Preoperative versus postoperative ultrasound-guided rectus sheath block for acute postoperative pain relief after laparoscopy: A retrospective cohort study.

Although rectus sheath block (RSB) is routinely used in laparoscopic surgeries to reduce mid-abdominal pain, whether RSB should be performed before or after surgery remains unclear. Herein, the optimal timing for RSB in patients undergoing laparoscopic surgery was investigated. This retrospective cohort study analyzed the data of patients who underwent RSB during laparoscopic procedures at our hospital between January 2013 and December 2018. The primary outcome was the time to rescue analgesia within 24 hours postanesthesia. The patients were divided into preoperative (pre-) and postoperative (post-) RSB groups. A multivariable Cox proportional hazards regression model was used to analyze the time to rescue analgesia in the unmatched and propensity score (PS)-matched patient populations. In total, 609/14,284 patients were included (pre-RSB group, 227 patients; post-RSB group, 382 patients). After PS matching, 97 patients were assigned to both groups. Although the time from extubation to the first analgesic request was not significantly different between the 2 groups (322 vs 294 minutes, P = .57), the patients in the pre-RSB group showed a lower risk of postoperative first analgesic administration after PS matching (adjusted hazard ratio, 0.71; 95% confidence interval, 0.53-0.95; P = .023). Among patients undergoing laparoscopic surgery, those in the pre-RSB group tended to have a longer time to the first analgesic request and had a lower risk of analgesic administration within the first 24 hours than those in the post-RSB group. Thus, performing RSB preoperatively may be preferable.

Reduction of leakage from insertion site during continuous femoral nerve block with catheter-through-needle versus catheter-over-needle technique for postoperative analgesia after total knee arthroplasty: a randomized controlled trial.

BACKGROUND: Continuous femoral nerve block (CFNB) is a common procedure used for postoperative analgesia in total knee arthroplasty. Continuous nerve block using a conventional needle (catheter-through-needle/CTN) is complicated by leakage of the anesthetic from the catheter insertion site. A different type of needle (catheter-over-needle/ CON) is now available, which is believed to reduce leakage as the diameter of the catheter is larger than that of the needle. The purpose of this study was to compare the incidence of leakage from the catheter insertion site during CFNB while using CTN and CON for postoperative analgesia after total knee arthroplasty (TKA). METHODS: This prospective, randomized, single-blinded controlled study included 60 patients who were scheduled for TKA at our facility between May 2016 and November 2017. Patients were randomly allocated to the CTN or CON groups. All patients in both groups received CFNB and sciatic nerve block for postoperative analgesia. The administration of 0.16% levobupivacaine mixed with 6 mg of indigo carmine (a dye added to easily identify leakage) was started at 6 ml/h at the end of surgery. The primary outcome was the incidence of leakage from the catheter insertion site. We further investigated the degree of leakage, the incidence of catheter migration, pain scores using the numerical rating scale at 48 h postoperatively, and the number of days until the operated knee could be flexed 120 degrees postoperatively in both groups. RESULTS: The CON group had a significantly lower incidence and degree of leakage from the catheter insertion site. There were no significant differences in other measurement outcomes. CONCLUSIONS: Use of CON reduces the incidence of leakage from the catheter insertion site during CFNB in the use of postoperative analgesia for total knee arthroplasty. Future research is needed to determine additional benefits of using CON related to decreased leakage. TRIAL REGISTRATION: The study was registered in the University Hospital Medical Information Network (UMIN) Clinical Trials Registry ( UMIN000021537 ), prospectively registered on 18 March 2016.

Indwelling catheters increase altered mental status and urinary tract infection risk: A retrospective Cohort Study.

BACKGROUND: Although indwelling urinary catheters (IUCs) are used intraoperatively and may cause complications (e.g., delirium), only few robust studies have investigated the association between intraoperative IUC use and complications. We hypothesized that IUC use might increase the postoperative incidence of altered mental status and/or urinary catheter infection. MATERIALS AND METHODS: In this retrospective single-center cohort study, we analyzed the data of adult patients undergoing surgery at our facility between January 2013 and December 2018. The primary endpoint was altered mental status and/or incidence of urinary catheter infections. The patients were divided into IUC and control groups. A multivariable logistic regression model was used to identify the predictors of postoperative complications, and a multivariable Cox proportional hazards regression model was used to analyze hospital discharge in unmatched and inverse propensity-weighted patients. RESULTS: Of the 14,284 patients that were reviewed, we analyzed 5112 patients (control group, 44.0%; IUC group, 56.0%). Almost all procedures comprised less invasive surgeries. The prevalence of postoperative altered mental status and postoperative urinary catheter infection were 3.56% and 0.04%, respectively. After inverse propensity weighting, all baseline characteristics were similar between the two groups. However, patients with IUCs had a higher risk of postoperative complications (adjusted odds ratio, 1.97; 95% confidence interval [CI], 1.50-2.59) and prolonged hospital stays (hazard ratio, 0.84; 95% CI, 0.80-0.89). CONCLUSION: In patients undergoing less invasive surgery, IUCs may be associated with a relatively high risk of altered mental status or urinary catheter infection. These data may facilitate preoperative discussions regarding the perioperative use of IUCs.

The effects of a preoperative multidisciplinary conference on outcomes for high-risk patients with challenging surgical treatment options: a retrospective study.

BACKGROUND: Surgical options for patients vary with age and comorbidities, advances in medical technology and patients' wishes. This complexity can make it difficult for surgeons to determine appropriate treatment plans independently. At our institution, final decisions regarding treatment for patients are made at multidisciplinary meetings, termed High-Risk Conferences, led by the Patient Safety Committee. METHODS: In this retrospective study, we assessed the reasons for convening High-Risk Conferences, the final decisions made and treatment outcomes using conference records and patient medical records for conferences conducted at our institution from April 2010 to March 2018. RESULTS: A total of 410 High-Risk Conferences were conducted for 406 patients during the study period. The department with the most conferences was cardiovascular surgery (24%), and the reasons for convening conferences included the presence of severe comorbidities (51%), highly difficult surgeries (41%) and nonmedical/personal issues (8%). Treatment changes were made for 49 patients (12%), including surgical modifications for 20 patients and surgery cancellation for 29. The most common surgical modification was procedure reduction (16 patients); 4 deaths were reported. Follow-up was available for 21 patients for whom surgery was cancelled, with 11 deaths reported. CONCLUSIONS: Given that some change to the treatment plan was made for 12% of the patients discussed at the High-Risk Conferences, we conclude that participants of these conferences did not always agree with the original surgical plan and that the multidisciplinary decision-making process of the conferences served to allow for modifications. Many of the modifications involved reductions in procedures to reflect a more conservative approach, which might have decreased perioperative mortality and the incidence of complications as well as unnecessary surgeries. High-risk patients have complex issues, and it is difficult to verify statistically whether outcomes are associated with changes in course of treatment. Nevertheless, these conferences might be useful from a patient safety perspective and minimize the potential for legal disputes.

Anesthetic cardioprotection in relation to mitochondria: basic science.

Anesthetic pre- and postconditioning pharmacologically reduces ischemia/reperfusion injury. Mitochondria play a central role in these myocardial protective salvage effects. In the preconditioning, low levels of reactive oxygen species, which are produced by anesthetics in the mitochondria, act as a trigger to prevent cardiomyocytes death and modify intracellular signaling mechanisms. In the postconditioning, decreased mitochondrial matrix pH, which was caused by anesthetics, triggers the onset of a rapid protective effect. The mitochondrial membranes have several ion channels that act as major determining factors of cellular life and death under pathophysiological conditions. In these channels, the mitochondrial adenosine triphosphate-sensitive K(+) channels, the mitochondrial Ca(2+)-activated K(+) channels and mitochondrial permeability transition pores play critical roles in cardioprotection against ischemia/reperfusion injury. Mitochondrial permeability transition pores are end effectors, which contribute to myocardial preconditioning and postconditioning. Activation of intracellular signaling and acidification of mitochondrial matrix pH prevent the mitochondrial permeability transition pore opening, and therefore, preserve the mitochondrial function to supply adenosine triphosphate, resulting in myocardial protection due to the maintenance of intracellular homeostasis.

Monitoring mitochondrial electron fluxes using NAD(P)H-flavoprotein fluorometry reveals complex action of isoflurane on cardiomyocytes.

Mitochondrial bioenergetic studies mostly rely on isolated mitochondria thus excluding the regulatory role of other cellular compartments important for the overall mitochondrial function. In intact cardiomyocytes, we followed the dynamics of electron fluxes along specific sites of the electron transport chain (ETC) by simultaneous detection of NAD(P)H and flavoprotein (FP) fluorescence intensities using a laser-scanning confocal microscope. This method was used to delineate the effects of isoflurane, a volatile anesthetic and cardioprotective agent, on the ETC. Comparison to the effects of well-characterized ETC inhibitors and uncoupling agent revealed two distinct effects of isoflurane: uncoupling-induced mitochondrial depolarization and inhibition of ETC at the level of complex I. In correlation, oxygen consumption measurements in cardiomyocytes confirmed a dose-dependent, dual effect of isoflurane, and in isolated mitochondria an obstruction of the ETC primarily at the level of complex I. These effects are likely responsible for the reported mild stimulation of mitochondrial reactive oxygen species (ROS) production required for the cardioprotective effects of isoflurane. In conclusion, isoflurane exhibits complex effects on the ETC in intact cardiomyocytes, altering its electron fluxes, and thereby enhancing ROS production. The NAD(P)H-FP fluorometry is a useful method for exploring the effect of drugs on mitochondria and identifying their specific sites of action within the ETC of intact cardiomyocytes.

Anesthetic-induced preconditioning delays opening of mitochondrial permeability transition pore via protein Kinase C-epsilon-mediated pathway.

BACKGROUND: Cardioprotection by volatile anesthetic-induced preconditioning (APC) involves activation of protein kinase C (PKC). This study investigated the importance of APC-activated PKC in delaying mitochondrial permeability transition pore (mPTP) opening. METHODS: Rat ventricular myocytes were exposed to isoflurane in the presence or absence of nonselective PKC inhibitor chelerythrine or isoform-specific inhibitors of PKC-delta (rottlerin) and PKC-epsilon (myristoylated PKC-epsilon V1-2 peptide), and the mPTP opening time was measured by using confocal microscopy. Ca-induced mPTP opening was measured in mitochondria isolated from rats exposed to isoflurane in the presence and absence of chelerythrine or in mitochondria directly treated with isoflurane after isolation. Translocation of PKC-epsilon was assessed in APC and control cardiomyocytes by Western blotting. RESULTS: In cardiomyocytes, APC prolonged time necessary to induce mPTP opening (261 +/- 26 s APC vs. 216 +/- 27 s control; P < 0.05), and chelerythrine abolished this delay to 213 +/- 22 s. The effect of isoflurane was also abolished when PKC-epsilon inhibitor was applied (210 +/- 22 s) but not in the presence of PKC-delta inhibitor (269 +/- 31 s). Western blotting revealed translocation of PKC-epsilon toward mitochondria in APC cells. The Ca concentration required for mPTP opening was significantly higher in mitochondria from APC rats (45 +/- 8 microM x mg control vs. 64 +/- 8 microM x mg APC), and APC effect was reversed with chelerythrine. In contrast, isoflurane did not protect directly treated mitochondria. CONCLUSION: APC induces delay of mPTP opening through PKC-epsilon mediated inhibition of mPTP opening, but not through PKC-delta. These results point to the connection between cytosolic and mitochondrial components of cardioprotection by isoflurane.

Xenon preconditioning: the role of prosurvival signaling, mitochondrial permeability transition and bioenergetics in rats.

BACKGROUND: Similar to volatile anesthetics, the anesthetic noble gas xenon protects the heart from ischemia/reperfusion injury, but the mechanisms responsible for this phenomenon are not fully understood. We tested the hypothesis that xenon-induced cardioprotection is mediated by prosurvival signaling kinases that target mitochondria. METHODS: Male Wistar rats instrumented for hemodynamic measurements were subjected to a 30 min left anterior descending coronary artery occlusion and 2 h reperfusion. Rats were randomly assigned to receive 70% nitrogen/30% oxygen (control) or three 5-min cycles of 70% xenon/30% oxygen interspersed with the oxygen/nitrogen mixture administered for 5 min followed by a 15 min memory period. Myocardial infarct size was measured using triphenyltetrazolium staining. Additional hearts from control and xenon-pretreated rats were excised for Western blotting of Akt and glycogen synthase kinase 3 beta (GSK-3beta) phosphorylation and isolation of mitochondria. Mitochondrial oxygen consumption before and after hypoxia/reoxygenation and mitochondrial permeability transition pore opening were determined. RESULTS: Xenon significantly (P < 0.05) reduced myocardial infarct size compared with control (32 +/- 4 and 59% +/- 4% of the left ventricular area at risk; mean +/- sd) and enhanced phosphorylation of Akt and GSK-3beta. Xenon pretreatment preserved state 3 respiration of isolated mitochondria compared with the results obtained in the absence of the gas. The Ca(2+) concentration required to induce mitochondrial membrane depolarization was larger in the presence compared with the absence of xenon pretreatment (78 +/- 17 and 56 +/- 17 microM, respectively). The phosphoinositol-3-kinase-kinase inhibitor wortmannin blocked the effect of xenon on infarct size and respiration. CONCLUSIONS: These results indicate that xenon preconditioning reduces myocardial infarct size, phosphorylates Akt, and GSK-3beta, preserves mitochondrial function, and inhibits Ca(2+)-induced mitochondrial permeability transition pore opening. These data suggest that xenon-induced cardioprotection occurs because of activation of prosurvival signaling that targets mitochondria and renders them less vulnerable to ischemia-reperfusion injury.

Near infrared light protects cardiomyocytes from hypoxia and reoxygenation injury by a nitric oxide dependent mechanism.

Photobiomodulation with near infrared light (NIR) provides cellular protection in various disease models. Previously, infrared light emitted by a low-energy laser has been shown to significantly improve recovery from ischemic injury of the canine heart. The goal of this investigation was to test the hypothesis that NIR (670 nm) from light emitting diodes produces cellular protection against hypoxia and reoxygenation-induced cardiomyocyte injury. Additionally, nitric oxide (NO) was investigated as a potential cellular mediator of NIR. Our results demonstrate that exposure to NIR at the time of reoxygenation protects neonatal rat cardiomyocytes and HL-1 cells from injury, as assessed by lactate dehydrogenase release and MTT assay. Similarly, indices of apoptosis, including caspase 3 activity, annexin binding and the release of cytochrome c from mitochondria into the cytosol, were decreased after NIR treatment. NIR increased NO in cardiomyocytes, and the protective effect of NIR was completely reversed by the NO scavengers carboxy-PTIO and oxyhemoglobin, but only partially blocked by the NO synthase (NOS) inhibitor L-NMMA. Mitochondrial metabolism, measured by ATP synthase activity, was increased by NIR, and NO-induced inhibition of oxygen consumption with substrates for complex I or complex IV was reversed by exposure to NIR. Taken together these data provide evidence for protection against hypoxia and reoxygenation injury in cardiomyocytes by NIR in a manner that is dependent upon NO derived from NOS and non-NOS sources.

Age-related attenuation of isoflurane preconditioning in human atrial cardiomyocytes: roles for mitochondrial respiration and sarcolemmal adenosine triphosphate-sensitive potassium channel activity.

BACKGROUND: Clinical trials suggest that anesthetic-induced preconditioning (APC) produces cardioprotection in humans, but the mechanisms of APC and significance of aging for APC in humans are not well understood. Here, the impact of age on the role of two major effectors of APC, mitochondria and sarcolemmal adenosine triphosphate-sensitive potassium (sarcKATP) channels, in preconditioning of the human atrial myocardium were investigated. METHODS: Right atrial appendages were obtained from adult patients undergoing cardiac surgery and assigned to mid-aged (MA) and old-aged (OA) groups. APC was induced by isoflurane in isolated myocardium and isolated cardiomyocytes. Mitochondrial oxygen consumption measurements, myocyte survival testing, and patch clamp techniques were used to investigate mitochondrial respiratory function and sarcKATP channel activity. RESULTS: After in vitro APC with isoflurane, the respiratory function of isolated mitochondria was better preserved after hypoxia-reoxygenation stress in MA than in OA. In isolated intact myocytes, APC significantly decreased oxidative stress-induced cell death in MA but not in OA, and isoflurane protection from cell death was attenuated by the sarcKATP channel inhibitor HMR-1098. Further, the properties of single sarcKATP channels were similar in MA and OA, and isoflurane sensitivity of pinacidil-activated whole cell KATP current was no different between MA and OA myocytes. CONCLUSION: Anesthetic-induced preconditioning with isoflurane decreases stress-induced cell death and preserves mitochondrial respiratory function to a greater degree in MA than in OA myocytes; however, sarcKATP channel activity is not differentially affected by isoflurane. Therefore, effectiveness of APC in humans may decrease with advancing age partly because of altered mitochondrial function of myocardial cells.

The A3 adenosine receptor agonist CP-532,903 [N6-(2,5-dichlorobenzyl)-3'-aminoadenosine-5'-N-methylcarboxamide] protects against myocardial ischemia/reperfusion injury via the sarcolemmal ATP-sensitive potassium channel.

We examined the cardioprotective profile of the new A(3) adenosine receptor (AR) agonist CP-532,903 [N(6)-(2,5-dichlorobenzyl)-3'-aminoadenosine-5'-N-methylcarboxamide] in an in vivo mouse model of infarction and an isolated heart model of global ischemia/reperfusion injury. In radioligand binding and cAMP accumulation assays using human embryonic kidney 293 cells expressing recombinant mouse ARs, CP-532,903 was found to bind with high affinity to mouse A(3)ARs (K(i) = 9.0 +/- 2.5 nM) and with high selectivity versus mouse A(1)AR (100-fold) and A(2A)ARs (1000-fold). In in vivo ischemia/reperfusion experiments, pretreating mice with 30 or 100 microg/kg CP-532,903 reduced infarct size from 59.2 +/- 2.1% of the risk region in vehicle-treated mice to 42.5 +/- 2.3 and 39.0 +/- 2.9%, respectively. Likewise, treating isolated mouse hearts with CP-532,903 (10, 30, or 100 nM) concentration dependently improved recovery of contractile function after 20 min of global ischemia and 45 min of reperfusion, including developed pressure and maximal rate of contraction/relaxation. In both models of ischemia/reperfusion injury, CP-532,903 provided no benefit in studies using mice with genetic disruption of the A(3)AR gene, A(3) knockout (KO) mice. In isolated heart studies, protection provided by CP-532,903 and ischemic preconditioning induced by three brief ischemia/reperfusion cycles were lost in Kir6.2 KO mice lacking expression of the pore-forming subunit of the sarcolemmal ATP-sensitive potassium (K(ATP)) channel. Whole-cell patch-clamp recordings provided evidence that the A(3)AR is functionally coupled to the sarcolemmal K(ATP) channel in murine cardiomyocytes. We conclude that CP-532,903 is a highly selective agonist of the mouse A(3)AR that protects against ischemia/reperfusion injury by activating sarcolemmal K(ATP) channels.

Isoflurane preconditioning uncouples mitochondria and protects against hypoxia-reoxygenation.

Ischemic cardiac injury can be substantially alleviated by exposing the heart to pharmacological agents such as volatile anesthetics before occurrence of ischemia-reperfusion. A hallmark of this preconditioning phenomenon is its memory, when cardioprotective effects persist even after removal of preconditioning stimulus. Since numerous studies pinpoint mitochondria as crucial players in protective pathways of preconditioning, the aim of this study was to investigate the effects of preconditioning agent isoflurane on the mitochondrial bioenergetic phenotype. Endogenous flavoprotein fluorescence, an indicator of mitochondrial redox state, was elevated to 195 +/- 16% of baseline upon isoflurane application in intact cardiomyocytes, indicating more oxidized state of mitochondria. Isoflurane treatment also elicited partial dissipation of mitochondrial transmembrane potential, which remained depolarized even after anesthetic withdrawal (tetramethylrhodamine fluorescence intensity declined to 83 +/- 3 and 81 +/- 7% of baseline during isoflurane exposure and washout, respectively). Mild uncoupling, with preserved ATP synthesis, was also detected in mitochondria that were isolated from animals that had been previously preconditioned by isoflurane in vivo, revealing its memory nature. These mitochondria, after exposure to hypoxia and reoxygenation, exhibited better preserved respiration and ATP synthesis compared with mitochondria from nonpreconditioned animals. Partial mitochondrial depolarization was paralleled by a diminished Ca(2+) uptake into isoflurane-treated mitochondria, as indicated by the reduced increment in rhod-2 fluorescence when mitochondria were challenged with increased Ca(2+) (180 +/- 24 vs. 258 +/- 14% for the control). In conclusion, isoflurane preconditioning elicits partial mitochondrial uncoupling and reduces mitochondrial Ca(2+) uptake. These effects are likely to reduce the extent of the mitochondrial damage after the hypoxic stress.

[New ultra-short-acting beta-blockers: landiolol and esmolol--the effects on cardiovascular system].

Esmolol and landiolol are ultra-short-acting intravenous beta-blockers. Both drugs have high cardioselectivity (beta1/beta2 selectivity of esmolol : 33, landiolol: 255) and short elimination half time (esmolol : 9 min, landiolol : 4 min). Since the duration of beta-adrenergic blockade is short and cardioselectivity is high compared with traditional intravenous beta-blocker propranolol, both drugs are titrated easily. Its use is particularly suited to critically ill patient and for perioperative period. In clinical settings, both drugs have been used for prevention of perioperative tachycardia after endotracheal intubation or surgical incision and treatment of supuraventricular arrhythmias. Esmolol also has been used for treatment of perioperative hypertension and for reducing cardiac work in patients with ischemic heart disease. Recently, it was reported that prophylactic administration of esmolol may prevent perioperative myocardial ischemia in high risk group. Landiolol is a newer drug compared with esmolol. There are not many clinical trials on landiolol. However, since landiolol has higher cardioselectivity and tends to have less cardiodepressant effect than esmolol, clinical indication of landiolol may be extended. Additional data from large studies are required to evaluate the clinical efficacy and safety of landiolol for a variety of diseases.

Monitoring consciousness in the pediatric patient: not just a small adult.

Intraoperative awareness, defined as postoperative memory for intraoperative events, is believed to occur about 0.2% of the time in a general adult surgical population. A recent large-scale prospective study from a single institution revealed a strikingly high incidence (0.8%) of intraoperative awareness in children aged 5-12 years although the sequelae of awareness during surgery in children were reported to be relatively minor. This contrasts with awareness in adult patients, for whom this complication often causes psychological trauma, thus having medico-legal implications. Various monitors to detect intraoperative awareness have been used with varying success in adults. To date, however, no monitor has been shown to be effective in detecting intraoperative awareness during surgery in pediatric patients. Further research is required to clarify the rates of intraoperative awareness in the pediatric population as well as the need for monitoring this event during the clinical practice of pediatric anesthesiology.

Comparative effects of bupivacaine and ropivacaine on intracellular calcium transients and tension in ferret ventricular muscle.

BACKGROUND: Recent evidence suggests that ropivacaine exerts markedly less cardiotoxicity compared with bupivacaine; however, the mechanisms are not fully understood at the molecular level. METHODS: Isolated ferret ventricular papillary muscles were microinjected with the Ca-binding photoprotein aequorin, and intracellular Ca transients and tension were simultaneously measured during twitch in the absence and presence of bupivacaine or ropivacaine. RESULTS: Bupivacaine and ropivacaine (10, 30, and 100 microm) reduced peak systolic [Ca]i and tension in a concentration-dependent manner. The effects were significantly greater for bupivacaine, particularly on tension (approximately twofold). The percentage reduction of tension was linearly correlated with that of [Ca]i for both anesthetics, with the slope of the relationship being approximately equal to 1.0 for ropivacaine and approximately equal to 1.3 for bupivacaine (slope difference, P < 0.05), suggesting that the cardiodepressant effect of ropivacaine results predominantly from inhibition of Ca transients, whereas bupivacaine suppresses Ca transients and the reaction beyond Ca transients, i.e., myofibrillar activation, as well. BAY K 8644, a Ca channel opener, abolished the inhibitory effects of ropivacaine on Ca transients and tension, whereas BAY K 8644 only partially inhibited the effects of bupivacaine, particularly the effects on tension. CONCLUSION: The cardiodepressant effect of bupivacaine is approximately twofold greater than that of ropivacaine. Bupivacaine suppresses Ca transients more markedly than does ropivacaine and reduces myofibrillar activation, which may at least in part underlie the greater inhibitory effect of bupivacaine on cardiac contractions. These results suggest that ropivacaine has a more favorable profile as a local anesthetic in the clinical settings.

Bupivacaine attenuates contractility by decreasing sensitivity of myofilaments to Ca2+ in rat ventricular muscle.

BACKGROUND: Bupivacaine exhibits a cardiodepressant effect, the molecular mechanism(s) of which have yet to be fully understood. Bupivacaine may directly act on contractile proteins and thereby decrease myofibrillar Ca2+ sensitivity. METHODS: Rat ventricular muscle was used. First, the effect of bupivacaine was examined on tetanic contractions in isolated intact myocytes. Next, Triton X-100-treated ventricular trabeculae were used to investigate the effect of bupivacaine on the pCa (= -log [Ca2+ ])-tension relation as well as on maximal Ca2+ -activated tension. Furthermore, to test whether bupivacaine inhibits the pathway downstream from Ca2+ binding to troponin C, tension was elicited in the skinned preparations by lowering the Mg-adenosine triphosphate (MgATP) concentration in the absence of Ca2+. The effect of bupivacaine on the pMgATP (= -log [MgATP])-tension relation was examined. RESULTS: In myocytes, 3 microm bupivacaine significantly (P < 0.01) increased intracellular Ca2+ concentration required for 5% cell shortening from the resting cell length. In skinned preparations, bupivacaine shifted the pCa-tension relation to the lower pCa side; the midpoint of the pCa curve (pCa50) was significantly (P < 0.05) changed by 10 and 100 microm bupivacaine. A highly correlated linear relation (R = 0.81; P< 0.0005) was present between pCa50 and maximal Ca2+ -activated tension. Bupivacaine (10 and 100 microm) significantly (P < 0.05) shifted the midpoint of the pMgATP-tension relation to the higher pMgATP side. CONCLUSIONS: Bupivacaine decreases myofibrillar Ca2+ sensitivity in ventricular muscle, and this is coupled with the compound's inhibitory effect on the pathway beyond Ca2+ binding to troponin C, possibly on the actomyosin interaction. The current results may partly explain the overall cardiodepressant effect of bupivacaine in vivo.