The combined effects of endurance run training and renal hypertension on cytosolic Ca2+ concentration ([Ca2+]c) dynamics and Na+-dependent Ca2+ regulation in rat left ventricular cardiomyocytes were examined. Male Fischer 344 rats underwent stenosis of the left renal artery [hypertensive (Ht), n = 18] or a sham operation [normotensive (Nt),n = 20]. One-half of the rats from each group were treadmill trained for >16 wk. Cardiomyocyte fura 2 fluorescence ratio transients were recorded for 7 min during electrical pacing at 0.5 Hz, 2 mM extracellular Ca2+ concentration, and 29°C. The rate of [Ca2+]c decline was not changed by run training in the Nt group but was reduced in the Ht group. At 7 min, cardiomyocytes were exposed to 10 mM caffeine in the absence of Na+ and Ca2+, which triggered sarcoplasmic reticular Ca2+ release and suppressed Ca2+efflux via Na+/Ca2+ exchanger. External Na+ was then added, and Na+-dependent Ca2+ efflux rate was recorded. Treadmill training significantly enhanced Na+-dependent Ca2+efflux rate under these conditions in the Nt group but not in the Ht group. These data provide evidence that renal hypertension prevents the normal run training-induced modifications in diastolic [Ca2+]c regulation mechanisms, including Na+/Ca2+ exchanger.
- sodium ion/calcium ion exchange
- sodium ion/calcium ion exchanger
- fura 2
- sarcoplasmic reticulum
cardiac dysfunction during renal hypertension has been attributed, in part, to altered regulation of cytosolic free Ca2+ concentration ([Ca2+]c) (6, 8, 16, 31, 32). Isolated cardiomyocytes of renal hypertensive (Ht) rats have been shown to possess a decreased rate of [Ca2+]cdecline during relaxation (16, 31) and an increased L-type Ca2+ current (8), whose combined effects include increased intracellular Ca2+ load and residual myocardial activation during diastole. Those [Ca2+]c regulatory mechanisms responsible for maintaining intracellular Ca2+ load are the sarcolemmal (SL) Na+/Ca2+ exchanger (NXC1) and the SL Ca2+-ATPase, both of which have been found to operate at depressed activities in renal Ht rats (1). Because NCX1 is thought to contribute significantly more than SL Ca2+-ATPase to the maintenance of intracellular Ca2+ load on a beat-by-beat basis (3), it has been proposed that an agent or condition that would augment NCX1 may reestablish normal intracellular Ca2+ load and thereby improve cardiac diastolic function during renal hypertension.
The restoration of cardiac diastolic function has been proposed to be possible through physical exercise like run training (7,22), which has been thought to elicit beneficial effects on [Ca2+]c regulation through enhanced myocardial vascularization (23) and metabolic responses (4), as well as through increased Ca2+affinity of NCX1 (29) and overall activity of NCX1 (9). An enhanced Ca2+ affinity and/or activity of NCX1 would directly reduce intracellular Ca2+ load and could provide some protection against relaxation dysfunction like that observed with renal hypertension (6, 9).
We hypothesized that run training would restore to normal cardiomyocyte [Ca2+]c dynamics and specifically would enhance Na+-dependent Ca2+efflux from cardiomyocytes of renal Ht rats. The present paper describes the effects of endurance run training on isolated cardiomyocyte [Ca2+]c dynamics of renal Ht Fischer 344 male rats, a well-characterized model of renal hypertension (1, 6, 8, 16). We report that cardiomyocyte [Ca2+]c dynamics of renal Ht rats did not respond to run training in a manner similar to those of normotensive (Nt) rats. We also infer that run training significantly enhanced the rate of Na+-dependent [Ca2+]cclearance, presumably via NCX1, in the Nt rat but not in the renal Ht rat.
Male Fischer 344 rats, 2–3 mo old, were housed in a 12:12-h light-dark cycle, given standard rat chow and water ad libitum, and randomly assigned to two blood pressure groups: Nt (n = 20) and Ht (n = 18). Rats in the Ht group underwent stenosis of the left renal artery using surgical hemoclips of 0.17- to 0.23-cm internal diameter to produce a Goldblatt (2 kidney-1 clip) model of renal hypertension as described previously (16). Rats in the Nt group underwent a sham operation.
After 4–6 wk of recovery from surgery, systolic blood pressure was recorded in each rat by using a tail-cuff sphygmomanometer (Gould Instruments, Cleveland, OH) to verify the blood pressure states of the Nt and Ht groups. About one-half of the rats in each group were randomly assigned to a training (Tr) or sedentary (Sed) subgroup. Rats of the Tr subgroups were treadmill trained for at least 24 wk, 5 days/wk. During the initial 8-wk conditioning program, the rats ran for 10 min/day at 20 m/min, and duration and intensity were increased until they ran for 60 min/day, which included 20 min at 20 m/min and 40 min at 26 m/min. The final intensity was maintained for 16–24 wk. Rats were then killed for left ventricular cardiomyocyte isolation. At the time of death, body mass, kidney masses, adrenal masses, spleen mass, and tibia length were recorded, and plantaris muscle was dissected, homogenized, and assayed for citrate synthase activity as previously described (27). Because the training state was established at ∼20 wk after renal artery stenosis, it should be noted that our model of experimental renal hypertension may have had early symptoms of heart failure (6, 13).
Animal care and use conformed to the guidelines accepted by the American Physiological Society. This study protocol was reviewed and received before approval from the Institutional Animal Care and Use Committee at the University of Colorado, Boulder.
Cardiomyocytes were obtained from the left ventricular free wall and septum from rat hearts using methods previously described (16). All chemicals and reagents were obtained from Sigma Chemical (St. Louis, MO) except where noted. Animals were heparinized (250 units ip) and then anesthetized with pentobarbital sodium (35 mg/kg body wt ip; Abbott Laboratories, North Chicago, IL). Hearts were rapidly excised and placed in ice-cold saline solution. The aorta was then cannulated, and the heart was retrogradely perfused by using a modified Langendorff perfusion apparatus that could deliver three different solutions maintained at pH 7.4 and 37°C and bubbled with 95% O2-5% CO2 gas. The first solution was a bicarbonate-based modified Krebs-Henseleit buffer, the second solution was a Krebs-Henseleit buffer containing nominal Ca2+, and the third solution contained an additional 375 U/ml collagenase (Worthington, Freehold, NJ) and 420 U/ml hyaluronidase. Left ventricular and septal myocardium were minced and placed in a collagenase and hyaluronidase solution. Myocyte isolation continued with mechanical agitation. Isolated left ventricular cardiomyocytes were suspended in bicarbonate-based medium 199, plated onto laminin-coated glass coverslips, and incubated for between 2 and 8 h at 37°C in a humidified 5% CO2-20% O2atmosphere.
Coverslips were incubated for 5 min in the presence of 0.05% volume DMSO + 2 μM fura 2-AM (Molecular Probes, Eugene, OR). Each coverslip was removed from the fura 2 loading medium and used to form the bottom plate of a custom-built flow-through chamber (28). The chamber was placed on the stage of an inverted microscope (Nikon Diaphot) fitted with a ×40 oil-immersion objective. Coverslips were superfused with a normal Tyrode solution (in mM: 140 NaCl, 6 KCl, 1 MgCl2, 2 CaCl2, 10 glucose, 2 pyruvate, 5 HEPES, pH 7.4) maintained at 29°C. Cardiomyocytes were electrically paced via field stimulation using platinum electrodes with a stimulus duration of 0.5 ms and voltage of 1.5 × stimulation threshold and at a pacing frequency of 0.5 Hz (Grass Instruments, Boston, MA).
After a cardiomyocyte was identified for study, electrical pacing was ceased for 2 min to reduce any possible discrepancies in cardiomyocyte contractile states due to differential times to identification. Continuous electrical pacing began again, and fura 2 fluorescence ratio (R) and shortening dynamics were recorded at times of 5 and 7 min. At 7 min, and synchronized to the pacing period, the superfusate was rapidly switched to a Na+-free and Ca2+-free Tyrode solution + 10 mM caffeine (in mM: 140 LiCl, 6 KCl, 1 MgCl2, 10 glucose, 2 pyruvate, 5 HEPES, 10 caffeine, pH 7.4). After 5 s, during which time [Ca2+]c reached a new steady state, the superfusate was rapidly switched to a Ca2+-free Tyrode solution + 10 mM caffeine (in mM: 140 NaCl, 6 KCl, 1 MgCl2, 10 glucose, 2 pyruvate, 5 HEPES, 10 caffeine, pH 7.4). During this latter caffeine exposure, Ca2+ was removed from the cytosol via Na+-dependent efflux across the SL. R dynamics were recorded during caffeine exposures and underwent characterization only if the respective cardiomyocyte had functionally recovered after the caffeine exposure. The criteria used to indicate functional recovery were the maintenance of resting length and the preservation of monophasic fluorescence and shortening dynamics elicited by electrical stimulation. The numbers of cardiomyocytes that underwent the above protocol were 50 Nt+Sed, 69 Nt+Tr, 54 Ht+Sed, and 59 Ht+Tr.
Measurements of [Ca2+]c dynamics.
Fura 2 fluorescence was monitored at 510 nm and induced with a fluorescence system (IonOptix, Milton, MA) fitted with optical filters of 400 and 360 nm. This choice of filters takes advantage of a linear relationship between [Ca2+]c and R when one excitation wavelength ≥400 nm is used (18). Fluorescence intensities were recorded as photon-counting rates using a personal computer. The value for myocyte fluorescence background was determined for each cell by superfusion of Ca2+-free Tyrode + 1 μM digitonin for 4 min, which released cytosolic fura 2, and the subsequent measure of fluorescence with Ca2+-free Tyrode as superfusate. Another measure of myocyte fluorescence with Ca2+-free Tyrode + 10 mM caffeine as superfusate was also taken and incorporated as fluorescence background for the caffeine exposures.
Custom-made software was used to analyze the R transients recorded during electrical pacing, and the characteristics of resting R (Rrest), peak minus resting R (Rdiff), and two exponential rate constants, k rise andk fall, which are the rate of [Ca2+]c rise during electrical pacing and decline, respectively, were determined by nonlinear, least squares fitting of the following double-exponential function to the recorded R transient Equation 1where Ramp is a theoretical amplitude att = 0.
Peak R after caffeine exposure (Rcaff) was measured as an estimate of sarcoplasmic reticulum (SR) Ca2+ load. The fraction of SR Ca2+ load released by electrical stimulation was also estimated as the value of Rdiff immediately before caffeine exposure divided by Rcaff. A single-exponential function was fit to the R transients recorded during the last 3.5 s of the first caffeine exposure to determine the R at the new [Ca2+]c equilibrium (Requil) and the rate constant to reach that equilibrium (k equil). The first 1.5 s were considered to be strongly influenced by relatively fast Ca2+regulatory events, i.e., high-affinity Ca2+ buffering, whose time constants are on the order of 10 ms (2). Therefore, analyzing the last 3.5 s was conservatively selected as the time frame within which to characterize the slower Ca2+handling mechanisms, i.e., SL Ca2+-ATPase, mitochondrial uptake, low-affinity Ca2+ buffering, and the cycling of Ca2+ through the SR. A single-exponential function was also fit to R transients recorded during the subsequent Na+-rich caffeine exposure to determine the rate constant of Na+-dependent Ca2+ clearance during efflux across the SL (k efflux). An example of a recorded R transient during electrical stimulation and caffeine exposure, the quality of fits, and the meanings of the R characteristics are illustrated in Fig.1.
All analyses were performed using SPSS version 6.1 (SPSS, Chicago, IL). To test for morphological differences between the Nt and Ht groups and between the Sed and Tr subgroups, a 2(Nt, Ht) × 2(Sed, Tr) ANOVA was performed on all variables describing body mass, systolic blood pressure, kidney masses, adrenal masses, spleen mass, and citrate synthase activity. To test for the effects of blood pressure state, training state, and pacing duration on cardiomyocyte [Ca2+]c dynamics, a 2(Nt, Ht) × 2(Sed, Tr) × 2(5 min, 7 min) repeated-measures ANOVA was performed on all variables recorded during electrical pacing. To test for the effects of blood pressure state and training state on variables recorded during the caffeine exposures, a 2(Nt, Ht) × 2(Sed, Tr) ANOVA was performed. For all variables, Duncan's multirange post hoc test was applied to determine significant differences among Nt+Sed, Nt+Tr, Ht+Sed, and Ht+Tr subgroups at each time point. All data are presented as means ± SE, and statistical significance was assigned at the P < 0.05 and P < 0.01 levels.
Characteristics of the animal model used in this study are presented in Table 1. The systolic blood pressure in the Ht group, ∼190 mmHg, was ∼35 mmHg higher than that in the Nt group and has been termed severe hypertension (14). Increased right kidney mass (∼25%) and decreased left kidney mass (∼50%) in the Ht group collectively suggested that stenosis of the left renal artery successfully reduced blood flow to the left kidney and induced renal hypertension like that described by others (6,13, 14, 16, 31, 32). In addition, because the time between renal artery stenosis and death was on the order of ≥20 wk, the hearts of the Ht group may have been close to a state of decompensation, as described previously (6, 13).
Treadmill training induced an increase in plantaris muscle citrate synthase activity (∼20%) consistent with the known effects of endurance run training (11, 15, 17, 21), and the depressed body mass (∼12%) of the Tr subgroups was also consistent with the known effects of run training in male rats (11, 15, 21). It is interesting to note that both renal hypertension and treadmill training induced an increase in adrenal masses and a decrease in spleen mass (Table 1). These results may be indicative of a morphological manifestation of a physiological and/or psychological stress in these male Fischer 344 rats that may be associated with renal hypertension and treadmill training (5, 25).
[Ca2+]c dynamics during electrical pacing.
There was no significant “pacing duration” effect for the [Ca2+]c characteristics Rrest, Rdiff, k rise, ork fall between 5 and 7 min of electrical pacing, thus signifying that the [Ca2+]c regulatory mechanisms of these cardiomyocytes had achieved steady state after 5 min of electrical pacing under these conditions.
Measures for resting and peak [Ca2+]c, reflected by Rrest and Rdiff (Fig.2 A), respectively, were not different between the Nt and Ht groups and their respective Tr subgroups after 5 and 7 min of electrical pacing. The temporal characteristics of the R transients, however, highlighted some important differences in the training adaptations of cardiomyocyte [Ca2+]c regulation in the Nt and Ht groups. The rate constant k rise, which characterized the rate of [Ca2+]c rise during electrical pacing, was increased significantly (P < 0.05) by run training across both groups (Fig. 2 B). The results fork rise suggested that the rates of inward Ca2+ current and/or SR Ca2+ release were enhanced by run training in both the Nt and Ht groups.
Values for k fall, which characterized the rate of [Ca2+]c decline, were not significantly changed by run training in the Nt group but were significantly lower after run training in the Ht group (Fig. 2 C). Becausek fall characterized the sum of the rates of those mechanisms responsible for cytosolic Ca2+ removal, no net change in k fall found for the Nt group after run training may be the result of no change in any of the Ca2+ removal mechanisms or the result of an increase (or decrease) in the rate of SR Ca2+-ATPase accompanied by a commensurate decrease (or increase) in the rate of NCX1. The dramatically lower k fall in the Ht+Tr subgroup compared with Ht+Sed implied that either one or both of the rates of SR Ca2+-ATPase and NCX1 were significantly reduced by run training during renal hypertension.
[Ca2+]c dynamics during caffeine exposures.
Characteristics of the caffeine-induced [Ca2+]c transients are presented in Table2. Rcaff, which indicated peak [Ca2+]c after caffeine exposure, was not significantly different among any of the four subgroups. Values for Rdiff for the electrically stimulated [Ca2+]c transient immediately before caffeine exposure were significantly higher in the Tr subgroups (P < 0.01), specifically by ∼100% in the Nt group and by ∼30% in the Ht group. The fractions of SR Ca2+release, which was defined as the ratio of Rdiff to Rcaff, were higher in the Tr subgroups of these cardiomyocytes (P < 0.05). These results suggested that, of those cardiomyocytes that remained functional after full SR Ca2+ release, the total SR Ca2+ load was not changed by run training, but the fraction of SR Ca2+released during a single contraction was increased significantly by run training. This result indicated a modification in systolic [Ca2+]c regulation that was achieved by run training in both the Nt and Ht groups.
The values for k equil, which represented the rate at which a [Ca2+]c steady state was reached when SR Ca2+ release channels were open and NCX1 was blocked, were reduced by run training in the Nt group but not in the Ht group. This indicated that run training in the Nt group reduced the rate at which a [Ca2+]c steady state could be achieved under these conditions and, therefore, induced a net reduction in one or more of the following: the rate of SR Ca2+-ATPase, the SR release channel conductance, the rate of Ca2+ transport within the SR, or the rates of other slower Ca2+ removal mechanisms. Because there was no change in k equil after run training in the Ht group, either these Ca2+ regulatory mechanisms were left relatively unchanged by run training or some of these mechanisms were oppositely and proportionally changed by run training.
The values for R at the new [Ca2+]cequilibrium, which represented the new [Ca2+]c steady state after caffeine exposure, were not significantly different among the four subgroups. This result indicated that [Ca2+]c at the time of initiating Na+-dependent Ca2+ efflux was similar in all four subgroups. The values ofk efflux, which reflected the rate of Na+-dependent [Ca2+]c clearance during caffeine exposure, were enhanced significantly by run training in the Nt group but not in the Ht group (Table 2 and Fig.3). It should be noted thatk efflux was recorded during the same conditions as k equil with one added avenue of Ca2+ removal, namely through NCX1. Therefore, to conclude the resultant effect of run training on the rate of NCX1 required a simultaneous consideration of the results found for bothk efflux and k equil, as described below.
For the Nt+Sed subgroup, the rate of Na+-dependent [Ca2+]c clearance during caffeine exposure,k efflux, was relatively low, and the rate of reestablishing [Ca2+]c equilibrium during caffeine exposure, k equil, was relatively high. Therefore, the rate of reestablishing [Ca2+]cequilibrium did not significantly suppress the value for the rate of Na+-dependent [Ca2+]c clearance, and the rate of NCX1 was unquestionably relatively low for the Nt+Sed subgroup. For the Nt+Tr subgroup, the rate of Na+-dependent [Ca2+]c clearance during caffeine exposure was high, and the rate of reestablishing [Ca2+]c equilibrium was low. Therefore, the rate of reestablishing [Ca2+]c equilibrium significantly suppressed the value for the rate of Na+-dependent [Ca2+]c clearance, and the rate of NCX1 was unquestionably relatively high or perhaps even higher than the value of k efflux recorded for the Nt+Tr subgroup. In other words, the values recorded fork efflux afforded conservative comparisons for any modification in the rate of Na+-dependent [Ca2+]c clearance by NCX1 that may have occurred with run training. The simultaneous increase ink efflux and decrease ink equil found after run training in the Nt group collectively suggested that the rate of NCX1 was significantly enhanced by run training. However, there was no similar apparent change in either k efflux or k equiland, therefore, no similar apparent change in the rate of NCX1 with run training in the Ht group.
The present study provides direct evidence to suggest that some cardiomyocyte systolic Ca2+ regulatory mechanisms are enhanced by run training in both Nt and renal Ht male rats. For example, the rate of [Ca2+]c rise after electrical stimulation and fractional SR Ca2+ release was found to increase with run training in both the Nt and renal Ht populations studied. However, the present study also provides evidence to suggest that the cardiomyocyte diastolic Ca2+ regulatory mechanisms of renal Ht male Fischer 344 rats do not adapt to run training the same as those mechanisms of their Nt counterparts. Specifically, cardiomyocyte Ca2+ regulation of these Nt rats adapted to run training in a manner consistent with an increased reliance on Na+-dependent transsarcolemmal Ca2+removal. This apparent heavier reliance on transsarcolemmal Ca2+ removal after run training could enhance left ventricular relaxation during diastole and protects against intracellular Ca2+ overload but was evidently unavailable during renal hypertension in this animal model.
Of particular importance in considering the normal effects of run training on diastolic [Ca2+]c regulation, we found k fall to be unchanged by run training in the Nt group. Therefore, the SR Ca2+-ATPase and NCX1 activity either were unchanged or were oppositely and commensurately changed by run training. To further identify which, if any, cytosolic Ca2+ removal mechanisms were affected by run training, we subsequently observed the rate of Na+-dependent [Ca2+]c clearance,k efflux, which was increased after run training in the Nt rats. These results in isolated cardiomyocytes were consistent with previous reports that run training in Nt rats resulted in an increase in the Ca2+ affinity of NCX1 of isolated vesicles (29) and in the functional activity of NCX1 of isovolumic hearts (9). Although we do not have direct evidence for run training effects on SR Ca2+-ATPase and NCX1, we surmise that the normal cardiomyocyte adaptation of male Fischer 344 rats to run training includes a decrease in the rate of SR Ca2+-ATPase and a commensurate increase in the rate of NCX1 activity.
The influence of run training on cardiomyocyte diastolic [Ca2+]c regulation of renal Ht rats, however, was strikingly dissimilar to that of Nt rats. We observed a significant decrease in the rate of [Ca2+]c decline during electrical pacing, k fall, after run training of renal Ht rats. This effect alone leads us to conclude that diastolic [Ca2+]c regulation is not improved, but rather diminished, on a beat-by-beat basis by run training during renal hypertension. We further observed no significant change in the Na+-dependent [Ca2+]c clearance,k efflux, during caffeine exposure in cardiomyocytes of run-trained Ht rats. Collectively, these data suggested that run training in renal Ht rats reduced the rate of SR Ca2+-ATPase but did not significantly affect the rate of NCX1 activity. Therefore, instead of inducing an enhanced transsarcolemmal Ca2+ removal, run training diminished diastolic [Ca2+]c regulation during renal hypertension.
Taken at face value, the above inferences indicate that the state of renal hypertension prevents the enhancement of NCX1 that would otherwise normally be expected after endurance run training. However, it must be recognized that, because caffeine exposure to cardiomyocytes opens and maintains open the SR release channels, our measure of Na+-dependent [Ca2+]c clearance,k efflux, under these conditions relates indirectly to the rate of NCX1 activity during relaxation after an electrically stimulated contraction. During caffeine exposure, cytosolic Ca2+ can reach the NCX1 by way of the SR, which is a route normally unavailable during relaxation. Nevertheless, the simultaneous consideration of the two rates of [Ca2+]c equilibration and subsequent Na+-dependent [Ca2+]c clearance, both measured during caffeine exposure, provided a reasonable albeit qualitative conclusion that run training normally enhances NCX1 (see last paragraph of results).
The present results imply that the intrinsic activity, capacity, or driving force for Na+/Ca2+ exchange is increased after treadmill training in male Fischer rats. It is possible that the intrinsic NCX1 activity or density was enhanced in the Nt male Fischer rats after run training (10, 12, 20, 29) and yet did not occur in the renal Ht rats. In addition, the driving force for Na+/Ca2+ exchange, which is theoretically determined as the difference between the Nernst potential for Na+/Ca2+ exchange (E NaCa), i.e., E NaCa= 3E Na − 2E Ca(19, 26), and the membrane potential, may have been enhanced by run training through one of the following three conditions:1) a greater [Ca2+]c, which reduces E Ca, 2) a lower cytosolic Na+ concentration, which elevatesE Na, or 3) a lower membrane potential. At the present time, we do not have or know of any direct evidence to better identify which of these possibilities may have occurred. Other direct measures of NCX1 activity by patch-clamp analysis, for example, may be useful for identifying the degree to which run training modifies the NCX1 intrinsic activity, although any significant effects of run training on intracellular Na+and/or Ca2+ regulation must be examined by other techniques.
The present demonstration of a run training-induced increase in the Na+-dependent [Ca2+]c clearance rate in cardiomyocytes of the Nt male Fischer 344 rats contradicts our earlier finding of a run training-induced decrease in the Na+-dependent [Ca2+]c clearance rate in cardiomyocytes of female Sprague-Dawley rats (17). Considering that these two studies were performed under identical laboratory conditions, it is highly likely that these differential effects of endurance run training on cardiomyocyte function were sex and/or strain dependent (21). In addition, treadmill training of male Fischer 344 rats elicited increases in adrenal masses and a decrease in spleen mass in both the Nt and Ht groups, whereas treadmill training had no significant effect on the adrenals and spleen masses of female Sprague-Dawley rats (17). The observed training-induced increase in the rate of Na+-dependent Ca2+ efflux may be thought to be secondary to the increased adrenal masses and/or decreased spleen mass and/or associated psychological stress of treadmill training (5, 25). However, because we observed similar morphological responses in the adrenals and spleen for both the Nt and Ht groups without witnessing similar responses in diastolic [Ca2+]cregulation for both the Nt and Ht groups, we conclude at this time that the renal hypertensive state inhibited the normal run training-induced changes in diastolic [Ca2+]c regulation independent of the possible psychological stress of treadmill training.
In conclusion, the hypothesized protective benefits of run training on cardiomyocyte diastolic [Ca2+]c regulation are apparently unavailable in male rats with renal hypertension. It is clear from the present study that the state of renal hypertension significantly suppressed or modified the normal effects of run training on cardiomyocyte diastolic [Ca2+]c regulation after electrical stimulation. Therefore, run training in this animal, which we infer normally enhances diastolic [Ca2+]c regulation by Na+/Ca2+ exchange, cannot be considered a predictable device for improving diastolic function and reducing intracellular Ca2+ load during renal hypertension.
The authors are grateful for the expert technical assistance of Nathan J. Cleveland, Jinger S. Gottschall, Sarah J. Nickoloff, and M. Charlotte Olsson.
This study was supported by National Heart, Lung, and Blood Institute Grant R01-HL-40306.
Present address of B. M. Palmer: Department of Molecular Physiology and Biophysics, University of Vermont, Burlington, VT 05405.
Address for reprint requests and other correspondence: R. L. Moore, Campus Box 354, Dept. of Kinesiology and Applied Physiology, Univ. of Colorado at Boulder, Boulder, CO 80309–0354 (E-mail:).
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.
- Copyright © 2001 the American Physiological Society