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H Refsum

Publications and source records attributed to H Refsum.

At least 127 records · Page 7Linked to original sources
PubMed1995

Sodium-calcium relationships and cardiac function during coronary bolus perfusion.

The present review deals with the side-effects of contrast media (CM) on cardiac function during coronary angiography. A physiological approach is used to redefine existing concepts of CM osmotoxicity and chemotoxicity in terms of osmolal, ionic and molecular effects. The main idea conveyed is that purely ionic effects are of central importance during and immediately following the transit of a brief coronary bolus. Ionic effects result largely from rapid transient washout of normal extracellular ions, but are also influenced by ions present in the CM. In particular, the calcium (Ca) and sodium (Na) ions controlling cardiac function are easily affected. The myocardial Na-Ca exchange, which is mainly a physiological mechanism for cellular Ca efflux during cardiac relaxation, is therefore highlighted in detail. The importance of avoiding a potential Na-Ca mismatch is shown by examples from basic physiology, cardiac surgery and coronary angiography and by results of experiments with Visipaque. In the isomolal and isotonic CM Visipaque, which is based on the dimer isodixanol (320 mg I/ml), an available osmolal space is filled with an appropriately balanced supplement consisting of NaCl (19mM) and CaCl2 (0.3 mM).

Animals↗
PubMed1995

Cardiac effects of iodixanol compared to those of other nonionic and ionic contrast media on the isolated rat heart.

This study was designed to compare the cardiac electrophysiology and mechanical effects of iodixanol to those of iotrolan, iopromide, ioxaglate and diatrizoate. Two consecutive injections of contrast media (CM) (0.3 g I/kg and 0.9 g I/kg b.w.) were given to spontaneously beating, Langendorff-perfused rat hearts. CM were given as a single, short-lasting bolus injection (i.e. over 2 and 5 s). Changes in aortic pressure, left ventricular pressures and ECG were continuously recorded during constant volume perfusion. The nonionic CM had less pronounced effects on aortic pressure than had the ionic media. The peak rate of isovolumetric contraction (LV dP/dt(max)) was slightly decreased by iodixanol and iotrolan, slightly more decreased by iopromide and markedly decreased by ioxaglate and diatrizoate. Similarly, the peak rate of pressure decline (LV dP/dt (min)) was only slightly decreased by iodixanol and iotrolan. Also, the 2 nonionic dimers had the smallest effects on the left ventricular end diastolic pressure (LVEDP) and heart rate. Ioxaglate lengthened the PQ-interval, but less so than diatrizoate. THe QT-interval was only slightly lengthened by iodixanol and iotrolan, as compared to the lenghthening caused by iopromide, ioxaglate and diatrizoate. Single ventricular extrasystoles were seen in all groups. Extrasystoles up to 3 coupled beats were registered after ioxaglate and diatrizoate. No episodes of ventricular fibrillation occurred with any CM. In conclusion, the nonionic dimers, and in particular iodixanol, induce only minor changes in cardiac function, whereas the ionic dimer ioxaglate and the ionic monomer diatrizoate induce pronounced effects.

Animals↗
PubMed1995

Absorption and excretion of iodixanol after intragastric administration to rats.

Absorption and excretion of iodixanol 320 mg I/ml were investigated in rats after intragastric administration of 2.5 g I/kg b.w. Animals were observed for up to 96 hours after treatment, and blood, urine and feces taken at several time-points throughout the experiment. Concentrations of iodixanol in serum and urine were measured by means of reversed-phase high-performance liquid chromatography. Fecal concentrations of iodixanol, based on iodine measurements, were determined by X-ray fluorescence spectrometry. Serial radiographs were obtained and histopathological examination was performed on selected tissues. The results indicate that less than 1% of the intragastric dose of iodixanol is absorbed from the intestine into the blood stream. No adverse clinical signs were observed, and there were no treatment-related histomorphological findings.

Animals↗
PubMed1995

Cardiac effects of adding electrolytes and oxygen to iohexol in a dog model of contrast media-induced ventricular fibrillation.

We investigated whether addition of a balanced electrolyte supplement and oxygen to the nonionic contrast medium iohexol reduces the risk of ventricular fibrillation (VF), and studied regional electrophysiology prior to the VF event. Twenty ml of each test solution were infused at a rate of 0.5 ml/s into the left anterior descending coronary artery (LAD) in 8 anesthetized dogs. LAD was externally occluded during infusion, to simulate a wedged catheter situation. ECG, hemodynamics, regional epicardial monophasic action potential duration (MAPD) and ventricular activation times (VAT) were calculated. All infusions with iohexol caused VF within 27 s. Five of 12 infusions with iohexol + 30 mmol NaCl, 3 of 11 infusions with iohexol+electrolytes (IPE) NaCl, KCl, CaCl2 and MgCl2) and 4 of 11 infusions with IPE with oxygen addition (IPE+O2) caused VF after 45 s. Iohexol did not change MAPD prior to the VF event. Iohexol + 30 mmol NaCl and the IPE solutions lengthened MAPD initially, but at the time of the VF event MAPD were normalized or shortened. We conclude that electrolyte supplement to iohexol may prevent VF, probably by lengthening MAPD.

Action Potentials↗
PubMed1994

Development and reversion of methionine dependence in a human glioma cell line: relation to homocysteine remethylation and cobalamin status.

We investigated the biochemical changes which accompanied the development and reversion of methionine dependence in a human glioma cell line GaMg. This cell line attained a higher proliferation rate and more malignant morphology with increasing passages in vitro. Early passages (P10, P25, and P45) were able to grow in a methionine-deficient medium supplemented with homocysteine (Met-Hcy+), while a later passage (P60) had lost this ability, i.e., it had become methionine-dependent. From P60 cells, a methionine-independent revertant (P60R) was established by exposing the cells to 5-aza-2-deoxycytidine, followed by culture in a Met-Hcy+ medium. In these genetically related cell lines, we investigated homocysteine remethylation and the functional state of cobalamin-dependent methionine synthase, the enzyme responsible for remethylation of homocysteine to methionine. The methionine synthase activity in cell extracts was similar in all cell sublines. Intact cell methionine biosynthesis and nitrous oxide-dependent homocysteine export reflect homocysteine remethylation in cells cultured in a Met-Hcy+ and methionine-containing (Met+Hcy-) medium, respectively. Both of these parameters, as well as the cellular content of the substrate 5-methyltetrahydrofolate, and the cofactor methylcobalamin, in addition to adenosylcobalamin, were high in P10, declined progressively in P45 and P60, and were restored in P60R. P25 cells had some unique features among the methionine-independent phenotypes because both homocysteine remethylation and the level of 5-methyltetrahydrofolate were low in Met+Hcy- medium. The maximal homocysteine export rate in the presence of nitrous oxide, which reflects the overall transmethylation rate, was high in P60 and even higher in P60R compared to the lower passages. The basis for development of methionine dependence during culture of this glioma cell line seems related to the combined effects of reduced methionine biosynthesis and an increased overall transmethylation rate. The single parameter which most closely correlated to the ability to use homocysteine for growth was methylcobalamin. These data support a model for methionine dependence, which implies impaired provision of cobalamin to methionine synthase.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
PubMed1994

Effect of bretylium tosylate on ventricular fibrillation threshold during hypothermia in dogs.

How bretylium tosylate affected the ventricular fibrillation threshold, electrophysiological parameters, and plasma catecholamine levels during hypothermia in dogs was studied. Threshold for ventricular fibrillation was determined by programmed electrical stimulation using a stimulation protocol that involved applying a maximum of five extrastimuli at body temperatures 37, 34, 31, 28, and 25 degrees C, and at the same temperatures during rewarming. Electrocardiogram, epicardial monophasic action potentials (MAP), and electrograms were recorded, and ventricular effective refractory period (VERP) was determined at each of the above temperatures. In one group (n = 7), a bolus dosage of bretylium tosylate (BT), 6 mg/kg body wt, was administered at 25 degrees C before rewarming. Another group (n = 4) was exposed to cooling and rewarming without addition of BT. Cooling to 25 degrees C reduced ventricular fibrillation threshold linearly, reduced heart rate, increased VERP and MAP, and slowed myocardial conduction velocity in both groups. There was no overall increase in plasma catecholamine levels during cooling. Addition of BT at 25 degrees C increased ventricular fibrillation threshold during rewarming compared with cooling. Addition of BT at 25 degrees C increased VERP by +/- 32 milliseconds and the corrected JT time by 0.06 +/- 0.02 seconds. VERP and JTc increased during rewarming with BT compared with cooling with no drug. BT had no effect on conduction velocity, and plasma catecholamine levels were not reduced. The antiarrhythmic effect of BT during hypothermia was attributed to an increased wavelength of refractoriness by its increase in the refractory period. This increased wavelength of refractoriness may prevent excitable gaps or increase circuit pathway in the setting of reentry arrhythmias.

Action Potentials↗
PubMed1994

Role of sodium addition to nonionic contrast medium in preventing ventricular fibrillation during coronary arteriography in dogs.

RATIONALE AND OBJECTIVES: We studied the effect of the addition of sodium to nonionic contrast medium (CM) on the incidence of ventricular fibrillation (VF) during coronary arteriography in dogs. METHODS: We infused 20 ml (0.5 ml/sec) of iohexol, iohexol plus 30 mmol of Na+ per liter, and NaCl-Ringer's acetate in randomized order through a wedged catheter placed in the right coronary artery (RCA) or in the left anterior descending coronary artery (LAD) in 12 anesthetized dogs. In addition to electrocardiographic and hemodynamic measurements, epicardial monophasic action potential durations and ventricular activation times were recorded during infusions into the LAD. RESULTS: All infusions with iohexol into the RCA and the LAD (n = 16) caused VF. Seven of 19 infusions with iohexol plus 30 mmol of Na+ per liter caused VF. Infusions with iohexol plus 30 mmol of Na+ per liter that did not cause VF lengthened monophasic action potential durations and increased ventricular activation times more in the CM-perfused area than in the control area. CONCLUSION: The addition of sodium to iohexol reduces the incidence of VF when infused through a wedged catheter. The protective mechanisms may be attributable to a lengthened repolarization phase and an increased activation time in the CM-perfused area.

Action Potentials↗
PubMed1994

Contrast media-induced ventricular fibrillation: an experimental study of the effects of dimeric contrast media during wedged catheter injection in dogs.

RATIONALE AND OBJECTIVES: We investigated the cardiac effects of an ionic dimer, ioxaglate and two nonionic dimers, iotrolan, and iodixanol. METHODS: During a simulated wedged catheter situation, 22 ml of each contrast medium was injected into the left anterior descending branch of the left coronary artery in seven open-chested, anesthetized dogs. RESULTS: Of 13 injections with each contrast medium, ioxaglate induced ventricular fibrillation in 11 after 34 +/- 5 sec, iotrolan in 6 after 42 +/- 4 sec, and iodixanol in 3 after 61 +/- 1 sec. Ioxaglate markedly lengthened monophasic action potential duration in contrast medium-perfused myocardium. Iotrolan, and iodixanol induced biphasic changes, first lengthening and then shortening action potential duration. The electrophysiological changes occurred later when using iodixanol. CONCLUSIONS: The risk of ventricular fibrillation during long-lasting contrast media exposure to the myocardium, as in a wedged catheter situation, appears to be much lower with iodixanol compared with ioxaglate and also lower than when using iotrolan.

Animals↗
PubMed1994

Prevention of some hypothermia induced electromechanical changes by calcium channel blockade.

OBJECTIVE: Cooling induces electromechanical changes in the heart. The aim of the study was to examine how the calcium channel blocker, nisoldipine (NIS), altered these changes compared to those induced by other drugs that shorten action potential duration such as tetrodotoxin and nicorandil. METHODS: Guinea pig papillary muscle action potentials and developed force were recorded using the conventional microelectrode technique and a force transducer. Restitution of action potential duration was determined by introducing extrastimuli at progressively longer diastolic intervals from 40 to 9000 ms. Preparations were divided into four groups: (1) no drug (control); (2) 1 microM tetrodotoxin, a sodium channel blocker; (3) 1 mM nicorandil, an ATP sensitive potassium channel activator; and (4) 1 microM nisoldipine (n = 6 in each group). Action potential duration and developed force were recorded after addition of drug at 37 degrees C, and at each 1 degree C change in temperature during cooling to 27 degrees C. The restitution protocol was performed at 37 degrees C and 27 degrees C. RESULTS: Tetrodotoxin had no effect on action potential duration at 90% of repolarisation (APD90) while nisoldipine and nicorandil greatly shortened APD90. Cooling from 37 degrees to 27 degrees C with nisoldipine produced less hypothermia induced lengthening in APD90 than in the other group. Developed force did not increase with reduction in temperature in the presence of nisoldipine. The range of premature action potential durations was defined as the difference in APD90 at diastolic interval of 40 and 100 ms. This range decreased with nisoldipine in contrast to the marked increases that occurred in the other groups during cooling. CONCLUSIONS: Increased intracellular Ca2+ might be responsible for the hypothermia induced increase in APD90, developed force, and range of premature action potential durations, since calcium channel blockade, which prevents an increase in intracellular Ca2+, greatly reduced these changes. The reduced range of premature action potential durations may reduce dispersion of ventricular refractoriness, and hence be expected to decrease hypothermia induced arrhythmias.

Action Potentials↗
PubMed1994

Preoperative methionine loading enhances restoration of the cobalamin-dependent enzyme methionine synthase after nitrous oxide anesthesia.

BACKGROUND: Prolonged exposure to nitrous oxide causes adverse effects mimicking those of cobalamin deficiency. This is explained by irreversible oxidation of cobalamin bound to the enzyme methionine synthase. The inactivation of methionine synthase by nitrous oxide in cultured human fibroblasts is decreased at high concentrations of methionine in culture medium. METHODS: We investigated the possible protection against cobalamin inactivation by preoperative methionine loading in patients undergoing nitrous oxide anesthesia. Fourteen patients receiving anesthesia for 75-230 min were included. Half of these patients received a peroral methionine loading dose 2 h before anesthesia. RESULTS: After nitrous oxide exposure, a considerable inactivation of methionine synthase in mononuclear white blood cells was seen in all patients, reaching a nadir after 5-48 h. In the patients not subjected to a methionine load, recovery of enzyme activity was not complete within 7 days. In the patients receiving a methionine load, the kinetics of inactivation of methionine synthase were similar, but the rate and extent of enzyme recovery was higher than in patients not receiving methionine, and in four patients, the enzyme activity even exceeded the preoperative level. The inactivation of methionine synthase was associated with a transient increase in plasma homocysteine, and the homocysteine concentration was still increased (mean 28.7%) 7 days after anesthesia in the patients not receiving methionine. A marked peak in homocysteine concentration was observed immediately after anesthesia in the methionine-loaded patients, but the homocysteine level was still increased (mean of 30.5%) after 7 days. The activity of the other cobalamin-dependent enzyme, methylmalonyl coenzyme A mutase, in the mononuclear white blood cells, and the serum concentration of the cobalamin marker methylmalonic acid, were not altered after nitrous oxide anesthesia or methionine loading or both. CONCLUSIONS: Our data suggest that short time exposure to nitrous oxide selectively impairs the function of the cobalamin-dependent methionine synthase. Furthermore, preoperative administration of methionine should be considered as a means to counteract adverse effects of nitrous oxide.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
PubMed1994

Methylmalonic acid and homocysteine in plasma as indicators of functional cobalamin deficiency in infants on macrobiotic diets.

Methylmalonic acid and total homocysteine in plasma and serum have previously been used as indicators of intracellular cobalamin function in adults. To assess the usefulness of quantitation of these metabolites in the diagnosis of dietary cobalamin deficiency in infants, they were determined in plasma from 41 infants (aged 10-20 mo) on a macrobiotic diet and in 50 healthy group-matched omnivorous controls. In the macrobiotic infants, both methylmalonic acid and total homocysteine were markedly increased compared with controls (8-fold and 2-fold, respectively). Both metabolites showed an inverse relation to the plasma cobalamin level. The very low cobalamin content of the macrobiotic diet and low plasma cobalamin in macrobiotic infants makes an impaired cobalamin function likely in these infants. We therefore used dietary group as an independent indicator of cobalamin status. Different test parameters for cobalamin status were evaluated by comparing their ability to discriminate between the two dietary groups. Logistic regression analysis showed that methylmalonic acid followed by total homocysteine and cobalamin, in that order, were the strongest predictors of dietary group. Mean corpuscular volume and Hb had low discriminative power. We conclude that the determination of methylmalonic acid and total homocysteine represents a sensitive and specific test for the diagnosis and follow-up of nutritional cobalamin deficiency in infants. Furthermore, the finding of high methylmalonic acid and total homocysteine in plasma of most macrobiotic infants demonstrates a functional cobalamin deficiency in these subjects.

Diet, Macrobiotic↗
PubMed1994

Experimental hypothermia: effects of core cooling and rewarming on hemodynamics, coronary blood flow, and myocardial metabolism in dogs.

Conflicting results have been reported as to the extent that cardiovascular function can be reestablished after rewarming from hypothermia. We measured hemodynamic function, myocardial metabolism and tissue water content in dogs core-cooled to 25 degrees C and later rewarmed. At 25 degrees C left ventricular (LV) systolic pressure (LVSP) was 54% +/- 4%, maximum rate of LV pressure rise (LV dP/dtmax) 44% +/- 5%, aortic pressure (AOP) 50% +/- 6%, heart rate (HR) 40% +/- 0%, cardiac output (CO) 37% +/- 5%, myocardial blood flow (MBF) 34% +/- 5%, and myocardial oxygen consumption (MVO2) 8% +/- 1%, compared to precooling. Stroke volume (SV) and LV end-diastolic pressure (LVEDP) were unchanged. As normothermia (37 degrees C) was reestablished, the depression of cardiac function and myocardial metabolism remained the same as that at 25 degrees C: LVSP 71% +/- 6%, LV dP/dtmax 73% +/- 7%, SV 60% +/- 9%, AOP 70% +/- 6%, CO 57% +/- 9%, MBF 53% +/- 8%, and MVO2 44% +/- 8% HR, in contrast, recovered to precooling values. The arterial concentrations of glucose and free fatty acids (FFA) did not change significantly during the experimental period, whereas an increase in lactate of nonmyocardial origin appeared after rewarming. Increased myocardial contents of creatine phosphate and water were found during both hypothermia and rewarming. The present study demonstrates a persistent depression of cardiac function after hypothermia and rewarming in spite of adequate energy stores. Thus, a direct influence on myocardial contractile function by the cooling and rewarming process is suggested.

Adenosine Triphosphate↗
PubMed1994

Cardiac effects of coronary arteriography with electrolyte addition to iohexol. A study in dogs with and without heart failure.

Electrolyte addition to nonionic contrast media has been suggested to further reduce the incidence of ventricular fibrillation during coronary arteriography. The present study was designed to investigate the effects of adding 30 mM NaCl, 0.9 mM KCl, 0.15 mM CaCl2 and 0.1 mM MgCl2 to iohexol on cardiac electrophysiology and hemodynamics (iohexol+electrolytes = IPE). Contrast media were injected into the left main coronary artery in 9 open-chest, anesthetized dogs before and after induction of acute ischemic heart failure. IPE increased left ventricular inotropy (LV dP/dtmax) with no initial decrease, even during heart failure. During heart failure IPE induced the same hemodynamic effects as iohexol without electrolyte addition. IPE slightly lengthened epicardial monophasic action potential duration before heart failure. We conclude that IPE appears to be well tolerated hemodynamically. The electrophysiologic differences between IPE and iohexol are small when the injection time is not longer than 5 s.

Animals↗
PubMed1993

Proliferation, migration and invasion of human glioma cells exposed to antifolate drugs.

The present study describes the effects of 2 folate antagonists, methotrexate (MTX) and the lipophilic antifolate trimetrexate (TMX) on 2 permanent human glioma cell lines (GaMg and D-54Mg) grown as monolayers and as multicellular tumor spheroids. In addition, the effects of drug exposure on tumor cell invasion was studied using a three-dimensional organ co-culture system. In monolayer cultures, TMX was a more potent inhibitor of cell growth than MTX, especially towards the GaMg cell line. The 2 drugs, however, showed similar cytotoxicity as assessed by the plating efficiency assay. Reduced ability of directional migration of cells on a plastic surface was seen by either antifolate usually at concentrations to 10-fold higher than those exerting a cytotoxic effect in the plating efficiency assay. TMX was somewhat more potent than MTX as an inhibitor of spheroid growth. When tumor spheroids were exposed to MTX or TMX at concentrations that caused 65 to 70% inhibition of cell migration, there was a latent period of 4 to 5 days before inhibition of spheroid growth ensued. Invasion was investigated in a co-culture system, where tumor spheroids were confronted with fetal rat brain cell aggregates. Neither drug reduced tumor cell invasion, although histological examination revealed toxic effects both in GaMg and in D-54Mg spheroids. We conclude that spheroids from human glioma cells were less sensitive to the antifolates than monolayers. For both drugs a latency period was observed before inhibition of spheroid growth. The spheroids retained their ability to invade normal brain tissue when exposed to levels of folate antagonists inhibiting spheroid growth.

Animals↗
PubMed1993

Effects of temperature on cycle length dependent changes and restitution of action potential duration in guinea pig ventricular muscle.

OBJECTIVE: The aim was to investigate the effects of temperature on cycle length dependent changes of action potential duration and on restitution of action potential duration. METHODS: Guinea pig papillary muscle action potentials were recorded using conventional microelectrode techniques. Action potential duration was measured at cycle lengths ranging from 500 to 2000 ms at both 27 degrees C and 37 degrees C. Restitution of action potential duration was determined by introducing an extra stimulus at progressively longer diastolic intervals from 40 to 9000 ms at pacing cycle lengths of 500, 1000, and 2000 ms. RESULTS: At 37 degrees C, action potential duration measured at 90% of repolarisation (APD90) during continuous pacing and the maximum value of APD90 achieved during restitution (APD90pl) decreased by 18(SEM 6) ms (n = 7) and 24(7) ms (n = 6), respectively, when pacing cycle length was reduced from 2000 to 500 ms. At 27 degrees C, the magnitude of the shortening of APD90 and APD90pl observed when pacing cycle length was similarly reduced was greater than at 37 degrees C, ie, 143(21) ms (n = 6) and 115(11) ms (n = 6), respectively. Thus the relation for restitution of action potential duration shifted downwards with reduction in pacing cycle length, and the magnitude of this shift was greater at 27 degrees C than at 37 degrees C. The difference between APD90 at the shortest diastolic interval (40 ms) and at diastolic interval of 100 ms (range of premature action potential durations) was much greater at 27 degrees C than at 37 degrees C at all three pacing cycle lengths. CONCLUSIONS: Reduction in temperature magnifies the cycle length dependent changes in action potential duration both during abrupt changes in cycle length, as with an extra stimulus, and during changes of steady state cycle length. This may indicate a greater dispersion of premature action potential durations during hypothermia, and hence predispose to hypothermia induced arrhythmias.

Action Potentials↗
PubMed1993

Repeated intracoronary injections of contrast media. Additive hemodynamic and electrophysiologic effects in a dog model.

RATIONALE AND OBJECTIVES: Coronary arteriography in patients implies several selective injections into the coronary arteries. The authors investigate whether repeated injections cause additive cardiac hemodynamic and electrophysiologic effects in dogs. METHODS: Five repeated injections of 5 mL iohexol (Omnipaque 350 mgI/mL, Nycomed Imaging AS, Oslo, Norway), ioxaglate (Hexabrix 320 mgI/mL, Laboratory Guerbet, Cedex, France), and sodium meglumine-diatrizoate (Renografin-76 370 mgI/mL, Squibb Diagnostics, Princeton, NJ) were given into the left coronary artery in 7 anesthetized dogs and were compared with the effects after a 5 mL single injection of the same medium. Left ventricular (LV) pressures, LV dP/dtmax (inotropy) and epicardial monophasic action potential were recorded, from which monophasic action potential duration (MAPD) was measured. RESULTS: Repeated injections of ioxaglate and sodium meglumine-diatrizoate did not potentiate initial decrease in LV pressures and inotropy, but the secondary increase in LV inotropy increased more after repeated injections than after a single injection. Repeated injections of iohexol increased LV inotropy more than a single injection. All contrast media prolonged MAPD more after repeated injections than after single injections. MAPD was prolonged 30 sec after the last injection. CONCLUSION: Repeated injections of contrast media cause greater cardiac hemodynamic and electrophysiologic effects than a single injection during selective coronary arteriography.

Action Potentials↗
PubMed1993

Mechanisms for hypothermia-induced increase in contractile force studied by mechanical restitution and post-rest contractions in guinea-pig papillary muscle.

Lowering myocardial temperature increases contractile force, presumably by increasing intracellular calcium content. To study the mechanisms behind this, we compared the effects of some known inotropic interventions with hypothermia on mechanical restitution and post-rest contractile force in isolated guinea-pig papillary muscles. In four groups (n = 6 per group), the effects of: (1) reducing the ability for Na/Ca exchange to extrude Ca2+ (a) by increasing [Na+]i with ouabain or (b) by increasing [Ca2+]o; and (2) activation of calcium channels with Bay-K 8644, were compared with lowering temperature from 37 to 27 degrees C. Normally (at 37 degrees C and 2 mM CaCl2), mechanical restitution could be described by a rapid recovery phase with a time constant between 180 and 220 ms, followed by a slowly decaying phase with a time constant between 5000 and 8000 ms and post-rest contractions (1-10 min rest) were markedly depressed compared to steady-state contractions. Steady-state developed force was markedly increased at 27 degrees C, after 1 microM ouabain, 6 mM CaCl2 or 0.1 microM Bay-K 8644. At 27 degrees C the rapid recovery phase of restitution was delayed while the slowly decaying phase was not affected. Ouabain and increased [Ca2+]o caused elevation of the slowly decaying phase of restitution and markedly attenuated the post-rest depression of developed force, which may be attributed to a reduced diastolic extrusion of Ca2+ via the Na/Ca exchanger. Hypothermia and Bay-K 8644 on the other hand, augmented this post-rest depression. Hence, this study suggests that increased Ca2+ influx due to delayed inactivation of calcium channels may account for the increased developed force during hypothermia rather than reduced diastolic extrusion of Ca2+ via the Na/Ca exchanger.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗