Chest compression duration influences outcome between integrated load-distributing band and manual CPR during cardiac arrest.

BACKGROUND: The Circulation Improving Resuscitation Care (CIRC) Trial found equivalent survival in adult out-of-hospital cardiac arrest (OHCA) patients who received integrated load-distributing band CPR (iA-CPR) compared to manual CPR (M-CPR). We hypothesized that as chest compression duration increased, iA-CPR provided a survival benefit when compared to M-CPR. METHODS: A pre-planned secondary analysis of OHCA of presumed cardiac etiology from the randomized CIRC trial. Chest compressions duration was defined as the total number of minutes spent on compressions during resuscitation and identified from transthoracic impedance and accelerometer data recorded by the EMS defibrillator. Logistic regression was used to model the interaction between treatment and duration of chest compressions and was covariate-adjusted for trial site, patient age, witnessed arrest, and initial shockable rhythm. Primary outcome was survival to hospital discharge. RESULTS: We enrolled 4231 subjects and of those, 2012 iA-CPR and 2002 M-CPR had complete outcome and duration of chest compressions data. While covariate-adjusted odds ratio for survival to hospital discharge was 1.86 in favor of iA-CPR (95% CI 1.16-3.0), there was an interaction between duration and study arm. When this was factored into the multivariate equation, the odds ratio for survival to hospital discharge showed a significant benefit for iA-CPR vs. M-CPR for chest compression duration greater than 16.5 min. CONCLUSION: After adjusting for compression duration and duration-treatment interaction, iA-CPR showed a significant benefit for survival to hospital discharge vs. M-CPR in patients with OHCA if chest compression duration was longer than 16.5 min.

Interstitial fluid flow and cyclic strain differentially regulate cardiac fibroblast activation via AT1R and TGF-ß1.

Cardiac fibroblasts are exposed to both cyclic strain and interstitial fluid flow in the myocardium. The balance of these stimuli is affected by fibrotic scarring, during which the fibroblasts transition to a myofibroblast phenotype. The present study investigates the mechanisms by which cardiac fibroblasts seeded in three-dimensional (3D) collagen gels differentiate between strain and fluid flow. Neonatal cardiac fibroblast-seeded 3D collagen gels were exposed to interstitial flow and/or cyclic strain and message levels of collagens type I and III, transforming growth factor ß1 (TGF-ß1), and α-smooth muscle actin (α-SMA) were assessed. Flow was found to significantly increase and strain to decrease expression of myofibroblast markers. Corresponding immunofluorescence indicated that flow and strain differentially regulated α-SMA protein expression. The effect of flow was inhibited by exposure to losartan, an angiotensin II type 1 receptor (AT1R) blocker, and by introduction of shRNA constructs limiting AT1R expression. Blocking of TGF-ß also inhibited the myofibroblast transition, suggesting that flow-mediated cell signaling involved both AT1R and TGF-ß1. Reduced smad2 phosphorylation in response to cyclic strain suggested that TGF-ß is part of the mechanism by which cardiac fibroblasts differentiate between strain-induced and flow-induced mechanical stress. Our experiments show that fluid flow and mechanical deformation have distinct effects on cardiac fibroblast phenotype. Our data suggest a mechanism in which fluid flow directly acts on AT1R and causes increased TGF-ß1 expression, whereas cyclic strain reduces activation of smad proteins. These results have relevance to the pathogenesis and treatment of heart failure.

In vivo acceleration of heart relaxation performance by parvalbumin gene delivery.

Defective cardiac muscle relaxation plays a causal role in heart failure. Shown here is the new in vivo application of parvalbumin, a calcium-binding protein that facilitates ultrafast relaxation of specialized skeletal muscles. Parvalbumin is not naturally expressed in the heart. We show that parvalbumin gene transfer to the heart in vivo produces levels of parvalbumin characteristic of fast skeletal muscles, causes a physiologically relevant acceleration of heart relaxation performance in normal hearts, and enhances relaxation performance in an animal model of slowed cardiac muscle relaxation. Parvalbumin may offer the unique potential to correct defective relaxation in energetically compromised failing hearts because the relaxation-enhancement effect of parvalbumin arises from an ATP-independent mechanism. Additionally, parvalbumin gene transfer may provide a new therapeutic approach to correct cellular disturbances in calcium signaling pathways that cause abnormal growth or damage in the heart or other organs.

Chimera analysis of troponin I domains that influence Ca(2+)-activated myofilament tension in adult cardiac myocytes.

The goal of this study was to investigate isoform-specific functional domains of the inhibitory troponin subunit, troponin I (TnI), as it functions within the intact myofilaments of adult cardiac myocytes. Adenovirus-mediated gene transfer was used to deliver and express a TnI chimera composed of the amino terminus of cardiac TnI (cTnI) and the carboxy terminus of slow skeletal TnI (ssTnI) in adult rat cardiac myocytes. The TnI chimera, designated N-card/slow-C TnI, was expressed and incorporated into myofilaments after gene transfer, without detectable changes in contractile protein stoichiometry or sarcomere architecture. Interestingly, force at submaximal Ca(2+) levels was markedly elevated in single permeabilized myocytes expressing the N-card/slow-C TnI chimera relative to force generated in adult myocytes expressing ssTnI or cTnI. Based on these results, a hierarchy of myofilament Ca(2+) sensitivity is emerging by use of TnI chimera analysis, with the order of sensitivity being N-card/slow-C TnI>>ssTnI>>cTnI. These results also strongly suggest that independent isoform-specific domains in both the amino and carboxy portions of TnI influence myofilament Ca(2+) sensitivity. In additional studies carried out under pathophysiological ionic conditions (pH 6.2), the dramatic acidosis-induced decrease in myofilament Ca(2+) sensitivity observed in myocytes expressing cTnI was blunted in myocytes expressing N-card/slow-C TnI in a manner similar to that in ssTnI-expressing myocytes. These results demonstrate that there is a pH-sensitive domain residing in the carboxy-terminal portion of TnI. The dissection of isoform-specific functional domains under physiological and acidic pH conditions demonstrates the utility of TnI chimeras for analysis of TnI function and provides important insights into the overall function of TnI within the intact myofilament of adult cardiac myocytes.

Embryonic stem cell cardiogenesis applications for cardiovascular research.

Mouse embryonic stem (ES) cells are pluripotent cells derived from the inner cell mass of the preimplantation blastocyst. These cells can be maintained in culture in an undifferentiated state, or they can be induced to differentiate in vitro into multiple cell types, including spontaneously beating cardiac myocytes. The ability to engineer these ES cells genetically, together with their noted rapid differentiation into cardiac myocytes in vitro, makes this a useful tool for the study of cardiac gene expression and function. This in vitro cardiogenesis system may be particularly advantageous for pharmacological studies focusing on discovery of cardioactive drugs and for specifying the functional alterations associated with ablated or mutated cardiac genes that result in a lethal phenotype in vivo. (Trends Cardiovasc Med 1997;7:63-68). © 1997, Elsevier Science Inc.

Brain metabolic correlates of hypoxic-ischemic cerebral necrosis in mid-gestational sheep fetuses: significance of hypotension.

Mid-gestational sheep fetuses exposed to marked hypoxia for 2 h remain brain intact if MABP is maintained above 30 mm Hg. On the other hand, similarly hypoxic fetuses, if they experience reductions in MABP below 30 mm Hg, develop foci of necrosis that predominantly affect hemispheric white matter and neostriatum. Cortex damage is more restricted and is usually associated with more massive underlying white matter damage. The present study examines the brain metabolic basis for the important role of hypotension in brain injury development in marked hypoxia. Sheep fetuses rendered hypoxic by respiring their ewes with 11% oxygen (fetal PaO2 = 8-12 mm Hg) in which MABP was maintained above 30 mm Hg showed increases in brain lactic acid concentrations to 7-13 mumol/g but unaltered energy charge. In contrast, fetuses that sustained MABP reductions below 30 mm Hg showed increases in lactic acid concentrations in vulnerable structures to 16-24 mumol/g accompanied by marked decreases in energy charge. The vulnerable structures also showed reductions in fructose concentrations but a variable behavior of other brain metabolites including phosphocreatine, glycogen, and glucose. Thus, the present findings suggest a relation between hypotension during marked hypoxia, low energy charge, lactic acid accumulation in brain at high concentrations, and fetal brain injury. The ewes of hypoxic hypotensive fetuses received pentobarbital at lower doses than did those of fetuses that maintained blood pressure. This suggests that pentobarbital plays an important role in protecting the fetal brain from asphyxia by extending the hypoxic fetus's ability to maintain blood pressure in addition to reducing its brain metabolism.

p53-dependent expression of PIG3 during proliferation, genotoxic stress, and reversible growth arrest.

The p53-inducible gene 3 (PIG3) was recently identified in a screen for genes induced by p53 before the onset of apoptosis. PIG3 shares significant homology with oxidoreductases from several species. In this study, PIG3-specific antibodies were used to analyze cellular PIG3 protein levels under control and genotoxic stress conditions. PIG3 protein was localized to the cytoplasm and induced in primary, non-transformed, and transformed cell cultures after exposure to genotoxic agents. The induction of PIG3 was p53-dependent and occurred with delayed kinetics as compared with other p53 downstream targets, such as p21 and MDM2. Using a p53-inducible cell model system, in which p53-mediated growth arrest is reversible, we found that PIG3 levels were increased during p53-mediated growth arrest. Interestingly, elevated levels of PIG3 were maintained in cells that resumed cycling in the absence of ectopic p53 expression, suggesting that PIG3 is a long-lived reporter, which may be useful for detecting transient activation of p53.

Gene transfer into mouse embryonic stem cell-derived cardiac myocytes mediated by recombinant adenovirus.

The main purpose of this study was to examine, for the first time, the ability of recombinant adenovirus to mediate gene transfer into cardiac myocytes derived from mouse embryonic stem (ES) cells differentiating in vitro. In addition, observations were made on the effect of adenovirus infection on cardiac myocyte differentiation and contractility in this in vitro system of cardiogenesis. ES cell cultures were infected at various times of differentiation with a recombinant adenovirus vector (AdCMVlacZ) containing the bacterial lacZ gene under the control of the cytomegalovirus (CMV) promoter. Expression of the lacZ reporter gene was determined by histochemical staining for beta-galactosidase activity. LacZ expression was not detected in undifferentiated ES cells infected with AdCMVlacZ. In contrast, infection of differentiating ES cell cultures showed increasing transgene expression with continued time in culture. Expression in ES-cell-derived cardiac myocytes was demonstrated by codetection of beta-galactosidase activity and troponin T with indirect immunofluorescence. At 24 h postinfection, approximately 27% of the cardiac myocytes were beta-galactosidase positive, and lacZ gene expression appeared to be stable for up to 21 d postinfection. Adenovirus infection had no apparent effect on the onset, extent, or duration of spontaneously contracting ES-cell-derived cardiomyocytes, indicating that cardiac differentiation and contractile function were not significantly altered in the infected cultures. The demonstration of adenovirus-mediated gene transfer into ES-cell-derived cardiac myocytes will aid studies of gene expression with this in vitro model of cardiogenesis and may facilitate future studies involving the use of these myocytes for grafting experiments in vivo.

A 33-year-old white female with abdominal pain, nausea, vomiting and hypotension.

A thirty-three year old female presented to our emergency department complaining of severe abdominal pain, nausea, and vomiting. On physical examination she was hypotensive with a firm, tender abdomen, cervical motion tenderness and a diffuse erythematous rash. A surgical diagnosis of Acute Pelvic Inflammatory Disease was made during laparoscopy. Coagulant studies, liver function tests, culture results, and the desquamation of the patient's palms led to the additional diagnosis of Toxic Shock Syndrome. A literature search failed to reveal any similar cases of Pelvic Inflammatory Disease (PID) and Toxic Shock Syndrome (TSS) occurring concomitantly. Patients may present severely ill with either of these disease entities but potential for serious illness is greater when both of these syndromes occur in the same patient. We conclude that in patients with a similar presentation, the symptoms should not be attributed completely to PID without further investigation and consideration of a concomitant disease process including TSS.

An adolescent male with an arteriovenous malformation presenting with reproducible seizures.

The patient who presents with new onset seizure is a difficult but common problem in emergency medicine. It is more difficult to make a specific etiologic diagnosis when the seizure patient is without fever, focal neurological deficit, prior medical history, electrolyte or acid-base imbalance. Such a patient with new onset seizures presented to our emergency department. The seizures were induced by a specific right arm position. The patient's initial evaluation included a normal physical examination, screening chemistries, and an unenhanced computed tomography (CT scan) of the head. Subsequent contrast-enhanced head CT scan and eventual magnetic resonance imaging (MRI) of the brain revealed a large arteriovenous malformation (AVM). The differential diagnosis of seizures is long and involved, but a majority of these diagnoses can be ruled in or out by simple and inexpensive screening examinations. Occasionally, more involved studies are indicated than the routine electroencephalogram (EEG) and CT scan. CT scan with contrast, angiography, and magnetic resonance imaging (MRI) may be required to elucidate the cause of the seizure. Of these, angiography and MRI are the most sensitive for AVM, but contrast CT scan is the most readily available with acceptable sensitivity and is therefore potentially more beneficial.

Human RFamide-related peptide-1 diminishes cellular and integrated cardiac contractile performance.

Peptides influence cardiac dysfunction; however, peptidergic modulation of contractile performance remains relatively uncharacterized. We identified a novel human peptide that modulates mammalian contractile performance. Members of the FMRFamide-related peptide (FaRP) family contain a C-terminal RFamide but structurally variant N-terminal extension. We report human RFamide-related peptide-1 (hRFRP-1) and rat RFRP-1 rapidly and reversibly decreased shortening and relaxation in isolated mammalian cardiac myocytes in a dose dependent manner. The mammalian FaRP, 26RFa, structurally related to RFRP-1 by only an RFamide did not influence myocyte contractile function. The protein kinase C (PKC) inhibitor bisindolylmaleimide-1 blocked hRFRP-1 activity. Pretreatment with pertussis toxin (PTX) did not diminish hRFRP-1 influence on contractile function. In addition, intravenous injection of hRFRP-1 in mice decreased heart rate, stroke volume, ejection fraction, and cardiac output. Collectively these findings are consistent with the conclusion RFRP-1 is an endogenous signaling molecule that activates PKC and acts through a PTX-insensitive pathway to modulate cardiac contractile function. Taken together these negative chronotropic, inotropic, and lusitropic effects of hRFRP-1 are significant; they suggest direct acute cellular and organ-level responses in mammalian heart. This is the first known study to identify a mammalian FaRP with cardio-depressant effects, opening a new area of research on peptidergic modulation of contractile performance. The high degree of RFRP structure conservation from amphibians to mammals, and similarity to invertebrate cardioinhibitory peptides suggests RFRP-1 is involved in important physiological functions. Elucidation of mechanisms involved in hRFRP-1 synthesis, release, and signaling may aid the development of strategies to prevent or attenuate cardiac dysfunction.

Basal and insulin-stimulated skeletal muscle sugar transport in endotoxic and bacteremic rats.

Membrane glucose transport with and without insulin was studied in soleus muscle from 5-h endotoxic rats (40 mg/kg Salmonella enteritidis lipopolysaccharide), and in soleus and epitrochlearis muscles from 12-h bacteremic (Escherichia coli, 4 X 10(10) CFU/kg) rats. Glucose transport was measured in muscles by evaluating the fractional efflux of 14C-labeled 3-O-methylglucose (14C-3-MG) after "loading" muscles with 14C-3-MG. Basal 3-MG transport was elevated in soleus muscles from endotoxic as well as in soleus and epitrochlearis muscles from bacteremic rats compared with time-matched controls. Low insulin concentrations stimulated 14C-3-MG transport more in bacteremic and endotoxic rat muscles than in controls. However, sugar transport in the presence of high insulin dose was attenuated in soleus and epitrochlearis muscles from bacteremic rats and soleus muscles from endotoxic rats compared with controls. Analysis of the dose-response relationship with ALLFIT revealed that the maximal transport response to insulin was significantly decreased in both models of septic shock. Sensitivity to insulin (EC50) was increased in endotoxic rat muscles, and a somewhat similar tendency was observed in bacteremic rat soleus muscles. Neural and humoral influences and/or changes in cellular metabolic energy may contribute to the increase in basal transport. Shifts in insulin-mediated transport may be due to alterations in insulin-receptor-effector coupling and/or the number of available glucose transporters.

3-O-methylglucose transport in soleus muscle of bacteremic rats.

Basal and insulin-stimulated soleus muscle 3-O-[14C]methylglucose ([14C]-3-O-MG) transport was studied in vitro and in vivo during bacteremia in rats. Fasted rats were injected with Escherichia coli to produce bacteremia (B), and controls (C) received saline. In vitro studies using soleus muscles were carried out 8 or 12 h after bacterial injection, and transport was measured using the rate coefficient (lambda = min-1). Although insulin-stimulated (10 mU/ml) [14C]-3-O-MG transport was decreased in 12-h bacteremic rat muscles (lambda B = 0.041 +/- 0.003; lambda C = 0.055 +/- 0.002), the basal [14C]-3-O-MG transport rate coefficient was elevated (lambda B = 0.027 +/- 0.004; lambda C = 0.019 +/- 0.001). For in vivo studies, [14C]-3-O-MG with or without insulin was injected into rats 10-40 min prior to removing soleus muscles at 12 h postbacterial or postsaline injection. Transport was measured as the ratio of [14C]-3-O-MGintracell/[14C]-3-O-MGextracell. Basal ratios were not different and muscles from both control and bacteremic rats responded comparably to insulin with increased [14C]-3-O-MG transport during the initial 30 min. At 35-40 min postinsulin injection there was a further stimulation of [14C]-3-O-MG transport in control but not in 12-h bacteremic rat muscles. The changes in [14C]-3-O-MG transport observed in vitro and in vivo after 12 h of bacteremia may be due to circulating mediators and/or changes in membrane function.

Alterations in myofibrillar function and protein profiles after complete global ischemia in rat hearts.

We studied changes in myofibrillar function and protein profiles after complete global ischemia with anoxia in rat hearts. Hearts were exposed to global ischemia and anoxia (CGI) for 30 or 60 minutes at 37 degrees C, and myofibrils were prepared for measurement of Ca(2+)-dependent Mg(2+)-ATPase activity at pH 7.0 and 6.5. Hearts incubated in cold saline (1 +/- 1 degrees C) and nonincubated hearts served as controls. Maximum ATPase activity was unchanged at pH 7.0 and pH 6.5 in myofibrils from hearts treated with 30 or 60 minutes of CGI. At pH 7.0, the Hill coefficient, which is an index of cooperative interactions among thin-filament proteins, was unchanged after 30 minutes of CGI but was significantly increased after 60 minutes of CGI. A similar trend for increased cooperativity was observed when myofibrillar ATPase activity was measured at pH 6.5 in myofibrils from rat hearts made ischemic for 30 or 60 minutes. Both 30 and 60 minutes of CGI resulted in increased pCa50 values (half-maximally activating free [Ca2+]) at pH 7.0 and pH 6.5. Densitometric analysis of myofibrillar proteins separated with sodium dodecyl sulfate-polyacrylamide gel electrophoresis indicated that troponin I and troponin T were degraded during 60 minutes of CGI. Two new protein bands appearing in ischemia-treated myofibrils were identified as partially degraded troponin I and troponin T with Western blots. The troponin I fragment could be phosphorylated by cAMP-dependent protein kinase. In addition, we observed phosphorylation of a protein band that corresponded to myosin light chain-2 in myofibrils from CGI-treated hearts. These results suggest that degradation of thin-filament proteins may contribute to the changes in cooperativity of Ca2+ regulation of ATPase activity observed in the myofibrils from rat hearts exposed to CGI.

Effect of bacteremia on skeletal muscle glucose transport in fed rats.

Basal and insulin-stimulated membrane glucose transport was studied in soleus muscles from fed rats given Escherichia coli intraperitoneally (ip, 4 X 10(10) colony forming units (CFU)/kg) or saline. Glucose transport was measured in muscles by evaluating the fractional efflux (lambda, min-1) of [14C]3-O-methylglucose (14C-3MG) after "loading" muscles with 14C-3MG. Basal glucose transport was similar in muscles from 8-hr bacteremic (B) and time-matched control (C) rats, but it was elevated significantly in muscles 12 hr after bacterial injection (B lambda = 0.0227 +/- 0.0010, n = 41, C lambda = 0.0159 +/- 0.0008, n = 42; P less than .05). The effect of insulin on transport was determined from the peak response and from the percent increase in transport for each insulin dose. At low insulin concentrations, peak glucose transport was increased in muscles from 8-hr bacteremic rats compared to controls, while the response to 10.0 mU/ml of insulin was similar in bacteremic and control rat muscles. The maximum percent increase in transport and the EC50 for insulin-mediated 3MG transport were not different in muscles from 8-hr bacteremic and time-matched control rats. Twelve hr after bacterial injection, low insulin doses stimulated sugar transport to greater peak values in bacteremic rat muscles compared to time-matched control values. However, peak 14C-3MG transport with 10.0 mU/ml of insulin was attenuated in bacteremic rat muscles compared to controls. An attenuated maximum response and slightly diminished EC50 were evident in muscles from 12-hr bacteremic rats compared to controls when the percent increase in transport at each insulin concentration was analyzed. The results of the current study were similar to results obtained in fasted rats [1] which indicates that alterations in muscle glucose transport during bacteremia are independent of dietary state.

Effect of diltiazem on skeletal muscle 3-O-methylglucose transport in bacteremic rats.

This study examined whether alterations in cellular Ca2+ regulation contribute to previously observed changes in skeletal muscle sugar transport during bacteremia. Fasted male rats received saline (control) or bacteria (4 X 10(10) Escherichia coli/kg) intraperitoneally. Twelve hours later, basal and insulin-mediated 3-O-methylglucose (3MG) transport was measured in isolated soleus muscles. Measurements of 3MG transport in the presence of cytochalasin b or at a low temperature (0.5 degree C) indicated that altered sugar transport in bacteremic rat muscles was not due to nonspecific membrane permeability changes. To determine the role of Ca2+ in the pathogenesis of altered sugar transport during bacteremia, rats were treated with the Ca2+ antagonist diltiazem (DZ, 0.6-2.4 mg/kg) at various times (0, 0 + 7.5, 10 h) after saline or bacterial injection. In bacteremic rats given 2.4 mg/kg DZ at 10 h, basal and insulin-mediated transport were similar to control values. This dose of DZ had little effect on control muscles. The addition of 20 microM DZ to the incubation media did not affect basal or insulin-mediated 3MG transport in bacteremic rat muscles. Addition of the Ca2+ agonist BAY K 8644 to the incubation media had no effect on sugar transport in bacteremic rat muscles but caused alterations in control rat muscles that were comparable to those observed in bacteremia. These results suggest that alterations in Ca2+ regulation could contribute to the previously observed changes in sugar transport in skeletal muscles from bacteremic rats.

Suspected bentonite toxicosis in a cat from ingestion of clay cat litter.

A 2 1/2-y-old spayed female cat was presented for lethargy and weakness. The cat was hypokalemic (3.1 m Eq K/L) and severely anemic (60% PVC, 1.3 g hemoglobin/dL). The cat was known to ingest bentonite-containing cat litter. It recovered with treatment of i.v. fluids, electrolytes and whole blood transfusion and was discharged. Two months later the cat was presented again with signs similar to those seen previously. This occurred 1 mo after the owner resumed the use of bentonite-containing cat litter. The signs were remarkably similar to those reported in humans from the chronic ingestion of bentonite clays. Bentonite toxicosis is suggested by the coexistence of hypokalemia hypochromic anemia in cats presented with lethargy and muscle weakness.

Effect of Ca2(+)-channel agonists and antagonists on skeletal muscle sugar transport.

The purpose of this study was to determine whether changes in cellular Ca2+ caused by Ca2(+)-channel modifiers affect skeletal muscle sugar transport. Rat soleus muscles were isolated, and sugar transport was measured monitoring efflux of 3-O-methylglucose (3-MG). Muscles were "loaded" with 3-O-[methyl-14C]methyl-D-glucose in Krebs-Ringer-bicarbonate (KRB) media and then sequentially washed in radioisotope-free KRB. Cellular Ca2+ was modified by adding a Ca2+ agonist (BAY K 8644) and/or Ca2+ antagonists (nifedipine, nitrendipine, diltiazem) to the "load" and "wash" media. Alterations in cellular Ca2+ were determined from soleus muscle 45Ca2+ uptake measurements. Addition of 0.25 microM BAY K 8644 enhanced insulin-mediated 3-MG transport and 1 microM nifedipine prevented the agonist effect. A high concentration of BAY K 8644 (6 microM) led to increased basal but attenuated insulin-mediated 3-MG transport. Nifedipine (4 microM) and diltiazem (20 microM) blocked the BAY K 8644-induced changes in basal and insulin-mediated 3-MG transport. Nifedipine (4 microM) also attenuated the stimulation of cellular Ca2+ uptake by 6 microM BAY K 8644. Nitrendipine was unable to reverse the changes in basal or insulin-mediated 3-MG transport caused by BAY K 8644. These results indicate that a low concentration of BAY K 8644 enhanced insulin-stimulated skeletal muscle sugar transport, whereas a high concentration of the agonist led to a diminished ability of insulin to stimulate sugar transport. The effects of the Ca2+ agonist were presumably mediated through modulation of cellular Ca2+ as these effects were blunted by the Ca2+ antagonists.

Skeletal muscle calcium uptake in bacteremic rats.

To determine whether cellular Ca2+ regulation is altered in bacteremic rat skeletal muscle, 45Ca2+ uptake was measured in soleus muscles 12 h after an intraperitoneal bacterial (Escherichia coli) injection. Some rats received diltiazem (2.4 mg/kg iv) 10 h after bacterial injection to determine whether calcium blockers could inhibit changes in Ca2+ regulation. Cellular exchangeable Ca2+ was measured in soleus muscles incubated for 5 min to 4 h in Krebs-Ringer bicarbonate (KRB) media (pH 7.4) containing 45Ca2+ (1.5 muCi/ml) and subsequently "washed" in La3+-containing, Ca2+-free KRB media. Bacteremia had no effect on steady-state exchangeable Ca2+, but it significantly reduced the time required to reach half-maximal uptake compared with controls. Diltiazem treatment returned the half-maximal Ca2+ uptake toward control values in bacteremic rat muscles. Depolarization of soleus muscles with high K+ (60 mM) transiently increased Ca2+ uptake in control and bacteremic rat muscles, although the increase was significantly greater (P less than 0.05) in bacteremic rat muscles. The altered skeletal muscle Ca2+ regulation may be due to excessive stimulation of Ca2+ messenger systems, sarcolemmal Ca2+ channels, and/or Ca2+ release from the sarcoplasmic reticulum in response to bacteremia.