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In vivo -adrenergic responses and troponin I phosphorylation: anesthesia interactions

¹Cardiovascular Institute and ²Department of Bioengineering, University of Pittsburgh, Pittsburgh, Pennsylvania; ³Department of Cardiology at the Freeman Hospital and ⁴University of Newcastle upon Tyne, Newcastle upon Tyne, United Kingdom

Submitted 2 September 2004 ; accepted in final form 29 November 2004

	ABSTRACT

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The mechanisms by which -adrenergic stimulation of the heart in vivo can cause contractile dysfunction are not well understood. We hypothesized that -adrenergic-mediated contractile dysfunction is mediated through protein kinase C phosphorylation of troponin I, which in in vitro experiments has been shown to reduce actomyosin Mg-ATPase activity. We studied pressure-volume loops in transgenic mice expressing mutant troponin I lacking protein kinase C phosphorylation sites and hypothesized altered responses to phenylephrine. As anesthesia agents can produce markedly different effects on contractility, we studied two agents: avertin and -chloralose-urethane. With -chloralose-urethane, at baseline, there were no contractile abnormalities in the troponin I mutants. Phenylephrine produced a 50% reduction in end-systolic elastance in wild-type controls, although a 9% increase in troponin I mutants (P < 0.05). Avertin was associated with reduced contractility compared with -chloralose-urethane. Avertin anesthesia, at baseline, produced a reduction in end-systolic elastance by 31% in the troponin I mutants compared with wild-type (P < 0.05), and this resulted in further marked systolic and diastolic dysfunction with phenylephrine in the troponin I mutants. Dobutamine produced no significant difference in the contractile phenotype of the transgenic mice with either anesthetic regimen. In conclusion, these data (-chloralose-urethane) demonstrate that -adrenergic-mediated force reduction is mediated through troponin I protein kinase C phosphorylation. -Adrenergic responses are not mediated through this pathway. Altering the myofilament force-calcium relationship may result in in vivo increased sensitivity to negative inotropy. Thus choice of a negative inotropic anesthetic agent (avertin) with phenylephrine can lead to profound contractile dysfunction.

protein kinase C; ventricular function

In vivo left ventricular function may differ in several respects to isolated tissue or whole heart studies in which loading is controlled. For instance, -adrenergic agonists produce marked increases in afterload and preload. With these changes in loading, dissociating direct myocardial inotropic effects is only possible by analyzing left ventricular function using the pressure-volume framework within which preload, afterload, and contractility can be individually quantified. Also, it is well recognized that the in vivo mouse model is particularly sensitive to the choice of anesthesia, with different anesthetic regimens producing markedly different effects on indexes of contractility (7, 8). Recently, Roman et al. (18) showed increased contractility in vivo in these troponin I mutants, although they did not study pressure-volume relationships or the effects of different anesthetic agents.

In the present study, we sought to determine the effects of reduced troponin I protein kinase C phosphorylation on in vivo left ventricular function. We hypothesized that this mutation would result in an altered phenotype in response to -adrenergic stimulation, which is known to activate protein kinase C. Conversely, we hypothesized that -adrenergic stimulation would not alter the phenotype of the transgenic mice, as in vitro protein kinase A troponin I phosphorylation is at serines 23 and 24 and not the mutated serines 43 and 45 in this model (15). Furthermore, we studied two anesthetic regimens given the marked discrepancies in indexes of contractility with different agents. We used avertin (2,2,2-tribromo-ethanol), an alcohol-based anesthetic, which results in heart rates and contractility below physiological levels, and -chloralose-urethane, which has been shown to produce values nearer to those of the conscious state. As our previous studies have shown an increased sensitivity to negative inotropic stimulation, we hypothesized that there would be a greater reduction in contractility in the transgenic mice with avertin compared with controls (12, 13).

	METHODS

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Troponin I transgenic mice.   The generation and characterization of the transgenic mice used in the present study were previously described in detail (12). In brief, the mutant troponin I lacking protein kinase C phosphorylation sites (S43A/S45A) was expressed using the -myosin heavy chain promoter. Several founders for these transgenic mice were generated that expressed levels of mRNA for the mutant protein up to levels similar to that of the wild-type protein, although not exceeding it. Total amount of troponin I protein, including wild-type and mutant protein, was similar in transgenic mice compared with wild-type controls, suggesting that excessive protein had been degraded and indicating that the phenotype was not merely the result of overexpression of troponin I protein. There was a 25% reduction in total troponin I phosphorylation (16), consistent with production of mutant protein. Age- and gender-matched transgenic mice and wild-type controls (FVB strain background) were used for these studies (age controls: 131 days (SD 34) vs. transgenic 129 days (SD 44), P = not significant), with 13 of 37 total control mice female and 12 of 39 total transgenic mice female.

Conductance catheter studies.   This study was approved by the Institutional Animal Care and Use Committee of the University of Pittsburgh and conforms with the Guide for the Care and Use of Laboratory Animals published by the National Institutes of Health. Two anesthetic regimens in two different groups of mice were studied. Avertin (Sigma, 250 mg/kg, 18 µl/g body wt ip) was used in one group and -chloralose-urethane with isoflurane inhalation for induction (75 mg/kg -chloralose ip and 1,125 mg/kg urethane ip, total volume 26 µl/g body wt ip) in the second group. An important consideration in choosing these anesthetics for comparison was that both were delivered by intraperitoneal injection, and so endotracheal intubation was not required.

A 0.5-cm skin incision was made in the right neck area, and the carotid artery was isolated using 0-silk sutures. The cranial aspect of the carotid artery was ligated, and a microsurgical clip was placed on the proximal carotid artery for hemostasis. An arteriotomy was performed with microsurgical scissors, and a 1.4-Fr. conductance catheter (Millar, Houston, TX) was introduced into the carotid artery and advanced retrogradely across the aortic valve into the left ventricle. The catheter was advanced under continuous hemodynamic monitoring to ensure proper placement in the left ventricle. The catheter was made secure within the carotid artery with the proximal suture. The left internal jugular vein was cannulated for saline and drug administration. A 0.5-cm longitudinal abdominal incision was made, and blunt dissection was used to expose the inferior vena cava.

Volume was calculated using the Relative Volume Units/Cuvette method in which external blood-filled standards of known volume are used to calculate a slope and intercept to convert the conductance catheter signal of relative volume units to volume (5). This volume needs to be corrected for parallel conductance, which was calculated using the hypertonic saline method, in which a bolus of 20 µl of 30% hypertonic saline was injected through the left internal jugular vein (1).

After baseline, steady-state measurements, inferior vena caval occlusions were performed by direct pressure through the abdominal incision to reduce preload used in determination of end-systolic elastance and other load-independent indexes of contractility. After the baseline inferior vena caval occlusions, either dobutamine (2.5 µg·kg^–1·min^–1 iv) or phenylephrine (0.1 µg·kg^–1·min^–1 iv) was administered, after which data were again recorded in steady state and during inferior vena caval occlusions. -Adrenergic blockade was not used during the phenylephrine experiments, as the troponin I transgenic mice have increased sensitivity to propanolol (18), which would make comparisons with controls problematic. Pressure and volume data were recorded using the BioBench data-acquisition software package and analyzed using the PVAN pressure-volume data analysis software package (Millar, Houston, TX).

Data and statistical analysis.   Indexes of systolic function included maximal pressure (P_max), stroke volume, cardiac output, ejection fraction, and stroke work. Contractility was assessed by maximal rate of pressure development (dP/dt_max), linear regression of dP/dt_max vs. end-diastolic volume (dP/dt_max-EDV slope) (10), end-systolic elastance (E_es) (21), preload recruitable stroke work (linear regression of stroke work vs. end-diastolic volume, PRSW slope) (6), and preload-adjusted maximal power (power = pressure x maximal rate of change of volume during systole) normalized to EDV² (20). Diastolic function was assessed by end-diastolic pressure, minimal diastolic pressure (P_min), tau (Weiss method, regression of log of pressure vs. time) (22), maximal rate of pressure decay (dP/dt_min), and dV/dt (maximal rate of volume increase in diastole). Ventricular volumes and loading were assessed with the end-diastolic and end-systolic volumes, arterial elastance (measure of afterload, E_a), and ventriculoarterial coupling as determined by the ratio of E_es/E_a.

Statistical analysis was performed using two-factor ANOVA comparing wild-type and transgenic mice (group) at baseline and with either of dobutamine or phenylephrine (drug). From this analysis, group differences and group x drug interactions between wild-type and transgenic mice are stated, with preference to state the more specific group x drug interaction. Group differences indicate that there was a difference between wild-type and transgenic mice, which was not significantly affected by the intervention. A group x intervention interaction was interpreted as there was a difference between wild-type and transgenic mice dependent on the response to the drug. Finally, the Scheffé's test was used for individual subgroup comparisons. Single comparisons were made with the Student's t-test. Data are presented as means (SD).

	RESULTS

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-Chloralose-urethane.   There were no significant differences in heart rates, indexes of systolic function, contractility, loading, ventricular volumes, or diastolic function between the transgenic mice and wild-type controls at baseline or with dobutamine (Tables 1 and 2, Fig. 1, A and B, and Fig. 2A). Phenylephrine produced sustained increases in pressure in both wild-type and transgenic mice (Fig. 3). In wild-type mice in response to phenylephrine, there was a significant reduction in indexes of contractility (dP/dt_max-EDV slope, E_es, and PRSW slope) compared with baseline; however, in the transgenic mice, the reduction in contractility was not seen, indicating a markedly altered response to -adrenergic stimulation (all P < 0.05 wild type vs. transgenic ANOVA group x drug interaction; Table 1 and Fig. 4A). Consistent with the preserved contractility in the transgenic mice with phenylephrine, there was marked attenuation of increases in end-diastolic and end-systolic volumes to the elevated afterload compared with the responses in the control mice (P < 0.05 wild type vs. transgenic; Table 2 and Fig. 1C). This altered volume response to loading occurred with the same degree of increase in P_max (Table 1) and afterload (E_a; Table 2).

View this table: [in this window] [in a new window]   Table 1. Heart rate, indexes of systolic function, and contractility with -chloralose-urethane anesthesia in WT and TG mice at baseline and after dobutamine or phenylephrine

View this table: [in this window] [in a new window]   Table 2. Indexes of preload, afterload, ventricularterial coupling and diastolic function with -chloralose-urethane anesthesia in WT and TG mice at baseline and after dobutamine or phenylephrine

View larger version (16K): [in this window] [in a new window]   Fig. 1. Examples of steady-state pressure-volume relations in wild-type (WT) and transgenic mice (TG) at baseline (A), with dobutamine (B), and phenylephrine (C) under -chloralose-urethane anesthesia. At baseline or with dobutamine there are no significant differences between WT and TG mice, although with phenylephrine there is a marked leftward shift in the pressure-volume relationship in TG compared with WT mice consistent with the increased contractility in the TG mice.

View larger version (43K): [in this window] [in a new window]   Fig. 2. Examples illustrating comparison of end-systolic elastance [Ees; obtained by linear regression analysis of end-systolic pressure-volume points using the iterative procedure described by Kono et al. (9)] at baseline in WT and TG mice under -chloralose-urethane anesthesia (A) and under avertin anesthesia (B). In both WT and TG mice, Ees is greater under -chloralose-urethane anesthesia compared with avertin. There are no significant differences in Ees between WT and TG under -chloralose-urethane anesthesia (A), although Ees is significantly reduced in the transgenic mice with avertin (B).

View larger version (13K): [in this window] [in a new window]   Fig. 3. Effects of phenylephrine on pressure over time in WT (A) and TG (B) mice. In both groups there is a sustained increase in pressure with phenylephrine.

View larger version (40K): [in this window] [in a new window]   Fig. 4. Examples illustrating comparison of Ees [obtained by linear regression analysis of end-systolic pressure-volume points using the iterative procedure described by Kono et al. (9)] with phenylephrine in WT and TG mice under -chloralose-urethane anesthesia (A) and under avertin anesthesia (B). Ees is increased in TG mice compared with WT (A), although Ees is reduced in TG (B).

Avertin.   At baseline in controls, avertin anesthesia compared with -chloralose-urethane was associated with lower heart rates, reduced contractility (Fig. 2, A and B), higher volumes, and higher end-diastolic pressures without differences in other indexes of diastolic function.

There was marked systolic dysfunction in the transgenic mice with avertin anesthesia. The transgenic mice had reduced P_max, stroke volumes, cardiac output, stroke work, dP/dt_max, and E_es (all P < 0.05 wild type vs. transgenic; Table 3 and Fig. 2B). Preload (end-diastolic volume) was significantly reduced at baseline in the transgenic mice (P < 0.05 wild type vs. transgenic; Table 4 and Fig. 5A), afterload (E_a) was increased, and ventriculoarterial coupling decreased (both P < 0.05 wild type vs. transgenic; Table 4). Thus the avertin anesthesia abnormalities in the transgenic mice can be summarized as reduced contractility and preload, with compensatory increase in afterload, all of which contribute to reduction in indexes of global systolic function.

View larger version (17K): [in this window] [in a new window]   Fig. 5. Examples of steady state pressure-volume relations in WT and TG mice at baseline (A), with dobutamine (B), and phenylephrine (C) under avertin anesthesia. At baseline there is a leftward shift in the pressure-volume relationship and reduction in stroke volume in the TG mice, although after dobutamine, the difference in end-diastolic volume between WT and TG mice is no longer seen, although stroke volume remains decreased. With phenylephrine there is a marked leftward shift in the pressure-volume relationship and reduction in the stroke volume in the TG mice. Axis scaling is the same as in Fig. 1 to allow direct comparisons.

In response to phenylephrine, the transgenic mice compared with wild type had a marked reduction in stroke work (P < 0.05 wild type vs. transgenic; Table 3) and significantly lower end-diastolic volumes (P < 0.05 wild type vs. transgenic; Table 4 and Fig. 5C). Phenylephrine produced marked relaxation abnormalities in the transgenic mice with increased P_min, prolonged tau, decreased dP/dt_min, and dV/dt (P < 0.05 wild type vs. transgenic; Table 4). Thus with phenylephrine in the transgenic mice under avertin anesthesia there are reduced volumes as are also seen with -chloralose-urethane. However, in the transgenic mice, in complete contrast to -chloralose-urethane, with avertin there is also marked systolic and diastolic dysfunction (Fig. 4).

To understand further the smaller volumes that are seen in the baseline avertin studies, an intravenous volume challenge (200 µl normal saline) was given to a group of mice under avertin anesthesia (wild type n = 7, transgenic n = 5). The end-diastolic pressure-volume relationships with this volume loading are presented in Fig. 6. There was no significant increase in end-diastolic pressure associated with an increase in end-diastolic volume in the wild-type mice, indicating a compliant diastolic pressure-volume relationship. However, there was a significant increase in end-diastolic pressure in the transgenic mice (P < 0.05 end-diastolic pressure wild-type vs. transgenic mice). This increase in end-diastolic pressure was at least in part resulting from abnormalities in active relaxation, as tau increased to a greater extent in the transgenic mice compared with wild type tau: wild type 0.07 (SD 0.18) vs. transgenic 0.60 ms (SD 0.50), P < 0.05). Whereas absolute values of end-diastolic pressure are not elevated compared with wild-type mice, these data suggest that the smaller volumes in the transgenic mice with avertin anesthesia maintain lower left ventricular filling pressures.

View larger version (12K): [in this window] [in a new window]   Fig. 6. Effects of volume loading on end-diastolic pressure-volume relationship in WT and TG mice under avertin anesthesia. Within each group, the left symbol indicates baseline values, and the right symbol is after the volume challenge. WT mice respond with an increase in end-diastolic volume, although minimal increases in end-diastolic pressure, indicating a compliant diastolic pressure-volume relationship. TG mice have a greater increase in end-diastolic pressure with volume (* end-diastolic pressure WT vs. TG; P < 0.05), indicating that the lower volumes seen in the TG mice may prevent excessive increases in left ventricular filling pressures.

	DISCUSSION

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In vivo -adrenergic agonist responses in the mouse.   Acute -adrenergic stimulation produces multiple cardiovascular effects, including increases in afterload and preload. Direct inotropic effects are varied as described in the literature. Both positive and negative inotropic effects are described in the same experiment over time. Ross et al. (19) described an initial negative inotropic effect followed by a positive inotropic effect in perfused mouse hearts, whereas Montgomery et al. (14) described the opposite in isolated mouse papillary muscles with early positive inotropy and late negative inotropy. In our studies, we see a sustained increase in pressure (Fig. 3). dP/dt_max increases as well in response to phenylephrine, although this index of contractility is sensitive to increases in preload (10), so positive inotropy cannot be inferred. When the load-independent variables of E_es, PRSW, and the dP/dt_max-EDV slope are used, we see that there is marked reduction in contractility with phenylephrine in wild-type mice in the -chloralose-urethane studies, indicating that the direct myocardial effect is negative inotropy. Of note, this important phenotypic characterization would not have been possible without simultaneous measurements of pressure and volume. Contractility is not significantly altered in the avertin phenylephrine studies, and this likely relates to the marked baseline depression in contractility that avertin produces.

Adrenergic agonist responses in troponin I mutant mice and interaction with anesthesia.   Insights into the mechanism underlying the contractile abnormalities can be found from previous isolated tissue and heart studies with the troponin I mutant mice. The absence of the protein kinase C phosphorylation sites predicts greater preservation of actomyosin ATPase activity (and thus force production) by the myofilament in response to protein kinase C agonists. Protein kinase C agonists include phenylephrine and high calcium (3, 11). In isolated papillary muscles, Montgomery et al. (14) studied responses to phenylephrine in these troponin I mutants and found a greater preservation of force in the transgenic mice. We studied the effects of various levels of extracellular calcium on perfused heart mechanics in the troponin I mutants (13). At lower levels of calcium there is relative dysfunction in the troponin I mutants, but at higher levels of perfusate calcium there is increased inotropy. Thus based on the isolated perfused heart studies we concluded that the troponin I mutants have an exaggerated response to a range of calcium, suggesting that a physiological role of these troponin I protein kinase C phosphorylation sites is to attenuate myofilament force responses to altered levels of calcium. With this steeper slope in response to calcium, the transgenic mice are especially sensitive to a transition from increased to decreased contractility compared with wild-type mice.

Thus with -chloralose-urethane anesthesia the response to phenylephrine results in preservation of contractility by maintaining actomyosin ATPase activity in the transgenic mice, and this is quite consistent with previous isolated papillary muscle studies (14). The opposite results with avertin are also consistent with our previous studies. We previously showed increased sensitivity to low calcium in perfused hearts from the transgenic mice (13). Avertin is an alcohol-based anesthetic, and alcohol reduces intracellular calcium in mouse myocytes (4). This may explain in part the increased sensitivity to avertin in the transgenic mice, although because dobutamine (which increases intracellular calcium) only partially restores contractility, other effects of avertin are also likely present.

Responses to dobutamine are also very different between -chloralose-urethane and avertin. There are minimal increases in contractility with -chloralose-urethane, although marked increases with avertin. This may again relate to the underlying differences in the two anesthetic agents. -Chloralose-urethane produces relatively high heart rates and contractility, so there is only a limited response to additional stimulation with dobutamine. This is consistent with findings from other investigators who have concluded that the mouse heart functions at near maximal contractility in the basal state (17). Conversely, avertin produces negative chronotropic and inotropic effects so that with -adrenergic stimulation there are marked inotropic and chronotropic responses. The absence of any differential response to dobutamine in the transgenic mice supports the hypothesis that protein kinase A phosphorylation of troponin I is predominantly at serines 23 and 24 and does not involve serines 43 and 45, which were mutated in the current mouse model (15).

Dynamic volume abnormalities.   In both the -chloralose-urethane and avertin studies we find leftward shifts in the pressure-volume relationships. These are dynamic and not related to structural abnormalities. Our previous studies have shown normal histology, heart weights, and heart-to-body weight ratios (12, 13). Furthermore, the volume abnormalities are only found at some interventions, illustrating the dynamic nature of this phenomenon. In the -chloralose-urethane studies these are seen in the presence of the preserved inotropy associated with phenylephrine and therefore may simply be a reflection of increased contractility. However, in the avertin studies, at baseline and with phenylephrine, we find reduced ventricular volumes associated with negative inotropy. The volume loading experiments provide a mechanistic understanding of the leftward volume shifts, as with volume loading there is evidence that there is a steeper diastolic pressure-volume relationship in the transgenic mice (Fig. 6). This indicates that the smaller volumes preserve lower filling pressures, and this appears, at least in part, due to abnormalities in active relaxation (tau). Similar findings are found in the transgenic mice with the avertin studies during pressure loading by phenylephrine, when volumes are at the highest of all the conditions studied (Table 4). At this relatively high volume there is also a marked increase in tau. Active pressure relaxation is closely related to the decay phase of the calcium transient (2), and consistent with this we previously found prolonged calcium transients with reduced levels of systolic and diastolic calcium in the transgenic mice (12). Thus the prolonged calcium transients may lead to an inability to increase volumes in response to volume or pressure loading.

In conclusion, these data support the hypothesis that -adrenergic reduction in myocardial force production is mediated in vivo through protein kinase C phosphorylation of troponin I (-chloralose-urethane). Conversely, in vivo -adrenergic responses are not mediated through troponin I protein kinase C phosphorylation. These data also illustrate that altering the myofilament force-calcium relationship may also result in in vivo increased sensitivity to negative inotropy. Thus choice of a negative inotropic anesthetic agent (avertin) can lead to profound contractile dysfunction. Finally, in vivo pressure-volume relationships indicate that the left ventricle may avoid elevated filling pressures due to delayed calcium transients by reducing ventricular volumes.

	GRANTS

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This work was supported in part by National Institutes of Health Grants HL-03826 (to G. A. MacGowan), DA-00401 (to M. Mathier), and HL-68083 (to S. G. Shroff), and the McGinnis Chair research funds (to S. G. Shroff).

	FOOTNOTES

 

Address for reprint requests and other correspondence: G. A. MacGowan, Freeman Hospital, Dept of Cardiology, Newcastle upon Tyne NE7 7DN, UK (E-mail: guy.macgowan{at}nuth.nhs.uk)

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.

	REFERENCES

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1. Baan J, van der Velde ET, de Bruin HG, Smeenk GJ, Koops J, van Dijk AD, Temmerman D, Senden J, and Buis B. Continuous measurement of left ventricular volume in animals and humans by conductance catheter. Circulation 70: 812–823, 1984.[Abstract/Free Full Text]
2. Camacho SA, Brandes R, Figuerdo VM, and Weiner MW. Ca²⁺ transient decline and myocardial relaxation are slowed during low flow ischemia in rat hearts. J Clin Invest 93: 951–957, 1994.[Web of Science][Medline]
3. Dorn GW II. Adrenergic pathways and left ventricular remodeling. J Card Fail 8, Suppl 6: S370–373, 2000.
4. Duan J, McFadden GE, Borgerding AJ, Norby FL, Ren BH, Ye G, Epstein PN, and Ren J. Overexpression of alcohol dehydrogenase exacerbates ethanol-induced contractile defect in cardiac myocytes. Am J Physiol Heart Circ Physiol 282: H1216–H1222, 2002.[Abstract/Free Full Text]
5. Feldman MD, Erikson JM, Mao Y, Korcarz CE, Lang RM, and Freeman GL. Validation of a mouse conductance system to determine LV volume: comparison to echocardiography and crystals. Am J Physiol Heart Circ Physiol 279: H1698–H1707, 2000.[Abstract/Free Full Text]
6. Glower DD, Spratt JA, Snow ND, Kabas JS, Davis JW, Olsen CO, Tyson GS, Sabiston DC Jr, and Rankin JS. Linearity of the Frank-Starling relationship in the intact heart: the concept of preload recruitable stroke work. Circulation 71: 994–1009, 1985.[Abstract/Free Full Text]
7. Hart CYT, Burnett JC, and Redfield MM. Effects of avertin versus xylazine-ketamine anesthesia on cardiac function in normal mice. Am J Physiol Heart Circ Physiol 281: H1938–H1945, 2001.[Abstract/Free Full Text]
8. Kass DA, Hare JM, and Georgakopoulos D. Murine cardiac function. A cautionary tail. Circ Res 82: 519–522, 1998.[Free Full Text]
9. Kono A, Maughan WL, Sunagawa K, Hamilton K, Sagawa K, and Weisfeldt ML. The use of left ventricular end-ejection pressure and peak pressure in the estimation of the end-systolic pressure-volume relationship. Circulation 70: 1057–1065, 1984.[Abstract/Free Full Text]
10. Little W. The left ventricular dP/dt max-end-diastolic volume relation in closed chest dogs. Circ Res 56: 808–815, 1985.[Abstract/Free Full Text]
11. MacGowan GA, Du C, and Koretsky AP. High calcium and dobutamine positive inotropy in the perfused mouse heart: myofilament calcium responsiveness, energetic economy, and effects of protein kinase C inhibition. BMC Physiol 1: 12, 2001.[CrossRef][Medline]
12. MacGowan GA, Du C, Cowan DB, Stamm C, McGowan FX, Solaro RJ, Koretsky AP, and Del Nido PJ. Ischemic dysfunction in transgenic mice expressing troponin I lacking protein kinase C phosphorylation sites. Am J Physiol Heart Circ Physiol 280: H835–H843, 2001.[Abstract/Free Full Text]
13. MacGowan GA, Evans C, Hu TCC, Debrah D, Mullet S, Chen HH, McTiernan CF, Stewart AFR, Koretsky AP, and Shroff SG. Troponin I protein kinase C phosphorylation sites and ventricular function. Cardiovasc Res 63: 245–255, 2004.[Abstract/Free Full Text]
14. Montgomery DE, Wolska BM, Pyle WG, Roman BB, Dowell JC, Buttrick PM, Koretsky AP, Del Nido P, and Solaro RJ. -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.[Abstract/Free Full Text]
15. Noland TA Jr, Guo X, Raynor RL, Jideama NM, Averyhart-Fullard V, Solaro RJ, and Kuo JF. Cardiac troponin I mutants. Phosphorylation by protein kinases C and A and regulation of Ca²⁺-stimulated MgATPase of reconstituted actomyosin S-1. J Biol Chem 270: 25445–25454, 1995.[Abstract/Free Full Text]
16. Pyle WG, Sumandea MP, Solaro RJ, and de Tombe PP. Troponin I serines 43/45 and regulation of cardiac myofilament function. Am J Physiol Heart Circ Physiol 283: H1215–H1224, 2002.[Abstract/Free Full Text]
17. Reyes M, Freeman GL, Escobedo D, Lee S, Steinhelper ME, and Feldman MD. Enhancement of contractility with sustained afterload in the intact heart. Circulation 107: 2962–2968, 2003.[Abstract/Free Full Text]
18. Roman BB, Goldspink PH, Spaite E, Urboniene D, McKinney R, Geenen DL, Solaro RJ, and Buttrick PM. Inhibition of PKC phosphorylation of cTnI improves cardiac performance in vivo. Am J Physiol Heart Circ Physiol 286: H2089–H2095, 2004.[Abstract/Free Full Text]
19. Ross SA, Rorabaugh BR, Chalothorn D, Yun J, Gonzalez-Cabrera PJ, McCune DF, Piascik MT, and Perez DM. The _1B-adrenergic receptor decreases the inotropic response in the mouse Langendorff heart model. Cardiovasc Res 60: 598–607, 2003.[Abstract/Free Full Text]
20. Sharir T, Feldman MD, Haber H, Feldman AM, Marmor A, Becker LC, and Kass DA. Ventricular systolic assessment in patients with dilated cardiomyopathy by preload-adjusted maximal power: validation and noninvasive application. Circulation 89: 2045–2053, 1994.[Abstract/Free Full Text]
21. Suga H and Sagawa K. Instantaneous pressure-volume relationships and their ratio in the excised, supported canine left ventricle. Circ Res 35: 117–128, 1974.[Abstract/Free Full Text]
22. Weiss JL, Frederiksen JW, and Weisfeldt ML. Hemodynamic determinants of the time-course of fall in canine left ventricular pressure. J Clin Invest 58: 751–760, 1976.[Web of Science][Medline]

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