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Biomedical subjects

H Refsum

Publications and source records attributed to H Refsum.

At least 37 records · Page 2Linked to original sources
PubMed1991

Homocysteine levels in patients with rheumatoid arthritis treated with low-dose methotrexate.

Plasma homocysteine levels were determined in patients who participated in a randomized, double-blind placebo-controlled trial of folate supplementation (1 mg/day) during methotrexate therapy for rheumatoid arthritis. Plasma and red blood cell folate levels before methotrexate therapy were significantly negatively correlated with homocysteine levels. Homocysteine levels were not significantly correlated with the initial C1 index (an assay that measures the folate status of blood mononuclear cells) or the C1 index during methotrexate therapy. There was no significant difference in homocysteine levels between pretreatment and levels drawn at 3 or 6 months. Initial homocysteine levels were predictive of toxicities, such as gastrointestinal intolerance and elevations of liver enzymes in the placebo group. There was no significant correlation between occurrence of toxicity and initial homocysteine levels in the folic acid-supplemented group. Homocysteine levels were not predictive of the efficacy of methotrexate therapy. We conclude that plasma homocysteine levels are correlated with plasma and red blood cell folate levels before methotrexate therapy but is not correlated with folate status in blood mononuclear cells.

Arthritis, Rheumatoid↗
PubMed1991

Monitoring cobalamin inactivation during nitrous oxide anesthesia by determination of homocysteine and folate in plasma and urine.

The effects of nitrous oxide-induced cobalamin inactivation on homocysteine and folate metabolism have been investigated. Plasma levels of cobalamin, folate, homocysteine, and methionine were determined in 40 patients before and after operation under nitrous oxide anesthesia (range of exposure time, 70 to 720 minutes). Twelve patients anesthetized with total intravenous anesthesia served as control subjects (range of exposure time, 115 to 600 minutes). Postoperative plasma levels of folate and homocysteine increased (p less than 0.001) up to 220% and 310%, respectively, in nitrous oxide-exposed patients, whereas plasma levels of methionine decreased (p less than 0.025). Response occurred after 75 minutes of nitrous oxide exposure. The percentage increase of plasma folate and homocysteine correlated significantly with exposure time (p less than 0.025 and p less than 0.0001, respectively). In eight patients receiving nitrous oxide anesthesia plasma homocysteine levels had not returned to preoperative levels within 1 week (p less than 0.01). Urinary excretion of folate and homocysteine increased during and after nitrous oxide exposure (p less than 0.01 and p less than 0.002, respectively) and correlated with exposure time (p less than 0.01 and p less than 0.005, respectively). It can be concluded that disturbance of homocysteine and folate metabolism by nitrous oxide develops with little delay and return to normal levels requires several days. Elevation of plasma homocysteine levels may therefore be used for monitoring nitrous oxide-induced cobalamin inactivation.

Adult↗
PubMed1991

Left and right ventricular diastolic function during acute pericardial tamponade.

The aim of the study was to determine the effect of acute pericardial tamponade on left (LV) and right ventricular (RV) intracavitary and transmural pressure-volume (P-V) relations and to assess the effect of changing blood volume during tamponade on LV and RV volumes. The experiments were done in 11 acutely instrumented anaesthetized dogs in which LV and RV volumes were determined by computed tomography (CT) (n = 5) and LV and RV diameters by sonomicrometry (n = 6). Pressures were measured in the pericardium (balloon transducer), in the aorta and in the ventricles. Incremental pericardial infusion (up to 180 ml) caused a progressive left and upward shift of the LV and the RV intracavitary P-V relationship. This shift was entirely due to increased pericardial pressure (PP). The induction of tamponade caused no change in the LV and RV transmural P-V relationship. During tamponade with ventricular filling pressures above 10-15 mmHg, blood volume expansion caused only minimal increase in LV and RV volumes. In conclusion, pericardial tamponade shifted the LV and the RV intracavitary diastolic P-V relation by increasing PP. However, there was no change in the transmural P-V relationship, indicating unchanged myocardial compliance. Volume loading caused only minimal increase in LV and RV volumes during tamponade.

Animals↗
PubMed1991

Negative chronotropic effect of a novel class III antiarrhythmic drug, UK-68,798, devoid of beta-blocking action on isolated guinea-pig atria.

1. The chronotropic effects of a novel class III antiarrhythmic drug, UK-68,798, and the beta-adrenoceptor blocker, propranolol, for comparison, were studied on spontaneously beating right atria isolated from guinea-pigs in the absence and presence of increasing concentrations of isoprenaline (10(-10)-10(-4) M). 2. UK-68,798 (10(-9)-10(-5) M) decreased spontaneous atrial rate by 6-21%. Propranolol (10(-8) -10(-6) M) also had a negative but significantly smaller chronotropic effect. 3. UK-68,798 dose-dependently reduced the maximal positive chronotropic effect induced by isoprenaline, but without significantly shifting the concentration-response curve for isoprenaline in a parallel fashion. A pD'2 value of 5.88 was obtained. As expected, propranolol displayed a competitive inhibition with a pA2 value of 8.21. 4. The results demonstrate a negative chronotropic effect of UK-68,798, which is not associated with a beta-adrenoceptor blocking action. We suggest that the negative chronotropic effect is linked with potassium channel blockade and thereby the class III antiarrhythmic action of UK-68,798.

Adrenergic beta-Antagonists↗
PubMed1991

Rate-dependent differences in dog epi- and endocardial monophasic action potential configuration in vivo.

A transient outward current (Ito), long considered to be a unique feature of Purkinje fiber tissue, has recently been demonstrated in dog ventricular tissue in vitro and most prominently in the epicardium. To investigate its possible contribution to ventricular repolarization in vivo, we recorded right ventricular endocardial and epicardial monophasic action potentials (MAP) simultaneously in pentobarbital-anesthetized open-chest dogs. Epicardial MAP had lower phase 1 than phase 2 amplitude at both spontaneous heart rate and paced cycle length of 300 and 400 ms. This "spike-and-dome" morphology of the epicardial MAP, possibly attributable to Ito, progressively disappeared at shorter extrastimulus intervals. In endocardium the phase 1 amplitude was always higher or equal to phase 2 amplitude and was not affected by shorter extrastimulus intervals. The action potential duration (APD) was shorter in epicardium than in endocardium. Both endocardial and epicardial APD shortened as the premature intervals were reduced, but the shortening was not parallel. The restitution curves converged so that, at the shortest intervals (160 ms), there were no longer any significant differences in APD between endocardium and epicardium. This study indicates that Ito contributes to ventricular repolarization in vivo, and most prominently in the epicardium. Unequal shortening of APD between endocardium and epicardium after progressively shorter diastolic intervals may thus partly result from uneven distribution of Ito across the ventricular wall.

Action Potentials↗
PubMed1991

An experimental model for the study of transcapillary fluid balance in hypothermia.

Disturbed fluid balance is a significant clinical problem in hypothermia and rewarming. We have therefore investigated whether the transcapillary fluid balance in rats exposed to hypothermia and rewarming could be studied with the use of a wick method. Double nylon wicks were sewn into the abdominal skin and left there for one hour, then removed to double-bottomed conic vials and centrifuged. Wick fluid was collected and colloid osmotic pressure measured. Blood samples were taken simultaneously for measurement of hematocrit, hemoglobin, red cell count and plasma colloid osmotic pressure. This was done at 37 degrees C (prehypothermic), 13 degrees C (hypothermic) and at 30 degrees C (during rewarming). Blood pressure was also recorded. The model provides a good method to investigate the colloid osmotic changes of both plasma and interstitium during hypothermic situations.

Animals↗
PubMed1991

Hemodynamic and metabolic effects of hypothermia and rewarming.

There is a lack of detailed knowledge of the pathophysiologic mechanisms initiated during and after rewarming. To study cardiac function after rewarming from hypothermia sodium pentobarbital anesthetized open chest-dogs were cooled to 25 degrees C and rewarmed. Myocardial blood flow was measured at different temperatures, and blood samples were drawn from the aorta and the coronary sinus for metabolic measurements. Mean aortic blood pressure (AOP) and aortic blood flow were recorded. Compared to precooling, AOP and heart rate were both significantly reduced during hypothermia. During rewarming stroke volume (SV) decreased significantly. At the end of rewarming AOP and SV were significantly lower than before cooling and myocardial blood flow, as well as oxygen and lactate uptake were only 50% of precooling levels. The present study demonstrated that hypothermia and rewarming depress cardiovascular function. Changes in peripheral vascular function, myocardial metabolism and contractility, may lead to the observed reduction in recovery upon rewarming.

Animals↗
PubMed1991

Cardiac electrophysiology during hypothermia. Implications for medical treatment.

Reduction in body temperature induces characteristic electrophysiological and mechanical alterations of the heart. The heart rate is markedly reduced. Myocardial conduction is slowed, partly due to reduced rate of depolarization of the action potential, and is reflected by widening of the QRS-complex in the ECG. There is also a fall in resting membrane potential. Action potential duration and refractory period are markedly lengthened during hypothermia, attributed to delayed repolarization. This is reflected by increased QT-time in the ECG. Since action potential duration changes significantly even after as small temperature changes as 1 to 2 degrees C, nonuniform cooling or rewarming of the heart may cause significant dispersion of conduction, action potential duration and refractoriness in the myocardium. This dispersion may cause unidirectional block, hence creating a substrate for reentry atrial and ventricular arrhythmias, and may be an important mechanism for explaining the hypothermia-associated arrhythmias. Class III antiarrhythmic drugs such as d-sotalol lengthen long action potentials at low temperatures to a greater extent than the shorter action potentials at higher temperatures. This may further increase dispersion and thereby the tendency towards arrhythmias. Sotalol as an example, shows that some antiarrhythmic drugs may have increased arrhythmogenic effect and should probably be contraindicated during hypothermia.

Electrocardiography↗
PubMed1991

Interaction between methotrexate, "rescue" agents and cell proliferation as modulators of homocysteine export from cells in culture.

Clinical studies on cancer and psoriasis patients have shown that plasma and urinary homocysteine (Hcy) responds to methotrexate (MTX) therapy, indicating that Hcy in extracellular fluids may be an indicator of the antifolate effect. However, the clinical data indicate that the burden of proliferating cells, cytotoxicity and the folate status are also determinants of extracellular Hcy. To evaluate this further, we investigated the modulation of cellular Hcy egress by MTX, rescue agents, cell proliferation and cytotoxicity. Nontransformed and chemically transformed fibroblasts and murine lymphoma cells, which are characterized by different growth behavior and MTX response, were used. The Hcy export rate was correlated positively with the proliferation rate in all cell types. 5-Formyltetrahydrofolate or 5-methyltetrahydrofolate added to fibroblasts not exposed to MTX reduced the Hcy export rate, whereas the export from the lymphoma cells was not affected. All cells types exposed to MTX were rescued by thymidine + hypoxanthine, and this allowed the assessment of Hcy export during MTX exposure without interference from cytotoxicity. In the fibroblasts, MTX with thymidine + hypoxanthine rescue induced a marked increase in Hcy export, and the dose-response paralleled the cytotoxicity curves obtained for MTX without rescue. Nontoxic concentrations of MTX without rescue enhanced the Hcy export. When MTX concentration was increased further, Hcy export was stimulated initially, and then declined rapidly as cell death ensued. MTX did not enhance the Hcy export from the lymphoma cells and, in the absence of rescue, the Hcy export from these cells declined in proportion to inhibition of cell growth.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Sodium addition to nonionic contrast media. Effects on cardiac monophasic action potentials and hemodynamics in a dog model.

In order to study the electrophysiologic and hemodynamic effects of sodium addition to low-osmolality contrast media during coronary arteriography, eight dogs with surgically opened thoraces were studied. Epicardial monophasic action potentials (MAP) were recorded from the contrast perfused area, using suction electrodes. Six milliliters of iohexol, iohexol with addition of 20 to 80 mmol/L Na+ and ioxaglate, were selectively administered into the left coronary artery. Only minor hemodynamic alterations occurred with the iohexol solutions, whereas ioxaglate decreased left ventricular (LV) inotropy and pressures initially. Iohexol and iohexol containing less than 40 mmol/L Na+ did not change MAP duration significantly. The addition of 80 mmol/L Na+ to iohexol lengthened MAP duration at 25%, 50%, and 90% repolarization by 14 +/- 2, 18 +/- 3, and 18 +/- 5 mseconds, respectively. Ioxaglate lengthened MAP duration by 14 +/- 3, 17 +/- 3, and 26 +/- 8 mseconds, respectively. Thus, during coronary arteriography in dogs, iohexol with sodium added, like ioxaglate, induced regional electrophysiologic changes in the contrast-perfused area of the myocardium, while sodium-free iohexol did not.

Action Potentials↗
PubMed1991

Left ventricular systolic and diastolic function during coronary arteriography before and after acute left ventricular failure in dogs. A comparison between iodixanol, iohexol and ioxaglate.

The hemodynamic side effects of intracoronary injection of low osmolality contrast media were studied in anesthetised dogs, both with and without left ventricular (LV) failure. LV failure was induced by microembolization of the area supplied by the left main coronary artery. LV pressure and volume, aortic pressure, and cardiac output were recorded. 6 ml iodixanol 320 mg I/ml containing 20 mmol Na+/l, a new non-ionic dimer, was compared to iohexol and ioxaglate. Iodixanol induced small systolic alterations both before and after LV failure. Iohexol increased LV inotropy while ioxaglate depressed myocardial function. Before failure iodixanol and ioxaglate impaired isovolumic relaxation, but early diastolic filling was not reduced. After failure the relaxation process was not affected, but ioxaglate reduced early diastolic filling. Ioxaglate also increased LV end-diastolic pressure and volume more than the non-ionic contrast media. In conclusion, iodixanol induced only small changes in systolic and diastolic function. Iodixanol should therefore be hemodynamically well tolerated during coronary arteriography, and also in acute ischemic heart failure.

Acute Disease↗
PubMed1990

[Do calcium antagonists protect the heart?].

There are several well-documented mechanisms by which calcium antagonists might reduce the size of an infarct and the complications that may result from it. They can improve flow, reduce demand, prevent calcium-induced damage and have an antiarrhythmic effect. In a large number of animal studies calcium antagonists have been shown to be cardioprotective, and some clinical trials have yielded encouraging results. These trials must be interpreted with some caution, however, since the relationship between various measures of infarct size, such as ECG changes and enzyme release, the amount of myocardial damage and the prognosis, may not be close. Furthermore, some trials yielded a negative result and further data are needed, based on large-scale double-blind controlled trials. Nevertheless, taken overall, the evidence suggests that calcium antagonists may play a cardio-protective role, and interest in this subject is certain to continue, and will probably increase.

Animals↗
PubMed1990

Clinical significance of pharmacological modulation of homocysteine metabolism.

The metabolic fate of homocysteine is linked to vitamin B12, reduced folates, vitamin B6 and sulfur amino acids. Clinical and experimental data suggest that elevated plasma homocysteine is an independent risk factor for premature vascular disease. This is particularly significant because plasma homocysteine levels are altered in several diseases, including folate and vitamin B12 deficiencies, and because many commonly used drugs have now been shown to interfere with homocysteine metabolism. In summarizing the data, Helga Refsum and Per Ueland highlight the clinical implications for these metabolic changes.

Animals↗
PubMed1990

Effect of intracoronary contrast medium on left ventricular diastolic pressure-volume relationships.

The purpose of this study was to investigate the effect of intracoronary injection of the contrast medium sodium-meglumine diatrizoate (CM) on left ventricular (LV) diastolic pressure-volume relationships. Seven closed-chest dogs were instrumented with pressure catheters in the left ventricle and aorta, a balloon transducer to measure pericardial pressure, and an aortic flow meter to determine stroke volume. We estimated LV volume from two diameters by sonomicrometry. Six milliliters of CM was injected into the left main coronary artery. Transmural LV end-diastolic pressure increased from 3.3 +/- 1.1 to 7.2 +/- 0.9 mm Hg and LV end-diastolic volume index from 40.8 +/- 6.8 to 44.7 +/- 7.4 ml. There was only a minor increase in pericardial pressure. Stroke volume decreased by 31 +/- 7%. There was no change in the intracavitary or transmural diastolic pressure-volume relationship, indicating unchanged LV "compliance." Increased LV filling pressure by CM reflected reduced systolic function.

Animals↗
PubMed1990

Positive inotropy linked with class III antiarrhythmic action: electrophysiological effects of the cardiotonic agent DPI 201-106 in the dog heart in vivo.

STUDY OBJECTIVE: The aim was to investigate whether the positive inotrope DPI 201-106 prolongs ventricular monophasic action potential duration and refractoriness in vivo without affecting conduction, thus possessing class III antiarrhythmic characteristics in vivo. DESIGN: Electrophysiological and haemodynamic effects of DPI 201-106 (0.5, 1.0, and 2.0 mg.kg-1 intravenously) were studied at spontaneous heart rate and at three different paced cycle lengths (353, 300, and 261 ms). The following were recorded: monophasic action potentials from right ventricular endocardium; intracardiac conduction times by His bundle electrocardiography; refractoriness by programmed electrical stimulation; and left ventricular (LV) pressures. SUBJECTS: Seven mongrel dogs of either sex, weighing 14-24 kg, were studied under sodium pentobarbitone anaesthesia. MEASUREMENTS AND MAIN RESULTS: DPI 201-106 prolonged ventricular monophasic action potential duration and refractoriness dose dependently and most effectively at long cycle lengths, with no effect on intracardiac conduction times. DPI 201-106 increased LV dP/dtmax, while LV systolic and end diastolic pressures were unchanged both during spontaneous and paced heart rate. DPI 201-106 decreased spontaneous heart rate. CONCLUSIONS: Prolonged monophasic action potential duration and increased refractoriness, with no effect on conduction, indicate class III antiarrhythmic action of DPI 201-106 in vivo.

Action Potentials↗