Treatment Efficiency of Different Routes of Bone Marrow-Derived Mesenchymal Stem Cell Injection in Rat Liver Fibrosis Model.

BACKGROUND/AIMS: The most appropriate route for bone marrow-derived mesenchymal stem cell (BM-MSC) transplantation in the management of liver fibrosis remains controversial. This study investigated the therapeutic efficacy of intravenous and intrasplenic BM-MSC transplantation on carbon tetrachloride (CCl4)-induced rat liver fibrosis. METHODS: Fifty rats were divided into 5 groups (n = 10 rats per group): healthy control group, CCl4 group, CCl4/ recovery group, CCl4/BM-MSC intravenous group, and CCl4/BM-MSC intrasplenic group. BM-MSCs were isolated, labeled with green fluorescent protein (GFP), and injected into fibrotic rats either intravenously or intrasplenically. Gene expression of interleukins (IL-1ß and IL-6), interferon (INF)-γ, hepatic growth factor, and the hepatocyte-specific marker cytokeratin 18 was estimated by quantitative real-time reverse transcription-polymerase chain reaction. Vascular endothelial growth factor and connective tissue growth factor was detected by western blot analysis and enzyme-linked immunosorbent assay, respectively. At 2 weeks after intravenous and intrasplenic BM-MSC injections, GFP-positive cells were detected in liver tissue. RESULTS: Both routes achieved a similar enhancement of liver function, which was confirmed by histopathological examination. The intravenous route was more effective than the intrasplenic route in reducing gene expression levels of IL-1ß, IL-6, and INF-γ. However, fibrotic changes were still observed in the recovery group. CONCLUSION: Intravenous BM-MSC injection was an efficient and appropriate route for BM-MSC transplantation for the management of liver fibrosis.

Physiological Responses and Gene Expression in Ultrasound-Guided Supraclavicular Brachial Plexus Block: a Comparative Study.

BACKGROUND/AIMS: Ultrasound-guided supraclavicular brachial plexus block (BPB) has come into wider use as a regional anesthetic during upper limb operations. This study assessed the neurological and hemodynamic changes and gene expression after co-administration of midazolam or neostigmine with bupivacaine during supraclavicular BPB. METHODS: The study involved 90 adults divided into three groups: control (bupivacaine), midazolam (bupivacaine plus midazolam), and neostigmine (bupivacaine plus neostigmine). Blood samples were taken and interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) mRNA levels were measured by real-time PCR, and oxidative stress markers were identified. In addition to the hemodynamic variables, the onset and duration of sensory and motor blockades, duration of analgesia, pain scores, time of first request for an analgesic, and amounts of analgesics ingested were evaluated. RESULTS: Compared with the control and neostigmine groups, the midazolam group experienced longer sensory and motor blockades, prolonged analgesia, lower pain scores at 12 h and 24 h, and lower need for postoperative analgesics. Moreover, the midazolam group exhibited lower oxidative stress markers with a higher fold change in IL-6 and TNF-α mRNA levels. CONCLUSION: Midazolam co-administered with bupivacaine provided better analgesic quality than did neostigmine with bupivacaine. This might be due to its superior antioxidant and anti-inflammatory effects.

The Number of GT(n) Repeats in the Hemeoxygenase-1 Gene Promoter is Increased in Pediatric Heart Failure but is Unrelated to Renal, Antioxidant and Anti-inflammatory Markers.

Products of hemeoxygenase (HO)-1 have anti-inflammatory and antioxidant functions. The HO-1 promoter has a variable number of GT(n) repeats: A low number (n < 23) is associated with high transcriptional activity in response to oxidative stress. We hypothesized that the frequency of GT(n) repeats in pediatric heart failure (HF) reflects plasma biomarkers of different disease processes: the soluble receptor for advance glycation end products (sRAGE, marking cellular activation), oxLDL (oxidative stress), NGAL (impaired renal function), HIF-1α (hypoxia) and hsCRP (inflammation). Sixty HF children [aged 4-14 years, 30 with HF due to idiopathic dilated cardiomyopathy (IDCM), 30 due to chronic renal failure (CRF)] were compared to 20 healthy controls (HC). Leukocyte HO-1 GT(n) repeats were determined by PCR, plasma markers by ELISA or nephelometry. The number of GT(n) repeats in the HF patients was higher than the number of repeats in the controls, with no difference between the patient groups (p < 0.001). sRAGE, oxLDL, HIF-1α, NGAL and hsCRP were higher in both HF groups compared to HC (all p < 0.01). IDCM had higher sRAGEs and HIF-1α compared to CRF patients (p < 0.01). NGAL was higher in CRF compared to IDCM (p < 0.01). None of the plasma/serum markers correlated with the number of GT(n) repeats in any group. The number of HO-1 promoter GT(n) polymorphism is increased in both IDCM and CRF children with HF, but is unrelated to plasma markers of different pathological processes. This casts doubts on the clinical value of the number of GT(n) repeats in pediatric HF.

The effect of melatonin on plasma markers of inflammation and on expression of nuclear factor-kappa beta in acetic acid-induced colitis in the rat.

BACKGROUND AND AIMS: Melatonin may be involved in gastrointestinal tract physiology and could affect inflammation-related gastrointestinal disorders. Rat models of ulcerative colitis imply melatonin is beneficial. To determine potential pathophysiological mechanisms, we assessed colonic nuclear factor-kappa beta expression and measured serum levels of pentraxin-3, lipid peroxides, and total thiols in an acetic acid model of this disease. MATERIALS AND METHODS: Thirty rats were divided into five groups: a control group, an acetic acid-induced colitis group, a group treated with melatonin before colitis induction, a group treated short-term after colitis induction, and a group treated long-term after colitis induction. After four weeks, blood samples were taken for measurement of pentraxin-3, lipid peroxide, and total thiols. Sections of the colon were taken for histopathological examination and immunohistochemical detection of nuclear factor-kappa beta expression. RESULTS: Melatonin administration reduced nuclear factor-kappa beta immunohistochemical expression, reduced serum levels of lipid peroxide and pentraxin-3, and maintained serum levels of total thiols. However, in long-term treatment the protective effect of melatonin was not as marked. CONCLUSION: Melatonin is effective in prevention and short-term treatment of the inflammatory process in acetic-acid induced colitis whereas the benefit of long-term treatment is unclear. Benefit may be linked to protection mechanisms against inflammatory processes by inhibiting the nuclear factor-kappa beta and conserving endogenous antioxidant reserves of total thiols, thus reducing the level of colonic damage possibly caused by lipid peroxides.

Augmentation of Docetaxel-Induced Cytotoxicity in Human PC-3 Androgen-Independent Prostate Cancer Cells by Combination With Four Natural Apoptosis-Inducing Anticancer Compounds.

Docetaxel (DTX) is the treatment of choice for metastatic castration-resistant prostate cancer. However, developing drug resistance is a significant challenge for achieving effective therapy. This study evaluated the anticancer and synergistic effects on DTX of four natural compounds (calebin A, 3'-hydroxypterostilbene, hispolon, and tetrahydrocurcumin) using PC-3 androgen-resistant human prostate cancer cells. We utilized the CellTiter-Glo® luminescent cell viability assay and human PC-3 androgen-independent prostate cancer cells to determine the antiproliferative effects of the four compounds alone and combined with DTX. Cytotoxicity to normal human prostate epithelial cells was tested in parallel using normal immortalized human prostate epithelial cells (RWPE-1). We used cell imaging and quantitative caspase-3 activity to determine whether these compounds induce apoptosis. We also measured the capacity of each drug to inhibit TNF-α-induced NF-kB using a colorimetric assay. Our results showed that all four natural compounds significantly augmented the toxicity of DTX to androgen-resistant PC-3 prostate cancer cells at IC50. Interestingly, when used alone, each of the four compounds had a higher cytotoxic activity to PC-3 than DTX. Mechanistically, these compounds induced apoptosis, which we confirmed by cell imaging and caspase-3 colorimetric assays. Further, when used either alone or combined with DTX, the four test compounds inhibited TNF-α-induced NF-kB production. More significantly, the cytotoxic effects on normal immortalized human prostate epithelial cells were minimal and non-significant, suggesting prostate cancer-specific effects. In conclusion, the combination of DTX with the four test compounds could effectively enhance the anti-prostate cancer activity of DTX. This combination has the added value of reducing the DTX effective concentration. We surmise that calebin A, 3'-hydroxypterostilbene, hispolon, and tetrahydrocurcumin were all excellent drug candidates that produced significant antiproliferative activity when used alone and synergistically enhanced the anticancer effect of DTX. Further in vivo studies using animal models of prostate cancer are needed to confirm our in vitro findings.

Is There a Feasible Link between Vitamin D Receptor Genotypic and Allelic Frequencies with Analytical Biomarkers of Rheumatoid Arthritis Disease?

Rheumatoid arthritis (RA) is one of the most widespread autoimmune disorders and it has a genetic background with a variety of genes affecting the degradation of the immune system. Along these lines, we assessed the relationship between the BsmI, and FokI VDR polymorphisms and inflammable records identified with infections activity. Such as interleukins (IL-6, IL-8), hypoxia inducible factor-alpha (HIF-α), soluble receptor of advanced glycation end product (sRAGE), oxidized low-density lipoprotein cholesterol (oxLDL), neutrophil gelatinase-associated lipocalin (NGAL) and procollagen N-propeptide of type III collagen (P3NP) and the allelic frequencies of BsmI VDR rs1544410 and FokI VDR rs2228570 polymorphism on the RA. Total of 131 subjects [70 RA patients and 61 age and sex matched apparently healthy controls (HC)] were monitored for inflammatory biomarkers using ELISA. All patients were screened for the BsmI and FokI using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The all biomarkers were significantly higher in RA patients in comparison with HC. There were positive correlations between NGAL, oxLDL and s-RAGE, oxLDL. On BsmI, 'GG' and 'AG' genotypes were significantly associated with high RA activity as well as the frequency of genotypes 'AG & GG" were higher in high activity RA as compared to low RA activity. However on FokI, was observed that in high activity patients the frequency of 'CC' & 'CT' was more prevalent as compared to low activity ones. These outcomes support the immunoregulatory role of vitamin D which is associated with several inflammatory diseases, signifying a credible anti-inflammatory role in perturbation of the RA.

Comparison of the therapeutic effectiveness of human CD34+ and rat bone marrow mesenchymal stem cells on improvement of experimental liver fibrosis in Wistar rats.

BACKGROUND AND OBJECTIVE: Human umbilical cord blood (UCB) cells and bone marrow mesenchymal stem cells (BM-MSCs) have numerous advantages as grafts for cell transplantation. We hypothesized differing impacts of human UCB cells and rat BM-MSCs on reversal of hepatic injury and revival of liver function in carbon tetrachloride (CCl4)-induced liver fibrosis. METHODS: Forty rats were divided into 4 groups; control group, CCl4 group, CCl4/CD34+ group and CCl4/BM-MSCs group. Blood samples were driven from rats at 4, 8 and 12 weeks to measure serum concentration of albumin and alanine aminotransferase (ALT). Quantitative expression of collagen Iα, TGF-ß, α-SMA, albumin, MMP-2, MMP-9 and TNF-α were assessed by polymerase chain reaction. Histopathological examination of the liver tissue was performed. GFP labeled cells were detected in groups injected with stem cells. RESULTS: Regarding liver function, CD34+ were more efficient than BM-MSCs in elevating albumin (P<0.05) and reducing ALT (P<0.05) concentrations. Concerning gene expression, CD34+ were more effective than BM-MSCs in reducing gene expressions of collagen Iα (P<0.01), TGF-ß1 (P<0.01) and α-SMA (P<0.01). Both CD34+ and BM-MSCs have the same efficacy in reducing TNF-α (P<0.001 and P<0.01, respectively). Furthermore, CD34+ were more valuable than BM-MSCs in increasing gene expression of albumin (P<0.05) and MMP-9 (P<0.01). CONCLUSION: Taken together; human UCB CD34+ stem cells were more efficient in improvement of experimental liver injury than BM-MSCs. This study highlighted an important role of human UCB CD34+ stem cells in liver fibrosis therapy.

Atrial linear ablations in pigs. Chronic effects on atrial electrophysiology and pathology.

BACKGROUND: Generation of long and continuous linear ablations is required in a growing number of atrial arrhythmias. However, deployment and assessment of these lesions may be difficult, and there are few data regarding their short- and long-term effects on atrial electrophysiology and pathology. METHODS AND RESULTS: A nonfluoroscopic mapping and navigation technique was used to generate 3-dimensional (3D) electroanatomic maps of the right atrium in 8 pigs. The catheter was then used to deliver sequential radiofrequency (RF) applications (power output gradually increased until 80% reduction in the amplitude of the unipolar electrogram) to generate a continuous lesion between the superior and inferior venae cavae. The animals were remapped 4 weeks after ablation during septal pacing. Lesion continuity was confirmed in all cases by the following criteria: (1) activation maps indicating conduction block [significant disparities in activation times (52.0+/-16.0 ms) and opposite orientation of the activation wave front on opposing sides of the lesion], (2) evidence of double potentials (interspike time difference of 52.3+/-17.1 ms), and (3) low peak-to-peak amplitude of the bipolar electrograms (0.7+/-0.6 mV) along the lesion. At autopsy, all lesions were continuous and transmural, averaged 50.5+/-6.7 mm, and were characterized histologically by transmural fibrosis throughout the length of the lesion. CONCLUSIONS: Long linear atrial ablation, created by sequential RF applications (using unipolar amplitude attenuation as the end point for energy delivery), results in long-term continuous and transmural lesions. Lesion continuity is associated with evidence of conduction block in the 3D activation maps and the presence of double potentials and low electrogram amplitude along the lesion.

Detailed endocardial mapping accurately predicts the transmural extent of myocardial infarction.

OBJECTIVES: This study delineates between infarcts varying in transmurality by using endocardial electrophysiologic information obtained during catheter-based mapping. BACKGROUND: The degree of infarct transmurality extent has previously been linked to patient prognosis and may have significant impact on therapeutic strategies. Catheter-based endocardial mapping may accurately delineate between infarcts differing in the transmural extent of necrotic tissue. METHODS: Electromechanical mapping was performed in 13 dogs four weeks after left anterior descending coronary artery ligation, enabling three-dimensional reconstruction of the left ventricular chamber. A concomitant reduction in bipolar electrogram amplitude (BEA) and local shortening indicated the infarcted region. In addition, impedance, unipolar electrogram amplitude (UEA) and slew rate (SR) were quantified. Subsequently, the hearts were excised, stained with 2,3,5-triphenyltetrazolium chloride and sliced transversely. The mean transmurality of the necrotic tissue in each slice was determined, and infarcts were divided into <30%, 31% to 60% and 61% to 100% transmurality subtypes to be correlated with the corresponding electrical data. RESULTS: From the three-dimensional reconstructions, a total of 263 endocardial points were entered for correlation with the degree of transmurality (4.6 +/- 2.4 points from each section). All four indices delineated infarcted tissue. However, BEA (1.9 +/- 0.7 mV, 1.4 +/- 0.7 mV, 0.8 +/- 0.4 mV in the three groups respectively, p < 0.05 between each group) proved superior to SR, which could not differentiate between the second (31% to 60%) and third (61% to 100%) transmurality subgroups, and to UEA and impedance, which could not differentiate between the first (<30%) and second transmurality subgroups. CONCLUSIONS: The degree of infarct transmurality extent can be derived from the electrical properties of the endocardium obtained via detailed catheter-based mapping in this animal model.

Effect of hypertonicity on contractility of isolated working rat left ventricle.

OBJECTIVE: The aim was to evaluate the effect of hypertonic perfusate on isolated left ventricular mechanical and energetic characteristics. METHODS: An isolated working rat heart model was perfused with a hyponatraemic Krebs-Heinseleit bicarbonate buffer (240 mOsmol.litre-1). To this buffer was added increasing amounts of mannitol to achieve 280, 320, and 360 mOsmol.litre-1 perfusates. RESULTS: Left ventricular peak pressure, maximum time derivative of left ventricular pressure (dP/dtmax), and end systolic pressure were all increased to a maximum value at 280 or 320 mOsmol.litre-1 perfusate tonicity. A similar response was evident with cardiac output, which changed from 33.7(SEM 0.6) to 43.5(0.8) ml.min-1 following changing the perfusate tonicity from 240 to 280 mOsmol.litre-1 (p less than or equal to 0.003). However, increasing perfusate tonicity further decreased cardiac output to 36.5(1.3) ml.min-1 at 360 mOsmol.litre-1. Maximal left ventricular elastance remained unchanged during perfusion with increasing perfusate tonicities. CONCLUSIONS: Changing perfusate osmolality using mannitol has a positive inotropic effect at low osmolalities and a negative inotropic effect at perfusate osmolality greater than 320 mOsm.litre-1.

Heart energetic efficiency in O2-exposed rats studied in isolated working heart.

Death in normobaric hyperoxia was related in the past to pulmonary insufficiency of the edematous lung. However, high arterial O2 tension on final collapse led to the suggestion that the heart and not the lung is the first organ that fails. We measured aortic flow, coronary flow, left ventricular pressure, affluent and effluent PO2, PCO2, and pH in the working heart excised from control and normobaric O2-exposed rats (51-63 h). The oxygen consumption (VO2) of experimental hearts was not different from control, but mechanical power output (PVAP) (calculated from pressure-volume area) was reduced as a function of O2 exposure time. Myocardial contractility indexes, maximal elastance and maximal time derivative of pressure, increased as a function of O2 exposure time, being below control values after 50 h and above control values after 60 h. The individual slopes for the regression of VO2 vs. PVAP rose as a function of exposure time from values below control after 50 h exposure to values above control after 60 h. Energetic efficiency (PVAP/VO2) decreased as a function of O2 exposure time and points to possible heart failure in the intact animal. After 50 h O2 exposure the heart was energetically more efficient than the control. Possible changes in the heart are discussed.

Characterisation of acute myocardial ischaemia in a canine model based on principal component analysis of unipolar endocardial electrograms.

The study presents a method for identifying endocardial electrical features relevant to local ischaemia detection at rest. The method consists of, first, normalisation of electrograms to a uniform representation; secondly, the use of principal component analysis to reduce the dimensionality of the electrogram vector space; and, thirdly, a search for a classification axis that matches the degree of ischaemia present in the tissue. Left ventricular myocardial states were assessed by echocardiography and NOGA mapping in eight dogs at baseline and then immediately after, 5h after and 3 days after occlusion of the left anterior descending coronary artery. Five principal components were required to approximate electrograms with an average error of less than 10% of the peak-to-peak amplitude. Correlations of 0.77, 0.80 and 0.84 were obtained between the principal component-based parameters and the echocardiography scores at the three ischaemic stages, respectively. Expression of these parameters in the time domain showed that the major changes occurred in the depolarisation segment of the endocardial electrogram as well as in the ST-segment. In conclusion, the proposed method provides a suitable alternative co-ordinate system for the classification of ischaemic regions and highlights signal segments that change as a result of pathology.

Epinephrine dose-response of the isolated working heart in O2-exposed rats.

BACKGROUND: Heart energy efficiency, which is affected by catecholamines, has previously been shown to decline in rats with prolonged normobaric O2 exposure. HYPOTHESIS: Oxygen exposure affects dose response of the heart to catecholamines. METHODS: Epinephrine dose-response (10(-10) - 5 x 10(-6) mol.L-1) was measured in the isolated working heart excised from control rats breathing air, and rats exposed to normobaric 100% oxygen for either 24 h or 49 h. The variables measured were input (oxygen consumption (VO2) and output power, cardiac contractility (Emax and maximal dP/dT), coronary resistance, heart frequency (fH) and left ventricular pressure. Variable (Y*) dose response to epinephrine concentration (C) was fitted to the equation: Y* = Ymax/(1 + (C/C50)n), Ymax--maximal Y*, C50--C for half Ymax and n--an empirical power. RESULTS: Oxygen exposure of the intact rat had little influence on baseline cardiac variables, but did affect sensitivity to catecholamines. A general effect of the O2 exposure was a left shift of the dose-response curve for example, C50 was reduced by 72, 41 and 43 x 10-8 mol.L-1 for VO2, fH and Emax, respectively, after the 24 h exposure. CONCLUSIONS: There was a pronounced change in the dose-response in hearts from 24 h O2-exposed rats, a change partially reversed in hearts from 49 h O2-exposed rats. The high dose, which had a stimulatory effect on hearts from control rats, failed to stimulate hearts from hyperoxic rats.

A novel method for nonfluoroscopic catheter-based electroanatomical mapping of the heart. In vitro and in vivo accuracy results.

BACKGROUND: Cardiac mapping is essential for understanding the mechanisms of arrhythmias and for directing curative procedures. A major limitation of the current methods is the inability to accurately relate local electrograms to their spatial orientation. The objective of this study was to present and test the accuracy of a new method for nonfluoroscopic, catheter-based, endocardial mapping. METHODS AND RESULTS: The method is based on using a new locatable catheter connected to an endocardial mapping and navigating system. The system uses magnetic technology to accurately determine the location and orientation of the catheter and simultaneously records the local electrogram from its tip. By sampling a plurality of endocardial sites, the system reconstructs the three-dimensional geometry of the chamber, with the electrophysiological information color-coded and superimposed on the anatomy. The accuracy of the system was tested in both in vitro and in vivo studies and was found to be highly reproducible (SD, 0.16 +/- 0.02 [mean +/- SEM] and 0.74 +/- 0.13 mm) and accurate (mean errors, 0.42 +/- 0.05 and 0.73 +/- 0.03 mm). In further studies, electroanatomical mapping of the cardiac chambers was performed in 34 pigs. Both the geometry and activation sequence were repeatable in all pigs. CONCLUSIONS: The new mapping method is highly accurate and reproducible. The ability to combine electrophysiological and spatial information provides a unique tool for both research and clinical electrophysiology. Consequently, the main shortcomings of conventional mapping-namely, prolonged x-ray exposure, low spatial resolution, and the inability to accurately navigate to a predefined site-can all be overcome with this new method.

Activation-repolarization coupling in the normal swine endocardium.

BACKGROUND: While abnormalities of activation and repolarization play an important role in arrhythmogenesis, little information is available on the interaction between their spatial dispersions in the heart. This study examined the effects of activation spread on the spatial distribution of the repolarization properties during different depolarization patterns. METHODS AND RESULTS: Left ventricular (LV) endocardial activation and repolarization patterns were mapped in 13 healthy pigs. LV local activation, repolarization, and activation-recovery interval (ARI) times were determined from the intracardiac unipolar electrograms, color-coded, and superimposed on a three-dimensional anatomic map of the ventricle generated with a nonfluoroscopic mapping system. ARI values correlated with the duration of monophasic activation potential recorded from onset of activation to time of 90% repolarization (r=.97, P<.01). Activation time range of the left ventricle was 42+/-5 ms (mean+/-SEM) during sinus rhythm and 54+/-5 ms during right ventricular septal pacing. ARI inversely correlated with the corresponding activation times during both sinus (r2=.76+/-.03) and paced (r2=.77+/-.02) rhythms. The longest ARIs were located at the sites of earliest activation and shortest at the latest activation areas, with gradual shortening between them. CONCLUSIONS: The spatial distribution of repolarization is dependent on the activation pattern. Repolarization dispersion in the healthy swine heart is relatively small as the result of tight coupling of the action potential duration to the activation process, assigning longer ARIs to sites activated earlier. This coupling reduces global and regional dispersion of repolarization and may serve as an important antiarrhythmic mechanism present in normal myocardium.

Sodium modulates inotropic response to hyperosmolarity in isolated working rat heart.

The present study was designed to examine the effects of acute changes in perfusate Na+ concentrations and osmolarities on left ventricular (LV) mechanics in the isolated working rat heart model. Specifically, we separated the effect of isosmotic perfusates with different Na+ concentrations on LV mechanics. After a control period during which the hearts were perfused in a working mode with a control solution of Krebs-Henseleit bicarbonate buffer (Na+ of 136 meq/l, Ca2+ of 2.6 mM, and osmolarity of 300 mosM), the hearts were subjected to different perfusates (Na+ of 96-156 meq/l and osmolarity of 240-380 mosM, using different mannitol concentrations) in a semirandom order. Peak LV pressure (PLVP), maximal time derivative of LV pressure (dP/dtmax), and cardiac output (CO) were recorded. Increasing Na+ concentrations from 96 to 156 meq/l, using isosmotic perfusates, decreased PLVP, dP/dtmax, and CO in a dose-dependent manner. The dose-dependent behavior was evident for tonicities of 240, 280, 320, and 360 but not for 380 mosM. Increasing Na+ concentration from 96 to 136 meq/l at constant perfusate tonicity (320 mosM) decreased dP/dtmax from 6,753 +/- 133 to 5,602 +/- 418 mmHg/s (P < 0.001). Rearranging the same results to examine the effect of perfusate tonicity with iso-Na+ concentration demonstrated that increasing perfusate osmolarity had a dose-dependent effect on PLVP, dP/dtmax, and CO. At a constant Na+ concentration of 116 meq/l, increasing perfusate osmolarity from 240 to 320 mosM increased dP/dtmax from 6,116 +/- 132 to 7,274 +/- 594 mmHg/s (P < 0.01). Further increase in perfusate tonicity to 380 mosM decreased dP/dtmax to 2,338 +/- 398 mmHg/s (P < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of phosphamidon and obidoxime on the QT-RR relationship of isolated rat heart.

We studied the effects of phosphamidon (an organophosphate compound), obidoxime (a cholinesterase reactivator), and their combination, phosphamidon/obidoxime (PD/OB) on cardiac cycle length (RR), QT interval, and on QT-RR relationship of isolated rat heart. Cardiac cycle length did not change significantly following perfusion with phosphamidon or obidoxime alone; however, following perfusion with PD/OB, RR significantly increased at high concentrations (10(-3) M) of both drugs. The QT interval lengthened by 5% following perfusion with phosphamidon, did not change following perfusion with obidoxime, and increased by 10% following perfusion with PD/OB. The QT-RR relationship without drugs was positive and linear. Following perfusion with phosphamidon alone, the slope of the relationship decreased significantly, while perfusion with obidoxime alone did not change the QT-RR relationship. Perfusion with PD/OB at low concentrations decreased the slope of the relationship; however, at the highest concentration (10(-3) M) the QT-RR relationship was inverted and became negative. Ventricular arrhythmias as premature ventricular beats, or bigeminies, were noted with increasing frequency following perfusion with increasing doses of phosphamidon. Perfusion with obidoxime did not cause arrhythmias, whereas perfusion with PD/OB caused premature ventricular beats, bigeminies, and ventricular tachycardias at high doses. We suggest that obidoxime modulates the direct effects of phosphamidon on the cardiac repolarization process. PD/OB at high concentrations invert the normal depolarization-repolarization coupling and may therefore potentiate arrhythmias.

Obidoxime augments the positive inotropic effect of phosphamidon on the isolated working rat heart.

The present study was designed to determine modulation of the direct inotropic effect of an anticholinesterase organophosphorus compound, phosphamidon, by the reactivator obidoxime. We investigated the effects of phosphamidon (n = 9), obidoxime (n = 5), and their combination (n = 5) on the mechanical and energetic indices of left ventricular function, in the isolated working rat heart model. Phosphamidon at a concentration range of 10(-6)-10(-3) M had a positive inotropic effect. Obidoxime at a concentration range of 10(-6)-10(-3) M had no significant effect on heart rate, but did have a statistically significant positive inotropic effect on end-systolic pressure, cardiac output, mean left ventricular pressure, and maximal time derivative of left ventricular pressure (dP/dtmax) (P less than 0.01). Perfusion with 10(-3) M obidoxime caused a 19% increase in left ventricular stroke work and a 31% increase in total pressure-volume area. Perfusion with phosphamidon and obidoxime at concentrations ranging from 10(-6) to 10(-3) M resulted in a more intense inotropic response than the separate drug effects. At the highest combined concentrations tested, cardiac output increased by 60%, left ventricular stroke work increased by 100%, and left ventricular total pressure volume area increased by 111% of their control values (P less than 0.001). We conclude that obidoxime augments the positive inotropic effect of phosphamidon on the isolated working rat heart.

Hemodynamic evaluation of the heart with a nonfluoroscopic electromechanical mapping technique.

BACKGROUND: Clinical cardiac volumetric measurement techniques are essential for assessing cardiac performance but produce significant inaccuracies in extrapolation of the volume of a three-dimensional (3D) object from two-dimensional images and lack the ability to associate cardiac electrical and mechanical activities. In this study, we tested the accuracy of cardiac volumetric measurements using a new catheter-based system. METHODS AND RESULTS: The system uses magnetic technology to accurately locate a special catheter at a frequency of 125 Hz and is currently used in the field of electrophysiology, in which activation maps are superimposed on the 3D geometry of the cardiac chamber. The mapping procedure is based on sequentially acquiring the location of the tip and local electrogram while in contact with the endocardium. The 3D geometry of the chamber is reconstructed in real time, and its volume could be calculated at every time step (8 ms). The volumetric measurements of the system were found to be highly accurate for simple phantoms (mean+/-SEM deviation, 2.3+/-1.1%), left ventricular casts (9.6+/-1.3%), and a dynamic test jig. In addition, left ventricular volumes of 12 swine were measured. Intraobserver and interobserver variabilities were found to be minimal (ejection fraction, 6.5+/-1.9% and 7.1+/-2.0%; stroke volume, 4.5+/-1.0% and 11.3+/-2.4%). Comparison with the thermodilution method for measuring stroke volume showed an average deviation of 8.1+/-2.2%. Typical pressure-volume loops were also obtained. CONCLUSIONS: The new mapping image provides, for the first time, simultaneous information regarding cardiac mechanics, hemodynamics, and electrical properties. Furthermore, all this information is achieved without the use of fluoroscopy, contrast medium, or complicated image processing.