INTRODUCTION

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FOOD RESTRICTION (FR) increases the life span of rodents (27). This intervention also retards the development and severity of age-related diseases and attenuates the physiological decline associated with aging (36, 39). Despite the large literature concerning the impact of FR on a variety of systems, little is known regarding precise effects of FR on the cardiovascular system. It has been observed that baroreflex sensitivity is enhanced (19) and the incidence of cardiomyopathies is reduced (4, 41) by FR. How FR affects the intrinsic characteristics of myocardial performance remains unknown.

Extensive work has been done, on the other hand, regarding the impact of age on myocardial performance, demonstrating that cardiac muscle exhibits a variety of age-related functional alterations. These include an increase in action potential duration and propagation time (7, 8, 24, 33), lengthening of both contraction and relaxation times (6-8, 24), and a decline in the sensitivity of the aged cardiac muscle to -adrenergic stimulation (1, 33, 38). A number of age-associated biochemical alterations may contribute to the aging changes seen at the cellular level. In rodents, one of the most prominent biochemical changes in the aging myocardium is the shift of the myosin isozyme profile from the fast, V₁ isoform to the slow, V₃ isoform (8, 15, 25, 34, 37). This shift is involved in and/or is associated with changes in many of the physiological parameters mentioned above.

If these changes in the mechanical performance and biochemical composition of cardiac muscle represent basic aging processes, then hearts from FR rats may exhibit a retardation in the age-associated changes. Available evidence, however, suggests that FR may actually amplify, rather than retard, some of these changes. Short-term (6 wk) FR prolongs the time to peak tension and relaxation time of papillary muscle (30). Similarly, time to peak tension and time to peak shortening are increased by FR in left ventricular columnar carnae muscle (10). Moreover, both short- (17, 28, 29) and long-term (22, 23) FR induce a shift in the myosin isozyme distribution toward the slow V₃ isoform, a shift which accentuates rather than retards age-associated changes. Not all changes induced by FR, however, enhance the aging phenotype. Short-term FR (11, 18) increased the inotropic response to -adrenergic stimulation in the atria. It also increased the inotropic and chronotropic responsiveness of the isolated working heart preparation to -adrenergic agonists (13).

Of note, most of the available information comes from studies in which animals were exposed to relatively short-term FR (several weeks), such that changes in cardiac performance that mimic aging may merely represent transient responses to energy deprivation. Because the life extension produced by FR is generally proportional to the duration of the treatment (2, 9, 40), knowledge of the changes induced by long-term FR is important for our understanding of the impact of FR on longevity. The aim of the present study was to directly determine whether long-term FR enhances age-associated changes in the heart by studying various parameters of myocardial performance over a wide range of inotropic states.

	MATERIALS AND METHODS

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Animals: housing and diet. Specific pathogen-free, male, Fischer 344 rats were obtained from Charles River at 4 wk of age and housed in the barrier facilities at the Health Science Center in San Antonio. The housing, care, and diet of these animals have been described elsewhere (21, 41). Briefly, rats were caged singly in a room illuminated artificially from 0530 to 1730 h daily. The young rats were allowed to accommodate to their new surroundings for 2 wk. At 6 wk of age they were separated into two groups. The ad libitum-fed rats were allowed free access to food, and their consumption was measured; the FR rats were fed 60% of the amount consumed by the ad libitum-fed animals. The FR rats were fed once a day at 1630 h. Barrier-reared rats were used for three of the groups. A fourth group of rats was purchased later and treated identically to the ad libitum-fed rats described above, except that they were housed in the regular animal facilities. These rats were used for the size control group (see below).

Animals: groups. Four dietary groups were used in this study. The ad libitum long-term group (ALLT) consisted of rats that were fed ad libitum up to the time of their death at 10-13 mo of age. The FR long-term group (FRLT) consisted of rats fed the restricted diet from 6 wk of age until their death at 10-13 mo. The hearts of animals from the ALLT and FRLT groups were quite different in size. Because it is not possible to reduce caloric intake without secondary effects on body weight and heart size, we chose to control for changes in heart size by including a group of younger animals (10 wk) with hearts of similar size to those of the FRLT animals (WC group). These animals, by design, were of different age, but allowed assessment of mechanical performance of hearts of the same size subjected to different dietary regimes. To define the rapidity with which diet induces changes in cardiac mechanics, a group of animals was included (FR short-term, FRST) in which a 3-wk period of FR was instituted after ad libitum feeding for 10-13 mo. This design also allowed evaluation of the impact of FR on hearts that had not undergone substantial anatomic remodeling, i.e., the heart weights of FRST rats do not differ as much from those of the ad libitum-fed controls (ALLT rats), thus alleviating one of the major problems in interpreting results, viz., the problem of normalization.

Surgical preparation. Rats were anesthetized with a standard rodent cocktail (65 mg/ml ketamine, 2 mg/ml acepromazine, and 13 mg/ml xylazine; 0.66 µl/g body wt), and the chest was rapidly opened. The right superior and inferior vena cavae were ligated immediately, and the heart was excised and submerged in oxygenated, cold (4°C) perfusate (composition given below). The severed end of the aorta was located, cleaned, and fed over a 1.2-mm glass tube covered with a silicon rubber tube. The glass tube was connected to a Langendorff perfusion system. The left superior vena cava was tied after the heart had been connected to the perfusion apparatus.

Langendorff preparation. We used a modification of the isovolumic heart preparation described by Wannenburg et al. (35). After the heart was mounted on the perfusion apparatus, a segment of silicon rubber tubing, fitted with glass tubing at the tip, was advanced into the right ventricle through the main pulmonary artery and sutured in place at the base of the pulmonary artery. The coronary sinus and right ventricular Thebesian perfusate flow was collected via this cannula. The left atrium was opened, and a custom-designed balloon made of polyethylene was placed in the left ventricle. The balloon was filled with water and connected to a syringe to manipulate balloon volume. The volume of the balloon wall, the tip of the tubing and pressure transducer, measured by water displacement after withdrawing all fluid from within the balloon, was usually 30-40 µl. This value was included in the calculation of intraventricular volume. The heart contracted isovolumically against the balloon. A pressure transducer (model SPR-524, Millar Instruments, Houston, TX) was placed inside the balloon. The apex of the heart was vented to allow for the drainage of left ventricular Thebesian flow and leak through the aortic valve. Initially, perfusion pressure was set at 60 mmHg and was maintained at this level by adjusting flow of a peristaltic pump (model 7518-00, Cole-Parmer Instruments, Chicago, IL) for ~20 min, the time usually required to instrument the heart. The flow was then kept constant throughout the remainder of the experiment. Pacing wires were attached within 1 mm of each other at the apex of the heart. Pacing rate was set at 300 beats/min. This value was chosen because preliminary trials showed it was higher than the spontaneous rate generated by the maximal dose of isoproterenol. After instrumentation, the heart was allowed 10 min to stabilize so that the experiments were usually started 30 min after the attachment of the heart to the perfusion system.

Pressure measurements. Pressure was recorded at different intraventricular volumes. The signal from the Millar pressure transducer was digitized using an analog-to-digital converter and an amplifier (MP 100 and DA 100, BIOPAC Systems, Goleta, CA) and visualized on a personal computer (Power Macintosh 6100/66, Apple Computer, Cupertino, CA). Data were stored on disk for off-line analyses. The recording system was calibrated to a mercury manometer. Balloons were used only if at 300-µl volume they generated pressures of <3 mmHg.

Perfusate. The perfusate was composed of (in mM) 15 glucose, 140 Na, 5 K, 1.25 Mg, 152 Cl, and 6 N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid. Lidocaine (5 µg/ml) was added to suppress ventricular ectopy. Calcium and isoproterenol were added to the perfusate as described in the experimental protocol (see below). The pH was adjusted to 7.4 at 37°C, and the solution was equilibrated with 100% oxygen. The perfusate was not recirculated.

Protocol. For mounting, instrumentation and equilibration the perfusate contained 1.5 mM calcium. After the stabilization period, pressure-volume curves were constructed with perfusates being changed for all hearts in the following sequence: 1) 1.5 mM, 2) 3.0 mM, 3) 1.0 mM, and 4) 0.85 mM calcium. To the fourth solution (0.85 mM calcium), increasing amounts of isoproterenol were added to yield concentrations of 5) 1 nM, 6) 3 nM, and 7) 10 nM. The volume of the balloon was increased, with increments of 20 or 40 µl, until a plateau of developed pressure (systolic minus diastolic) was reached, so that on average seven to nine measurements were taken for each pressure-volume curve with 2- to 2.5-min intervals. One pressure-volume run took ~25 min, and all pressure-volume runs were usually finished by 3.5 h after the initiation of perfusion.

Data analyses. Several parameters of cardiac mechanical performance were assessed. To characterize ventricular contractile state, developed pressure was plotted as a function of left ventricular volume. Because the hearts from different groups differed in size, the relationship between the developed pressure and the left ventricular volume normalized to left ventricular weight was also constructed. These relations were obtained for all seven perfusate compositions. Pressure-volume relations were usually concave to the abscissa (more so at higher inotropic states) and were approximated by a second-order polynomial. Because the goodness of fit was excellent (correlation coefficient >0.99), the subsequent analyses were all performed using this approximation, allowing precise matching of interpolated volumes for all hearts. Diastolic pressures, obtained by interpolation, at which the heart developed 75% of maximal developed pressure for a given perfusate composition, were compared among the groups.

Statistical analyses. Analysis of variance was used to determine significance of an effect of dietary manipulation. If repeated measurements were made at different calcium or isoproterenol concentrations in the perfusate and at different intraventricular balloon volumes, the analysis of variance for repeated measures was performed. Fisher protected least significant difference test was used for individual group comparisons.

	RESULTS

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Morphometry. As is seen in Fig. 1, FR decreased body weights. The FRLT rats had the lowest and ALLT rats had the highest body weight. The FRST animals had an intermediate body weight, although they were still rapidly losing weight and had not reached a steady state by the time of death (data not shown). The heart weights showed a similar pattern (Fig. 1B). By experimental design, the WC group had the same heart weight as the FRLT group. FRST decreased heart and body weights proportionally, so that the heart weight-to-body weight ratio for the FRST group was not different from that of the ALLT group (Fig. 1C). The heart weight-to-body weight ratio of the FRLT group was slightly, but statistically significantly, higher than that of the ALLT group, suggesting some degree of cardiac mass sparing with this regimen.

View larger version (25K): [in this window] [in a new window]   Fig. 1.   Body weights and heart weights. Body weights (A), heart weights (B), and heart weight-to-body weight ratios (C) for ALLT (10-13 mo old, long-term ad libitum fed, n = 10), WC (10 wk old, ad libitum fed; n = 8), FRST (10-13 mo old, short-term food restricted for last 3 wk before death, n = 8), and FRLT (10-13 mo old, long-term food restricted, n = 7) groups are shown. Vertical bars represent means ± SE. Groups that do not share a common symbol are statistically different (P < 0.05).

Pressure-volume characteristics. The isovolumic pressure-volume relation was defined for each heart under a variety of experimental conditions. Figure 2 illustrates the relations for a representative heart when the contractile performance of the heart was altered by changing either calcium or isoproterenol concentration in the perfusate. As shown in this example, each pressure-volume relation could be fitted by a quadratic equation (Fig. 2). The R² values for all hearts were generally >0.99, indicating that the fit was very good. For purposes of analyses, predicted pressure values at given volumes were calculated from the quadratic equations and were used to construct composite plots for each group and each experimental condition. In addition, because the hearts were of different sizes, the volume at which maximal pressure was developed differed, and this, by itself, influenced the slope of the pressure-volume relation. To avoid misinterpretation due to size effects, further analysis was performed after intraventricular volume was normalized to left ventricular weight.

View larger version (18K): [in this window] [in a new window]   Fig. 2.   Pressure-volume relations example. Representative results from a single heart (ALLT) show effects of increasing calcium (A) and isoproterenol (B) on pressure-volume relations. Increases in either calcium or isoproterenol moved pressure-volume relation upward. Relations were fitted by a second-order polynomial, and R2 values were all >0.99.

Effects of altered calcium and isoproterenol concentrations on developed pressure. Pressure-normalized volume curves obtained at different calcium and isoproterenol concentrations are shown in Figs. 3 and 4, respectively. Under conditions of low-calcium perfusate, at all volumes, hearts from both FR groups developed much higher pressures than the hearts from either of the ad libitum-fed groups. Regardless of whether contractile state was enhanced by addition of calcium or isoproterenol, the pressure-normalized volume relations for all groups converged. It is noteworthy that essentially the same results were obtained when the analysis was performed on the absolute volumes (data not shown). When pressures were normalized to maximal developed pressure, the normalized pressure-normalized volume relationships were superimposable for all four groups (data not shown), indicating that under a given experimental condition (calcium and isoproterenol concentrations in the perfusate), the shapes of the length-tension relation for the myocardial tissue from all four groups were similar. Thus maximal pressure was sufficient to characterize the effects of calcium and isoproterenol on contractile performance.

View larger version (22K): [in this window] [in a new window]   Fig. 3.   Pressure-normalized volume relations: calcium. Shown are effects of perfusate calcium on pressure-normalized volume (i.e., left ventricular volume per unit of left ventricular weight) relation. Under low-calcium conditions, hearts from both food-restricted groups developed much higher pressures than hearts from both ad libitum-fed groups. Group descriptions and animal numbers correspond to those shown in Fig. 1. A: 0.85 mM. B: 1.0 mM. C: 1.5 mM. D: 3.0 mM. SE is omitted here for simplicity.

View larger version (21K): [in this window] [in a new window]   Fig. 4.   Pressure-normalized volume relations: isoproterenol. Shown are effects of perfusate isoproterenol on pressure-normalized volume (i.e., left ventricular volume per unit of left ventricular weight) relation. Under low isoproterenol conditions, hearts from both food-restricted groups developed much higher pressures than hearts from both ad libitum-fed groups. Because isoproterenol concentrations were tested in presence of low calcium (0.85 mM), A in Figs. 3 and 4 are identical. Group descriptions and animal numbers correspond to those shown in Fig. 1. A: 0 nM. B: 1 nM. C: 3 nM. D: 10 nM. SE is omitted here for simplicity.

View larger version (35K): [in this window] [in a new window]   Fig. 5.   Maximal developed pressure. Effects of calcium (A) and isoproterenol (B) on maximal developed pressures are shown. At low inotropic states (low calcium and low isoproterenol concentrations), hearts from both food-restricted groups developed much higher pressures than hearts from both ad libitum-fed groups. Group descriptions and animal numbers correspond to those shown in Fig. 1. Because isoproterenol concentrations were tested in presence of low calcium (0.85 mM), left sets of columns in A and B are identical. Groups that do not share a common symbol are statistically different (P < 0.05).

Sensitivity to isoproterenol. Our data suggest that the sensitivity of the heart to isoproterenol is affected by both age and diet. The ALLT group responded minimally to the lowest concentration (1 nM) of isoproterenol (Fig. 6). The other three groups showed significantly greater response than the ALLT group (P < 0.05) and were not different from each other. The difference between the ALLT and WC groups suggests the presence of an age effect. Long-term and even short-term (3 wk) FR restored the sensitivity to isoproterenol in older animals.

View larger version (18K): [in this window] [in a new window]   Fig. 6.   Response to low concentration (1 nM) of isoproterenol. Increases in developed pressure due to 1 nM isoproterenol in low- calcium (0.85 mM) perfusate are shown. ALLT was least-sensitive group, significantly different from rest. No differences among other three groups were observed. Group descriptions and animal numbers correspond to those shown in Fig. 1. * P < 0.05 vs. all other groups.

Diastolic pressure. Figure 7 shows the impact of calcium (A) and isoproterenol (B) on diastolic pressure. An increase in either calcium or isoproterenol led to a decrease in diastolic pressure. At the lowest calcium concentration (0.85 mM), diastolic pressure tended to be lower in the FRLT group. These differences disappeared at the higher calcium concentrations. Likewise, although FRLT had a significantly lower diastolic pressure at the lowest isoproterenol concentration (1 nM), the difference among the groups disappeared at the higher concentrations.

View larger version (24K): [in this window] [in a new window]   Fig. 7.   Diastolic pressure. Effects of calcium (A) and isoproterenol (B) on diastolic pressures are shown. At lowest calcium (0.85 mM) and at lowest isoproterenol concentrations (1 nM), FRLT hearts had diastolic pressures lower than hearts from both ad libitum-fed groups. Diastolic pressure was measured at volume at which developed pressure was equal to 75% of maximal developed pressure. Group descriptions and animal numbers correspond to those shown in Fig. 1. Because isoproterenol concentrations were tested in presence of low calcium (0.85 nM), left sets of columns in A and B are identical. Groups that do not share a common symbol are statistically different (P < 0.05).

Maximal rate of pressure rise and decline. The effects of FR on the maximal rate of pressure rise (dP/dt_max; Fig. 8) were similar to those exerted on the maximal developed pressure (Fig. 5). FR groups had higher dP/dt_max at lower contractile states, but the difference disappeared at higher contractile states.

View larger version (35K): [in this window] [in a new window]   Fig. 8.   Maximal rate of pressure rise, dP/dtmax. Effects of calcium (A) and isoproterenol (B) on dP/dtmax are shown. At low inotropic states (low calcium and low isoproterenol concentrations), hearts from both food-restricted groups had much higher dP/dtmax than hearts from both ad libitum-fed groups. Group descriptions and animal numbers correspond to those shown in Fig. 1. Because isoproterenol concentrations were tested in presence of low calcium (0.85 mM), left sets of columns in A and B are identical. Groups that do not share a common symbol are statistically different (P < 0.05).

View larger version (35K): [in this window] [in a new window]   Fig. 9.   Maximal rate of relaxation, dP/dtmin. Effects of calcium (A) and isoproterenol (B) on dP/dtmin are shown. At low inotropic states (low calcium and low isoproterenol concentrations), hearts from both food-restricted groups had much higher dP/dtmin than hearts from both ad libitum-fed groups. Group descriptions and animal numbers correspond to those shown in Fig. 1. Because isoproterenol concentrations were tested in presence of low calcium (0.85 mM), left sets of columns in A and B are identical. Groups that do not share a common symbol are statistically different (P < 0.05).

Contraction and relaxation times. Contraction time was measured for two contractile states, high calcium and high isoproterenol and two intraventricular volumes (low and high) (Fig. 10). Contraction times for the FR groups were prolonged by ~5-10%.

View larger version (32K): [in this window] [in a new window]   Fig. 10.   Contraction times. Contraction time was measured for 2 highest inotropic states [3.0 mM calcium (A) and 10 nM isoproterenol (B) in perfusate] at low (left set of columns) and high (right set of columns) intraventricular volumes. Both food-restricted groups had longer contraction times than both ad libitum-fed groups. Group descriptions and animal numbers correspond to those shown in Fig. 1. Groups that do not share a common symbol are statistically different (P < 0.05).

View larger version (33K): [in this window] [in a new window]   Fig. 11.   Relaxation times. Relaxation time was measured for 2 highest inotropic states [3.0 mM calcium (A) and 10 nM isoproterenol (B) in perfusate] at low (left set of columns) and high (right set of columns) intraventricular volumes. Food-restricted groups tended to have longer relaxation times than ad libitum-fed groups. Group descriptions and animal numbers correspond to those shown in Fig. 1. Groups that do not share a common symbol are statistically different (P < 0.05).

	DISCUSSION

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This is the first study to examine the effects of long-term FR on cardiac mechanics, and the results show that FR substantially changes mechanical performance. The most pronounced effect was that under the low-calcium perfusate condition, the hearts from both long-term and short-term FR rats (the FRLT and FRST groups, respectively) could develop much higher pressures than the hearts from both young and adult ad libitum-fed rats (WC and ALLT groups, respectively). In addition, we confirmed that both contraction and relaxation times are prolonged by short-term FR and extended this observation to long-term FR. The results of the present study also agree with previous reports in that -adrenergic sensitivity was increased by short-term FR. We showed for the first time that the sensitivity was similarly increased by long-term FR. Although our oldest animals were mature adults, further studies will be needed in senescent rats to see if these changes are persistent, possibly participating in the life-prolonging effects of FR.

Low-calcium perfusate tolerance. The hearts of FR animals developed much higher pressures at 0.85 mM calcium than those of ad libitum-fed rats (Figs. 3 and 5). This observation agrees with previous findings (32) that short-term FR elicited a similar increase in inotropic state at low calcium. The differences in pressure development between the groups disappeared or were greatly decreased at high inotropic states regardless of whether calcium or isoproterenol was used to enhance contractility (Figs. 3-5). This suggests that although the contractile machinery is capable of developing similar maximal pressures, contractile performance is regulated differently among the groups.

Pressure-volume relations. Pressure-volume relations were examined for the four experimental groups (Figs. 3 and 4). Despite differences among the groups in the maximal developed pressure and in the volume at which maximal pressure was achieved, pressure-volume relations for a particular perfusate composition were practically superimposable when normalized to the maximal developed pressure and left ventricular weight. This suggests that cardiac dimensions, such as the unstressed left ventricular chamber volume and left ventricular weight, changed proportionally.

-Adrenergic sensitivity. The effect of short-term FR on -adrenergic sensitivity appears to be tissue specific. Earlier studies have shown that -adrenergic sensitivity was enhanced in adipose tissue (5) and reduced in vascular smooth muscle (18). In the atria, short-term FR (11, 18), but not protein deficiency (3), enhanced the sensitivity to -adrenergic stimulation. In the isolated working heart, protein-calorie malnutrition increased both the sensitivity and responsiveness to -adrenergic stimulation (13). Our results suggest that both short- and long-term FR enhanced isoproterenol sensitivity in the hearts of the same age. We found that in both FR groups and the ALLT group there was a larger increase in developed pressure after the lowest isoproterenol concentration (1 nM) (Fig. 6). Thus this study confirms the known effect of aging to reduce cardiac responsiveness and sensitivity to -adrenergic stimulation in the heart (1, 33, 38). The older ad libitum-fed group (ALLT, 10-13 mo old) responded to the lowest concentration of isoproterenol with a smaller increase in pressure than did the younger ad libitum-fed group (WC, 10 wk old). The age-related differences in inotropic response to isoproterenol were eliminated by either long- or short-term FR.

Contraction and relaxation rates. Changes in the maximal rate of pressure development and relaxation paralleled those of developed pressure. During low- calcium perfusion, hearts from both FR groups had much higher dP/dt_max and dP/dt_min than those from the ad libitum-fed groups (Figs. 8 and 9). When the inotropic state was enhanced by addition of either calcium or isoproterenol, the differences disappeared. These results are not surprising because for all four groups there was a very close linear correlation between the developed pressure and dP/dt_max when ventricular volume was changed.

Contraction and relaxation times. Our observations (Figs. 10 and 11) are in agreement with previous studies which demonstrated that FR prolonged both the contraction (10, 30) and relaxation (30, 31) phases of the cardiac cycle. Several biochemical changes may be responsible for the prolongation of contraction duration. One of the most important determinants of the rate of contraction is the cardiac myosin composition. Both short-term (17, 28, 29) and long-term (22, 23) FR shift the myosin composition from the V₁ to the V₃ isoform. This shift may in part explain prolongation of the time to peak tension.

Short- vs. long-term FR. We included the FRST group to provide data on the rapidity with which diet induces changes in cardiac mechanics and energetics. Prior observations on the time course of myocardial adaptation to dietary manipulations are conflicting. Although it is known that myosin isozyme redistribution occurs within 3 wk of the onset of FR (28, 29), mechanical changes may occur for up to 6 wk after the onset of FR (10). In addition, protein-calorie malnutrition enhances certain indexes of cardiac efficiency within 2 wk of treatment (12, 13), and the whole body basal metabolic rate declines very quickly after the initiation of FR (14, 16, 20, 26), suggesting that the myocardial basal metabolic rate may also decrease. Thus the time course of various adaptations may differ. In the present study, all effects were already present by 3 wk after the onset of FR. The magnitude of these effects was not different between short- and long-term FR, indicating that transformation of the heart in response to FR is a relatively rapid and long-lasting process.

Limitations of the study. This study must be interpreted in light of experimental limitations. First, the number of interventions necessitated that the experiments run for ~3.5 h. This is a relatively long time for the isolated heart preparation, especially in view of the fact that we used crystalloid perfusion. It was notable that we used coronary perfusion pressures of 60 mmHg, which tended to minimize edema. In addition, we found less than a 15% decline in peak systolic pressure within the first 2 h of the study (before isoproterenol infusion), suggesting our preparations were stable, and there was uniform and strong response to the -agonist. Thus we are comfortable that decay of the preparation did not substantially affect our data.

Summary. In summary, FR altered many aspects of cardiac mechanical performance. Both contraction and relaxation phases of the cardiac cycle were prolonged, the heart's ability to develop pressure under low perfusate calcium was enhanced, and the sensitivity to -adrenergic stimulation was increased. Most alterations were present within 3 wk of FR and persisted if FR was maintained. This was demonstrated by the similarity between FRST and FRLT groups. Some of the changes, such as the increase in the sensitivity to -adrenergic stimulation, were opposite to ordinary age-related trends. These changes may contribute to the beneficial effects of FR on age-related diseases. Others, such as prolongation of time to peak tension and half-relaxation time, amplified the aging trends. Thus FR has a complex impact on cardiac mechanical function that is not transient, but that represents long-term adaptation to reduced energy intake.