Biomedical subjects

D F Larson

Publications and source records attributed to D F Larson.

At least 19 recordsLinked to original sources

PubMed2005

Immunomodulation by immunopeptides and autoantibodies in aging, autoimmunity, and infection.

The operation of the immune system is a complex orchestration of specific self and non-self-recognition capacities mediated by cells of the innate system acting in coordination with T and B lymphocytes in a series of processes modulated by cytokines. We provide evidence for a natural immunomodulatory system involving autoantibodies directed against a controlling segment of T cell receptor Vbeta chains that downregulate production of stimulatory cytokines balanced by the peptides which in turn upregulate inflammatory activities mediated by TH1-type helper cells. TCR Vbeta-derived peptides effective in retrovirally induced immunosupression could also reverse the effects of immunosenescence in aged mice by restoring the balance of TH1- and TH2-type immunity and the resistance of the animals to cardiac pathology caused by infection with coxsackievirus. An unexpected finding was an adaptive role of the T cells from peptide-treated mice in remodeling damaged hearts by increasing net collagen synthesis by cardiac fibroblasts.

Aging↗

PubMed2004

Neuroendocrine properties of intrinsic cardiac adrenergic cells in fetal rat heart.

Intrinsic cardiac adrenergic (ICA) cells in developing rat heart constitute a novel adrenergic signaling system involved in cardiac regulation. Regulatory mechanisms of ICA cells remain to be defined. Immunohistochemical study of fetal rat hearts demonstrated ICA cells with catecholamine biosynthetic enzyme tyrosine hydroxylase (TH) and phenylethanolamine N-methyltransferase (PNMT). The mRNA of TH and PNMP was also detected in fetal rat hearts before sympathetic innervation. Immunoreactivity of norepinephrine transporter (NET) was localized to ICA cells in rat heart tissue and primary cell culture. For the functional study, the activity of intracellular Ca2+ concentration ([Ca2+]i) transients was quantified by a ratio fluorescent spectrometer in cultured ICA cells and myocytes. ICA cells generated spontaneous [Ca2+]i transients that were eliminated by tetrodotoxin or Ca(2+)-free solutions and showed greatly reduced amplitude with the addition of L-type Ca2+ channel blocker nifedipine. [3H]norepinephrine studies demonstrate release and uptake of norepinephrine. Functional interaction between catecholamines produced by the ICA cells and cocultured myocytes was evident by the effect of the beta-adrenergic blocker atenolol eliciting a dose-dependent reduction in the amplitude and frequency of [Ca2+]i transients of beating myocytes. Hypoxia inhibited [Ca2+]i transient activity of ICA cells, which subsequently produced a reoxygenation-mediated rebound augmentation of [Ca2+]i transients. We conclude that ICA cells are capable of catecholamine synthesis, release, and uptake. They generate spontaneous [Ca2+]i transient activity that can be regulated by oxygen tension. ICA cells may provide an alternative adrenergic supply to maintain cardiac contractile and pacemaker function at rest and during stress in the absence of sympathetic innervation.

Adrenergic beta-1 Receptor Antagonists↗

PubMed2001

Differential effects of acute ethanol treatment on cardiac contractile function in young adult and senescent mice.

It is understood that marked biochemical, molecular, and performance alterations occur in cardiovascular tissues related to aging. It is logical, therefore, that differences in the cardiovascular response to ethanol consumption, when comparing younger with older individuals, may exist. We compared the left ventricular function of 6- and 15-month-old (senescent) mice and 16-month-old (senescent) inducible nitric oxide synthase knockout mice (n=7 each) before and subsequent to acute treatment with 60% ethanol (2 g/kg, i.p.). A Millar 1.4 Fr conductance/micromanometer catheter was placed into the left ventricle of the mice for acquisition of pressure-volume loops. Heart contractile functions were significantly decreased in the senescent group, compared with findings in the younger mice. Subsequent to ethanol treatment, the younger mice showed a significant reduction in cardiac function, with a 28% decrease in cardiac index, a 29% decrease in end-systolic elastance, and a 16% decrease in preload recruitable stroke work (P<.01). Conversely, the senescent mice showed significantly increased contractile function, with a 40% increase in end-systolic elastance (P<.01) and a 19% increase in preload recruitable stroke work (P<.05). The myocardial cyclic guanosine monophosphate levels were significantly higher in the older group (P<.002), and subsequent to ethanol treatment, they were decreased by 68.5% (P<.001). Northern blot analysis demonstrated inducible nitric oxide synthase message only in senescent myocardial tissues. Moreover, the cardiac function of senescent inducible nitric oxide synthase knockout mice was comparable with that of young mice, and after ethanol treatment, cardiac function decreased significantly, just as that for young mice did, with a 26% decrease in cardiac index (P<.05) and a 23% decrease in preload recruitable stroke work (P<.01). It was concluded that the differential cardiovascular function and response to acute ethanol

Aging↗

PubMed2001

Comparison of tumor necrosis factor-alpha effect on the expression of iNOS in macrophage and cardiac myocytes.

Proinflammatory cytokines, including tumor necrosis factor-alpha (TNF-alpha), are elevated during cardiopulmonary bypass (CPB), heart failure, and inflammatory cardiac and systemic diseases. Elevated TNF-alpha has been linked to diminished cardiac function, decreased systemic vascular resistance, as well as renal and pulmonary dysfunction. It is understood that myocardial tissues can express TNF-alpha, which results in the induction of inducible nitric oxide synthase (iNOS) leading to a significant decline in cardiac function and other direct effects. The hypothesis of this study was to determine if TNF-alpha would stimulate iNOS and its product nitric oxide (NO) similarly in immortalized macrophage and cardiac myocytes. Cultured macrophages (RAW 264.7) and cardiac myocytes (HL-1) were placed into two treatment groups and a control. The treatments included: (1) TNF-alpha and lipopolysaccharide (LPS); and (2) LPS, TNF-alpha, interleukin-1beta (IL-1beta) and interferon-gamma (IFN-gamma) incubated for 8 h. The macrophage expression of iNOS increased by 365% (p < 0.01) and its product, NO, increased proportionally. The expression of iNOS in the cardiac myocyte did not increase with TNF-alpha and LPS. However, with the addition of IFN-alpha and IL-1beta iNOS increased to 140% of control (p < 0.05). Myocyte cGMP and NO did not increase significantly with TNF-alpha treatment. This study suggests that HL-1 myocyte iNOS cannot be induced by TNF-alpha, unlike macrophage iNOS. Furthermore, the resultant cardiac dysfunction, secondary to proinflammatory cytokines effects, is regulated via diverse pathways.

Animals↗

PubMed2001

Apoptosis in the ischemic reperfused myocardium.

Recovery of the myocardium from an ischemic event depends on the reperfusion of the ischemic area. Resumed blood flow to the tissue restores the metabolic substrates necessary for energy production and cell survival. Paradoxically, ischemic reperfusion (I/R) can result in further damage to the myocardium (I/R injury) through an acute inflammatory response mediated by cytokines, neutrophils, macrophages, and reactive oxygen species. These events can trigger cardiomyocyte death through either necrosis or apoptosis. This report will focus on the apoptosis process, which is an organized, active, and gene-directed process of cell self-destruction that can be initiated by intracellular genetic programs, or second messenger pathways inside the cell upon extracellular stimulation by signaling molecules or stress. Awareness of the apoptotic process in cardiomyocytes and endothelial cells is relevant to myocardial preservation during cardiopulmonary bypass compared with off-pump cornary artery bypass procedures. Pharmacological interventions of the signaling pathways that control apoptosis provide an opportunity for new therapeutic approaches to reduce I/R injury in the heart. This review of apoptosis will introduce the perfusionist to apoptosis in the I/R heart, discuss some of the metabolic pathways that initiate it, and report on developing strategies to prevent it.

Antioxidants↗

PubMed2001

Modulation of the inflammatory response in the cardiomyocyte and macrophage.

Numerous cardiac disease processes have been linked to the overproduction of nitric oxide (NO) via inducible nitric oxide synthase (iNOS) in the cardiovascular system. Chronic and acute exposure to hyperphysiologic levels of NO has been suggested as an agent in chronic transplant rejection, various cardiomyopathies, reperfusion injury, and the inflammatory state following cardiopulmonary bypass. Proinflammatory cytokines and inflammatory cell types, such as macrophage and neutrophils, have also been implicated in the pathophysiology associated with the previously mentioned syndromes. Previous work by this group has shown that lipopolysaccharide (LPS) in combination with tumor necrosis factor-alpha (TNF-alpha) can increase iNOS expression and the production of NO in macrophage. With this in mind, we hypothesized that increased iNOS expression and NO production generated by LPS and TNF-alpha in the macrophage could be mimicked in the cardiomyocyte and potentially account for some aspect of the cardiac dysfunction attributed to NO. Furthermore, this increased expression of iNOS and NO production could be returned to control using the glucocorticoid, dexamethasone, a known iNOS transcription blocker. Using fetal rat cardiomyocytes in primary culture cell line and a murine macrophage cell line, RAW 264.7, the expression of iNOS was quantified with specific FITC-conjugated antibodies using fluorescence activated cell sorter (FACS) and NO production with a Bioxytech nitric oxide spectrophotometric assay. The myocytes and macrophage were separated into three groups, Control, TNF + LPS, and (+) Dexamethasone. The control groups received no TNF or LPS or dexamethasone, TNF + LPS groups received TNF-alpha and LPS for 8 hours with no dexamethasone, and the (+) Dexamethasone groups were pretreated with dexamethasone for 8 hours and stimulated with TNF-alpha and LPS along with a second 8-hour treatment of dexamethasone. The macrophage cell groups treated with TNF-alpha and LPS showed a 335% increase over control in iNOS expression, and NO production was increased 494% from control. Macrophage treated with dexamethasone experienced an attenuation of iNOS expression of 200% toward control from stimulated levels and 202% decrease in NO production from stimulated levels toward control. Cardiomyocytes exhibited no statistically significant change in the expression of iNOS or NO production with stimulation or dexamethasone treatments. In conclusion, iNOS and NO were elevated in macrophage, which can be blunted in the presence of dexamethasone in the macrophage. Curiously, iNOS could not be stimulated in the cardiomyocyte, suggesting inflammatory cells may be largely responsible for the elevated iNOS and NO experienced in some cardiovascular diseases. The clinical relevance of this study is the introduction of specific iNOS inhibitors into the cardiopulmonary bypass circuit could serve as a potential mechanism for modulating the inflammatory response surrounding cardiopulmonary bypass. Likewise, therapeutic glucocorticoid administration could improve outcomes for patients with inflammatory cardiovascular disease states related to elevated NO production.

Animals↗

PubMed2000

Comparison of Sarns 3M heparin bonded to Duraflo II and control circuits in a porcine model: macro- and microanalysis of thrombi accumulation in circuit arterial filters.

Heparin-bonded perfusion circuits have been reported to reduce the thrombus formation during various levels of systemic heparinization. The goal of this study was to compare the efficacy of thrombo-resistance of the Sarns 3M heparin-bonded circuit to Baxter Duraflo II and untreated control in a porcine model. Fifteen Yorkshire pigs (60-65 kg) were anesthetized, heparinized with 3000 IU, intravenously (i.v.) and surgically cannulated with an internal jugular outflow and a femoral vein inflow. All circuits consisted of a 22-Fr venous cannula, centrifugal pump, arterial filter, an 18-Fr cannula for return and connected with equal lengths of 3/8" polyvinyl chloride tubing. The flows were maintained at 2.0 l/min for 4 h. Thrombus formation in filter samples were morphometrically analyzed through macro-densitometry, light microscopy, and scanning electron microscopy (SEM). Our findings revealed that the 3M circuit had significantly less gross thrombus (p < 0.001), 66% and 84% less microscopic thrombi and fivefold less SEM-measured aggregates (p = 0.03) compared to the Duraflo II and uncoated groups. This study demonstrated that the 3M heparin-bonded circuit had significantly reduced the formation of micro- and macro-thrombi in the minimally heparinized pig model compared to the Duraflo II and untreated control circuits.

Animals↗

PubMed2000

Senescent ventricular dysfunction: issues related to cardiopulmonary bypass.

The mean age of the open-heart surgical patient is increasing every year. Therefore, it is logical to define the aging-related changes in cardiovascular function. This study set forth to define the major molecular and performance alterations that occur in the left ventricle related to advanced aging or senescence. In the human, vascular pathologies usually accompany left ventricular dysfunction. The aim of this study was to associate the altered left ventricular mechanics with molecular pathways in mice who lacked these associated vascular pathologies. This study compared the left ventricular function of two groups of mice (N = 20 each), 6 months old and 16 months old (senescent). The mice were anesthetized with urethane and alpha-chloralose, and a Millar 1.4 Fr. conductance micromanometer catheter was placed into the left ventricle for acquisition of pressure-volume loops. Heart tissues were collected immediately for analysis of cGMP concentrations. The cardiac index, preload recruitable stroke work, and the slope (Ees) of the end-systolic pressure volume relationship were significantly less in the senescent group compared to the young mice. It was concluded that the aged heart has significantly reduced systolic and diastolic dysfunction compared to the young heart function and that this dysfunction may be related to pathways leading to increased myocardial cGMP concentrations.

Age Factors↗

PubMed2000

In vitro comparison of inhibitors of inducible nitric oxide synthase in a macrophage model.

Nitric oxide (NO) has been shown to decrease cardiac performance, induce global hypotension, and generate oxygen free-radicals. Nitric oxide is produced from the conversion of L-arginine to L-citrulline by inducible nitric oxide synthase (iNOS) and is a component of many cellular second messenger systems. It is not clearly understood if NO and iNOS are compensatory mechanisms or pathological processes in heart failure, and this study was designed to understand better inhibition of iNOS in a cell culture model. Inhibitors of iNOS were compared for in vitro capability of inhibiting the production of NO. Ethanol and S-methylisothiourea (MITU) were applied to macrophage populations in 120 microM and 1 microM, 100 and 10 nM for an 8-h incubation. Level of iNOS expression was measured in the ethanol-treated populations using an anti-iNOS primary antibody with a fluorescent labeled secondary antibody. Serum nitrites were measured in both treatment groups by the nonenzymatic Griess method to determine enzyme function. Our data indicate that ethanol demonstrates a stimulation and simultaneous inhibition of iNOS during an 8-h incubation. No dose-dependent correlation between amount of serum nitrites produced and ethanol treatment was observed. However, MITU demonstrated a clear inhibition of iNOS at 120 microM with a serum nitrite value of 25.7002 +/- 0.0647, with control values of 24.3421 microM. Lower concentrations of MITU also demonstrated no correlation. Although both agents display inhibitory effects upon iNOS, MITU seems to have no apparent simultaneous stimulation and may hold more potential as a post-translational inhibitor of iNOS.

Animals↗

PubMed1999

Age-related left ventricular function in the mouse: analysis based on in vivo pressure-volume relationships.

Our study compared left ventricular (LV) function between senescent and young adult mice through in situ pressure-volume loop analysis. Two groups of mice (n = 9 each), 6-mo-old and 16-mo-old (senescent) mice, were anesthetized with urethan and alpha-chloralose, and their LV were instrumented with a Millar 1.4-Fr conductance micromanometer catheter for the acquisition of the pressure-volume loops. The senescent mice had a significantly decreased contractile function related to load-dependent parameters, including stroke volume index, ejection fraction, cardiac output index, stroke work index, and maximum derivative of change in systolic pressure over time. The load-independent parameters, preload recruitable stroke work and the slope (end-systolic volume elastance) of the end-systolic pressure-volume relationship, were significantly decreased in the senescent mice. Heart rate and arterial elastance were not different between the two groups; however, the ventricular-to-vascular coupling ratio (ratio of elastance of artery to end-systolic volume elastance) was increased by threefold in the senescent mice (P < 0. 001). Thus there were significant decreases in contractile function in the senescent mouse heart that appeared to be related to reduced mechanical efficiency but not related to arterial elastance.

Aging↗

PubMed1999

Differential expression of inducible nitric oxide synthase in septic shock.

During cardiopulmonary bypass (CPB), the septic patient has markedly decreased peripheral vascular resistance as a consequence of endotoxin release from microorganisms. This decrease in peripheral vascular resistance is the result of endotoxin-induced nitric oxide (NO) produced by inducible nitric oxide synthase (iNOS) and endothelial nitric oxide synthase (eNOS). iNOS and eNOS are responsible for the synthesis of NO because of various stimuli, including the bacterial endotoxin, lipopolysaccharide (LPS). We tested the hypothesis that a differential expression of iNOS among human endothelial cells and murine macrophage is dependent upon exposure to endotoxin and various pro-inflammatory cytokines. Using a human endothelial cell line, ECV-304 and murine macrophage cell line, RAW 264.7, we quantified the expression of iNOS with specific FITC-conjugated antibodies using fluorescence activated cell sorter (FACS) and NO production with a Bioxytech nitric oxide spectrophotometric assay. This in vitro septic model utilized LPS supported with species-specific interferon-gamma, interleukin-1 beta, and tumor necrosis factor-alpha. The cell type were stimulated for 8 hours with combinations of the cytokines mentioned. The FACS data demonstrated a significant stimulus-dependent increase in iNOS expression among the macrophage groups; however, the stimulated endothelial cells showed no significant change in iNOS expression. The nitric oxide production data demonstrated significant increases in NO production among macrophage stimulated groups; whereas, endothelial stimulated groups exhibit no significant change. We conclude that NO secreted during septic shock is the result of activated macrophage, not the endothelium. The clinical relevance is that the more severe the infectious process, the lower the PVR may be during CPB because of increased NO production from activated macrophage.

Animals↗

PubMed1999

Pharmacological effect of nitroprusside on platelet aggregation.

Adequate platelet function and numbers are critical for postcardiopulmonary bypass patients. Endogenous and pharmacological sources of nitric oxide (NO) are known inhibitors of platelet aggregation. Sodium nitroprusside (SNP), used clinically to control blood pressure, is an inorganic source of NO. Our long-term goal is to determine if SNP infusion in the venous return line of the cardiopulmonary bypass system would preserve platelet numbers and function without affecting systemic vascular resistance. Our first requirement to accomplish this goal was to develop an assay that would detect the SNP effect on platelet aggregation. We, therefore, tested the hypothesis that clinical concentrations of SNP would inhibit platelet aggregation. We quantified platelet aggregation with the Medtronic Hepcon HMS whole blood aggregometer. Normal heparinized human blood was treated with 0.625 to 12.5 nM platelet activating factor (PAF), 0.25 to 5.0 microM epinephrine, or 0.20 to 10 microM adenosine 5'-diphosphate (ADP) to stimulate platelet aggregation. SNP was added at 10(-5) M to determine its affect on PAF, epinephrine, and ADP stimulated platelet aggregation. The results demonstrated that PAF-stimulated platelet aggregation was significantly inhibited with SNP (10(-5) M) to 82% (p < .05) of control and epinephrine and ADP mediated aggregation were not significantly affected. In conclusion, at clinically relevant concentrations SNP inhibits platelet aggregation by PAF but not with ADP or epinephrine.

Adenosine Diphosphate↗

PubMed1999

Plasmapheresis during cardiopulmonary bypass: a proposed treatment for presensitized cardiac transplantation patients.

Potential thoracic organ transplantation recipients who have positive cytotoxic antibody screens as quantified panel reactive antibodies (PRA) are at risk for immediate or long-term immunologic events that may affect the donor organ. The patient population at risk includes those who are supported with cardiac assist devices, multiparous women, and individuals receiving numerous homologous blood products. We treated three highly positive PRA patients with intraoperative plasmapheresis coupled to the cardiopulmonary bypass system to remove sufficient cytotoxic antibody. Upon the availability of donor hearts of an unknown HLA type, intraoperative plasmapheresis was performed using a Cobe Spectra Plasmapheresis system coupled to a Terumo CXSX18 oxygenator system. Three plasma volume exchanges of fresh frozen plasma (FFP) were performed while the patients were on cardiopulmonary bypass. One to one and one-half plasma volume exchange plasmaphereses were performed with a declining schedule for the next 30 days post-transplantation in combination with aggressive B-cell specific immunosuppressive therapy. The three patients are NYHA functional class I and free of rejection at 6 months post-transplantation. In conclusion, intraoperative plasmapheresis is effective and safe for the patient who would not be otherwise transplanted because of markedly elevated PRAs.

Adult↗

PubMed1998

Assessment of left ventricular compliance during heart preservation.

There is critical need for a greater number of donor hearts for transplantation. The demand can be relieved, in part, by an extension of preservation time. This necessitates new methods of preservation and development of means to assess the functional condition of the preserved heart. We report a heart-preservation system designed for long-term preservation support and discuss issues specifically related to extended heart preservation. This article presents methodology to assess ventricular compliance and to quantify coronary flow distribution during the use of microperfusion preservation. Ventricular adenosine triphosphate (ATP) concentrations are directly related to the immediate post-preservation function: however, direct measurement of ATP is not clinically available. Based on the premise that ventricular compliance relates directly to the ventricular ATP concentrations, we performed sequential ventricular compliance measurements using a simple left ventricular balloon during a 24 h preservation period. A porcine heart model was employed using a continuous, hypothermic, antegrade, microperfusion system for 24 h and measurements were made at specific intervals during the preservation time. The compliance measurements were ascertained by pressure-volume curves using a flaccid balloon inserted into the left ventricle through the mitral valve. In addition, to assess microvascular function during the preservation interval, regional coronary flow measurements were performed using a microsphere technique. We report that after 12 h of preservation there was a twofold reduction in ventricular compliance which decreased further by fivefold at 18 h. In contrast, there was a time-dependent decrease in left ventricular coronary flow, especially with the left-ventricular subendocardial region significantly decreasing by 50% at 12 h. In conclusion, a simple ventricular-compliance balloon provided a direct measurement of ventricular compliance of the preserved heart which may provide an indirect estimate of the ventricular high-energy phosphates of the preserved heart prior to transplantation.

Animals↗

PubMed1996

Neutrophil activation during cardiopulmonary bypass in paediatric and adult patients.

It has been reported that the 'systemic inflammatory' response occurring during cardiopulmonary bypass (CPB) may be responsible for postoperative complications. This inflammatory response is triggered by the platelet coagulation system, complement activation, resulting in neutrophil activation and degranulation. The aim of this study was to quantify the specific markers of neutrophil activation in the adult and paediatric patient during CPB. We report that neutrophil myeloperoxidase (MPO) and human neutrophil elastase (HNE) are significantly increased in both the paediatric and adult patients. This study utilized enzymatic assays that quantified the enzymatic activity in the blood circulation rather than measurement of the enzyme protein complex. Increased concentrations of MPO were, in part, related to the blood prime with the paediatric patients and the HNE concentrations were related to time on CPB in both the paediatric and adult patient. This study demonstrated that there are significantly elevated neutrophil enzyme activities in the CPB patient and underscores the pivotal role of the neutrophil in the pathophysiology of CPB.

Adult↗

PubMed1996

Cerebral blood flow in the diabetic patient.

Diabetes is a major risk factor for cardiovascular disease. Coronary revascularization utilizing cardiopulmonary bypass (CPB) is frequently required for the diabetic patient. Nondiabetic individuals can autoregulate cerebral blood flow (CBF) through metabolic and perfusion pressure mechanisms during CPB. However, it has been reported that diabetic patients have impaired CBF autoregulation during CPB. It is possible, therefore, that impaired CBF autoregulation may contribute to postoperative neuropsychologic dysfunction. The mechanisms for this defect may reside in impaired endothelial-dependent responses in the diabetic that are related to morphological and functional changes linking the vascular endothelium and the vascular smooth muscle. The morphological changes occurring in the diabetic include microangiopathy and macroangiopathy which are characterized by endothelial cell (EC) hyperplasia and basement membrane thickening. Also, significant functional changes in local control of vascular tone, such as an imbalance in the synthesis and secretion of vasoactive factors by the EC and abnormal reactivity of the vascular smooth muscle, are seen in the diabetic when compared to the nondiabetic. More specifically, vascular responses to both calcium-dependent pathways of vasoconstriction and nitric oxide pathways of vasorelaxation have been shown to significantly differ between the diabetic and nondiabetic. The emphasis of this discussion is to examine the molecular mechanisms by which diabetes alters vascular function, with emphasis placed on regulation of cerebral artery blood flow during CPB.

Cerebrovascular Circulation↗

PubMed1996

A novel mechanism for cyclosporine: inhibition of myocardial ischemia and reperfusion injury in a heterotopic rabbit heart transplant model.

BACKGROUND: Advances in myocardial preservation techniques and immunosuppressive drug therapy have resulted in heart transplantation as an acceptable treatment for end-stage heart failure. However, excessive periods of global myocardial ischemia followed by reperfusion can progress to irreversible graft injury. It has been reported that cyclosporine A (in addition to its well-characterized immunosuppressive actions) can blunt certain features of ischemia and reperfusion injury. This study was performed to examine the ability of cyclosporine A to attenuate such injury in a model of heart transplantation. METHODS: Twenty rabbit heterotopic transplants were divided into four study groups: (1) 30-minute ischemic control hearts; (2) 30-minute ischemic cyclosporine A-treated hearts; (3) 4-hour ischemic control hearts; and (4) 4-hour ischemic cyclosporine A-treated hearts. A single dose of cyclosporine A (10 mg/kg intravenously) or vehicle was administered to both the donor and recipient rabbits 45 minutes before heart explantation and heart transplantation, respectively. RESULTS: After transplantation and 30 minutes of reperfusion, the 4-hour ischemic control hearts showed a significant (p < 0.01) leftward shift in the left ventricular end-diastolic pressure versus left ventricular volume curve compared with the 30-minute ischemic control hearts. This finding represents higher end-diastolic pressures and incomplete diastolic relaxation caused by ischemia and reperfusion. Cyclosporine A administration to the donor and recipient rabbits resulted in a significant improvement (p < 0.01) in diastolic relaxation (shift in the left ventricular end-diastolic pressure versus left ventricular volume curve back to the right) compared with 4-hour ischemic control hearts. Cyclosporine A-treated hearts also showed significant improvements in the rate of diastolic pressure fall (p < 0.05) and tau (the isovolumetric pressure decay constant) (p < 0.01) compared with ischemic control hearts. CONCLUSIONS: These results indicate that single doses of cyclosporine A to both the donor and recipient inhibit the dysfunction in extent and rate of left ventricular relaxation caused by prolonged global ischemia and reperfusion. Possible mechanisms for cyclosporine A's myocardial protective actions are presented in the discussion.

Animals↗

PubMed1995

Hemofiltration: determinants of drug loss and concentration.

Ultrafiltration has proven to be an effective method of reducing post-cardiopulmonary bypass edema and the inflammatory response associated with activation of the complement cascade. Recently, a modified ultrafiltration process has been developed which allows further hemoconcentration after weaning from bypass. Both of these procedures can have an effect upon the concentrations of many of the pharmaceutical agents being used either pre- or perioperatively. Based upon work done by other investigators in the field of dialysis, we have developed sieving coefficients for many cardiovascular drugs in order to provide an estimation of their loss during extended periods of hemofiltration. Our study utilized the pharmacological and physical characteristics for volume of distribution and protein binding to determine the movement of drugs through a hemofilter. Our results demonstrated that concentrations of certain drugs used during open heart surgery may be significantly increased or decreased with the use of hemofiltration techniques.

Cardiopulmonary Bypass↗