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The present study investigated the effects of gender on intracellular [Ca2+] ([Ca2+]i) in freshly isolated rat cardiac myocytes. Changes in [Ca2+]i in response to varied extracellular [Ca2+], different stimulus frequencies and addition of caffeine and isoprenaline were monitored using fura-2 in both male and female cardiac myocytes. Increasing extracellular [Ca2+] and stimulus frequency resulted in significant increases in peak [Ca2+] and the amplitude of the Ca2+ transient in both male and female cardiac myocytes. However, as extracellular [Ca2+] was raised, peak [Ca2+] and the amplitude of the Ca2+ transient increased significantly more in male than female cardiac myocytes. In addition a significant difference between male and female cells at each stimulus frequency was apparent. The time course of decay of the Ca2+ transient was significantly slower in female cardiac myocytes when compared with male cardiac myocytes, along with significantly slowed times to peak shortening and 50% relaxation, and a reduced extent of shortening. There was no significant difference in the amplitude of caffeine-induced [Ca2+]i responses between male and female cells, however, [Ca2+]i increased more readily in male cells than in female cells when isoprenaline was added. The data demonstrate that, under a variety of conditions, intracellular [Ca2+] rises to higher levels in cardiac myocytes from male as compared to female rats.

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OBJECTIVE: The aim of this study was to gain further insights into the consequences of insulin-dependent diabetes mellitus on cardiomyocyte calcium handling. METHODS: The effects of steady state and transient changes in stimulus frequency on the intracellular Ca2+ transient and cell shortening were examined in left ventricular cardiomyocytes isolated from the hearts of control and streptozotocin-induced diabetic rats. RESULTS: During steady state stimulation diabetic rat cardiomyocytes displayed a slower decay of the Ca2+ transient and longer times for maximum cell shortening and re-lengthening. At 1.5 mM extracellular [Ca2+], increasing stimulus frequency over the range 0.2-1.0 Hz led to an increase in resting and peak [Ca2+]i as well as the amplitude of the transient in both the control and diabetic groups. At frequencies greater than 0.4 Hz the amplitude of the transient was significantly depressed in diabetic rat cells and this was not normalized by increasing extracellular [Ca2+] to 2.5 mM. Recovery of sarcoplasmic reticulum (SR) Ca2+ release was measured from the time course of restitution of the intracellular Ca2+ transient. In both control and diabetic rat cardiomyocytes recovery of the transient occurred in two phases. In diabetic rat myocytes, the initial rapid phase of restitution at intervals <1 s was markedly slowed. The fraction of Ca2+ recirculating between the SR and the cytosol was estimated from the decline in amplitude of transients following post-rest potentiation. There was no difference in this fraction between control and diabetic rat cells either at 1.5 or 2.5 mM extracellular [Ca2+]. CONCLUSION: The blunted frequency response of diabetic rat cardiomyocytes at frequencies greater than 0.4 Hz is consistent with reduced SR Ca2+ uptake leading to reduced SR Ca2+ content and subsequent release. At stimulus intervals greater than 1 Hz this is likely to be exacerbated by slower recovery of SR Ca2+ release. Despite the evidence for depressed SR Ca2+ uptake, the relative amount of Ca2+ recirculating within diabetic rat cardiomyocytes remains unaltered. This is most likely due to an accompanying reduction in Ca2+ efflux from the cell due either to depressed Na+/Ca2+ exchanger activity, or an elevation in intracellular Na+ levels.

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1. Pyruvate has been shown to enhance the contractile performance of cardiac muscle when provided as an alternative substrate to glucose. The aims of the present study were to determine whether the inotropic effects of pyruvate are due to increased mobilization of intracellular Ca2+ ([Ca2+]i) and to compare the effects of pyruvate on [Ca2+]i levels in myocytes from normal and diabetic animals. 2. Fura-2 was used to monitor [Ca2+]i in ventricular myocytes isolated from control and streptozotocin-treated male Wistar rats. The experiments were performed at 25 degrees C, with an extracellular [Ca2+] of 1.5 mmol/L and either 10 mmol/L glucose or 10 mmol/L pyruvate as the substrate. 3. In myocytes from both control and diabetic rats, increasing the stimulus frequency from 0.33 to 2.0 Hz resulted in significant increases in resting and peak [Ca2+]i as well as in the amplitude of the [Ca2+]i transient, irrespective of substrate. Compared with glucose, pyruvate significantly increased resting and peak [Ca2+]i and the amplitude of the [Ca2+]i transient at each stimulus frequency in myocytes from both control and diabetic animals. However, the extent of potentiation of the [Ca2+]i transient amplitude produced by pyruvate was significantly less in myocytes from the diabetic rats. 4. The rate of restitution of the [Ca2+]i transient was used as an index of the rate of Ca2+ cycling by the sarcoplasmic reticulum (SR). Pyruvate enhanced the rate of restitution in control but not diabetic rat cells. 5. The time course of decay of the [Ca2+]i transient was analysed as a measure of the rate of removal of Ca2+ from the cytosol. Pyruvate tended to increase the rate of decay in cells from control but not diabetic animals. The rate of decay was slower in cells from diabetic animals compared with controls. 6. The data reveal that pyruvate increases SR Ca2+ cycling, leading to greater Ca2+ release and an increase in the amplitude of the [Ca2+]i transient. Therefore, it seems highly likely that increased [Ca2+]i mobilization is responsible for the previously reported positive inotropic actions of pyruvate. These effects of pyruvate are attenuated in diabetic rat cells, which may reflect an impaired capacity of mitochondria in diabetic hearts to oxidize pyruvate, thus limiting potential energetic benefits.

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The present study investigated the acute effects of taurine on intracellular Ca2+ ([Ca2+]i) in normal and diabetic cardiac myocytes. [Ca2+]i was monitored using fura-2 in single myocytes isolated from control or streptozotocin-treated rats and paced at frequencies between 0.33 Hz and 2.0 Hz in the absence or presence of 20 mM taurine. Increasing stimulus frequency resulted in significant increases in resting and peak [Ca2+]i, and amplitude of the Ca2+ transient in both control and diabetic myocytes. The amplitude of the Ca2+ transient and the extent of its increase with increasing frequency was, however, significantly lower in the diabetic myocytes. Taurine significantly increased resting [Ca2+]i, peak [Ca2+]i, and the amplitude of the Ca2+ transient in both control and diabetic myocytes at all stimulus frequencies examined. The degree of potentiation of the Ca2+ transient decreased with increasing stimulus frequency in control cells but not in diabetic cells. In the absence of taurine the decay of the Ca2+ transient was significantly slower in diabetic than control myocytes. Taurine was without significant effect on the time course of the Ca2+ transient decay in control cells, however, in diabetic cells it significantly accelerated the rate of decay. The data demonstrate directly that taurine is able to increase [Ca2+]i and the amplitude of the Ca2+ transient in both normal and diabetic cardiac myocytes. In addition several of the effects of taurine appeared to be more pronounced in diabetic than control cells.

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1. The contractile function of diabetic hearts is impaired. In addition, the responsiveness of diabetic cardiac muscle to sympathetic stimulation is altered. Previous studies have revealed a depressed response to beta-adrenoceptor stimulation; however, the response to alpha-adrenoceptor activation remains controversial. Because alpha- and beta-adrenoceptor agonists increase cardiac contractility, largely through increased mobilization of intracellular Ca2+, the aim of the present study was to investigate the effects of alpha- and beta-adrenoceptor stimulation on intracellular Ca2+ handling in cardiac myocytes from streptozotocin-induced diabetic rats. 2. Intracellular Ca2+ was measured using fura-2. Under basal conditions (27 degrees C, 2.5 mmol/L extracellular [Ca2+], 0.3 Hz stimulation), there was no significant difference in resting or peak Ca2+ levels between control and diabetic cardiomyocytes. However, the time course of the intracellular Ca2+ transient was significantly prolonged in cells from diabetic hearts. 3. The beta-adrenoceptor agonist orciprenaline (at 10(-7) and 10(-6) mol/L) increased the amplitude of the Ca2+ transient in both groups; however, the extent of potentiation was less in diabetic compared with control cardiomyocytes. Orciprenaline decreased the duration of the transient to the same extent in both groups. 4. The alpha-adrenoceptor agonist phenylephrine (at 10(-7) and 10(-6) mol/L) had no effect on the Ca2+ transient in control myocytes but caused a significant concentration-dependent increase in its amplitude in diabetic cardiomyocytes. Phenylephrine had no effect on the time course of the transient in either group. 5. These results demonstrate differential effects of insulin-dependent diabetes on the responsiveness of cardiomyocytes to alpha- and beta-adrenoceptor stimulation. The heightened response to alpha-adrenoceptor stimulation observed in diabetic cardiomyocytes may partly compensate for the diminished myocardial beta-adrenoceptor response.

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The mechanisms underlying pulsus alternans in pressure-over-load (POL) cardiac hypertrophy were investigated. Simultaneous measurements of force and intracellular Ca2+ (using fura 2) in right ventricular papillary muscles under conditions that produced mechanical alternans, revealed alternation of the amplitude of the Ca2+ transient together with alternation of force in some POL muscles. Instances when alternation of force occurred without any apparent alternation of the Ca2+ transient were also observed. Exposure of muscles to 5 microM ryanodine significantly attenuated mechanical alternans, thereby implicating a role for the sarcoplasmic reticulum (SR) in this process. The time course of restitution of force and the intracellular Ca2+ transient were, however, unchanged in POL hearts, indicating that SR Ca2+ cycling was not appreciably slowed. The fraction of Ca2+ recirculated intracellularly was derived from studies of postextrasystolic potentiation and was significantly reduced in the POL hearts, suggesting additional differences in cellular Ca2+ regulation. We conclude that changes in Ca2+ handling play an important role in the onset of mechanical alternans in POL hypertrophy, but that additional factors, most likely a slowing of crossbridge cycling rate, are also likely to be important.

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1. Simultaneous recordings of tension and [Ca2+]i during NANC-mediated relaxation were made in the rat anococcygeus muscle under various conditions. 2. In muscles precontracted with guanethidine, nitrergic stimulations at 2 Hz produced a rapid decrease in both the tension and [Ca2+]i. 3. The nitric oxide synthase inhibitor, NG-nitro-L-Arginine (NOLA, 100 mumol/L) completely abolished the decreases in the [Ca2+]i and force response of the NANC-mediated relaxation. 4. Noradrenergic-mediated contractions elicited by electrical field stimulation were potentiated by the addition of NOLA. In the absence of NOLA, the motor responses were larger in magnitude at 10 Hz stimulation than at 2 Hz. After NOLA, both the force response and the associated rise in [Ca2+]i were substantially increased in comparison to the control stimulations. Proportionately the potentiation of the 2 Hz response was of a far greater magnitude than that of the 10 Hz response. 5. The guanylate cyclase inhibitor methylene blue (10 mumol/L), partially inhibited the force and [Ca2+]i response of the NANC relaxation. 6. Following exposure of the muscles to the sarcoplasmic reticulum Ca(2+)-ATPase inhibitor, cyclopiazonic acid, (10 mumol/L) the responses to NANC stimulation were inhibited. The attenuated relaxation response displayed a bi-phasic timecourse and the Ca2+ change in comparison to that of the control was markedly smaller. In some cases, a relaxation was observed with no detectable change in the [Ca2+]i. 7. The results suggest that part of the relaxation response observed with NANC-mediated relaxation in the rat anococcygeus is dependent on Ca2+ sequestration into the sarcoplasmic reticulum. However, other Ca2+ lowering mechanisms and possible Ca2+ independent mechanisms may also contribute to the NANC relaxation response.

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We have investigated the effects of 2,3-butanedione monoxime (BDM) and mannitol on Ca2+ metabolism in rabbit cardiac muscle. Simultaneous measurements of force and intracellular Ca2+ were made in right ventricular papillary muscles loaded with the fluorescent Ca2+ indicator fura-2. At a BDM concentration of 2 mM, peak isometric force was only 52% of control values and this was reduced to 18% at a concentration of 5 mM. The peak of the Ca2+ transient decreased by 8% at 2 mM BDM and by 18% at the higher concentration. In the presence of 362 mM mannitol peak isometric force decreased by 78% and there was a tendency for the peak of the Ca2+ transient to increase. A combination of 362 mM mannitol with 5 mM BDM completely inhibited force production despite peak Ca2+ levels that were no different from control values. In myothermic experiments under similar conditions the latency release protocol of Gibbs et al. (1988) and the BDM protocol of Alpert et al. (1989) were used to derive independent estimates of tension-independent (activation) heat in the same muscle. For both protocols the heat-stress relationship was well fitted by first-order linear regression. The activation heat estimate was significantly higher when measured with the latency release technique (2.31 mJ/g) compared with the BDM protocol (1.24 mJ/g). Our results confirm that in rabbit cardiac muscle low concentrations of BDM (2 mM) cause a marked inhibition of force development with little apparent effect on peak Ca2+ levels. Therefore, the lower activation heat estimates under these conditions may not be due to a reduced intracellular Ca2+ concentration. It is possible that the higher activation heat values obtained with protocols not involving chemical interventions may include the energy usage contributed by cellular processes that presumably do not occur in the presence of BDM and mannitol.

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The mechanical and energetic consequences of long-term volume-overload (VOL) hypertrophy have been investigated in rabbits and compared with the consequence in sham-operated controls (SOC). Hypertrophy was induced by creating an aortocaval shunt, and the mechanical, biochemical, and energetic properties of the compensated heart were examined approximately 12 wk later. At 27 degrees C and a stimulus frequency of 1 Hz there were no significant changes in peak stress development, 10-90% rise times, shortening velocity, work, and mechanical power output. There was, however, a prolongation of contractile duration. The inverse relationship between peak stress and cross-sectional area was unchanged in the VOL and SOC groups. Polarographic and myothermic experiments were made on papillary muscles. Hypertrophy produced a small increment in basal metabolism. In isometric studies there were no significant changes in either the activation heat magnitude or the slope of the heat-stress relationship. In isotonic contractions there was no change in work output or total enthalpy (heat + work), and as a result mechanical efficiency was unchanged. A force-length-area (FLA) analysis of the isotonic data showed no significant change in intercept or FLA contractile efficiency. Biochemical studies showed no significant difference in the myosin isoenzyme profile at the time of death. The Ca(2+)-stimulated adenosinetriphosphatase activity of the sarcoplasmic reticulum was unchanged as were the enzymatic activities of mitochondrial citrate synthase and alpha-ketoglutarate dehydrogenase. Interestingly essentially the same data were obtained from the hearts of four animals in failure and from the hearts of seven compensated animals.(ABSTRACT TRUNCATED AT 250 WORDS)

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The mechanical and energetic consequences of a short-term volume overload (STVOL) hypertrophy and short-term pressure overload (STPOL) hypertrophy have been investigated in rabbits and compared with short-term sham-operated controls (STSOC). Hypertrophy was induced either by creating an aortocaval shunt (volume overload) or by banding the pulmonary artery (pressure overload). Suitable papillary muscles were excised from the hearts 8-10 days after the surgical procedure. At 27 degrees C and a stimulus frequency of 1.0 Hz, peak stress development of the STVOL preparations was significantly reduced from the control group, whereas no significant difference in peak stress development was evident between the STPOL and STSOC groups. Surprisingly, the STPOL preparations displayed pulsus alternans after only 8-10 days of inducing the overload. At steady-state conditions, the isometric 10%-90% rise times, the 90%-10% relaxation times, and the 1/2-widths were not significantly different between the treated and control groups. In isotonically contracting muscles working against a range of afterloads, the enthalpy (energy) and work output of the STVOL and STPOL preparations were depressed compared to the STSOC preparations; the differences were statistically significant for the STVOL group. Due to the parallel change in work and enthalpy, the mechanical efficiency was unaltered. A force-length-area (FLA) analysis, analogue of the pressure-volume-area (PVA) analysis, was applied to the isotonic data of this study. The isotonic enthalpy at the various load levels was plotted against the measured FLA and the data were fitted by linear regression. It was evident that the FLA correlated closely with the energy used. The STVOL and STPOL mean total energy:FLA regression lines lay parallel to but were below the STSOC line, signifying a drop in the activation heat, although this reduction did not achieve statistical significance. It is concluded that significant mechanical and energetic changes are evident after a short-term volume overload although earlier work has shown that these differences are absent at the later, compensated stage of hypertrophy. Changes associated with the pressure overload model suggest a disturbance in calcium regulation: this effect is also seen in long-term pressure overload.

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The pattern of contractions elicited after rest periods of 0.25-10 min duration was investigated in right ventricular papillary muscles from control and hypertrophied rabbit hearts. Hypertrophy was induced by pressure overload following coarctation of the pulmonary artery. In control hearts, the first post-rest contraction was always of a smaller amplitude than the preceding steady-state (0.5 Hz stimulation) contractions, and the amplitude of this first post-rest contraction decreased as the rest interval increased. In contrast, the amplitude of the first post-rest contraction of muscles from hypertrophied hearts exceeded the steady-state amplitude for rest durations of up to at least 2 min. In the hypertrophied muscles, force in the first post-rest contraction (expressed as a percentage of the pre-rest steady-state) was potentiated compared to the control muscles at all rest intervals studied. There was no significant difference in the second post-rest contraction between control and hypertrophied muscles at any rest interval. Following the second post-rest contraction, force increased monotonically toward the steady-state levels in all the muscles. The recovery of force was, however, somewhat faster in the hypertrophied muscles. Upon resumption of 1-Hz stimulation following rest intervals of 2 min or greater, pulsus alternans were invariably observed in the hypertrophied muscles but never in the control muscles. These differences in the non-steady-state contractile behavior of ventricular muscle from normal and hypertrophied hearts are suggestive of some alteration in the normal pattern of Ca2+ translocation in pressure overload hypertrophy of rabbit ventricle.(ABSTRACT TRUNCATED AT 250 WORDS)

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The mechanical and energetic consequences of long-term pressure-overload (POL) hypertrophy have been investigated in rabbits and compared with sham-operated controls (SOC). Hypertrophy was induced by banding the pulmonary artery of young rabbits and examining the mechanical, biochemical, and energetic properties of the compensated heart 10-16 wk later. Experiments were undertaken on papillary muscles from the hypertrophic hearts. At 27 degrees C and a stimulus frequency of 1 Hz there was a modest depression of peak stress development but no significant changes in isometric rise times and one-half widths or in isotonic maximum velocity of shortening and power output. The inverse relationship between peak stress and cross-sectional area (CSA) was practically identical in the POL and SOC groups. Both polarographic and myothermic investigations were made on papillary muscles. Hypertrophy nearly halved basal metabolism, and in isometric contractions there was increased isometric economy due to a combination of a lower stress cost and a reduced activation heat. Hypertrophy did significantly depress the extent of shortening leading to a reduced work output per beat. In isotonic contractions the reduced work output was offset by a reduced energy output such that there was no significant change in suprabasal mechanical efficiency. Biochemical studies showed that the transition of myosin isoenzymes to the V3 form was essentially complete in the POL group, but that the SOC group was also predominantly V3 when the animals were killed. There was a significant 30% decline in the Ca2(+)-stimulated adenosinetriphosphatase activity of the sarcoplasmic reticulum. It is concluded that in long-term compensated hypertrophy of rabbit hearts there are only a few mechanical and energetic differences between control and hypertrophic muscles. The changes that can be detected appear to predominantly reflect disturbances in cellular Ca2+ regulation.

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The energy cost of the onset and relaxation phases of cardiac isometric contractions has been investigated by ergometer controlled-length releases occurring at different times during the contraction cycle, to test the hypothesis that the energy cost of relaxation is normally small. Energy flux has been measured myothermically in 20 or 30 contractions of rabbit papillary muscles. The ergometer releases took place after different delays, starting during the latency period and incrementing in 50 ms steps, until eventually, releases were occurring late into the relaxation phase. The release step was kept constant and of a magnitude sufficient to prevent significant redevelopment of active stress at any release interval. The rate of release was several times greater than the maximum shortening velocity of the papillary muscle preparations. The heat production in each train of contractions was measured, but in order to estimate the total energy output, the elastic energy in the muscle-lever system which was removed by the ergometer release had to be added to the heat. This was estimated by integration of the stress-strain relationship found for each muscle. In normal animals the contraction peak, at 27 degrees C and a 1.0 Hz stimulus rate, was located between the 215 and 265 ms release times, at which point the total energy flux was estimated to be 80%-90% of that measured in a normal isometric contraction. Additional experiments were performed in a group of volume-overloaded hearts and the data were compared with results from sham-operated controls.(ABSTRACT TRUNCATED AT 250 WORDS)

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Energy metabolism of quiescent cardiac muscle was studied in the isolated rabbit heart preparation perfused at constant pressure by the Langendorff technique. Oxygen consumption (MVo2), coronary flow rate (CFR) and the steady state concentrations of high energy phosphate compounds were determined in hearts rendered asystolic using modified Krebs-Henseleit (KH) media containing 11 mM glucose as substrate. Basal MVo2 and CFR were significantly higher in hearts arrested by Ca2+ depletion (low Ca KH) compared to K+ excess (high K KH). Substitution of glucose in low Ca KH with a mixture containing glutamate, fumarate and pyruvate (low Ca KH + GFP) resulted in a 25% increase in the basal MVo2 but a 20% decline in CFR. Supplementing the low Ca perfusate with 30 g/l dextran (low Ca KH + dextran) depressed both the basal MVo2 (35%) and CFR (75%). Differences in the basal MVO2 under the different perfusion conditions were not accompanied by significant changes in the tissue levels of ATP, CrP or Cr. Compared to low Ca KH arrested hearts, those perfused with low Ca KH + GFP or low Ca KH + dextran did, however, show significantly lower tissue levels of ADP, AMP and Pi, but higher cytosolic ratios of [ATP]/[ADP][Pi] and [CrP]/[Cr][Pi]. As a consequence of the higher phosphorylation potential the free energy of ATP hydrolysis increased. There was no significant difference in any of these parameters between high K KH and low Ca KH perfused hearts. It is concluded that in the perfused, arrested heart none of the parameters that are used to describe the myocardial energetic state, e.g. free [ADP] or the cytosolic [ATP]/[ADP][Pi] ratio, uniquely correlates with the basal metabolic rate as estimated from MVO2 measurements.

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Basal metabolism has been measured in isolated whole hearts from rabbits and compared with myothermic and polarographic measurements on isolated papillary muscles. Hearts were perfused at constant pressure (Langendorff method) using a modified Krebs-Henseleit solution (KH) with glucose as substrate. Higher levels of basal O2 consumption (MVO2) and coronary flow (CF) were observed when arrest was induced by calcium depletion (low Ca; 0.1 mM CaCl2, 10.0 mM KCl) rather than by potassium excess (high K; 30.0 mM KCl). The metabolic rate of high K arrested hearts was close to earlier myothermic estimates (J. Mol. Cell. Cardiol. 16: 953-962, 1984); polarographic values, however, were about twofold higher, and somewhat higher than the value obtained in low Ca arrested hearts. The addition of erythrocytes, albumin, or dextran significantly reduced CF but did not substantially alter basal MVO2. Basal metabolic rate was substrate- and O2 tension-dependent, and under all experimental conditions there was linear relationship between MVO2 and CF. Extrapolations to zero flow showed that the basal MVO2 values so obtained were similar in low Ca or high K and were not altered by the presence of erythrocytes. Our results show that there are several factors regulating basal metabolism.

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Daunomycin was administered to one of each pair of litter mate rabbits at a weekly dosage rate of 40 mg/m2. Treated animals were killed when their pre-ejection period: left ventricular ejection time ratio (PEP:LVET) reached 0.4 and there was other evidence of cardiac abnormalities or when they had received 12 doses of daunomycin. Langendorff-perfused hearts from the treated animals had lower intrinsic heart rates (16%) and decreased coronary resistance (31%) in the arrested state. There was no significant difference between the basal metabolism of the arrested control and treated hearts but the magnitude of the activation component, measured under beating non-working conditions, was depressed by daunomycin. After the whole heart perfusion studies were complete, approximately 2 h after cardiectomy, papillary muscles were dissected out from the right ventricles and mechanical, myothermic and polarographic studies were undertaken. The resting heat production, in support of the whole heart metabolic data, was practically unchanged by the treatment regime. Peak stress development and work output were similar in both the control and treated groups. In energetic terms the slope of the relationship between total stress development and active heat production per beat was unchanged but there was a 21% depression of the activation heat component in the treated animals. Daunomycin treatment had not altered the work output per contraction or significantly changed energy output and hence mechanical efficiency was unaltered. It is clear that 2 h of Langendorff perfusion does not produce any depression of contractile or energetic properties in papillary muscles.

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The mechanical and energetic performance of the rabbit rectococcygeus preparation have been studied at 27 degrees C. Energy flux has been measured either myothermically (heat production) or by recording the O2 consumption and lactate production of the muscle. The maximal active-to-basal O2 consumption ratio was 2.42. The peak oxidative energy flux was 3.5 mW/g, and the peak initial rate was about 5.0 mW/g. We could find no evidence for an increment in lactate production associated with mechanical activity. The effects of increasing the stimulus duration on the "economy" of force maintenance was assessed by plotting the heat-to-tension ratio against duration. For stimulus periods up to 20 s there was no evidence of a change in the economy: the slope of the relationship was similar in myothermic and O2 consumption experiments with split muscles. When total heat production was plotted against the stress-time integral for stimulus periods up to 60 s at both pH 7.4 and 6.7, there was no change in energy usage in the longer duration tetani (2-60 s). However, the reduction in pH, which had minimal mechanical effects other than prolonging relaxation, did slow the rate of evolution of recovery heat (time constant doubled) and reduced the rate of O2 consumption. It is concluded that the rectococcygeus preparation cannot make use of the energy-saving mechanisms that operate in arterial and several invertebrate smooth muscles.

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Daunorubicin (DNR) was administered to one of each pair of litter mate rabbits at a weekly dosage rate of 40 mg/m2. Treated animals were killed when their pre-ejection period: left ventricular ejection time ratio (PEP:LVET) reached or exceeded 0.4. Mechanical, myothermic and polarographic measurements were made upon papillary muscles obtained from the right ventricle of DNR treated rabbits and their litter mate controls. DNR treatment significantly increased the PEP:LVET ratio (41%) and increased the left ventricular: body weight ratio (24%). Basal metabolism, measured 2 h after cardiectomy, was significantly reduced whether measured myothermically or polarographically: both measurements were highly correlated but the O2 consumption values were higher. Peak stress development was 31% lower in the DNR treated rabbits but this reduction was largely accounted for by a larger cross-sectional area (CSA) of the papillary muscles in this group. There was no change in the slope of the active heat: stress relationships but the stress-independent (activation) heat intercept was depressed. In isotonic studies DNR treatment caused a 57% reduction in work output per beat (relative to controls) and a 39% decline in active energy output. Because of the approximately parallel shift in work and total energy output mechanical efficiency was not significantly changed. It is suggested that part of the basal energy production fall produced by DNR relates to protein synthesis inhibition but that most of the other mechanical and energetic effects are probably explicable in terms of the intrinsic hypertrophic response of the 'failing' heart.

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