Compensatory concentric hypertrophy is often regarded as an adaptational process to normalize wall stress with hypertension and is frequently manifest with metabolic and functional abnormalities (4). While recent reports have questioned the necessity of wall stress normalization (11), the mechanisms associated with the maladaptive aspects of myocardial hypertrophy are important to understand. To name a few, concentric hypertrophy secondary to pressure overload is associated with enhanced Na+/H+ exchange (24) (NHE), a reduction in beta-adrenergic receptor responsiveness (18), and subsequent altered myocardial inotropic and lusitropic function (4,6,11,18,22,24,25).
Acidosis has long been known to affect cardiac function, such that decrements in intracellular pH compromises protein structure and function and can lead to imbalances in intracellular ion concentrations (1-3,7-9,12-16,21,23,26-29). It has been widely reported that decreasing intracellular pH, as may occur during clinical syndromes such as myocardial ischemia, impairs contractile force (21). Mechanistically, acidosis can impair several key aspects of excitation-contraction coupling (1,7-9,12-16,21,23-29). Acidosis has been shown to inhibit the slow inward current, SR Ca2+ uptake and release, and Na+/Ca2+ exchange activity (7,21,23). However, acidosis has also been shown to increase the peak and time course of the Ca2+ transient (1), suggesting that the uncoupling between the peak Ca2+ transient and myocardial inotropy during acidosis is, in part, due to decreased Ca2+ sensitivity of the contractile elements (1,26).
Several recent studies have suggested that exercise training in normotensive animals increases myofilament Ca2+ sensitivity under normal pH conditions (17,30). Thus, we hypothesized that long-term aerobic exercise training (6 months) in the spontaneously hypertensive rat (SHR) model would likewise improve Ca2+ responsiveness during acidotic stress. While skinned muscle preparations (9,26) have been widely used to examine myofilament sensitivity during acidosis, the relationship between [Ca2+]i and tension in intact preparations differs considerably from that in skinned preparations (9). Therefore, in the present study, we used a whole-heart Langendorff preparation to test whether exercise training in SHR improved left ventricular (LV) Ca2+ responsiveness during hypercarbia-induced acidosis (pH = 6.8).
Animals and exercise training.
Thirty-five 16-wk-old female Wistar-Kyoto rats (WKY) (N = 12) and SHR (N = 23) were obtained from Charles River Laboratories (St-Constant, Quebec, Canada). SHR were randomly assigned to a sedentary (SHR-SED; N = 12) or an exercise-trained (SHR-TRD; N = 11) group. All rats were housed three per cage, maintained on a 12-h light/dark cycle, and fed ad libitum (Harlan Teklad Global Diets, 18% Protein Diet, Madison, WI). Training consisted of progressive low-intensity endurance training at speeds of 20-25 m·min−1, 0% grade, 60 consecutive minutes, 5 d·wk−1 for a period of 24 wk. SHR-SED and WKY were handled daily. Blood pressures and HR were collected throughout the protocol using a tail-cuff apparatus (XBP 1000; Kent Scientific, Torrington, CT). At 40 wk, animals were sacrificed and functional studies were performed. All animals received humane care in compliance with the Principles of Laboratory Animal Care formulated by the National Society for Medical Research and the Guide for the Care and Use of Laboratory Animals prepared by the Institute of Laboratory Animal Resources and published by the National Institutes of Health (NIH Publication No. 85-23, revised 1985).
Rats were studied using echocardiography prior to organ harvest. In brief, animals were lightly sedated with Xylazine (10 mg·kg−1) and ketamine (50 mg·kg−1) IP. After 5 min, images were acquired with the animals in the left lateral decubitus position. A Hewlett-Packard 5500 Sonos (Palo Alto, CA) was used to obtain both two-dimensional and M-mode images using a 12-MHz transducer. Doppler imaging was performed using a sample volume of 5 mm and a paper speed of 100 mm·s−1 at a depth of 4 cm. In accordance with the American Society of Echocardiography conventions, M-mode imaging of the parasternal short axis view allowed for measurement of LV end-diastolic and end-systolic internal dimensions (LVEDD and LVESD, respectively) and anterior and posterior wall thicknesses (AW and PW, respectively). Values were determined by averaging the measurements of three consecutive beats.
Pulsed-wave Doppler was used to assess isovolumic relaxation time (IVRT), isovolumic contraction time (IVCT), and LV ejection time (LVET) using the standard convention. The Doppler sample volume was placed at the entrance of the LV outflow tract and the mitral tip, allowing the acquisition of both the mitral inflow and LV outflow envelopes. The IVRT was defined as the time between aortic valve closure and mitral valve opening. The IVCT was defined as the time between mitral value closure and aortic valve opening. LVET was defined as the duration of the LV outflow envelope.
Rats were anesthetized with sodium pentobarbital (60 mg·kg−1, IP) and heparinized (500 U IV). A thoracotomy was performed and the heart was excised, trimmed of excess tissue, weighed, and immediately immersed in cold (4°C) calcium-free Krebs-Henseleit buffer as previously described (18). The heart was then placed on a Langendorff perfusion apparatus (ML785B2, ADI Instruments, Colorado Springs, CO) and perfused at 16 mL·min−1 (STH pump controller ML175, AD Instruments) with a modified Krebs-Henseleit solution containing, in millimoles per liter: 2.0 CaCl2, 130 NaCl, 5.4 KCL, 11 dextrose, 2.0 pyruvate, 0.5 MgCl2, 0.5 NaH2PO4, 25.0 NaHCO3, and aerated with 95% oxygen and 5% carbon dioxide, pH 7.4. The Langendorff coronary flow rate was selected to closely mimic the in situ perfusion pressure. A drainage cannula was inserted into the apex of the LV cavity through a left atrial incision, and a balloon was inserted into the left ventricle. The pressure-volume relationship was established over a range of filling volumes. Using a Hamilton syringe, balloon volume was increased in 5- to 10-μL increments until an end-diastolic pressure of 30 mm Hg was reached. The balloon volume was then readjusted to elicit an LV end-diastolic pressure (LVEDP) of 11 mm Hg with no further alterations in balloon volume. LV pressure, LVEDP, the maximum rate of positive and negative change in LV pressure (±dP/dT), and perfusion pressure were continuously recorded by means of a data acquisition system (Powerlab®/8SP, AD Instruments). LV developed pressure (LV Dev P) was calculated by subtracting LVEDP from LV systolic pressure. Hearts were paced at 5 Hz (Grass Instruments, Quincy, MA) and immersed in a water-jacketed organ chamber at 37°C.
Baseline was established at pH 7.4. LV performance was then measured in response to incremental [Ca2+]o infusions dissolved in isotonic saline. The peak [Ca2+]o was 4.0 mmol·L−1. To further perturb [Ca2+]i, we also infused the beta-adrenergic receptor agonist isoproterenol (ISO) (1 × 10−8 mol·L−1) concomitant with 4.0 mmol·L−1 Ca2+. Following a washout period, hearts were switched to hypercarbic perfusion (increased CO2 to elicit pH 6.8) and allowed to equilibrate for 7 min. LV performance was once again measured in response to incremental [Ca2+]o infusions and ISO. The peak response to incremental [Ca2+]o infusions and 4.0 mmol·L−1 Ca2+ + ISO were used for data analysis. Following the experimental protocol, LV apical samples were frozen in liquid nitrogen and stored at −80°C for subsequent molecular assays.
Protein assay/Western blot analysis.
Tissue protein abundance and phosphorylation levels in isolated protein were analyzed using Western blot analysis as previously described (18). Target antigens were probed with the following nonphosphorylation-specific monoclonal antibodies: phospholamban (PLB) (Upstate Biotechnology), L-type calcium channel α-1C subunit (Chemican), sodium-calcium exchanger (Swant), glyceraldehyde phosphate dehydrogenase (GAPDH) (Biogenesis), and NHE (Alpha). Phosphorylation-specific polyclonal antibodies Ser 16-PLB (Ser16) and Thr 17-PLB (Thr17) (gift from Dr. J. Colyer, University of Leeds, UK) were also probed. Target bands were normalized to GAPDH measured in the same sample.
Data analysis and interpretation.
Echocardiography-derived hemodynamics, animal/physical characteristics, and protein abundance were compared using a one-way ANOVA. The temporal responses of HR, blood pressure, rate-pressure product (RPP), and the Langendorff isolated heart variables were analyzed with an ANOVA with repeated measures. All ANOVA were followed by a Tukey post hoc analysis. All analyses were performed using SPSS version 12.0 (SPSS Inc., Chicago, IL). Significance was set at an alpha level of P < 0.05. Data are reported as the mean ± SEM.
Figure 1 illustrates the temporal responses of HR, systolic blood pressure (SBP), RPP, and body weight. Throughout the protocol HR, SBP, and RPP were greater in both groups of SHR than in WKY. By 28 wk of age, SHR-TRD showed resting bradycardia without a concomitant reduction in SBP. Table 1 lists the hemodynamic parameters at 40 wk of age. No differences in echocardiography-derived LVET or IVRT were observed between groups. IVCT was significantly lower in WKY compared with SHR-SED (P < 0.001) and SHR-TRD (P < 0.05). No group differences were noted for the Tei Index.
The physical characteristics of all groups are presented in Table 2. Prior to sacrifice, body weight in WKY was significantly greater than both groups of SHR (P < 0.001). Heart weight and heart weight-to-body weight ratio were significantly lower in WKY compared to both groups of SHR. Absolute tibial length was similar between groups; however, heart weight/tibial length was lower in WKY versus both groups of SHR (P < 0.05). Figure 2 illustrates echocardiography-derived LV AW and PW thickness during both the diastolic (panels A and C) and systolic (panels B and D) phases of the cardiac cycle. Figure 2 also illustrates LVEDD and LVESD. During diastole, AW thickness was significantly lower in WKY than both groups of SHR, while training further increased AW thickness compared with SHR-SED (P < 0.05). AW thickness during systole was greatest in SHR-TRD compared with WKY (P < 0.05) and tended to be greater than SHR-SED (P = 0.07). There were no group differences observed for PW thickness during diastole or systole. LVEDD (Fig. 2E) was significantly lower in WKY compared with SHR-SED (P < 0.05) and tended to be lower than SHR-TRD (P = 0.13), while LVESD (Fig. 2F) tended to be lower in WKY relative to SHR (main effect; P = 0.08).
Langendorff isolated heart performance.
Mean LV balloon volume tended to be lower in WKY compared with SHR-TRD (WKY: 64 ± 6 μL for SHR-SED: 86 ± 9 μL, and SHR-TRD: 99 ± 17 μL; P = 0.06). Baseline Langendorff performance is summarized in Table 3. At baseline, LVEDP, LV Dev P, and ±dP/dT were similar between groups. In our model, all hearts were perfused at a constant coronary flow of 16 mL·min−1 with a crystalloid perfusate, allowing for differences in coronary perfusion pressure to be illustrative of coronary vascular resistance. As listed in Table 3, baseline coronary perfusion pressure was greater in both groups of SHR compared with WKY. To quantify LV responsiveness under normal pH conditions, supraphysiologic Ca2+ and ISO were infused into hearts at pH 7.4. As Figure 3 illustrates, LV Dev P similarly increased by approximately 50 mm Hg in all groups with the addition of Ca2+ and ISO.
As Figure 4A illustrates, acidosis markedly impaired LV Dev P in all groups (P < 0.001), but was best preserved in both groups of SHR relative to WKY. With acidosis, LVEDP (panel B) tended to rise most prominently in SHRSED, while coronary perfusion pressure (panel E) tended to increase in all groups. In addition, +dP/dT (panel C) was attenuated during acidosis but was not different between groups (WKY, 2609 ± 277 mm Hg·s−1; SHR-SED, 2975 ± 367 mm Hg·s−1; SHR-TRD 3987 ± 621 mm Hg·s−1; P = not significant).
During acidosis, when the [Ca2+]o was increased to 4.0 mmol·L−1, inotropy (i.e., LV Dev P and +dP/dT) increased in all groups. The addition of 4.0 mmol·L−1 [Ca2+]o alone was sufficient to override the acidosis-induced impairment of inotropy in SHR-TRD but not WKY and SHR-SED. Furthermore, LV Dev P and +dP/dT was not significantly different from its respective baseline performance at pH 7.4 in SHR-TRD. As Figure 4 also illustrates, LV Dev P and +dP/dT were significantly greater in SHR-TRD versus WKY (P < 0.05) at 4.0 mmol·L−1 [Ca2+]o, while +dP/dT was significantly higher in SHR-TRD versus SHR-SED.
To further override the acidosis-induced impairment of inotropy and perturb [Ca2+]i, we superimposed ISO infusion on 4.0 mmol·L−1 [Ca2+]o. The addition of ISO rescued LV Dev P and +dP/dT in WKY (P < 0.05) such that +dP/dT was not different from its respective baseline performance at pH 7.4. Despite the addition of supraphysiologic [Ca2+]o and ISO, LV performance remained significantly impaired relative to baseline in SHR-SED.
Western blot analysis.
Western blot analyses are summarized in Table 4. LV inotropic functional recovery during acidosis with 4.0 mmol·L−1 [Ca2+]o and ISO was positively correlated with PLB phosphorylation at both the Ser16 and Thr17 residues (Fig. 5).
The contractility of striated muscle can be greatly altered by the cellular milieu. For example, myocardial ischemia and some metabolic disorders induce acidosis, which for over a century has been known to depress myocardial contractility (10). In cardiac muscle, acidosis exerts an array of effects on excitation-contraction coupling, with respiratory acidosis (increasing extracellular CO2) producing a more rapid decline in pHi and cardiac contraction than metabolic acidosis (8). To our knowledge, the present study is the first to examine how exercise superimposed on hypertension affects LV tolerance to acidosis. The results from the present study show that in vitro LV performance during respiratory acidosis was better maintained in hypertrophied hearts harvested from SHR relative to normotensive WKY controls. Six months of aerobic exercise training tended to further enhance inotropy during acidosis in SHR. A twofold increase in the [Ca2+]o rescued LV performance to the greatest extent in SHR-TRD. During acidosis, beta-adrenergic agonism coupled with elevated [Ca2+]o also improved the LV performance of WKY to near baseline levels at pH 7.4. Neither calcium nor ISO administration was effective in alleviating the negative inotropy associated with acidosis in SHR-SED. Both PKA- and CAM kinase-mediated PLB phosphorylation at Ser16 and Thr17 residues, respectively, were moderately correlated with LV functional recovery during acidosis. The abundance of other key regulatory proteins such as Na+/H+ exchanger, Na+/Ca2+ exchanger, the L-type Ca2+ channel, and PLB were not correlated to LV functional recovery. Despite our finding that compensated SHR-induced hypertrophy improves myocardial tolerance to acidosis, Ca2+-mediated inotropic strategies were ineffective in rescuing LV performance in the SHR-SED group. Conversely, exercise training induced a myocardial phenotype that preserved the responsiveness to Ca2+-mediated inotropic rescue strategies during acidosis.
A novel finding of the present study was that tolerance to acidosis was greater in both groups of SHR hearts compared with WKY. One explanation for this result is that intracellular pH may have been better maintained near normal physiological values in SHR, secondary to increased Na+/H+ exchanger activity. Enhanced NHE activity has previously been reported in the SHR model (24) and may be the result of either an increased abundance of the exchanger, increased activity of individual exchangers (3), or posttranslational modification of the exchanger (25). In the present study, NHE abundance tended to be greater in both groups of SHR hearts compared with WKY (main effect P = 0.10), perhaps in part providing the substrate for greater NHE activity and the preservation of LV performance during acidosis. Concentric hypertrophy is also associated with the recapitulation of a fetal phenotype (6), which is known to be more resistant to an acidosis-induced impairment in force generation than is adult myocardium (27).
Previous studies have also shown that acidosis impairs the regulation of Ca2+ by depressing SR Ca-ATPase (7), ryanodine gating (15), and Na+/Ca2+ exchange (23). However, despite these acidosis-induced alterations in Ca2+ regulation, the Ca2+ transient amplitude has been shown to be well maintained during acidosis (1,13). Thus, a reduction in myofilament responsiveness to [Ca]i (7,21) via a diminished Ca2+ binding affinity to troponin C (TnC) (29) has been proposed as a primary mechanism responsible for the negative inotropy associated with acidosis (7,14). Acidosis also alters the affinity of TnI for TnC (26) and attenuates myofibrillar ATPase activity (14), which reduces cross-bridge efficiency and cross-bridge cycling rate. In the present study, LV Dev P and +dP/dT were greatest in SHR-TRD, perhaps suggesting a possible mechanistic role for exercise-induced alterations in myofilament Ca2+ sensitivity during acidosis.
Exercise training in normotensive animals has been shown to increase myofilament Ca2+ sensitivity (17). Moore et al. (19) showed that the magnitude of LV cardiomyocyte twitch shortening was similar between exercise-trained and sedentary animals despite a lower cytosolic [Ca2+]i in exercise trained animals. More recently, Wisloff et al. (30), using both an intact and permeabilized cell preparation, demonstrated that intensity-controlled interval training increased myofilament Ca2+ sensitivity compared with sedentary controls. While the underlying molecular and cellular mechanisms for enhanced myofilament responsiveness to Ca2+ following training have not yet been identified, recent data suggest that atrial myosin light chain 1 (aMLC1), a protein correlated with enhanced myofilament Ca2+ sensitivity (20) is more abundant with exercise training (5).
In our study, we attempted to supersede the acidosis-induced alterations in Ca2+ regulation and responsiveness by administering supraphysiologic Ca2+ infusions alone and coupled with ISO. During acidosis, when the [Ca2+]o was increased to 4.0 mmol·L−1, LV contractility was increased in all groups. Although 4.0 mmol·L−1 [Ca2+]o overrode the acidosis-induced impairment of LV Dev P and +dP/dT in SHR-TRD (P = not significant vs baseline at pH 7.4), the magnitude of change from 2.0 to 4.0 mmol·L−1 [Ca2+]o was similar between groups. These data suggest that supraphysiologic Ca2+ infusion can augment LV performance during acidosis, however, at the expense of increasing the LVEDP and perfusion pressure in hypertensive hearts, particularly SHR-SED. With respect to LVEDP, it has been suggested that there is a progressive increase in diastolic [Ca2+]i during acidosis (16). One mechanism by which diastolic [Ca2+]i may increase is increased proton competition for Ca2+ at TnC (28). Another mechanism by which diastolic [Ca2+]i may increase is that proton extrusion via NHE is also increased with acidosis, thereby increasing [Na+]i (2). Thus, the increase in [Na+]i may in turn increase [Ca2+]i via Na+/Ca2+ exchange (2). Enhanced Na+/Ca2+ exchange contributes to the regulation of contractile force, with the caveat that Na+/Ca2+ exchange is also inhibited at low pH (23).
In the present study, the superimposition of ISO on 4.0 mmol·L−1 [Ca2+]o further rescued LV Dev P and +dP/dT in WKY (P < 0.05) such that +dP/dT was not different from baseline performance at pH 7.4. Despite the addition of supraphysiologic [Ca2+]o and beta-adrenergic stimulation, LV performance still remained significantly impaired in SHR-SED. This is consistent with our previous report showing impaired beta-adrenergic responsiveness in SHR-SED under physiologic pH and [Ca2+]o. Beta-adrenergic receptor signaling induces PKA-mediated "downstream" phosphorylation of key SR Ca2+ handling proteins such as PLB at the Ser16 residue (18). Beta-adrenergic receptor agonism also increases the calcium transient and subsequently activates a calcium/calmodulin-dependent protein kinase (CamKII) resulting in the phosphorylation of PLB at the Thr17 residue. Of note, acidosis itself results in CamKII-mediated phosphorylation of the Thr17 residue (12). In the present study, we observed a positive correlation between Ser16 and Thr17 phosphorylation and indices of functional recovery during acidosis. These data suggest that SR Ca2+ regulation is also mechanistically linked to myocardial inotropy during acidosis. However, given that these correlations were moderate in nature and there were no differences in our subset of key Ca2+ regulatory proteins, myofilament calcium sensitivity remains an important mechanistic target.
SBP was markedly elevated in SHR throughout the protocol, exhibiting a 36% increase above normotensive controls prior to sacrifice. The antihypertensive effect of exercise in the present study was comparable to that found in previous work using a shorter exercise protocol (18). In this investigation, we found that exercise training superimposed on hypertension further augmented the extent of myocardial hypertrophy. Echocardiography-derived AW thickness during both the systolic and diastolic phases of the cardiac cycle were greater in SHR-TRD than WKY. The observation that training potentiates LV hypertrophy associated with hypertension has been noted by other investigators (18). The enhanced LV hypertrophy observed with exercise training (AW) is interesting in light of the lower RPP in SHR-TRD than SHR-SED.
The SHR model was selected for our study because it closely mimics the clinical course of untreated essential hypertension in humans. It has been documented that concentric hypertrophy occurs in SHR between 6 and 12 months of age, decompensating to heart failure near 15 months (6). We chose to study these animals at 10 months of age for two reasons: 1) to characterize the effects of a 24-wk exercise training protocol in this model, and 2) because fibrosis is not yet accelerated in this model (22). There are several limitations that may affect the interpretability of the current study. First, the causes of hypertension in SHR are polygenic and do not necessarily reflect the genetic anomalies associated with hypertension in humans (6). Second, the absence of a normotensive exercise group limits our understanding of the exercise adaptation independent of hypertension. Third, despite monitoring the pH of the extracellular buffer, we were unable to assess the magnitude of change on intracellular pH of the myocyte. Fourth, we did not measure [Ca2+]i or the calcium transient amplitude. Fifth, coronary flow normalized to heart weight was significantly greater in WKY compared with SHR, perhaps exposing WKY to a more severe relative acidotic stress. Sixth, basal protein abundance and phosphorylation were not determined.
Despite these limitations, the present data suggest that hypertension-induced compensated hypertrophy, both alone and coupled with exercise training, improves myocardial tolerance to acidosis. Although calcium-mediated inotropic rescue strategies were effective in improving LV performance in SHR-TRD and WKY during acidosis, they were ineffective in rescuing SHR-SED. These data suggest that the functional recovery of SHR-TRD and WKY during acidosis may be due to the preservation of myofilament responsiveness to [Ca]i and Ca2+ regulatory mechanisms not evident in SHR-SED.
This study was supported by a BGIA from the American Heart Association (J.R.L.) and the National Institutes of Health (S.R.H., HL33921).
1. Allen, D. G., and C. H. Orchard. The effects of changes of pH
on intracellular calcium transients in mammalian cardiac muscle. J. Physiol. (Lond.)
2. Bountra, C., and R. D. Vaughan-Jones. Effect of intracellular and extracellular pH
on contraction in isolated mammalian cardiac tissue. J. Physiol.
3. Cingolani, H. E. Na+/H+ exchange hyperactivity and myocardial hypertrophy: are they linked phenomena? Cardiovasc. Res.
4. Cingolani, O. H., X. P. Yang, M. A. Cavasin, and O. A. Carretero. Increased systolic performance with diastolic dysfunction in adult spontaneously hypertensive rats. Hypertension
. 41:249-254, 2003.
5. Diffee, G. M., E. A. Seversen, T. D. Stein, and J. A. Johnson. Microarray expression analysis of effects of exercise
training: increase in atrial MLC-1 in rat ventricles. Am. J. Physiol.
6. Doggrell, S. A., and L. Brown. Rat models of hypertension
, cardiac hypertrophy and failure. Cardiovasc. Res.
7. Fabiato, A., and F. Fabiato. Effects of pH
on the myofilaments and the sarcoplasmic reticulum of skinned cells from cardiac and skeletal muscles. J. Physiol.
8. Fry, C. H., and P. A. Poole-Wilson. Effects of acid-base changes on excitation-contraction coupling in guinea-pig and rabbit cardiac ventricular muscle. J. Physiol.
9. Gao, W. D., P. H. Backx, M. Azan-Backx, and E. Marban. Myofilament Ca2+
sensitivity in intact versus skinned rat ventricular muscle. Circ. Res.
10. Gaskell, W. H. On the tonicity of the heart and blood vessels. J. Physiol.
11. Hill, J. A., M. Karimi, W. Kutschke, et al. Cardiac hypertrophy is not a required compensatory response to short-term pressure overload. Circulation
12. Hulme, J. T., J. Coyler, and C. H. Orchard. Acidosis alters phosphorylation of Ser16
of phospholamban in rat cardiac muscle. Pflugers Arch.
13. Hulme, J. T., and C. H. Orchard. Effect of acidosis on Ca2+
uptake and release by sarcoplasmic reticulum of intact rat ventricular myocytes. Am. J. Physiol.
14. Kentish, J. C., and W. G. Nayler. The influence of pH
on the Ca2+
-regulated ATPase of cardiac and white skeletal myofibrils. J. Mol. Cell Cardiol.
15. Kentish, J. C., and J. Z. Xiang. Ca2+
-and caffeine-induced Ca2+ release from the sarcoplasmic reticulum in rat skinned trabeculae: effects of pH
and Pi. Cardiovasc. Res.
16. Kohmoto, O., K. W. Spitzler, M. A. Movesian, and W. H. Barry. Effects of intracellular acidosis on [Ca2+
] transients, transsarcolemmal Ca2+
fluxes, and contraction in ventricular myocytes. Circ. Res.
17. Lankford, E. B., D. H. Korzick, B. M. Palmer, B. L. Stauffer, J. Y. Cheung, and R. L. Moore. Endurance exercise
alters the contractile responsiveness of rat heart to extracellular Na+
. Med. Sci. Sports Exerc.
18. MacDonnell, S. M., H. Kubo, D. L. Crabbe, et al. Increased phospholamban phosphorylation with exercise
training improves diastolic function in hypertension
19. Moore, R. L., T. I. Musch, R. V. Yelamarty, et al. Chronic exercise
alters contractility and morphology of isolated rat cardiac myocytes. Am. J. Physiol.
20. Morano, I., K. Hädicke, H. Haase, M. Böhm, E. Erdmann, and M. C. Schaub. Changes in essential myosin light chain isoform expression provide a molecular basis for isometric force regulation in the failing human heart. J. Mol. Cell Cardiol.
21. Orchard, C. H., and J. C. Kentish. Effects of changes of pH
on the contractile function
of cardiac muscle. Am. J. Physiol.
22. Pfeffer, J. M., M. A. Pfeffer, M. C. Fishbein, and E. D. Frohlich. Cardiac function and morphology with aging in the spontaneously hypertensive rat. Am. J. Physiol.
23. Philipson, K. D., M. M. Bersohn, and A. Y. Nishimoto. Effects of pH
exchange in canine cardiac sarcolemmal vesicles. Circ. Res.
24. Schussheim, A. E., and G. K. Radda. Altered Na+
-exchange activity in the spontaneously hypertensive perfused rat heart. J. Mol. Cell Cardiol.
25. Siczkowski, M., J. E. Davies, and L. L. Ng. Na+
exchanger isoform 1 phosphorylation in normal Wistar-Kyoto and spontaneously hypertensive rats. Circ. Res.
26. Solaro, R. J., S. C. El-Saleh, and J. C. Kentish. Ca2+
and the regulation of cardiac myofilament force and ATPase activity. Mol. Cell. Biochem.
27. Solaro, R. J., J. A. Lee, J. C. Kentish, and D. G. Allen. Effects of acidosis on ventricular muscle from adult and neonatal rats. Circ. Res.
28. Vaughan-Jones, R. D., W. J. Lederer, and D. A. Eisner. Ca2+
ions can affect intracellular pH
in mammalian cardiac muscle. Nature
. 301:522-524, 1983.
29. Wattanapermpool, J., P. J. Reiser, and R. J. Solaro. Troponin I isoforms and differential effects of acidic pH
on soleus and cardiac myofilaments. Am. J. Physiol.
30. Wisloff, U., J. P. Loennechen, G. Falck, et al. Increased contractility and calcium sensitivity in cardiac myocytes isolated from endurance trained hearts. Cardiovasc. Res.
Keywords:©2006The American College of Sports Medicine
EXERCISE; HYPERTENSION; pH; CONTRACTILE FUNCTION; MYOCARDIUM