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This work presents the preliminary results obtained with a high-resistivity magnetic Czochralski (MCz) silicon diode processed at the Helsinki Institute of Physics as a high-dose gamma dosimeter in radiation processing. The irradiation was performed using a 60 Co source (Gammacell 220, MDS Nordion) within total doses from 100 Gy up to 3 kGy at a dose rate of 3 kGy/h. In this interval, the dosimetric response of the diode is linear with a correlation coefficient ( r 2 ) higher than 0.993. However, without any irradiation procedure, the device showed a small sensitivity dependence on the accumulated dose. For total dose of 3 kGy, the observed decrease was about 2%. To clarify the origin of this possible radiation damage effect, some studies are under way.

Background Dysrhythmias and death occur in patients with acquired long QT syndrome (LQTS). Little information exists regarding interactions between anesthetics and drugs that prolong ventricular repolarization. Therefore the effects of three commonly used intravenous anesthetics on ventricular repolarization were investigated in the setting of drug-induced, long QT syndrome. Methods The effects of increasing concentrations (0, 10, 25, and 50 microM) of propofol, ketamine, and thiopental on ventricular repolarization were evaluated by measuring the monophasic action potential duration at 90% repolarization (MAPD90) in guinea pig Langendorff-perfused hearts in the absence or presence of erythromycin (100 microM). If an anesthetic enhanced erythromycin-induced prolongation of MAPD90, its effects on the delayed rectifier (I[K]) and inward rectifier (I[Kl]) potassium currents were measured using the whole-cell patch-clamp technique. Results At clinically relevant concentrations, only thiopental significantly modulated erythromycin's effect on MAPD90. Thiopental at 10, 25, and 50 microM prolonged MAPD90 from a control of 163 +/- 6 ms by 18 +/- 4, 30 +/- 3, and 31 +/- 4 ms, respectively. In a separate group, erythromycin prolonged MAPD90 from 155 +/- 2 ms to 171 +/- 2 ms (n = 21, P < 0.001). In the presence of erythromycin, thiopental at 10, 25, and 50 microM caused significantly greater prolongation from a control of 171 +/- 2 ms by 39 +/- 2, 58 +/- 3, and 72 +/- 6 ms, respectively. Whole-cell patch-clamp experiments indicated that thiopental inhibited I(K) and I(Kl). Conclusions Intravenous anesthetics caused markedly different effects on ventricular repolarization. Thiopental, unlike propofol and ketamine, potentiated the effects of erythromycin on ventricular repolarization by inhibiting I(K) and I(Kl).

Background Supraventricular tachydysrhythmias such as atrial fibrillation frequently complicate the perioperative period. Two electrophysiologic factors critical to the pathogenesis of supraventricular tachydysrhythmias are: 1) atrial wavelength, the product of atrial conduction velocity (CV) and effective refractory period (ERP), and 2) atrioventricular nodal conduction. Modulation of these factors by drugs has important clinical ramifications. The authors studied the effects of propofol, thiopental, and ketamine on atrial wavelength and atrioventricular nodal function in guinea pig isolated atrial trabeculae and hearts, respectively. Methods Electrocardiogram recordings in superfused atrial tissue were obtained using hanging microelectrodes. A stimulating and two recording electrodes were placed on a single atrial trabecula, and the interelectrode distance was measured. Atrial ERP determinations were made using a premature stimulus protocol. The time (t) required for a propagated impulse to traverse the interelectrode distance (d) was measured. Conduction velocity was calculated as d/t. Langendorff-perfused guinea pig hearts were instrumented for low atrial pacing (cycle length = 300 ms) and for measurements of stimulusto-His bundle interval, an index of atrioventricular nodal conduction. To investigate the frequency-dependent behavior of the atrioventricular node, computer-based measurements were made of Wenckebach cycle length (WCL) and atrioventricular nodal ERP. Results Thiopental significantly prolonged atrial ERP in a concentration-dependent manner, whereas propofol and ketamine had no significant effect on atrial refractoriness. In contrast, ketamine caused a dose-dependent decrease in atrial CV, but propofol and thiopental had no significant effect on CV. Therefore, thiopental, ketamine, and propofol caused an increase, a decrease, and no change, respectively, in atrial wavelength. All anesthetics caused a concentration-dependent prolongation of the stimulus-to-His bundle interval, atrioventricular nodal ERP, and WCL. However, on an equimolar basis, significant differences in potencies were found. The concentrations of drug that caused a 20% increase in ERP (ERP20) and WCL (WCL20) for propofol, thiopental, and ketamine were 14 +/- 2 microM, 26 +/- 3 microM, and 62 +/- 11 microM, and 17 +/- 2 microM, 50 +/- 1 microM, and 123 +/- 19 microM (mean +/- SEM), respectively. Therefore, the rank order of potency for frequency-dependent atrioventricular nodal effects is propofol > thiopental > ketamine. Conclusion The authors' results indicate that propofol would be most effective at filtering atrial impulses during supraventricular tachydysrhythmias, whereas thiopental would be most effective at preventing atrial reentrant dysrhythmias. In contrast, ketamine may be most likely to promote atrial reentry while having minimal effect on atrioventricular nodal conduction.

Survival after the rupture of the both mitral and tricuspid valves in blunt thoracic trauma is uncommon and requires prompt diagnosis and treatment. We present a case in which transesophageal echocardiography performed in the operating room by the anesthesiologist identified the etiology of hemodynamic instability and facilitated successful emergency replacement of both valves.

Supraventricular tachydysrhythmias such as atrial fibrillation frequently complicate the perioperative period. Two electrophysiologic factors critical to the pathogenesis of supraventricular tachydysrhythmias are: 1) atrial wavelength, the product of atrial conduction velocity (CV) and effective refractory period (ERP), and 2) atrioventricular nodal conduction. Modulation of these factors by drugs has important clinical ramifications. The authors studied the effects of propofol, thiopental, and ketamine on atrial wavelength and atrioventricular nodal function in guinea pig isolated atrial trabeculae and hearts, respectively.Electrocardiogram recordings in superfused atrial tissue were obtained using hanging microelectrodes. A stimulating and two recording electrodes were placed on a single atrial trabecula, and the interelectrode distance was measured. Atrial ERP determinations were made using a premature stimulus protocol. The time (t) required for a propagated impulse to traverse the interelectrode distance (d) was measured. Conduction velocity was calculated as d/t. Langendorff-perfused guinea pig hearts were instrumented for low atrial pacing (cycle length = 300 ms) and for measurements of stimulusto-His bundle interval, an index of atrioventricular nodal conduction. To investigate the frequency-dependent behavior of the atrioventricular node, computer-based measurements were made of Wenckebach cycle length (WCL) and atrioventricular nodal ERP.Thiopental significantly prolonged atrial ERP in a concentration-dependent manner, whereas propofol and ketamine had no significant effect on atrial refractoriness. In contrast, ketamine caused a dose-dependent decrease in atrial CV, but propofol and thiopental had no significant effect on CV. Therefore, thiopental, ketamine, and propofol caused an increase, a decrease, and no change, respectively, in atrial wavelength. All anesthetics caused a concentration-dependent prolongation of the stimulus-to-His bundle interval, atrioventricular nodal ERP, and WCL. However, on an equimolar basis, significant differences in potencies were found. The concentrations of drug that caused a 20% increase in ERP (ERP20) and WCL (WCL20) for propofol, thiopental, and ketamine were 14 +/- 2 microM, 26 +/- 3 microM, and 62 +/- 11 microM, and 17 +/- 2 microM, 50 +/- 1 microM, and 123 +/- 19 microM (mean +/- SEM), respectively. Therefore, the rank order of potency for frequency-dependent atrioventricular nodal effects is propofolthiopentalketamine.The authors' results indicate that propofol would be most effective at filtering atrial impulses during supraventricular tachydysrhythmias, whereas thiopental would be most effective at preventing atrial reentrant dysrhythmias. In contrast, ketamine may be most likely to promote atrial reentry while having minimal effect on atrioventricular nodal conduction.

In this study the acute effects of ATI-2001, a recently developed ester derivative of amiodarone, on heart rate, atrioventricular conduction and frequency-dependent prolongation of ventricular conduction, repolarization and refractoriness were investigated in guinea pig isolated heart. Compared with amiodarone, an equimolar concentration of ATI-2001 (1 microM) caused significantly greater slowing of heart rate, depression of atrioventricular and intraventricular conduction and prolongation of ventricular repolarization. Unlike amiodarone, the effects of ATI-2001 were significantly reversed during washout of the drug. ATI-2001 exhibited frequency-independent effects on ventricular repolarization and refractoriness. It prolonged base-line ventricular monophasic action potential duration by 10%, 8%, 9% and 9% and ventricular effective refractory period by 24%, 20%, 22% and 26% at cycle lengths of 350, 300, 250 and 200 msec, respectively. Thus, ATI-2001 (1 microM) increased the ventricular effective refractory period/action potential duration ratio, suggesting both time- and voltage-dependent prolongation of ventricular refractoriness. In addition, ATI-2001 lengthened ventricular conduction times (QRS interval and basic conduction time) significantly more at shorter cycle lengths. Conversely, d-sotalol, a pure class III antiarrhythmic agent, had no effect on ventricular conduction times and exhibited a reverse frequency-dependent effect on ventricular repolarization. In summary, the electrophysiological effects of ATI-2001 were greater and more rapidly reversible than those of amiodarone. The lack of reverse frequency-dependent effects on ventricular repolarization and refractoriness suggests that ATI-2001 may be more efficacious than d-sotalol or other pure class III drugs in treating ventricular tachycardias and less likely to become proarrhythmic at normal or slow heart rates.

The interaction of micromolar concentrations of palmitic and oleic acids with the sarcoplasmic reticulum membrane was studied by electron microscopic techniques in an attempt to define their different effects on ATP-induced calcium sequestration in sarcoplasmic reticulum vesicles. Oleic acid had a concentration-dependent effect on the morphology of sarcoplasmic reticulum vesicles, promoting vesicle fusion and eventual solubilization. Palmitic acid did not alter the morphology of sarcoplasmic reticulum, but its probable site(s) of interaction could be determined. In the presence of palmitic acid, large lamellar structures that formed external to sarcoplasmic reticulum vesicles are probably composed of pure palmitic acid and/or palmitic acid/phospholipid mixed "micelles," but internalization of palmitic acid into sarcoplasmic reticulum vesicles was not detected. Palmitic acid reduced the phospholipid content of sarcoplasmic reticulum membranes with a preservation of the average interparticle protein spacing as observed in freeze-fracture electron micrographs. Thus, palmitic acid appears to be incorporated into the sarcoplasmic reticulum lipid bi-layer. Oleic acid inhibition of ATP-induced calcium sequestration by sarcoplasmic reticulum vesicles is probably caused by net permeability changes of the membrane. A structural mechanism for palmitic acid stimulation of ATP-induced calcium sequestration is proposed in light of the probable insertion of palmitic acid into the sarcoplasmic reticulum lipid bilayer.

The distribution of calcium in lamellar phases of dipalmitoyllecthin (DPPC) multilayers was directly determined by neutron diffraction and stable isotope substitution of 44Ca for 40Ca. A significant resonance effect on the intensities of the lamellar diffraction pattern was observed for millimolar concentrations of these calcium isotopes. The calcium difference profile indicated that calcium was localized in the phospholipid headgroup region, being excluded from the hydrocarbon core as was water separately determined from the water profile structure obtained by H2O/D2O exchange. A reciprocal space analysis of the difference structure factors indicated that calcium binds preferentially to within 1–2 A of the phosphate moiety of the phospholipid head groups of the DPPC bilayer.

Mechanical alternans developed spontaneously in 5 of 17 right ventricular papillary muscles from atherosclerotic rabbits. The rabbits had eaten an atherogenic diet of 5% lard, 5% peanut oil, 0.5% cholesterol, and 89.5% rabbit pellets for 116-184 days. In one muscle mechanical alternans developed slowly and persisted. When the condition had developed fully, in the weaker contraction the muscle shortened only 20% as far when contracting isotonically and developed only 38% as much tension when contracting isometrically. Added to the superfusate, calcium (5.0 mM) or norepinephrine (1.5 X 10(-5) M) abolished the alternans. In four muscles mechanical alternans was only temporary. Compared with the 12 muscles that did not develop alternans, these 4, when contracting isometrically 12 times/min but not in alternans, had longer latency and required more time to develop tension at the maximum rate and to develop peak tension. Contracting isotonically, they required more time to accelerate to maximum velocity of shortening and to shorten maximally. Raising the contraction frequency to 24/min decreased the differences in performance between the two groups. Norepinephrine (1.5 X 10(-5) M) made the differences smaller still. We think that both the mechanical alternans and the differences in performance between the muscles that developed alteranans and those that did not resulted from a defect in the cardiac cell's handling of calcium. Diet-induced changes in the lipid composition of the sarcoplasmic reticulum or sarcolemma or both seem probable causes.

The nonspecific interactions of propranolol, timolol, and ethanol with model and sarcoplasmic reticulum membranes were determined utilizing radioisotopic association, differential scanning calorimetry, and neutron diffraction. Differential scanning calorimetry performed on mixtures of these amphiphilic compounds and model membrane bilayers composed of dimyristoyllecithin showed that propranolol was approximately 25 times more lipid-soluble than timolol and at least 100 times more lipid-soluble than ethanol. Neutron diffraction showed that the solvation of propranolol was within the fatty acyl chain region of the lipid bilayer. This solvation correlated with the effect of propranolol to inhibit ATP-dependent calcium transport in isolated rabbit skeletal muscle sarcoplasmic reticulum, a membrane that lacks β-adrenergic receptors. In contrast, the major site of interaction of ethanol was within the aqueous compartment hydrating the sarcoplasmic reticulum membrane. A model for nonspecific drug interaction with the sarcoplasmic reticulum membrane based on the site of interaction of these amphiphiles and their relative potencies to inhibit calcium transport by these membranes is proposed. In principle, this model could be extended to specific drug interactions with membranes.

The nonspecific interactions of propranolol, timolol, and ethanol with model and sarcoplasmic reticulum membranes were determined utilizing radioisotopic association differential scanning calorimetry, and neutron diffraction. Differential scanning calorimetry performed on mixtures of these amphiphilic compounds and model membrane bilayers composed of dimyristoyllecithin showed that propranolol was approximately 25 times more lipid-soluble than timolol and at least 100 times more lipid-soluble than ethanol. Neutron diffraction showed that the solvation of propranolol was within the fatty acyl chain region of the lipid bilayer. This solvation correlated with the effect of propranolol to inhibit ATP-dependent calcium transport in isolated rabbit skeletal muscle sarcoplasmic reticulum, a membrane that lacks beta-adrenergic receptors. In contrast, the major site of interaction of ethanol was within the aqueous compartment hydrating the sarcoplasmic reticulum membrane. A model for nonspecific drug interaction with the sarcoplasmic reticulum membrane based on the site of interaction of these amphiphiles and their relative potencies to inhibit calcium transport by these membranes is proposed. In principle, this model could be extended to specific drug interactions with membranes.

To determine the effect atherosclerosis has on myocardial contractility, we studied the contractile properties of right ventricular papillary muscles from 34 atherosclerotic and 17 control rabbits. We produced atherosclerosis by feeding for 2 to 8 months a diet of 5% lard, 5% peanut oil, 0.5% cholesterol, and 89.5% rabbit pellets. The controls received only rabbit pellets during the same time interval. Contracting isometrically 12 times per minute at 25 degrees C, muscles from the atherosclerotic rabbits developed tension at a lower maximum rate (max dT/dt), had a longer latency, and required longer to develop tension at the maximum rate and to develop peak tension. In isotonic contractions, they shortened with lower maximum velocities and required longer to accelerate to maximum velocity and to shorten maximally. We found no evidence that developed tension or distance shortened differed between the two groups of muscles. Raising the contraction frequency to 24 contractions per minute between the two groups of muscles. Raising the contraction frequency to 24 contractions per minute brought performance of the two groups of muscles closer in both types of contraction. Norepinephrine (1.5 x 10-5 M) nearly abolished differences between performance of the two groups. The loss of contractility correlates poorly with coronary and aortic atherosclerosis. It occurred early in the feeding of the atherogenic diet. We think it was due to a lipid-induced defect in the cardiac cell's handling of calcium.

The interaction of micromolar concentrations of palmitic and oleic acids with the sarcoplasmic reticulum membrane was studied by electron microscopic techniques in an attempt to define their different effects on ATP-induced calcium sequestration in sarcoplasmic reticulum vesicles. Oleic acid had a concentration-dependent effect on the morphology of sarcoplasmic reticulum vesicles, promoting vesicle fusion and eventual solubilization. Palmitic acid did not alter the morphology of sarcoplasmic reticulum, but its probable site(s) of interaction could be determined. In the presence of palmitic acid, large lamellar structures that formed external to sarcoplasmic reticulum vesicles are probably composed of pure palmitic acid and/or palmitic acid/phospholipid mixed "micelles," but internalization of palmitic acid into sarcoplasmic reticulum vesicles was not detected. Palmitic acid reduced the phospholipid content of sarcoplasmic reticulum membranes with a preservation of the average interparticle protein spacing as observed in freeze-fracture electron micrographs. Thus, palmitic acid appears to be incorporated into the sarcoplasmic reticulum lipid bi-layer. Oleic acid inhibition of ATP-induced calcium sequestration by sarcoplasmic reticulum vesicles is probably caused by net permeability changes of the membrane. A structural mechanism for palmitic acid stimulation of ATP-induced calcium sequestration is proposed in light of the probable insertion of palmitic acid into the sarcoplasmic reticulum lipid bilayer.