Associations between oral complications and days to death in palliative care patients.

PURPOSE: Adverse oral symptoms gradually appear in advanced cancer patients as the disease progresses. We retrospectively investigated the associations between the incidence of oral problems and the days to death (DTD) in patients receiving palliative care. METHODS: The dental assessment sheets and medical charts of 105 patients who had been admitted into the palliative care unit at our hospital were examined. Case data included evaluations of organic and functional oral conditions at the time of admission for all patients. The cohort was divided into two groups according to the DTD as the short group (<28 days from the time of dental assessment until death) and the long group (≥28 days). We compared the incidences of organic and functional oral problems between these groups. RESULTS: Dry mouth, tongue inflammation, and bleeding spots were significantly more frequent in the short group than in the long group (78 vs. 54% for dry mouth, 67 vs. 46% for tongue inflammation, 35 vs. 14% for bleeding spots, respectively; p < 0.05). Tongue coating and candidiasis were comparable between the two groups. Dysphagia was significantly more common in the short group (43%) than in the long group (20%) (p = 0.01), as was assistance with oral health care (76 vs. 50%) (p = 0.01). CONCLUSIONS: Our findings suggest that, during palliative care, oral complications appear more frequently when the DTD period is shorter. These symptoms may be useful indicators when deciding on the proper timing of intensive oral care intervention to decrease oral problems and pain in terminally ill patients.

New-onset rectoanal intussusception may not result in symptomatic improvement after laparoscopic ventral rectopexy for external rectal prolapse.

BACKGROUND: This study was designed to assess defecatory function in patients who underwent laparoscopic ventral rectopexy (LVR) for external rectal prolapse (ERP). METHODS: Thirty-one patients who underwent evacuation proctography 6 months postoperatively were assessed. Preoperative proctography had been performed in 21 patients of these patients. Defecatory function was evaluated using the constipation scoring system (CSS) and fecal incontinence severity index (FISI). RESULTS: The findings of postoperative proctography revealed no full-thickness ERP in any patient, although in 10 patients the ERP was replaced by rectoanal intussusception (RAI). Of the 31 patients, 30 presented with fecal incontinence preoperatively. Ten of 30 had new-onset RAI. Six months postoperatively, a reduction of at least 50 % in the FISI score of the patients with new-onset RAI tended to be significantly smaller than in the patients without RAI (6/10 vs. 18/20, p = 0.141). Seventeen patients presented with obstructed defecation preoperatively. Seven of them had new-onset RAI. Six months postoperatively, a reduction of at least 50 % in their CSS score in the patients with new-onset RAI was significantly smaller than in patients without RAI (0/7 vs. 8/10, p = 0.002). CONCLUSIONS: Evacuation proctography showed new-onset RAI in some patients with ERP who underwent LVR, which was associated with a lack of symptomatic improvement.

Anterior intussusception descent during defecation is correlated with the severity of fecal incontinence in patients with rectoanal intussusception.

BACKGROUND: Rectoanal intussusception (RAI) is a common finding on evacuation proctography in patients with defecation disorders. However, it remains unclear whether intussusception morphology affects the severity of fecal incontinence (FI). The aim of this study was to examine the effect of morphology during defecation on the severity of FI in patients with RAI. METHODS: We included 80 patients with FI who were diagnosed as having RAI on evacuation proctography. Various morphological parameters were measured, and the level of RAI was divided by the extent of descent onto (level I) or into (level II) the anal sphincter. FI symptoms were documented using the FI Severity Index (FISI). RESULTS: Twenty-eight patients had level I and 52 had level II RAI. The mean (range) FISI score was 24.0 (8-47). FISI scores tended to be significantly higher in level II than in level I [26.3 (10-47) vs. 21.8 (8-42); p = 0.05]. The mean anterior intussusception descent was significantly greater in level II than in level I [24.2 (9.2-39.5) vs. 17.7 (7.8-39.4) mm; p < 0.0001]. Regression analysis showed that anterior intussusception descent was predictive of increased FISI scores. CONCLUSIONS: The severity of FI may be affected by anterior intussusception descent in patients with RAI.

Prolongation of Oral Phase for Initial Swallow of Solid Food is Associated with Oral Diadochokinesis Deterioration in Nursing Home Residents in Japan: A Cross-Sectional Study.

Background: Prolongation of bolus forming complicates ingestion, in particular in older adults. Objectives: The purpose of this study is to examine which oral functions are associated with prolongation of the oral phase of forming a bolus until swallowing in older adults. Design: Cross-sectional study. Setting: three nursing homes in Kitakyushu, Japan from August 2017 to October 2018. Participants: 39 adults >60-years. Measurements: Number of functional teeth, chewing ability, swallowing ability, tongue and cheek pressure, saliva flow rate, oral diadochokinesis, global cognitive function, and body mass index, were examined. Time of oral phase until the first swallowing of solid food was measured as the outcome of the study using video, and audio recording of the swallowing sound by a throat microphone, with the cutoff point designated at 30 s. Based on the oral phase, participants were divided in two groups: normal and prolonged. Results: The 39 enrolled participants had a median age of 87 years, 17.3% were men, and 48.7% had prolonged oral phase. In the prolonged group, the swallowing ability, saliva flow rate, tongue and cheek pressure, and oral diadochokinesis were significantly lower than in the normal group. Binomial logistic regression analysis revealed that oral phase prolongation was associated with oral diadochokinesis (odds ratio 0.81, 95% confidence interval 0.67-0.98) after adjusting for potential covariates. Conclusion: Oral diadochokinesis deterioration is significantly associated with oral phase prolongation for initial swallowing of solid food in older adults.

Stimulatory effect of insulin on H+-ATPase in the proximal tubule via the Akt/mTORC2 pathway.

PURPOSE: Acid-base transport in renal proximal tubules (PTs) is mainly sodium-dependent and conducted in coordination by the apical Na+/H+ exchanger (NHE3), vacuolar H+-adenosine triphosphatase (V-ATPase), and the basolateral Na+/HCO3- cotransporter. V-ATPase on PTs is well-known to play an important role in proton excretion. Recently we reported a stimulatory effect of insulin on these transporters. However, it is unclear whether insulin is involved in acid-base balance in PTs. Thus, we assessed the role of insulin in acid-base balance in PTs. METHODS: V-ATPase activity was evaluated using freshly isolated PTs obtained from mice, and specific inhibitors were then used to assess the signaling pathways involved in the observed effects. RESULTS: V-ATPase activity in PTs was markedly enhanced by insulin, and its activation was completely inhibited by bafilomycin (a V-ATPase-specific inhibitor), Akt inhibitor VIII, and PP242 (an mTORC1/2 inhibitor), but not by rapamycin (an mTORC1 inhibitor). V-ATPase activity was stimulated by 1 nm insulin by approximately 20% above baseline, which was completely suppressed by Akt1/2 inhibitor VIII. PP242 completely suppressed the insulin-mediated V-ATPase stimulation in mouse PTs, whereas rapamycin failed to influence the effect of insulin. Insulin-induced Akt phosphorylation in the mouse renal cortex was completely suppressed by Akt1/2 inhibitor VIII and PP242, but not by rapamycin. CONCLUSION: Our results indicate that stimulation of V-ATPase activity by insulin in PTs is mediated via the Akt2/mTORC2 pathway. These results reveal the mechanism underlying the complex signaling in PT acid-base balance, providing treatment targets for renal disease.

Progression of nephropathy in spontaneous diabetic rats is prevented by OPB-9195, a novel inhibitor of advanced glycation.

Levels of tissue advanced glycation end products (AGEs) that result from nonenzymatic reactions of glucose and proteins are high in both diabetic and aging people. Irreversible AGE formation is based on increases in AGE-derived protein-to-protein cross-linking and is considered to be a factor contributing to the complications of diabetes. A novel inhibitor of advanced glycation, OPB-9195, belongs to a group of thiazolidine derivatives, known as hypoglycemic drugs; however, they do not lower blood glucose levels. We did studies to determine if OPB-9195 would prevent the progression of nephropathy in spontaneous diabetic rats. In vitro inhibitory effects of OPB-9195 on AGE formation and AGE-derived cross-linking were examined by enzyme-linked immunosorbent assay (ELISA) and SDS-PAGE, respectively. Otsuka-Long-Evans-Tokushima-Fatty (OLETF) rats, a model of NIDDM, were used to evaluate the therapeutic effect of OPB-9195. Light microscopic findings by periodic acid-Schiff (PAS) staining, the extent of AGE accumulation detected by immunohistochemical staining in the kidneys, the levels of serum AGEs by AGE-specific ELISA, and urinary albumin excretion were examined. OPB-9195 effectively inhibited both AGE-derived cross-linking and the formation of AGEs, in a dose-dependent manner in vitro. In addition, the administration of OPB-9195 prevented the progression of glomerular sclerosis and AGE deposition in glomeruli. Elevation of circulating AGE levels and urinary albumin excretion were dramatically prevented in rats, even at 56 weeks of age and with persistent hyperglycemia. We concluded that a novel thiazolidine derivative, OPB-9195, prevented the progression of diabetic glomerular sclerosis in OLETF rats by lowering serum levels of AGEs and attenuating AGE deposition in the glomeruli.

Adenosine inhibits efferent function of extrinsic capsaicin-sensitive sensory nerves in the enteric nervous system.

Capsaicin (1-3 microM) and electrical stimulation of mesenteric nerves in the presence of hexamethonium and guanethidine antidromically stimulate extrinsic sensory nerve fibers to produce a specific slow depolarizing response of myenteric neurons and a contractile response of muscles in the isolated guinea-pig ileum, mediated by release of substance P and acetylcholine. Adenosine (1-100 microM) inhibited the response to mesenteric nerve stimulation. Adenosine (10-100 microM) suppressed the contractile response to a threshold concentration of capsaicin (1 microM) while leaving the contractile response to a submaximal concentration of substance P (1 nM) and acetylcholine (0.1 microM) intact. Adenosine (1-10 microM) inhibited dose dependently the capsaicin 10 microM)-induced depolarization of myenteric neurons, but did not inhibit the depolarizing response to exogenous substance P. The adenosine P1 receptor antagonist, 8-phenyltheophylline (1-10 microM), antagonized the inhibitory effect of adenosine (1-10 microM) on the mechanical responses. We conclude that adenosine-induced prejunctional inhibition of the mechanical responses is mediated by adenosine P1 receptors.

Left ventricular mechanoenergetics under altered coronary perfusion in guinea pig hearts.

Coronary perfusion pressure (CPP) is well known to affect left ventricular (LV) mechanoenergetics (Gregg's phenomenon). The garden hose effect via the Frank-Starling mechanism caused by coronary distension has long been considered to be the underlying mechanism of this phenomenon. However, recent studies have revealed a close correlation between CPP and the excitation-contraction coupling in myocytes. The aim of this study was to investigate the mechanoenergetic aspects of Gregg's phenomenon by the ventricular contractility (Emax) dependency of the myocardial oxygen consumption (VO2)-total mechanical energy (PVA, systolic pressure-volume area) relationship. Experiments were performed in the excised, cross-circulated guinea pig heart preparation. The protocol consisted of LV volume loading (VOL run), changing coronary perfusion pressure at a fixed LV volume (CPP run) and intracoronary calcium (Ca) infusion also at the same LV volume (Ca run). In all seven hearts, we obtained a linear VO2-PVA relation in VOL run. The VO2-PVA relations in CPP and Ca runs, which equally enhanced Emax, were highly linear and had no significant difference in their slopes, both significantly steeper than in VOL run. These findings suggest no significant difference in the oxygen cost of Emax between CPP and Ca runs. The enhanced LV mechanoenergetics under increasing CPP is characterized by increases in the VO2 component primarily for the excitation-contraction coupling to a greater degree than expected from the mechanical (garden hose) effect.

Effects of intracoronary caffeine on left ventricular mechanoenergetics in Ca2+ overload failing rat hearts.

How different the effects of caffeine on cardiac mechanoenergetics in failing hearts are from those of normal hearts remains to be fully elucidated. First we successfully instituted a new experimental model of acute mild heart failure in the rat by 0.005 mM Ca2+ Tyrode perfusion. These failing hearts neither decreased left ventricular end-systolic pressure nor increased left ventricular end-diastolic pressure, indicating unchanged left ventricular mechanics. However, their myocardial mitochondrial respiratory function examined by respiratory control index (RCI) and oxygen consumption rate in state III (State III O2) was significantly depressed compared with normal hearts. From these results, we judged that this Ca2+ protocol could make mild Ca2+ overload acute failing hearts and that this model would be appropriate for comparing the effects of caffeine on cardiac mechanoenergetics between normal hearts and these failing hearts. We investigated the effects of caffeine on cardiac mechanoenergetics above a concentration of 0.05 mM that corresponds to the maximum blood concentration after a healthy human subject drinks a cup of coffee or tea. We obtained results indicating that caffeine depressed left ventricular systolic and diastolic functions and decreased a measure of total mechanical energy per beat in terms of systolic pressure-volume area (PVA) more severely in these failing hearts at concentrations (20-fold higher than the concentration in a cup of coffee) lower than those in normal hearts. This result implies that these acute failing hearts are Ca2+ overloaded.

Left ventricular ORS widening decreases Emax without lowering VO2-PVA relation in dog hearts.

We observed a few rare spontaneous cases of a suddenly widened QRS wave of left ventricular ECG associated with a simultaneous decrease in left ventricular (LV) contractility (Emax, end-systolic pressure-volume ratio) in excised cross-circulated dog heart experiments. The decreased Emax was not associated with a descent of the relation between cardiac oxygen consumption (VO2) and LV systolic pressure-volume area (PVA, a measure of total ventricular mechanical energy). This result is intriguing because ventricular VO2-PVA relation generally changes its elevation in proportion to Emax under various inotropic interventions. We suspected the unusual observation to reflect no change in myocardial contractility despite ventricular asynchrony augmented by an intraventricular conduction defect.

[Bioactive constituents of Chinese natural medicines. III. Absolute stereostructures of new dihydroflavonols, hovenitins I, II, and III, isolated from hoveniae semen seu fructus, the seed and fruit of Hovenia dulcis THUNB. (Rhamnaceae): inhibitory effect on alcohol-induced muscular relaxation and hepatoprotective activity].

The methanol-soluble fraction from a Chinese natural medicine Hoveniae Semen Seu Fructus, the seed and fruit of Hovenia dulcis THUNB. (Rhamnaceae) was found to show an inhibitory effect on the alcohol-induced muscular relaxation and a protective activity on the D-galactosamine/lipopolysaccharide or carbon tetrachloride-induced liver injury. Through bioassay-guided separation using a traction performance test, three new dihydrofravonols named hovenitins I, II, and III were isolated from Hoveniae Semen Seu Fructus together with four known flavonoids, (+)-ampelopsin, laricetrin, myricetin, and (+)-gallocatechin. The absolute stereostructures of hovenitins I, II, and III were determined on the basis of chemical and physicochemical evidence to be (2R, 3R)-5,7,4',5'-tetrahydroxy-3'-methoxydihydroflavonol, (2R,3S)-5,7,4',5'-tetrahydroxy-3'-methoxy-dihydroflavonol, and (2R, 3S)-5,7,3',4',5'-pentahydroxydihydro-flavonol, respectively. Hovenitin I and (+)-ampelopsin, both of which were principal ingredients of the active fractions from this natural medicine, were found to show an inhibitory activity on the ethanol-induced muscle relaxation in rats. In addition, hovenitin I showed a protective activity on the liver injury induced by D-galactosamine/lipopolysaccharide or carbon tetrachloride in mice.

[Physiology of cardiac performance].

We previously proposed i) Emax (end-systolic maximum elastance of the ventricle) as an index of contractility independent of preload and afterload and ii) PVA (systolic pressure-volume area of the ventricle) as a measure of the total mechanical energy generated by the ventricular contraction. Emax is defined as the slope of the end-systolic pressure-volume relation, which is relatively linear within the normal working range of the left ventricle. A working pressure-volume point starts from the end-diastolic pressure-volume curve, comes close to or slightly exceeds the end-systolic pressure-volume line, and returns to the end-diastolic curve. Thus, the end-diastolic and end-systolic pressure-volume curves envelop a family of pressure-volume trajectories of variously loaded contractions in a stable contractility. Emax increases with enhanced contractility and decreases with depressed contractility. PVA is an area between the end-diastolic and end-systolic pressure-volume curves on the origin side of the systolic pressure-volume trajectory. PVA linearly correlates with myocardial oxygen consumption regardless of ventricular loading conditions in a given Emax and this load-independent oxygen consumption-PVA relation is elevated with an enhanced Emax. Consequently, Emax and PVA have proved to be key measures and concepts in the physiology of cardiac performance.

Cross interaction between methamphetamine and scopolamine by means of ambulatory activity in mice.

Interaction between methamphetamine (MAP; 1 and 2 mg/kg, s.c.) and scopolamine (SCP; 0.5 and 2 mg/kg, s.c.) was investigated by means of ambulatory activity in mice of the dd strain. The single administration of MAP and SCP increased the ambulatory activity in a dose-dependent manner. The repeated administration of SCP, 5 times at intervals of 3-4 days, elicited a tolerance to its ambulation-increasing effect. The SCP-experienced mice showed no marked change in their sensitivity to the ambulation-increasing effect of MAP. However, when MAP was additionally administered, these mice showed a reverse tolerance to MAP. Such repeated administration of MAP was effective for attenuating the SCP-tolerance. On the other hand, the repeated MAP administration produced not only reverse tolerance to MAP itself but also cross reverse tolerance to SCP. However, as observed in the drug-naive mice, the MAP-experienced mice also exhibited tolerance to the additionally administered SCP. The repeated SCP administration scarcely modified the acquired MAP-reverse tolerance. The present results suggest that a cross reverse tolerance from MAP to SCP, but not from SCP to MAP, is developed in this mouse strain. It is also suggested that the reverse tolerance to MAP and tolerance to SCP appear regardless of the pretreatment of SCP and MAP, respectively, and that the reverse tolerance to MAP is well-maintained.

Interaction between caffeine and methamphetamine by means of ambulatory activity in mice.

Effects of repeated administration of caffeine as well as interaction between caffeine and methamphetamine were investigated by means of ambulatory activity in mice. The single administration of caffeine increased the ambulatory activity at 10 and 30 mg/kg, sc, but scarcely increased at 3 mg/kg and at 100 mg/kg which is a subconvulsive dose. Methamphetamine 2 mg/kg, sc also increased the ambulatory activity. The combined administration of caffeine (1-100 mg/kg) and methamphetamine (2 mg/kg) showed a synergistic action as compared with the effects of the individual drugs. The repeated 5-times administration of caffeine (10, 30, and 100 mg/kg) at intervals of 3-4 days produced neither tolerance nor reverse tolerance to caffeine. The caffeine-experienced mice showed no marked change in the sensitivity to the ambulation-increasing effect of methamphetamine 2 mg/kg. In contrast, the repeated administration of methamphetamine 2 mg/kg induced not only reverse tolerance to methamphetamine itself but also cross reverse tolerance to caffeine (30 mg/kg). Furthermore, the methamphetamine-experienced mice also showed an increased activity after challenge administration of saline. The present results suggest that, although caffeine showed central stimulant effect, the characteristics are different from those of methamphetamine.

Nucleotide sequences of fic and fic-1 genes involved in cell filamentation induced by cyclic AMP in Escherichia coli.

The nucleotide sequences of fic-1 involved in the cell filamentation induced by cyclic AMP in Escherichia coli and its normal counterpart fic were analyzed. The open reading frame of both fic-1 and fic coded for 200 amino acids. The Gly at position 55 in the Fic protein was changed to Arg in the Fic-1 protein. The promoter activity of fic was confirmed by fusing fic and lacZ. The gene downstream from fic was found to be pabA (p-aminobenzoate). There is an open reading frame (ORF190) coding for 190 amino acids upstream from the fic gene. Computer-assisted analysis showed that Fic has sequence similarity with part of CDC28 of Saccharomyces cerevisiae, CDC2 of Schizosaccharomyces pombe, and FtsA of E. coli. In addition, ORF190 has sequence similarity with the cyclosporin A-binding protein cyclophilin.

Simple and rapid purification of brevin.

Brevin or plasma gelsolin, a calcium dependent actin-binding and actin-severing protein, was purified from bovine plasma by a very rapid and simple procedure; ammonium sulfate fractionation and only one step of anion exchange column chromatography by a convenient use. It takes only 24 hrs to complete all the procedure. The purity of brevin prepared by this method was more than 95% on SDS-PAGE and total recovery was much better than previous preparation methods. This brevin preparation has about 8 isomers on 2-D PAGE and strong severing activity on F-actin under electron microscopic observation.

Cloning of the fic-1 gene involved in cell filamentation induced by cyclic AMP and construction of a delta fic Escherichia coli strain.

PA3092 is an Escherichia coli mutant that forms filaments at 43 degrees C in the presence of cyclic AMP (cAMP). The mutation responsible for this phenotype is called fic-1. We cloned fic-1 from PA3092 by selection for the neighboring argD gene. The fic-1 gene product had a relative molecular mass of 21 kilodaltons by the maxicell method. A strain with the fic gene completely deleted was constructed by replacing fic with a kanamycin resistance gene. In one of the fic-deleted strains derived from PA3092, cAMP did not induce cell filamentation at 43 degrees C, but it did in the same strain harboring a plasmid containing the fic-1 gene. These results indicate that the fic-1 gene product is necessary for the induction of cell filamentation by cAMP but is dispensable to the cell. We also found that high levels of NaCl suppressed the cell filamentation induced by cAMP.

Effects of capsaicin on mechanoenergetics of excised cross-circulated canine left ventricle and coronary artery.

Capsaicin selectively acts on sensory nerve endings in cardiac muscles and coronary arterial smooth muscles. Capsaicin at high doses has cell-nonselective effects including both inhibition of cardiac muscle exciteability and enhancement of vascular smooth muscle tone. We studied whether and how intracoronary infusion of capsaicin affects mechanoenergetics of the excised blood-perfused canine heart and coronary vascular resistance. We found that capsaicin at low concentrations increased Emax (a contracility index) and oxygen consumption (VO2) possibly due to a specific action on capsaicin-sensitive sensory nerves in left ventricular muscles, though in a small number of hearts (3/10). This result coincides with the reported histochemical observations that the distribution of capsaicin-sensitive sensory nerves in the canine left ventricle is not dense. Capsaicin at high doses dose-dependently decreased Emax and proportionally decreased coronary flow. It also lowered the linear VO2-PVA (pressure-volume area; total mechanical energy) relationship without a change in the slope, decreasing unloaded VO2 (VO2 intercept of the VO2-PVA relation). These effects of high-dose capsaicin seem to be direct negative inotropic action on cardiac muscles associated with enhancement of coronary arterial smooth muscle tone, since these effects were not desensitized. No morphological changes of myocardial cells or mitochondria were detected. Therefore, the negative inotropic action is not due to the toxic effect of capsaicin.

Estrogenic xenobiotics affect the intracellular activation signal in mitogen-induced human peripheral blood lymphocytes: immunotoxicological impact.

The present study was an attempt to elucidate the effect of estrogenic xenobiotics on the proliferation of mitogen-stimulated human peripheral blood lymphocyte (PBL). Our findings follow: (a) the proliferation of PBL in response to phytohemagglutinin (PHA) was mediated by protein kinase C activity, but estrogenic xenobiotics had a strong inhibitory effect on protein kinase C activity of PHA-stimulated PBL; (b) cytoplasmic extracts from PHA-stimulated PBL greatly activated DNA replication, but estrogenic xenobiotics had a strong inhibitory effect on these activities. The results suggest that the cytoplasmic signal-generating system in mitogen-treated PBL is inhibited by estrogenic xenobiotics, and that the defect occurs at all stages in the sequence of events leading to DNA synthesis and cell proliferation.

Ca2+ sensitivity of contractile machinery and Ca2+ handling energy. Simulation.

Myocardial Ca2+ handling during excitation-contraction coupling has been modelled mathematically to gain a better insight into the expectation that Ca2+ sensitization of contractile machinery may save myocardial energy utilization for Ca2+ handling. The basic model of myocardial Ca2+ kinetics and mechanoenergetics involved the sarcoplasmic reticulum (SR), sarcoplasm, troponin C (Tn) and crossbridges (CB). The relations among the released Ca2+ ions from the SR, peak concentrations of sarcoplasmic free Ca2+ ([Ca2+]i) and Ca(2+)-bound troponin ([TnCa]) and peak contractile force were computed, based upon the assumptions that the released Ca2+ ions diffuse as free Ca2+ in sarcoplasm, bind kinetically with Tn with an association rate constant of k1, dissociate from TnCa with a dissociation rate constant of k2, and are sequestered into the SR with consumption of ATP. TnCa was associated with CB cycling to develop force with a set of given on and off rate constants. The association constant Ka (= k1/k2) of TnCa as an index of Ca2+ sensitivity of Tn was varied 32-fold from 0.25 to 8/microM. Results showed that Ca2+ sensitization from a lower Ka level could most sharply decrease the total Ca2+ release required to develop the same contractile force. Thus, it would reduce the total Ca2+ handling energy that the SR uses to maintain the same contractility.