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Endometrial cancer recurrences are usually either pelvic or distant metastases. Isolated scar recurrence is a rare entity, with approximately 43 cases being reported in the literature. The study highlights that most scar recurrences can be offered curative treatment with radical surgery. In our series, all the recurrences were in a previous Pfannenstiel incision scar. We report a series of four cases of isolated Pfannenstiel scar recurrences in patients with endometrial cancer who had undergone total abdominal hysterectomy and salpingo-oophorectomy. All four patients underwent curative radical surgery. Two patients had associated inguinal lymph node involvement, for which ilio-inguinal block dissection was done for one patient and en bloc resection of the node along with the recurrent disease was done for the other patient. We reviewed the previous literature to ascertain the possible aetiology of incisional recurrence, especially the isolated scar recurrences. In patients presumed to be having carcinoma endometrium, proper incision and surgical technique with good exposure, during the initial surgery, is important so as to minimise scar recurrence. Most of the isolated scar recurrences can be surgically resected with a curative intent.

Introduction The increasing incidence of cesarean sections in India has caused a rise in the incidence of postpartum hemorrhage (PPH). There has been expanding interest in the role of misoprostol and tranexamic acid (TXA) in preventing and managing PPH during lower (uterine) segment cesarean section (LSCS). However, the lack of a published study comparing the efficacies of these drugs prompted us to conduct this study. Aims and objectives To compare the efficacies of sublingual misoprostol (600 μg) and intravenous TXA injection (500 mg) in reducing blood loss during LSCS by assessing intraoperative blood loss, perioperative hemoglobin (Hb) fall, and need for additional uterotonic agents. Materials and methods A total of 163 pregnant patients undergoing emergency/elective LSCS during the study period from 2013 to 2014 were randomly assigned to two groups — group I (82) received sublingual misoprostol 600 μg and group II (81) intravenous TXA 500 mg at cord clamping. Visual estimation of blood loss was done and 48 hours postoperative Hb and packed cell volume were measured to compare with preoperative values. Need for added uterotonics, blood transfusion, and adverse effects of drugs was assessed. The two groups were again subgrouped based on presence or absence of risk factors for PPH. Results The TXA significantly reduced blood loss compared with misoprostol (416 vs 505 mL) in patients without high-risk factors for PPH. Misoprostol caused significantly higher minor side effects while TXA reduced operation time. Conclusion The TXA can be routinely used after cord clamping along with oxytocin in patients undergoing elective/emergency LSCS to reduce perioperative blood loss, especially in those without risk factors for PPH. How to cite this article Bose D, Beegum R. Sublingual Misoprostol vs Intravenous Tranexamic Acid in reducing Blood Loss during Cesarean Section: A Prospective Randomized Study. J South Asian Feder Obst Gynae 2017;9(1):9-13.

In laparoscopy, tissue extraction might require morcellation for larger intra-abdominal specimens, especially in gynecological patients. specimen, the specimen needs to be reduced. The Food and Drug Administration (FDA) issued a press release in April 2014 that discouraged the use of devices used for morcellation - power morcellators. This article has the objective to review the literature related to complications by power morcellation of uterine fibroids in laparoscopy and offer recommendations to laparoscopic surgeons in gynaecology. Respecting women who have leiomyosarcoma, it can be concluded that the FDA directive was based on a mis­leading analysis due to inherent flaws in the trials analysed by it. Hence, the need of the hour are more accurate esti­mates regarding the prevalence of leiomyosarcoma among women having surgery for presumed leiomyomas. Modification of the FDA’s current restriction regarding power morcellation would empower each woman to allow surgeons and hospitals to make the most appropriate, informed choices regarding utilization of tissue extraction in individual patients undergoing uterine surgery without undermining the freedom of the woman to choose the best-suited procedure.

The objective of the present study was to identify the nature of a filterable cardiodepressant substance (FCS) that contributes to myocardial dysfunction in a canine model of Escherichia coli septic shock. In a previous study, it was found that FCS increased in plasma after 4 h of bacteremia (Am J Physiol 1993;264:H1402) in which FCS was identified by a bioassay that included a right ventricular trabecular (RVT) preparation. In that study, FCS was only partially identified by pore filtration techniques and was found to be a protein of molecular weight between 10 and 30 K. In the present study, FCS was further purified by size exclusion high-pressure liquid chromatography, until a single band was identified on one-dimensional gel electrophoresis. This band was then subjected to tandem mass spectrometry and protein-sequencing techniques and both techniques identified FCS as lysozyme c (Lzm-S), consistent with that originating from the canine spleen. Confirmatory tests showed that purified Lzm-S produced myocardial depression in the RVT preparation at concentrations achieved during sepsis in the in vivo preparation. In addition, Lzm-S inhibited the adrenergic response induced by field stimulation and the β- agonist isoproterenol in in vitro preparations, these results suggesting that Lzm-S may inhibit the sympathetic response in sepsis. The present findings indicate that Lzm-S originating from disintegrating leukocytes from organs such as the spleen contributes to myocardial dysfunction in this model. The mechanism may relate to its binding or hydrolysis of a cardiac membrane glycoprotein thereby interfering with myocardial excitation–contraction coupling in sepsis.

Objective: Histamine H3 receptors and α2-adrenoceptors are presynaptic receptors that modulate norepinephrine (NE) release from sympathetic nerves innervating the cardiovascular system. We previously showed that cardiac H3 receptors are activated in sepsis, and that this activation leads to a decrease in the adrenergic response (AR) [J. Appl. Physiol. 85 (1998) 1693-1701] H3-receptors and α2-receptors appear to be coupled to GTP binding regulatory proteins (G) that modulate transmitter release by reducing calcium current into the nerve terminals through neuronal calcium channels. There may also be interaction between H3-receptors and α2-receptors on AR that may occur either at the receptor or a more downstream level. Methods: In the present study, we examined the effect of septic plasma on AR in a canine ventricular preparation in which field stimulation was used to produce AR. We determined whether there was interaction between H3-receptors and α2-adrenoceptors and tested whether H3 activation would attenuate the α2-agonist and α2-antagonist effects of clonidine and yohimbine, respectively. We also determined whether the mechanism by which septic plasma decreases the adrenergic response involves inactivation of an inhibitory G protein and used pertussis toxin (PTX) to assess this effect. Results: We found that septic plasma attenuated AR produced by field stimulation, and that this decrease was mediated by a PTX sensitive inhibitory G protein. H3 activation also attenuated the α2-agonist and α2-antagonist effects on adrenergic activation as compared with nonseptic plasma. Conclusion: We conclude that presynaptic sympathetic dysfunction may contribute to cardiovascular collapse in sepsis.

Purpose: In septic shock, myocardial dysfunction develops over the course of illness, but the mechanism of this depression is not clear. In this study, mechanisms of myocardial dysfunction were examined in a porcine model of Escherichia coli sepsis. Materials and Methods: Animals were subjected to 4 hours of bacteria infusion (n = 5) (septic group) or saline infusion (n = 5) (nonseptic group), after which trabeculae were removed from the right ventricle and placed into a recirculating water bath. Measurements of steady-state contraction (SSC) were obtained at 0.5, 1, and 2 Hz. Indirect indices were used to assess abnormalities in myocardial calcium metabolism in sepsis. Extrasystoles (ES) were used to assess transsarcolemmal (TSL) calcium flux and were measured at 300 milliseconds, 400 milliseconds, and 500 milliseconds after the preceding stimulus. Postrest contraction (PRC) is an indicator of SR recirculation from the uptake to the release site and was obtained after interposing intervals of rest between steady-state beats at 0.5 Hz. Rapid-cooling contracture (RCC) is an indicator of sarcoplasmic reticulum (SR) content and was obtained at 0.5, 1, and 2 Hz and after interposing intervals of rest at 0.5 Hz. Results: SSC was not different between groups at 0.5 Hz, but compared with the nonseptic group, SSC decreased at 1 and 2 Hz in the septic group (P < .05). PRC and TSL were not different between groups. During rest intervals, calcium leaks out of SR through the ryanodine channel (ie, SR calcium release channel). In the septic group, as assessed by RCC, SR calcium leak was less than that found in the nonseptic group. Conclusion: These results indicate that myocardial dysfunction in sepsis is frequency dependent, and that the mechanism is most likely caused by inhibition of SR calcium release owing to blockade of the ryanodine channel. Copyright © 2000 by W.B. Saunders Company

In the heart, histamine (H3) receptors may function as inhibitory presynaptic receptors that decrease adrenergic norepinephrine release in conditions of enhanced sympathetic neural activity. We hypothesized that H3-receptor blockade might improve cardiovascular function in sepsis. In a canine model of Escherichia coli sepsis, we found that H3-receptor blockade increased cardiac output (3.6 to 5.3 l/min, P< 0.05), systemic blood pressure (mean 76 to 96 mmHg, P < 0.05), and left ventricular contractility compared with pretreatment values. Plasma histamine concentrations increased modestly in the H3-blocker–sepsis group compared with values obtained in a nonsepsis–time-control group. In an in vitro preparation, histamine H3 activation could be identified under conditions of septic plasma. We conclude that activation of H3 receptors may contribute to cardiovascular collapse in sepsis.

In sepsis, myocardial depression may be caused by mediators released as part of the inflammatory reaction, lumour necrosis factor alpha (TNF alpha) is one mediator that may contribute to this depression. In the present study, we contrasted the effects of TNF alpha and septic plasma fraction (SP) obtained from an E. coli model on contractile tension in intact and skinned canine ventricular trabecular (VT) preparations. The objectives were to determine whether SP or TNF alpha could impair contractile tension at the level of the myofilaments, and to determine the extent to which TNF alpha may account for myocardial depression found in E. coli sepsis.Measurements of isometric tensions were made after TNF alpha and SP (10,000 to 30,000 MW fraction) were added to respective intact or skinned canine VT preparations. In the skinned preparation, trabeculae were chemically skinned with Triton X-100.Septic plasma caused a decrease in contraction in the intact preparation compared with preseptic plasma (50 +/- 7 vs 33 +/- 7%, P0.05), but had no effect in the skinned preparation. On the other hand, TNF alpha (30 ng.ml-1) caused an approximately 50% reduction in tension (29 +/- 2 mg vs 16 +/- 5 mg) in the skinned preparation (P0.05), but had no effect in the intact preparation.These results suggest that TNF alpha and SP act through different mechanisms. While SP requires an intact membrane, TNF alpha impairs function by a direct effect on the myofilaments.

We examined whether depressed left ventricular (LV) contractility during Escherichia coli sepsis in dogs was due to a decrease in the fractional release of calcium from the sarcoplasmic reticulum (SR) or a reduction in calcium content in this organelle. To indirectly assess SR calcium availability in a right ventricular (RV) trabecular muscle preparation, we utilized functional indexes of cellular myocardial calcium metabolism, which included rapid-cooling contracture (RCC), an indicator of SR calcium content, and postrest contraction (PRC), an index of calcium availability from the release compartment of the SR. Measurements were made during steady-state stimulation at 0.5 and 1.5 Hz, during which time rest intervals of 30-240 s were periodically imposed. SR calcium availability was measured in RV trabeculae of dogs subjected to 4 h of E. coli sepsis and was compared with calcium availability measured in nonseptic dogs. We further characterized a filterable cardiodepressant substance (FCS), which has been previously shown to be associated with LV depression in this model, to determine whether it produced changes in calcium metabolism similar to those found in sepsis. The results showed that calcium availability from the SR of septic dogs was not impaired. Furthermore, FCS was found in the 10,000- to 30,000-mol wt fraction of plasma and produced changes in PRC in canine trabeculae that were similar to those produced during sepsis. We conclude that, as assessed by PRC and RCC, SR calcium content and release are not impaired in sepsis.

The aim of this work was to determine the relationship between peak twitch amplitude and sarcoplasmic reticulum (SR) Ca2+ content during changes of stimulation frequency in isolated canine ventricle, and to estimate the extent to which these changes were dependent upon sarcolemmal Na(+)-Ca2+ exchange. In physiological [Na+]o, increased stimulation frequency in the 0.2-2-Hz range resulted in a positive inotropic effect characterized by an increase in peak twitch amplitude and a decrease in the duration of contraction, measured as changes in isometric force development or unloaded cell shortening in intact muscle and isolated single cells, respectively. Action potentials recorded from single cells indicated that the inotropic effect was associated with a progressive decrease of action potential duration and a marked reduction in average time spent by the cell near the resting potential during the stimulus train. The frequency-dependent increase of peak twitch force was correlated with an increase of Ca2+ uptake into and release from the SR. This was estimated indirectly using the phasic contractile response to rapid (less than 1 s) lowering of perfusate temperature from 37 degrees C to 0-2 degrees C and changes of twitch amplitude resulting from perturbations in the pattern of electrical stimulation. Lowering [Na+]o from 140 to 70 mM resulted in an increase of contractile strength, which was accompanied by a similar increase of apparent SR Ca2+ content, both of which could be abolished by exposure to ryanodine (1 x 10(-8) M), caffeine (3 x 10(-3) M), or nifedipine (2 x 10(-6) M). Increased stimulation frequency in 70 mM [Na+]o resulted in a negative contractile staircase, characterized by a graded decrease of peak isometric force development or unloaded cell shortening. SR Ca2+ content estimated under identical conditions remained unaltered. Rate constants derived from mechanical restitution studies implied that the depressant effect of increased stimulation frequency in 70 mM [Na+]o was not a consequence of a decreased rate of refilling of a releasable pool of Ca2+ within the cell. These results demonstrate that frequency-dependent changes of contractile strength and intracellular Ca2+ loading in 140 mM [Na+]o require the presence of a functional sarcolemmal Na(+)-Ca2+ exchange process. The possibility that the negative staircase in 70 mM [Na+]o is related to inhibition of Ca(2+)-induced release of Ca2+ from the SR by various cellular mechanisms is discussed.

Summary Myocardial pump failure during ischemia and hypoxia is often a reversible dysfunction. Contractile changes can occur in several different ways: during acute ischute ischemia, during chronic ischemia as an adaptive process, and during reperfusion following ischemia. Both systolic and diastolic contractile properties are impaired. Although a number of processes, e.g., the failure of the action potential generation mechanisms and reduced energy supply, have been suspected as causes of systolic impairment, the most likely factors appear to be H+ and inorganic phosphate concentrations. The increase in diastolic stiffness is most likely due to an increase in intracellular Ca2+ and, in severe instances, to rigor linkages between actin and myosin filaments. The extent of diastolic dysfunction depends on the nature of ischemia, being more marked in demand ischemia as compared with supply ischemia. Useful criteria to delineate the transition from reversible to irreversible ischemic damage are lacking. Nevertheless, assessment of the reversibility of ischemic contractile changes by nitroglycerin, inotropes, and postextrasystolic potentiation before surgical correction of the flow obstruction may have value in predicting outcome. Several adaptive biochemical changes are known to occur after stress. Hyperthermia produces a family of heat stress proteins that have been found to offer protection against ischemic cardiac damage. Future studies need to be performed to understand the mechanism of the regulation of production of these substances and how they afford protection to the ischemic myocardium. Furthermore, improvements in methods for imaging cardiac metabolic and perfusion status and the development of newer pharmacologic tools to alter intracellular pH regulation are expected to improve our understanding of the mechanism of ischemic cardiac damage and offer better possibilities of therapeutic management.

This retrospective study was undertaken to examine the management and outcome of children who developed isolated masseter muscle spasm (MMS) after the administration of intravenous succinylcholine during anesthetic induction. The inhalation anesthetics used for induction were continued in all of these cases. The medical records of 68 patients (male/female ratio, 1.7:1), identified from approximately 42,000 anesthetics given during the period 1980-1989, were reviewed. Fifty-seven children (2.3-12 yr old) were diagnosed as having isolated MMS, i.e., MMS without spasm of other muscles; 11 experienced generalized rigidity in combination with MMS. Anesthetic and postoperative management of these two groups differed. The overall incidence of MMS was 0.3% of inhalation anesthetics during which succinylcholine was given. Intraoperative arrhythmias occurred in 33% of the patients who developed isolated MMS and more frequently in older children. Most children experienced some degree of hypercarbia and/or metabolic acidosis, but the significance of these abnormalities in the spontaneously ventilating, fasting child is unknown. Serum creatine kinase levels when measured 18-24 h postoperatively were elevated in all but one child (n = 45). There was no long-term morbidity and no mortality. We conclude that failure of the masseter muscles to relax after succinylcholine is not uncommon in children. Based on our experience, and accepting that MMS may be part of the clinical spectrum of malignant hyperthermia, we believe that anesthesia can be continued safely in cases of isolated MMS when careful monitoring accompanies diagnostic evaluation. This differs from the current practice of discontinuing the anesthetic or switching to a nontriggering anesthetic technique.

We examined whether the decrease in cardiac contractility in streptozotocin-induced diabetes in the rat is accompanied by reduced or excessive loading of the sarcoplasmic reticulum (SR) with Ca2+. Pooled SR Ca2+ content and fractional release on stimulation were estimated with rapid cooling contracture (RCC) and twitch height measurements, respectively. Interval-force relation was studied to assess the ability of diabetic tissue to alter the relative contribution of SR Ca2+ for contraction. Two months after injection with streptozotocin, peak isometric contraction and steady-state RCC decreased in parallel to approximately 50% of control values. The time to peak force development and complete relaxation was prolonged to 156 and 161% in diabetes in the presence of 1.25 and 2.5 mM extracellular Ca2+ concentration [Ca2+]o, respectively. A stepwise increase in the rate of stimulation from 0.2 to 0.5 and 1.0 Hz resulted in a negative force staircase, the slope of which was identical in control and diabetic animals in each [Ca2+]o tested. Postrest contractions and RCC, after variable test intervals, were significantly depressed after 0.2 and 0.5 Hz stimulation in diabetic muscles at 1.25 mM [Ca2+]o. This defect of SR Ca2+ availability was reversed by increasing the stimulation frequency to 1.0 Hz or by elevating [Ca2+]o to 2.5 mM. The results suggest that the marked reduction of developed tension in diabetic tissues was a consequence of depleted SR Ca2+ stores, rather than a result of chronic SR Ca2+ overloading. The maintained integrity of the interval-force relation in the presence of diabetes implies that the cellular mechanisms responsible for frequency- and time-dependent alterations in SR Ca2+ availability are not disturbed at this stage of disease.

Inflammatory mediators have been implicated as a cause of reversible myocardial depression in septic shock. We previously reported that the release of lysozyme-c (Lmz-S) from leukocytes from the spleen or other organs contributes to myocardial dysfunction in Escherichia coli septic shock in dogs by binding to a cardiac membrane glycoprotein [J. Mol. Cell. Cardiol. 35 (2003) 265]. However, the mechanism by which Lzm-S causes this depression has not been elucidated. In the present study, we tested the hypothesis that the binding of Lzm-S to a membrane glycoprotein causes myocardial depression by the formation of nitric oxide (NO). NO generation then activates soluble guanylyl cyclase and increases cyclic guanosine monophosphate (cGMP), which in turn triggers contractile impairment via activation of cGMP-dependent protein kinase (PKG). We examined these possibilities in a right ventricular trabecular preparation in which isometric contraction was used to measure cardiac contractility. We found that Lzm-S's depressant effect could be prevented by the non-specific NO synthase (NOS) inhibitor NG-monomethyl- l -arginine ( l -NMMA). A guanylyl cyclase inhibitor (ODQ) and a PKG inhibitor (Rp-8-Br-cGMP) also attenuated Lzm-S's depressant effect as did chemical denudation of the endocardial endothelium (EE) with Triton X-100 (0.5%). In EE tissue, we further showed that Lzm-S caused NO release with use of 4,5 diaminofluorescein, a fluorescent dye that binds to NO. The present study shows that the binding of Lzm-S to EE generates NO, and that NO then activates the myocardial guanosine 3′,5′ monophosphate pathway leading to cardiac depression in sepsis.

Objective: Lactic acidosis is an important complication of septic shock. Alkali treatment such as sodium bicarbonate is often used to treat the low pH level that develops in sepsis. The effect of this treatment on lactate (Lac) clearance is not clear. In the present study, the objective was to examine whether blood pH level alters Lac metabolism in sepsis. Measurements were determined in a canine model of Escherichia coli sepsis after bolus infusion (5 mmol/kg) of either lactic acid (LA) or sodium lactate (NaL). In one preparation, Lac uptake by the splanchnic organs (SP), liver, lung, kidneys (Kid), and soft tissues of the lower extremity (SOL) was primarily determined, whereas in another preparation, Lac uptake by the head and neck region and lung was obtained. Methods: The dogs were studied while anesthetized and ventilated. After 4 hours of sepsis, either LA or NaL was given through a catheter positioned in the abdominal aorta in respective sepsis (SepLA, SepNaL) and nonsepsis groups (ConLA, ConNaL) (n ≈ 6 in each preparation). Catheters and flow probes were used to measure organ Lac uptake. Measurements were obtained at end infusion and at 15-minute intervals after infusion until 75 minutes after infusion. Results: Arterial clearance of Lac in the sepsis groups was slower as compared with the nonsepsis groups. In the liver, sepsis inhibited the uptake of LA as compared with the nonseptic group. In SP, both sepsis and pH affected Lac uptake in which an increase in uptake was found only after NaL infusion in the nonseptic group. In the head and neck region, Lac uptake was pH-level dependent and was found after LA infusion in the sepsis and nonsepsis groups. In the lung, Lac was produced after either LA or NaL infusion in all groups. Neither Kid nor SOL contributed to Lac uptake in any of the groups. Conclusion: Lactate clearance was reduced in sepsis. Both effects of pH level and sepsis modulated the organ uptake of Lac in septic shock. Only a small amount of the total Lac infused could be accounted for by the organs measured in the present study. This suggests that additional organs may account for lactate removal in sepsis. Copyright 2002, Elsevier Science (USA). All rights reserved.

We report some of the unique pharmacological properties of a semipurified endogenous inotropic factor (EIF) present in the extract of the porcine left ventricle. EIF produced the following effects: (a) increase in isometric contractile force developed by electrically driven canine right ventricular trabecula, reaching a maximum with 60-100 microliters/ml concentration; (b) inhibition of Na-pump activity in canine portal vein; (c) no digitalis-like cardiac toxicity, e.g., increased diastolic tension or spontaneous diastolic mechanical oscillatory activity, despite inhibition of the sodium pump; (d) a small increase in sarcoplasmic reticular Ca release from the heart but a large increase in transsarcolemmal Ca influx as seen in biphasic contractions, an action similar to that produced by digitalis-like substances; and (e) prolongation of the action potential duration and refractory period of the canine isolated trabeculae. This latter action may confer a unique antiarrhythmic property to EIF.

In septic shock, the extent to which lactic acidosis (LA) is a consequence of splanchnic lactate overproduction (SLP) or impaired hepatic lactate extraction (HLE) is not clear. We examined SLP and HLE in E. coli sepsis in dogs. We further determined the effects of vasopressor treatments, which included phenylephrine, dopamine, norepinephrine, and a combination of dobutamine and norepinephrine treatment, on SLP and HLE in respective groups. The animals were studied while anesthetized and ventilated. During sepsis, SLP increased as compared with presepsis (-0.017 versus 0.07 mmol/min, p < 0.05), but this increase could not be explained by reduced splanchnic oxygen delivery (SOD). During sepsis, HLE increased as compared with baseline (0.8 versus 8%, p < 0.05), but was significantly lower than that found during lactic acid loading in nonseptic dogs. None of the vasopressor treatments had a detrimental effect on SLP. These results indicate that LA in sepsis occurs secondary to an increase in splanchnic lactate production that is not related to reduced splanchnic oxygen delivery, as well as to a decrease in hepatic lactate extraction. Effects of different vasoactive agents did not alter either splanchnic lactate production or hepatic lactate extraction in this sepsis model.

We have isolated an endogenous positive inotropic factor (EPIF) from porcine left heart ventricular tissue, which demonstrated to have only weak digitalis-like properties including the inhibition of myocardial Na+,K+-ATPase. EPIF completely lacks digitalis-like toxicity such as after-contractions in larger doses. In our recent studies, we have demonstrated that EPIF produces a decrease in the amplitude of the post-rest rapid cooling contracture which indicated that EPIF may release Ca2+from the sarcoplasmic reticulum. In the present study, the effects of EPIF were investigated on the Ca2+uptake and release properties of SR enriched membrane vesicles from rat heart. At pH 6.8 and in the presence of oxalate, EPIF dose-dependently inhibited the ATPdependent uptake of Ca2+by SR vesicles. Concentrations as low as 25 ul (in 1 mL uptake medium) of EPIF caused a 45-47% reduction in the uptake of Ca2+within 3-4 min. Increases in EPIF concentration to 50 ul/mL caused additional reduction of only 15-20% in the uptake of Ca2+. Concentrations of 25 ul/mL of EPIF had little or no effects on passive release of actively loaded Ca2+in SR vesicles. On doubling the concentrations to 50 ul/mL EPIF, however, enhanced the release of Ca2+by 25-28% during 1-2 min. and 44-48% after 4 min of incubation of Ca2+loaded vesicles in the release medium. Relatively smaller effects of EPIF on Ca2+release implies that EPIF may mainly lower the uptake of Ca2+in SR. This reduced uptake of Ca2+may be explained by the EPIF-induced inhibition of Ca2+pump.

Background Malignant hyperthermia (MH) is an important cause of anesthesia-induced death. Malignant hyperthermia susceptibility is diagnosed using the in vitro caffeine/halothane contracture test (CHCT) in fresh muscle biopsy specimens. The CHCT test is highly invasive, expensive, and lacks 100% specificity. Genetic and biochemical evidence provide strong support for the view that the substitution of cysteine for arginine 614 (Arg614Cys) in the human ryanodine receptor gene is one of several mutations that are likely to cause human MH. DNA testing was compared with CHCT as a means of predicting MH susceptibility in a large MH family in which the Arg614Cys mutation was detected. Methods A comparison of CHCT and DNA-based diagnosis was conducted in a large Manitoba Mennonite MH kindred identified by an index patient who died at age 45 yr of an MH crisis after general anesthesia. The presence of the Arg614Cys mutation was detected through a combination of polymerase chain reaction and restriction endonuclease digestion. Blood samples for DNA analysis were obtained from 68 family members, including 19 who had undergone muscle biopsies and 1 who had a documented crisis but did not undergo biopsy. Family members were classified as MH-susceptible or MH-normal on the basis of the CHCT. Results Twenty-two persons were found to be heterozygous for the Arg614Cys mutation. Five of these persons had prior positive CHCT results and one had an MH crisis but did not undergo biopsy. On DNA testing, 44 persons were found to be homozygous for the normal allele. Of these, ten had been classified as MH-normal and five as MH-susceptible on the basis of the CHCT. On reevaluation of the data obtained in our earlier CHCT diagnoses, we found that the condition of the muscle was poor, with no twitch, for three of five individuals homozygous for the normal allele but originally classified as MH-susceptible and for one who was homozygous for the normal allele and originally classified as MH-normal. Caffeine/halothane contracture test results for these four persons were considered invalid. The twitch response was good for the two remaining persons who were homozygous for the normal allele but classified as MH- susceptible, because contracture was observed with appropriately low levels of both caffeine and halothane. Conclusions An absolute correlation between DNA test results and CHCT assignment could not be made in this kindred. Possible explanations for discordance are that the Arg614Cys mutation is not linked to MH, that a second MH mutation is segregating in the family, or that there are errors in the CHCT. Because there is strong evidence supporting the causal nature of the Arg614Cys mutation, the discordant persons are not closely related within the pedigree as they would be if a second MH mutation were segregating, and the CHCT is not 100% accurate, we propose that the observed discordance between DNA test results and CHCT assignment in this kindred results from two false-positive diagnoses by the CHCT.

We studied the changes in pial arteriolar diameter during hypoxia and 60 and 120 min after restoration of normoxia, using the closed cranial window technique in artificially ventilated and normocapnic rats. Pial arteriolar diameter increased 16 +/- 4% during hypoxia (PaO2 less than 25 mm Hg, lasting 10 min). Although blood pressure (BP), heart rate (HR), and blood gases returned to prehypoxic level when measured at 60 and 120 min after hypoxia, pial arterial diameter decreased significantly (13 +/- 5 and 16 +/- 6% below control levels, respectively). This posthypoxic vasoconstriction was reversed by treatment of the brain surface with L-660,711 (10(-5) M), a specific leukotriene D4 receptor antagonist. These data suggest that leukotrienes may be involved in delayed cerebral vasoconstriction that follows a brief period of hypoxia.

1. Hypoxia reversibly increased isometric tension in unstimulated canine isolated basilar artery rings. 2. Nordihydroguaiaretic acid (NDGA; 5 x 10(-6) M), an inhibitor of lipoxygenase and quinacrine (10(-5) M), which blocks the release of arachidonic acid from phospholipids by inhibiting the enzyme phospholipase A2, blocked hypoxia-induced contractions. 3. The preferential leukotriene D4 (LTD4) antagonist, L-660,711, also inhibited the hypoxia-induced contractions in concentrations ranging from 10(-8) M to 10(-5) M. The effects seen were statistically significant (P less than 0.05). Two components of inhibition were seen. 4. Arachidonic acid (5 micrograms ml-1) caused contraction of the isolated basilar artery rings. This response was inhibited by NDGA (5 x 10(-6) M) and L-660,711 (10(-5) M). 5. The LTD4 (10(-8) M-10(-7) M)-induced contraction was relaxed by L-660,711 in a dose-dependent manner. Both the contraction caused by LTD4 as well as that caused by hypoxia were relaxed by 5 x 10(-6) M adenosine. 6. Leukotriene(s) may be involved in hypoxia-induced contraction of canine isolated basilar artery. However, they may not be the sole mediator(s).

1. We previously isolated an extract from porcine left ventricle that possessed digitalis-like properties such as inhibition of cardiac and kidney Na+, K(+)-ATPase, displacement of [3H]-ouabain from its binding sites and cross reactivity with digoxin antibodies. The extract also had a positive inotropic effect on the guinea-pig heart. 2. In the present study the positive inotropic response of the extract was characterized in canine right ventricular trabeculae. Maximum inotropic response (501 +/- 20%) was produced by 300 microliters and the half maximal increase occurred with 125 microliters of the extract. 3. Ouabagenin produced aftercontractions in rapidly paced trabeculae. Equipotent and even greater amounts of the extract did not produce aftercontractions. 4. The extract increased the amplitude of the delayed component (P2) of biphasic contractions produced by replacing about 92-96% of the external Ca with Sr. A smaller increase in the size of the early component (P1) was also seen. 5. The extract decreased post-rest potentiation after rest for 30s and 2 min. After 8 min of rest, post-rest potentiation was converted to post-rest depression. 6. The extract (20 microliters) produced a decrease in the amplitude of the post-rest rapid cooling contracture (RCC) at all rest intervals. The steady state RCC, although greater than that in the control muscle, was increased to a lesser extent than the size of the steady state electrically driven contractions. 7. It is suggested that the extract from porcine left ventricle produces a positive inotropic response by increasing the trans-sarcolemmal influx of Ca. It also has additional effect(s) on the sarcoplasmic reticulum in that it may facilitate the loss of Ca from the sarcoplasmic reticulum and/or inhibit the uptake of Ca by the organelle.

1 Ouabain (10 mug/ml) caused an initial increase followed by a decrease in tension in guinea-pig taenia coli bathed in normal sodium and potassium containing medium. 2 The excitatory effect of ouabain was prevented by the elevation of extracellular potassium while the inhibitory effect was abolished in the absence of sodium in the bathing medium. 3 In the presence of sodium, the inhibitory effect of ouabain disappeared when the drug was washed out, but in the presence of lithium (which is not extruded by the Na-K pump) the inhibition was not abolished. 4 The inhibitory effect of ouabain was accompanied by an increase in tissue Na and a decrease in tissue K concentration. The increase in intracellular [45Ca] which occurred when extracellular [k] was varied, was also reduced by ouabain. 5 It is concluded that a high intracellular level of sodium inhibits contractions in visceral smooth muscle probably by a mechanism involving decreased Ca influx.

Previous studies have suggested that prazosin is a selective post-synaptic alpha-receptor blocker. It has also been suggested that it may have greater blocking actions on arterioles than on venous beds. These aspects have been investigated in cats anesthetized with pentobarbital. Prazosin had no effect on conductance in the acutely denervated hindlimb bed but caused a slowly developing vasoconstriction in the acutely denervated intestinal bed. The vasoconstrictor responses to sympathetic nerve stimulation were reduced to a similar extent in both vascular beds. Since maximal doses of prazosin produce only partial block of the alpha-receptor responses, there may be more than one type of postsynaptic alpha-receptor, and it is suggested that the postsynaptic receptors are of both alpha 1- and alpha 2-types. In the intestinal bed, prazosin produced similar reductions in both resistance and capacitance responses to sympathetic nerve stimulation. In isolated guinea pig aorta and portal vein, prazosin blocked the responses to noradrenaline competitively, and the pA3 values for the aorta and portal vein were similar. Thus, no selectivity for resistance vessels compared to capacitance vessels could be demonstrated in the intestine, and this result is compared to our previous observations in the liver. Although prazosin only reduced the vasoconstrictor responses to sympathetic nerve stimulation in the intestine, phenoxybenzamine reversed the response to a beta-receptor-mediated vasodilatation, as reported some years ago. These observations support our earlier hypothesis that nerve stimulation does not normally activate beta-receptors, but after phenoxybenzamine, the increased release of noradrenaline combined with alpha-receptor blockade results in a beta-receptor-mediated vasodilatation in the intestinal bed.

Rest potentiation, believed to be due to increased utilization of sarcoplasmic reticular calcium, was converted to rest depression by BAY K 8644 (1 microM). Plateau height and duration of the postrest beat were enhanced by BAY K 8644, suggesting an enhancement of extracellular calcium entry. Caffeine (3 mM) also produced depression at all rest intervals, although to a lesser extent than BAY K 8644. Compared with BAY K 8644, treatment with caffeine resulted in an elevation of plateau amplitude and a shortening of action potential duration. Action potential configuration changes induced by rest were unaltered by caffeine despite reduction in rest potentiation. Caffeine-induced rest depression was associated with an increase in the time to peak tension. This was not observed with BAY K 8644. Treatment with both caffeine (3 mM) and BAY K 8644 (1 microM) greatly prolonged time to peak tension. Action potential duration and plateau height were either maintained or increased. Less rest depression was observed with the combination than with either agent alone. These results suggest that 1) BAY K 8644 and caffeine inhibit rest potentiation by different mechanisms, and 2) caffeine-induced inhibition of calcium uptake by the sarcoplasmic reticulum may enhance the effect of BAY K 8644-induced increase in calcium influx on the contractile apparatus.

A computer-controlled tissue stimulator interface will be described. This device can generate a basic train at a predetermined rate. An extra pulse is introduced after a selected number of pulses. The initial latency of this extra pulse is shorter than the tissue refractory period. The latency is increased, automatically, until the tissue produces a conducted response. This is made possible by the computer checking the tissue response. The device is inexpensive and can be readily controlled by any 8 bit microcomputer, such as the Commodore PET or VIC-20. The use of a signal conditioner has been discussed. Such a circuit facilitates detection of the often slowly occurring action potential of the premature beat riding on the repolarization phase of the normal action potential.

The synthesis of the glucoside, 3β-[(β-D-glucopyranosyl)oxy]-14-hydroxy-14β-pregn-4-en-20-one, a 14β-hydroxyprogesterone glucoside (14β-OHP-glu), is described. This compound has an IC50 of 1 μM in a [3H]ouabain binding assay, and is about 10 times more potent than the aglycone. Like 14β-hydroxyprogesterone, the glucoside enhances contractility of isolated cardiac muscle. 14β-OHP-glu or ouabain, when infused at comparable doses into the renal artery of the anesthetized rat, markedly increases urine volume. Whereas ouabain significantly enhances urinary potassium excretion with little or no effect on sodium excretion, 14β-OHP-glu promotes a marked natriuresis with no significant effect on potassium excretion.

The mechanism of the negative force staircase in thin rat ventricular trabeculae was investigated and compared with the positive force staircase in dog ventricular muscles of comparable diameter. Increasing stimulus frequency from 0.2 to 0.5 and 1 Hz resulted in a stepwise reduction of twitch amplitude that was demonstrated in both 1.25 and 2.5 mM external calcium concentration ([Ca]o). The negative staircase was associated with no change in the amplitude of postrest contraction or rapid-cooling contracture at either [Ca]o investigated. Hence, neither decreased loading nor overloading of the rat sarcoplasmic reticulum with calcium during the steady state can be invoked as a likely explanation for the negative staircase. The results are consistent with a frequency-dependent increase in the refractoriness of the sarcoplasmic reticular calcium release process or a decrease in the amount of trigger for calcium release, assuming that the amount of calcium present in the release pool is constant from one frequency to the next. In contrast to the rat, canine ventricular muscle exhibited a positive force staircase, the slope of which depended on [Ca]o, as well as a frequency-dependent increase in postrest contraction and rapid-cooling contracture. Data obtained from this series of experiments suggests that increased filling of the release pool within the sarcoplasmic reticulum with calcium underlies the inotropic effect of high-frequency stimulation in canine ventricular muscle.

Positive inotropic concentration of the Ca-channel agonist, Bay K 8644, depressed contraction of canine right ventricular trabecula immediately after a rest period of 8 min, without decreasing action potential plateau amplitude. In contrast, high external Ca and ouabagenin caused only a slight decrease in post-rest contraction. Bay K 8644-induced post-rest depression was inversely related to the extracellular Ca concentration. Hence it could not be due to cellular Ca overload. Since post-rest potentiation is due to increased contribution of Ca from the sarcoplasmic reticulum, these results suggest that Bay K 8644 decrease the amount of releasable Ca from this structure during rest.

The neuromuscular response to a reduction of temperature from 34 to 26°C was examined in vitro in the avian biventer cervicis preparation. Cooling over this range potentiated neuromuscular transmission 104% although there was a 35% depression of direct muscle contractility. This potentiation was reduced 53% when the stimulation frequency was increased from 6/min to 24/min, suggesting the involvement of prejunctional processes in the cold response. When the safety margin of neuromuscular transmission was narrowed either prejunctionally with Mg2+ or postjunctionally with d-tubocurarine, cooling potentiated transmission to 127 and 212% respectively. After cholinesterase (ChE) inhibition by eserine the cold potentiation was not observed but this does not indicate that the neuromuscular response to cooling involves substantial inhibition of ChE since the potentiation in muscles treated with both eserine and tubocurarine was restored to within 20% of the response in untreated muscles. Postjuctional sensitivity, which was studied with the tonic response of the muscle to acetylcholine, did not change substancially at 26°C. These results indicate that the potentiation of neuromuscular transmission that occurs with cooling is due primarily to an increased release of neurotransmitter rather than ChE inhibition or an increased postjunctional sensitivity.

The perioperative period, and most particularly the anaesthetic itself, creates an interface between chronic and acute drug therapy. As the primary managers of this interface, anaesthetists must be aware of the actions and interactions of varied and complex medications. Antihypertensive agents present a significant potential for drug interactions during anaesthesia. With the exception of monoamine inhibitors, anti-hypertensives should be continued up to the time of surgery, Safe anaesthetic management requires anticipation of drug interactions, recognition of their effects, and knowledge of appropriate corrective therapy. This review has provided information and guidelines which help to accommodate these needs.

Contraction of canine ventricular trabeculae were recorded at a stimulation frequency of 0.5 Hz and after rest periods of 2 and 8 min to analyze the effect of the Ca channel agonist BAY k 8644, on sarcoplasmic reticular function. Short periods of rest interposed between steady trains of stimuli caused a potentiation of the postrest beat. This is believed to be due to the mobilization of activator Ca from the sarcoplasmic reticulum (SR). Racemic BAY k 8644 and its Ca channel agonist enantiomer, (−) BAY k 8644, both produced an increase in contraction in response to a steady train of stimuli but converted rest potentiation into rest depression. This has been interpreted as increased loss of Ca from the SR during diastole. Addition of Ca channel antagonists, (+) BAY k 8644, nitrendipine, or nifedipine, to reverse the agonistic effect of (−) and racemic BAY k 8644 on the Ca channel did not convert the rest depression into rest potentiation. In the presence of any of the Ca channel antagonist alone, rest potentiation was not reversed but enhanced. The rank order of rest potentiation after these drugs was nifedipine > nitrendipine > (+) BAY k 8644. It is concluded that (−) BAY k 8644 enhances the ongoing loss of Ca from the SR during diastole in a manner similar to that of racemic BAY k 8644. However, its depressant effect on the postrest tension cannot be attributed to an increase in Ca current because (+) BAY k 8644 and other Ca channel antagonists did not reverse rest depression due to (−) or racemic BAY k 8644 even though they normalized steady-state tension. The difference between the effects of the three Ca channel antagonists on the postrest contraction suggests that they may have variable effects on the release of Ca from the SR in addition to causing inhibition of transsarcolemmal Ca influx. This difference may be related to different degrees of intracellular penetration of these compounds.Key words: cardiac, contractility, excitation – contraction coupling, heart.

Ouabain or replacement of NaCl by LiCl abolishes the relaxation due to addition of KCl to sodium-rich cat carotid artery strips kept in a K+-free medium. Neither treatment antagonizes the relaxation due to β-adrenoceptor stimulation by l-isoprenaline. Unlike KCl-induced relaxation, the relaxation induced by l-isoprenaline is not due to stimulation of an electrogenic sodium pump.

Isolated capsular muscle from cat spleen did not contract on exposure to a potassium-free bathing fluid. After exposure to conditions favouring downhill sodium and potassium movement (i.e. stimulation by noradrenaline in the absence of external potassium), subsequent reactivation of the sodium pump inhibited responses to noradrenaline. Under these special conditions, but not normally, the sodium pump may be behaving in an electrogenic manner.