium proprionate, 6.59 magnesium chloride, 100 BES, 5 sodium azide, 1 DTT, 10 phosphoenolpyruvate, 0.01 leupeptin, 0.001 pepstatin, 0.01 oligomycin, 0.01 PMSF, and 0.01 A2P5. Relaxing solution was identical except it contained (in mM) 20 EGTA, 21.2 potassium proprionate, and 7.11 MgCl2. Preactivating solution contained (in mM) 0.5 EGTA, 19.5 (Fluka) HDTA, 7.11 MgCl2, and 21.8 potassium proprionate. All solutions contained 1.0 mg/ml pyruvate kinase (386 U/mg) and 0.1 mg/ml lactate dehydrogenase (880 U/mg; Sigma, St. Louis, MO). All solutions had an ionic strength of 180 mM, 5 mM free ATP, and 1 mM free magnesium as determined using the methods of Fabiato and Fabiato assuming an apparent stability constant of the Ca2+-EGTA complex of 106.58 (4, 10). A cocktail of inhibitors, containing 10 µM leupeptin, 1 µM pepstatin, and 10 µM PMSF, was included in all the buffers. To determine the pCa-tension and pCa-ATPase activity relationships at short (2.0 µm) and long (2.3 µm) SLs, fiber bundles were sequentially bathed in solutions with pCa values ranging from 4.3 to 8.0.
The ATPase activity of a fiber bundle was measured by a coupled enzyme assay, as described previously (5, 15). The ATPase measurements were carried out in a buffer that included 0.9 mM NADH, 5 mM NaN3, 10 mM phosphoenolpyruvate, 4 mg/ml pyruvate kinase (500 U/mg), and 0.24 mg/ml lactate dehydrogenase (870 U/mg). Myofibrillar ATPase activity in skinned fiber bundles was measured as follows: ATP regeneration from ADP was coupled to the breakdown of phosphoenolpyruvate to pyruvate and ATP, catalyzed by pyruvate kinase, which was linked to the synthesis of lactate, catalyzed by lactate dehydrogenase. The breakdown of NADH, which is proportional to the amount of ATP consumed, was measured by UV absorbance at 340 nm. The ratio of light intensity at 340 nm (sensitive to NADH concentration) and 410 nm (reference signal) was obtained by means of an analog divider. After each recording, the UV absorbance signal of NADH was calibrated with multiple rapid injections of 0.25 nmol ADP (0.025 µl of 10 mM ADP) into the bathing solution with a motor-controlled calibration pipette.
Echocardiography. Transthoracic two-dimensional targeted M-mode and pulsed Doppler echocardiography was performed as previously described (8). To examine changes in diastolic compliance of the LV, E/A ratio of the mitral inflow [ratio of the maximal velocity of LV early filling (E wave) and the maximal velocity of the left atrial contraction (A wave)], and LV isovolumic relaxation time (IVRT), which was measured from the aortic valve closure to the mitral valve opening, was also determined (23). All calculations were made from at least three consecutive cardiac cycles.
Gel electrophoresis.
The separation of the isoforms of the MHC by SDS-PAGE was performed as recently described (22). Densitometry was performed to quantify the relative MHC isoform content using the ImageJ open-source software (v1.33 NIH). Data are expressed as the percent -MHC expressed.
Statistics.
Data from the normalized Ca2+-tension and Ca2+-ATPase activity measurements were fitted to the Hill equation {P/Po = [Ca2+]
)} by using nonlinear least-squares regression to obtain the EC50 (k) and the Hill coefficient (nH). All data are expressed as means ± SE unless otherwise stated in the figure legend. Student's unpaired t-test was used to determine differences between two groups. Differences among groups larger than two were determined by one-way ANOVA. Student-Newman-Keuls was used for post hoc analysis. Across all data, P value 
0.05 indicated a statistical significance.
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RESULTS |
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vs. wild-type mice.
LV dysfunction is depicted in the representative M-mode echocardiogram in Fig. 1A, which shows that the PKC mice not only display marked septal and posterior wall hypokinesis, but they also have higher systolic and diastolic dimensions, consistent with increased volumes of the dilated ventricle. Importantly, the left atria of the PKC hearts were invariably calcified and markedly enlarged (Fig. 1B), which led us to question the effectiveness of the atrial component of ventricular filling. Diastolic dysfunction may also be masked in the dilated ventricle, so examination of LV filling was important. In Fig. 1C, the pulsed-wave Doppler images indicate that there is no diastolic dysfunction across groups, as measured by the E/A ratios. There was no significant difference in the E/A ratios between groups (E/A ratio 1.13 ± 0.27 vs. PKC 1.37 ± 0.29, P = 0.34). The A-component of the E/A ratio, which indicates the velocity of blood flow during atrial contraction, was similar [wild-type (WT) A 0.32 ± 0.06 m/s vs. PKC A 0.31 ± 0.06 m/s, P = 0.66] between groups, suggesting that the calcification did not compromise the atrial contribution to LV filling. Another measure of diastolic function, the LV IVRT, was also not significantly different (IVRT WT 26.0 ± 4.4 and PKC 27.7 ± 6.1, P = 0.72). Pseudonormalization of the E/A ratio in the PKC mice could not be ruled out using these echocardiographic techniques (3), but is unlikely in the absence of marked increased end-diastolic pressure (Fig. 2).
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-adrenergic system at this stage of failure could augment the systolic effort was speculative. Figure 2A shows representative pressure-volume loops from WT animals before and after the treatment with the -agonist Dob. With Dob treatment, the WT animals responded with a significant increase in LV end-systolic pressure (control 97.6 ± 0.9 vs. Dob 111.7 ± 3.9, P < 0.001). The contractility was also significantly increased, as measured by Emax (Fig. 2C) and the first derivative of pressure development (+dP/dt; Fig. 2D). In Fig. 2B, the pressure-volume loops from the PKC animals show a lack of effect of Dob treatment on pressure-volume loop contour and LV systolic pressure (control 78.6 ± 2.6 vs. Dob 83.5 ± 2.3, P > 0.05). However, there were small, but significant, increases in the Emax (Fig. 2C) and +dP/dt (Fig. 2D). Moreover, the increases in contractility seen in the PKC animals were considerably smaller than the changes seen in the WT animal. Figure 3A shows that even in the context of increased contractility, the PKC animals were unable to increase the CO significantly. Of note, the CO measured by the conductance catheter after parallel conductance adjustment was similar to that calculated by aortic dimensions with echocardiography (data not shown). An important observation was that the heart rate before and after treatment with Dob was not different (Fig. 3C) between groups, indicating that this effect is not the result of differences in -adrenoceptor signaling.
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on length-dependent (F-S mechanism) activation.
We hypothesized that the PKC heart would also demonstrate a compromised F-S mechanism given the lack of augmentable CO in the context of increased LV volumes. Figure 4 shows the results from examining the length dependence of Ca2+-activated tension development (i.e., the myofilament correlate to F-S mechanism) in skinned cardiac muscle preparations. The change in the half-maximal Ca2+-activated force (
EC50; Fig. 4, inset) from the short to long SL was not significantly different in the WT (EC50 = 0.22 ± 0.04) compared with PKC (EC50 = 0.16 ± 0.04) mice. Both groups were particularly sensitive to length changes over a range of physiological Ca2+ concentrations indicating robust Starling excursion at the myofilament level in these hearts. The EC50 and Hill coefficient (i.e., measure of thin filament cooperativity) at both SL were also similar between groups (Table 1).
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on maximal tension, ATPase, and the economy of tension development.
Figure 5 shows that the non-normalized tension developed over the range of Ca2+ concentrations was significantly diminished in the PKC compared with WT at short (Fig. 5A) and long (Fig. 5B) SLs. Indeed, the maximal tension and ATPase activity in PKC mice were both significantly depressed (30 and 50%, respectively) at short and long SL (Table 1). We examined the effect of PKC overexpression on the economy of tension development (tension cost) by simultaneous measurement of myofibrillar ATPase rate and steady-state tension development. Figure 5, C and D, shows that the PKC mice used significantly less ATP per unit tension developed at both SL and over the entire range of Ca2+ concentrations. The tension cost, which is the slope of the tension-ATPase relationship, was 32% lower in the PKC mice compared with the WT controls at short SL (tension cost WT 7.9 ± 0.7 vs. PKC 5.4 ± 0.7, P = 0.03; Fig. 5C, inset) and 39% reduced at the long SL (tension cost WT 7.5 ± 1.1 vs. PKC 4.6 ± 0.6, P = 0.03; Fig. 5D, inset).
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mice display increased MHC isoform switching that was not attributable to aging (8). Because MHC content affects the economy of tension, it was important to quantify changes in MHC isoforms in the 12-mo-old animals. Densitometric analysis of the bands from SDS-PAGE of the myofibrillar preparations from the hearts used in these experiments corresponding to - and -MHC shows that the -MHC protein content in PKC mice makes up only 40% of total (60% -MHC) in the PKC mice, whereas -MHC content was 85% (15% -MHC) in the WT animals (Fig. 6A). However, there was only a fair correlation between -MHC content and decreasing tension cost (r = 0.72; Fig. 6B). Furthermore, the actual tension cost in the PKC mice was lower than the predicted tension cost (i.e., tension cost = -MHC x -fraction + -MHC x -fraction). Together, these observations suggested that some non-cross-bridge-related phenomenon was also affecting overall tension cost in the PKC animals.
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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in the transition to decompensated failure is to enhance contractile efficiency in exchange for reduced CO and contractile reserve. This mechanism may represent a previously speculated physiological role for PKC-mediated myofilament phosphorylation during beat-to-beat regulation. Our data support the idea that the cardiac myofilaments serve as a final point of convergence for altered cellular function in heart failure.
Costs and benefits of submaximal myofilament activation.
One of the principal ways in which CO is augmented is through increases in Ca2+-induced recruitment of contractile units (25). An important finding of this study was that chronic, unchecked PKC activity appeared to offset the increase in recruited contractile units due to -stimulation. This occurred in the presence of apparently intact adrenergic signaling, as suggested by analogous heart rate responses to Dob stimulation in the WT and PKC groups. Moreover, there were no changes in the Ca2+ handling proteins in this model, as previously shown by our group and others (4, 8, 19). Still, it must be underscored that there was severely diminished contractile activity even at saturating levels of Ca2+ (i.e., >10 mM) in the skinned preparations. This indicates that even if Ca2+ levels could increase in the intact myocardium, recruitment of more contractile units would not further increase pressure development or CO. Thus simply overexpressing PKC, as is done here, is not sufficient to cause the well-appreciated downregulation of -receptors or compromised Ca2+ handling commonly observed in naturally occurring cardiac failure. This model, however, demonstrates the progression of a primary myofilament contractilopathy, which is sufficient to lead to dilated pump failure at its end point and supports a role for myofilament phosphorylation in the development of failure.
We showed that not only are the maximum tension and ATPase markedly depressed but they are both also depressed over the entire range of Ca2+ concentrations in the PKC mice. The decrease in tension development is most likely due to PKC-mediated phosphorylation, as nearly complete substitution of the MHC complement with the slower -isoform does not affect peak tension (21). Exactly how prolonged PKC-mediated phosphorylation causes myofilament contractilopathy is not certain. However, we previously showed that PKC-mediated phosphorylation of troponin I and troponin T depresses myofilament activity and that the targeted regions on the thin filament are exquisitely sensitive to charge changes (14–16). It is likely that this phosphorylation-dependent charge effect maintains the thin filament in a submaximal orientation. This, in turn, hinders full excursion of the thin filament regulatory unit and precludes actin and myosin from achieving the most favorable interaction.
Another important finding of the current study was the increased economy of tension generation in the PKC mice. This was surprising in the context of significantly increased EDVs and depression in both myofilament tension and ATPase. The economy difference was largely attributed to the dramatic increase in the -MHC in the PKC mice, an alteration shown to change economy (21). However, the measured tension cost in these experiments was lower than predicted from an MHC shift alone and suggested that some non-cross-bridge-related process was affecting tension cost. This suggests a possible role for PKC-mediated phosphorylation in altered efficiency in this study. Of note, Pyle et al. (20) showed that modulation of the level of phosphorylation of troponin I and troponin T changed the economy of force in young mice with normal, adult MHC ratios. Whatever the exact mechanism for these changes, it appears that the permissive role of the thin filament in the normal heart is amplified in the PKC-induced myofilament contractilopathy. Similar findings have also been demonstrated in human heart failure (18).
An interesting question is whether submaximal activation translates into suboptimal activation of the myofilaments. Our data here and elsewhere (14–16) suggest, in fact, that the opposite is true. We previously theorized that PKC assumes the physiological role of tempering the contractile machinery in the setting of increased catecholamine release. In the current study, we show direct evidence that this is accomplished through increases in the economy of force development. Our data suggest that PKC is a likely intracellular effector of transiently optimized efficiency, in contrast to PKA, which has no effect on the economy of force (5), but does increase cellular ATP usage (9, 26). Indeed, it is attractive to postulate that during sympathetic norepinephrine release, the -receptor signaling (i.e., PKC) tempers the economics of contraction without counteracting the increased Ca2+ activation via the -receptor (i.e., PKA).
PKC and the F-S mechanism.
The activity of the myofilaments and therefore the performance of the myocardium at any given level of Ca2+ are rigidly dependent on the end-diastolic length, the so-called F-S law of the heart. The role of the F-S mechanism in heart failure is debated. Whereas some authors report a compromised F-S mechanism in human failure (24, 28), others report that this intrinsic property functions normally in humans with failure (10, 29). In the current experiments, the intact PKC animals showed a blunted response to changes in EDV. The natural extension of this finding was to confirm these changes using the benchmark measurement of F-S mechanism in skinned muscle, namely the length-dependent Ca2+ activation at the myofilament level. We hypothesized that the length-dependent relationship would also be compromised. However, we demonstrated in this model of end-stage DCM that the cellular correlate to the F-S law was unchanged at the myofilament level. Moreover, we show for the first time that PKC does not affect the length-sensing ability of the sarcomere.
An explanation for this paradoxical finding lies in the fact that these distinct mechanisms not only coexist on a beat-to-beat basis but are also interdependent (12, 28). That is to say, decreased Ca2+-dependent activation can blunt the excursion of the Starling curve and vice versa. This is evidenced in our experiments where the normally functioning cellular F-S mechanism was masked by compromised myofilament effort induced by phosphorylation. The work of Arteaga et al. (1) suggests that the cellular mechanism for the F-S law of the heart is saturable. These authors showed that transgenic hearts expressing the slow skeletal variant of troponin I operate at a high level of Ca2+ sensitivity. However, increased SL in these preparations resulted in significantly smaller increases in Ca2+ sensitivity compared with controls, while synthetic Ca2+ sensitizers were completely ineffective. This is important because the different stages of heart failure, particularly the early compensatory stages, may manifest increased Ca2+ sensitivity, as has been shown in this model (8). It is plausible that the myofilament mechanism in other forms of failure could be masked by the preexisting increased myofilament Ca2+ sensitivity. The myocardium would therefore be unable to mount a full response to increased stretch and manifest as a blunted F-S mechanism.
In conclusion, unchecked expression of PKC causes a primary myofilament contractilopathy that, over time, is sufficient to lead to end-stage dilated cardiac failure. The mechanism by which PKC does this is phosphorylation-induced suppression of the contractile effort, which also obscures the normally functioning Starling mechanism in the beating myocardium. A possible physiological role for PKC is tempering contractile economy by maximizing the tension produced per cross bridge. This role may be exploited by the compensating, loaded myocardium but ultimately exacerbates pump failure. Despite advances in current therapy for cardiac failure, millions of individuals remain in persistent, ultimately worsening failure. It follows that a rational drug design that directly or indirectly targets the site(s) of phosphorylation at the myofilament level (i.e., troponin I or troponin T), thus altering the covalent charge change, could provide the next generation of effective heart failure drugs. Indeed, drugs, such as the myofilament Ca2+ sensitizer levosimendan, have demonstrated that myofilament targeting is not only feasible but efficacious (27, 30).
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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REFERENCES |
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protein kinase C. Cardiovasc Res 50: 65–74, 2001.-Adrenergic response and myofilament activity in mouse hearts lacking PKC phosphorylation sites on cardiac TnI. Am J Physiol Heart Circ Physiol 282: H2397–H2405, 2002. and PKC in cardiac ischemia and reperfusion: targeting the apoptotic machinery. Arch Biochem Biophys 420: 246–254, 2003.[CrossRef][Web of Science][Medline]
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-myosin heavy chain isoform expression on cross-bridge cycling kinetics. Am J Physiol Heart Circ Physiol 288: H896–H903, 2005.This article has been cited by other articles:
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  T. Koyanagi, L. Y. Wong, K. Inagaki, O. V. Petrauskene, and D. Mochly-Rosen Alteration of gene expression during progression of hypertension-induced cardiac dysfunction in rats Am J Physiol Heart Circ Physiol, July 1, 2008; 295(1): H220 - H226. [Abstract] [Full Text] [PDF]
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J. H. Hankiewicz, P. H. Goldspink, P. M. Buttrick, and E. D. Lewandowski Principal strain changes precede ventricular wall thinning during transition to heart failure in a mouse model of dilated cardiomyopathy Am J Physiol Heart Circ Physiol, January 1, 2008; 294(1): H330 - H336. [Abstract] [Full Text] [PDF]
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 R. J. Belin, M. P. Sumandea, E. J. Allen, K. Schoenfelt, H. Wang, R. J. Solaro, and P. P. de Tombe Augmented Protein Kinase C-{alpha}-Induced Myofilament Protein Phosphorylation Contributes to Myofilament Dysfunction in Experimental Congestive Heart Failure Circ. Res., July 20, 2007; 101(2): 195 - 204. [Abstract] [Full Text] [PDF]
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P < 0.05, compared with PKC
) and long (2.15 µm; 
) sarcomere length (SL) compared with the Ca2+-tension relationships in PKC
) and long SL (
). Ca2+ concentrations over the physiological range were used and expressed as µM (10–6 M). Inset: change in effective Ca2+ concentration (
