[Traffic medicine in rehabilitation]. / Verkehrsmedizin in der Rehabilitation.

Participation in road traffic in Germany is governed by various laws and acts. Physicians are obliged to decide whether, in the presence of medical conditions and handicaps, a patient is fit to drive a car safely. Following myocardial infarction this decision is generally made by specialized cardiologists (specialization in social medicine) in rehabilitation centers. If a patient does not undergo rehabilitation after an acute event, this decision must be made by the invasive cardiologist, who is often not skilled in this kind of assessment. The second problem faced in Germany is the discrepancy between outdated legal regulations, modern cardiology and the current standard of medical knowledge, especially in terms of treatment for acute coronary syndrome. According to current legal regulations, no patient at all is allowed to drive a car in Germany after any form of myocardial infarction, regardless of ejection fraction, for at least 3 months. In contrast, a working group for the German Society of Cardiology published a position paper in 2010 in which patients could be allowed to drive a car 2 weeks after an AMI with an EF >30. The third problem in this context in Germany is that, due to a decision by the Federal High Court of Justice, physicians are not only responsible to inform the patient, if he is not allowed to drive a car, but also have to assure that he does not leave the hospital or practice by car, if he is not allowed to. If the patient however opposes, drives home and has an accident, the physician is liable for the damages. The fourth and final problem lies in the fact that most cardiologists in Germany are neither skilled in legal traffic assessment, nor are they familiar with this field and its problems.

Testosterone modulates cardiomyocyte Ca(2+) handling and contractile function.

The extent to which sex differences in cardiac function may be attributed to the direct myocardial influence of testosterone is unclear. In this study the effects of gonadal testosterone withdrawal (GDX) and replacement (GDX+T) in rats, on cardiomyocyte shortening and intracellular Ca(2+) handling was investigated (0.5 Hz, 25 oC). At all extracellular [Ca(2+)] tested (0.5-2.0 mM), the Ca(2+) transient amplitude was significantly reduced (by approximately 50 %) in myocytes of GDX rats two weeks post-gonadectomy. The time course of Ca(2+) transient decay was significantly prolonged in GDX myocytes (tau, 455+/-80 ms) compared with intact (279+/-23 ms) and GDX+T (277+/-19 ms). Maximum shortening of GDX myocytes was markedly reduced (by more than 60 %) and relaxation significantly delayed (by more than 35 %) compared with intact and GDX+T groups. Thus testosterone replacement completely reversed the cardiomyocyte hypocontractility induced by gonadectomy. These results provide direct evidence for a role of testosterone in regulating functional Ca(2+) handling and contractility in the heart.

Stimulus interval-dependent differences in Ca2+ transients and contractile responses of diabetic rat cardiomyocytes.

OBJECTIVE: The aim of this study was to gain further insights into the consequences of insulin-dependent diabetes mellitus on cardiomyocyte calcium handling. METHODS: The effects of steady state and transient changes in stimulus frequency on the intracellular Ca2+ transient and cell shortening were examined in left ventricular cardiomyocytes isolated from the hearts of control and streptozotocin-induced diabetic rats. RESULTS: During steady state stimulation diabetic rat cardiomyocytes displayed a slower decay of the Ca2+ transient and longer times for maximum cell shortening and re-lengthening. At 1.5 mM extracellular [Ca2+], increasing stimulus frequency over the range 0.2-1.0 Hz led to an increase in resting and peak [Ca2+]i as well as the amplitude of the transient in both the control and diabetic groups. At frequencies greater than 0.4 Hz the amplitude of the transient was significantly depressed in diabetic rat cells and this was not normalized by increasing extracellular [Ca2+] to 2.5 mM. Recovery of sarcoplasmic reticulum (SR) Ca2+ release was measured from the time course of restitution of the intracellular Ca2+ transient. In both control and diabetic rat cardiomyocytes recovery of the transient occurred in two phases. In diabetic rat myocytes, the initial rapid phase of restitution at intervals <1 s was markedly slowed. The fraction of Ca2+ recirculating between the SR and the cytosol was estimated from the decline in amplitude of transients following post-rest potentiation. There was no difference in this fraction between control and diabetic rat cells either at 1.5 or 2.5 mM extracellular [Ca2+]. CONCLUSION: The blunted frequency response of diabetic rat cardiomyocytes at frequencies greater than 0.4 Hz is consistent with reduced SR Ca2+ uptake leading to reduced SR Ca2+ content and subsequent release. At stimulus intervals greater than 1 Hz this is likely to be exacerbated by slower recovery of SR Ca2+ release. Despite the evidence for depressed SR Ca2+ uptake, the relative amount of Ca2+ recirculating within diabetic rat cardiomyocytes remains unaltered. This is most likely due to an accompanying reduction in Ca2+ efflux from the cell due either to depressed Na+/Ca2+ exchanger activity, or an elevation in intracellular Na+ levels.

Effects of cyclopiazonic acid on [Ca2+]i and contraction in rat urinary bladder smooth muscle.

Cyclopiazonic acid (CPA) has been reported to inhibit the Ca(2+)-ATPase of the sarcoplasmic reticulum (SR) in skeletal and smooth muscle. In the present study the effect of CPA on [Ca2+]i and force in rat urinary bladder smooth muscle was examined. The fluorescent Ca2+ indicator Fura-2 was used to monitor intracellular Ca2+, simultaneously with isometric force production. Addition of CPA to unstimulated muscles bathed in 2.5 mM Ca2+ containing Krebs solution resulted in a significant and sustained increase in [Ca2+]i from 99 +/- 7 to 273 +/- 51 nM. This increase in [Ca2+]i was dependent upon the presence of extracellular Ca2+ since when CPA was added to muscles in Ca(2+)-free media it produced only a small, transient increase in [Ca2+]i that was not sustained. Peak force levels produced by transmural stimulation, carbachol and high KCl solution were not altered by the presence of CPA, however, the increase in [Ca2+]i associated with these contractions was larger when CPA was present. In response to transmural stimulation, the times taken for both force and [Ca2+]i to rise to 50% of their peak values were attenuated in the presence of CPA. Conversely, there was no effect of CPA on the times taken for force or [Ca2+]i to fall to 50% of their stimulated values upon the cessation of stimulation. Under control conditions both carbachol and high KCl could initiate transient increases in [Ca2+]i and force in the absence of extracellular Ca2+. In the presence of CPA, the response to carbachol was virtually completely inhibited, however, the response to high KCl was only partially inhibited. The ability of CPA to inhibit the carbachol response in Ca(2+)-free media suggests that this response is due to release of Ca2+ from the SR. The incomplete inhibition of the response to KCl indicates other Ca2+ storage sites may also be mobilised by sarcolemmal depolarisation. Although the mechanism whereby CPA induces a large, sustained rise in [Ca2+]i remains unknown, the data lend support to the suggestion that depletion of intracellular Ca2+ storage sites may activate a Ca2+ entry pathway across the sarcolemma.

Force and intracellular Ca2+ during cyclic nucleotide-mediated relaxation of rat anococcygeus muscle and the effects of cyclopiazonic acid.

1. Simultaneous recordings of tension and [Ca2+]i were made in rat anococcygeus muscle strips to investigate possible mechanisms involved during cyclic nucleotide-mediated relaxation. Relaxation of pre-contracted muscles was induced by sodium nitroprusside (SNP) or forskolin and the effects of cyclopiazonic acid (CPA) on these responses were examined. 2. In muscles pre-contracted with 0.2 microM phenylephrine addition of SNP (10 microM) caused a rapid and near complete relaxation of force. This was accompanied by a decrease in [Ca2+]i, however, this was not of a comparable magnitude to the decrease in force. The level of [Ca2+]i in muscles relaxed with SNP was shown to be associated with substantially higher force levels in the absence of SNP. Forskolin (10 microM) caused a slower, essentially complete relaxation which was associated with a proportional decrease in [Ca2+]i. 3. In muscles pretreated with SNP or forskolin subsequent responses to phenylephrine were attenuated with both force and [Ca2+]i rising slowly to attain eventually levels similar to those observed when the relaxant was applied to pre-contracted muscles. 4. Exposure of the muscles to the sarcoplasmic reticulum Ca(2+)-ATPase inhibitor, CPA (10 microM), resulted in a sustained increase in [Ca2+]i which, in most cases, was not associated with any force development. The relaxation and decrease in [Ca2+]i in response to both SNP and forskolin were attenuated and substantially slowed in the presence of CPA. Overall the extent of this attenuation was greater for SNP. For both SNP and forskolin, CPA attenuated the decrease in [Ca2+]i to a greater extent than the decrease in force. In some cases, SNP-mediated relaxation in the presence of CPA was observed with almost no detectable change in [Ca2+]i. 5. The results suggest that, in the rat anococcygeus muscle under normal circumstances, a lowering of [Ca2+]i can fully account for the relaxation induced by forskolin but not for that induced by SNP, where mechanisms independent of changes in [Ca2+]i appear to contribute. Whilst Ca2+ sequestration into the sarcoplasmic reticulum plays a role in the relaxation mediated by both SNP and forskolin other Ca2+ lowering mechanisms may also be involved, especially in the response to forskolin.

Force, membrane potential and cytoplasmic Ca2+ responses to cyclic nucleotides in rat anococcygeus muscle.

Simultaneous recordings of membrane potential and force, and cytoplasmic calcium ([Ca2+]i) and force were made in rat anococcygeus to determine whether membrane hyperpolarisation plays a role in cyclic nucleotide-induced relaxation. In the presence of phenylephrine (0.2 microM), which evoked sustained contraction, an elevation in [Ca2+]i, and depolarisation, nitroprusside (5 microM) caused 96+/-3% relaxation, 77+/-3% decrease in suprabasal [Ca2+]i, and 16+/-2 mV hyperpolarisation. Forskolin (1 microM) caused 98+/-1% relaxation, 92+/-2% decrease in suprabasal [Ca2+]i, and 18+/-1 mV hyperpolarisation. These responses persisted in the presence of a variety of K+ channel blockers or in ouabain. The decrease in [Ca2+]i preceded the commencement of relaxation whereas the onset of hyperpolarisation lagged behind. Thus, cyclic nucleotide-mediated relaxation in rat anococcygeus is not dependent on hyperpolarisation mediated by the opening of K+ channels. Rather, it is suggested that the decrease in [Ca2+]i gives rise to hyperpolarisation, which reflects a decline in the Ca2+ dependent conductance(s) activated by phenylephrine.

Transducing chemical energy into mechanical function: a comparative view.

The energetics of muscle contraction can be understood in terms of the major cellular ATPases. The twitch isometric transduction efficiency is relatively constant across muscle types and species. Although many of the factors that alter the shape of the enthalpy:load relation in isotonic twitch contractions have been identified our molecular understanding is unsatisfactory and more studies are needed of mammalian muscles working closer to 37 degrees C. The thermodynamic efficiency of CB activity seems quite high, probably in excess of 70%. During maintained (tetanic) force there can be greater than a 1000 fold difference in energy usage across muscle types and there are factors that can down regulate CB activity: these factors remain to be fully identified in both skeletal and smooth muscles. The very diversity of muscle types and the different biochemical solutions that have emerged to match energy supply and demand should lead to important insights into the contractile mechanism. The corollary however also applies, it may be dangerous to take results obtained in one muscle type under a particular set of conditions, and extrapolate those findings to muscles in general.

[Preoperative coagulation screening prior to adenoidectomy and tonsillectomy]. / Präoperatives Screening auf Gerinnungsstörungen vor Adenotomie und Tonsillektomie.

BACKGROUND: Laboratory tests are widely used to screen children with planned surgery to detect unknown coagulation defects. This study investigates the predictive value of commonly used coagulation tests (thromboplastin time, partial thromboplastin time and thrombocyte count) compared with a standardized bleeding history. PATIENTS: In 702 patients 500 adenoidectomies and 500 tonsillectomies were done, results of laboratory evaluation and individual bleeding history were evaluated. RESULTS: 9.4 % of all laboratory tests showed abnormal results. 30.5 % of the children awaiting adenoidectomy had a suspicious bleeding history as had 22 % of patients undergoing tonsillectomy. In the clinical course of adenoidectomy no bleeding occurred. After tonsillectomy 15 children (3 %) showed moderate, 12 patients (2.4 %) severe postoperative bleeding. The positive predictive value of coagulation screening reached 6.8 % whereas history alone predicted 9.2 % of observed post tonsillectomy bleeding. CONCLUSIONS: The results of this study demonstrate the lacking effect of laboratory tests to predict postoperative bleeding complications. Taking a careful history of bleeding risks and testing only patients with suspicious history reduces the risk of bleeding more effective. Counseling about bleeding symptoms and postoperative survey of patients are additional measures which may protect the children.

Effects of substrate and hypoxia on smooth muscle metabolism and contraction.

Suprabasal heat production, oxygen consumption, and lactate production were measured, together with force, in 30-s isometric contractions of longitudinal smooth muscle from rabbit urinary bladder at 27 degrees C. Either glucose or pyruvate was provided as exogenous substrate. Under aerobic conditions with glucose as substrate, force averaged 95 mN/mm2 and heat production 121 mJ/g. Oxygen consumption (0.18 mumol/g) could account for only two-thirds of the total energy expenditure represented as heat production. The remaining one-third was accounted for by aerobic lactate production (0.36 mumol/g). When pyruvate replaced glucose as substrate, both the force developed and the total heat liberated were unchanged. Oxygen consumption, however, increased by approximately 40% (to 0.25 mumol/g) and was able to fully account for the measured heat production. The frequency of spontaneous contractions under aerobic conditions was always reduced in the presence of pyruvate. Under anaerobic conditions force was essentially unaltered, and heat production was only slightly reduced (101 mJ/g) with glucose present. Lactate production increased threefold over that under aerobic conditions. With pyruvate as substrate both force and heat production declined markedly (to less than 5% of the aerobic values). The results indicate that under aerobic conditions and with glucose as substrate, smooth muscle of rabbit urinary bladder generates about one-third of its suprabasal energy requirements through glycolysis and that glycolysis can be further accelerated under anaerobic conditions to provide sufficient energy to sustain contraction. If pyruvate replaces glucose as substrate, the metabolism shifts to being virtually all oxidative, and contraction can no longer be sustained in the absence of oxygen.

Contractile and metabolic properties of longitudinal smooth muscle from rat urinary bladder and the effects of aging.

Longitudinal smooth muscle strips taken from the urinary bladders of Sprague-Dawley rats, aged approximately 6 months and 24 months, were examined under a variety of conditions. Force development in response to electrical field stimulation and to cumulative addition of Ca2+ in the continual presence of 64 mM. KCl was the same in both adult and aged preparations. In response to cumulative additions of carbachol, however, it was observed that there was a shift to the right of the dose-response curve and a decrease in maximal force in the aged muscle strips. The maximal velocity of shortening was significantly lower in muscles from aged animals than in those from young adult animals. The metabolic tension cost during isometric contraction was, however, the same in both groups suggesting that the decline in Vus is largely due to factors not influencing energetic cost. The aged muscles also exhibited a lower basal metabolic rate and a reduced contribution of aerobic glycolysis to total metabolic energy production during both quiescence and stimulation under normoxic conditions than did muscles from young adult animals. They were, however, able to increase their rate of lactate production to the same levels as young adult muscles when stimulated under anoxic conditions.

Metabolism of toad ventricle during alterations to the inotropic state.

The heat produced by toad ventricle during manipulations of the inotropic state was measured using thermopiles, and some comparisons made to rat ventricle. The tension-independent heat, peak stress, and the tension-dependent heat increased when [Ca2+]o increased from 0.25 to 2 mM in Ringer. In 2 mM [Ca2+]o, tension-independent heat, peak stress, and tension-dependent heat were 3.1 +/- 0.4 mJ/g, 38.4 +/- 5.5 mN/mm2, and 0.49 +/- 0.06 units; about 25% of the tension-independent heat may relate to the Na(+)-K+ pump. At similar [Ca2+]o, rat ventricle produced a smaller tension-independent heat (1.6 +/- 0.2 mJ/g), and active heat per unit stress (0.22 +/- 0.01 units) than toad. Tension-independent heat, stress, and tension-dependent heat were increased by orciprenaline, and decreased by BDM. Ouabain increased the stress and tension-dependent heat but not the tension-independent heat. Five millimolar [Ca2+]o in HEPES buffer decreased the stress but increased the tension-dependent heat compared to 2 mM [Ca2+]o in Ringer. Ryanodine and CPA caused major reductions in force and tension-independent heat in rat, but had little effect on toad ventricle. In conclusion, our results suggest that in toad ventricle (a) the sarcoplasmic reticulum plays only a minor role in activation and relaxation, (b) the Na(+)-K+ pump contributes substantially to activation metabolism, (c) active metabolism is stimulated by increases in [Ca2+]o and (d) there is a larger tension-independent heat, a larger active metabolism per unit stress, and a lower basal metabolism than in rat papillary muscle. The energy cost of removing intracellular Ca2+ through the sarcolemma appears to be greater than uptake into sarcoplasmic reticulum.

Effects of anoxia on force, intracellular calcium and lactate production of urinary bladder smooth muscle from control and diabetic rats.

PURPOSE: To examine the effects of inhibiting oxidative metabolism on lactate production (J(Lac)), force and [Ca2+]i in longitudinal smooth muscle from urinary bladders of control and diabetic rats. MATERIALS AND METHODS: Strips of longitudinal smooth muscle were isolated from urinary bladders of diabetic rats and their age-matched controls. Force and [Ca2+]i were measured simultaneously in muscle strips loaded with the calcium indicator, fura-2. Separate muscle strips were used to determine J(Lac) by standard enzymatic assay. The muscles were stimulated to contract with 65 mM K+ or 1 microM carbachol (CCh) in the presence of 2.5 mM Ca2+ and either 5, 10 or 25 mM glucose. Oxidative metabolism was inhibited either by replacing O2 in solution with N2, or by addition of 2 mM NaCN. RESULTS: J(Lac) was significantly less in diabetic muscles than control muscles under both normoxic and anoxic conditions. During stimulation under anoxic conditions, the diabetic muscles were less able to maintain force than the controls. Despite a marked decline in force in both diabetic and control muscles under anoxic conditions, [Ca2+]i remained elevated to levels that were in fact higher than those observed during stimulation under normoxic conditions. Increasing the glucose concentration had no significant effect during normoxia, however, under anoxic conditions, the higher concentration improved force maintenance in both control and diabetic muscles. There were no apparent effects of the glucose concentration on [Ca2+]i in either diabetic or control muscles. CONCLUSION: The results reveal that urinary bladder smooth muscle from diabetic rats has a reduced ability to maintain contraction under anoxic conditions. This most likely reflects a greater energy limitation as evidenced by the reduced J(Lac) in diabetic muscles. In both diabetic and control muscles there was a marked dissociation between force and [Ca2+]i when oxidative metabolism was inhibited. This may indicate preferential use of glycolytically produced ATP for maintenance of [Ca2+]i homeostasis under these conditions.

Effects of procaine on calcium accumulation by the sarcoplasmic reticulum of mechanically disrupted rat cardiac muscle.

The ability of the sarcoplasmic reticulum of skinned cardiac muscle of the rat to accumulate and release Ca2+ was studied in the presence and absence of procaine. Ca2+ accumulation was estimated from the magnitude of the caffeine- (30 mM) induced force transient in a weakly Ca2+ buffered solution. The relative area under the caffeine-induced force transient was up to 4-fold greater when 5 mM-procaine had been present during the preceding period of Ca2+ loading, than that after an equivalent period of Ca2+ loading in the absence of procaine. Procaine antagonized the caffeine-induced release of Ca2+ when present in the Ca2+ releasing solution, however, the ability of procaine to attenuate the caffeine-induced Ca2+ release diminished as the extent to which the sarcoplasmic reticulum was loaded with Ca2+ increased. In the presence of 1 mM-Mg2+ procaine also markedly attenuated the small spontaneous force oscillations (5-10% P0) associated with the cyclic release and reuptake of Ca2+ by the sarcoplasmic reticulum. When the Mg2+ concentration was reduced to 0.1 mM, procaine initially suppressed the small spontaneous oscillations in force, however, large force oscillations (40-80% P0) of lower frequency were invariably initiated after 20-60 s exposure to 5 mM-procaine. Procaine (5 mM) produced a slight shift (approximately 0.04 pCa unit) of the force-pCa relation toward lower Ca2+ concentrations. This effect is too small to influence in any substantial way the apparent effects of procaine on the sarcoplasmic reticulum. The results indicate that whilst procaine is indeed able to suppress Ca2+ release under certain circumstances, in its presence the net accumulation of Ca2+ by the sarcoplasmic reticulum can be markedly enhanced.

Intracellular Ca2+ and adrenergic responsiveness of cardiac myocytes in streptozotocin-induced diabetes.

1. The contractile function of diabetic hearts is impaired. In addition, the responsiveness of diabetic cardiac muscle to sympathetic stimulation is altered. Previous studies have revealed a depressed response to beta-adrenoceptor stimulation; however, the response to alpha-adrenoceptor activation remains controversial. Because alpha- and beta-adrenoceptor agonists increase cardiac contractility, largely through increased mobilization of intracellular Ca2+, the aim of the present study was to investigate the effects of alpha- and beta-adrenoceptor stimulation on intracellular Ca2+ handling in cardiac myocytes from streptozotocin-induced diabetic rats. 2. Intracellular Ca2+ was measured using fura-2. Under basal conditions (27 degrees C, 2.5 mmol/L extracellular [Ca2+], 0.3 Hz stimulation), there was no significant difference in resting or peak Ca2+ levels between control and diabetic cardiomyocytes. However, the time course of the intracellular Ca2+ transient was significantly prolonged in cells from diabetic hearts. 3. The beta-adrenoceptor agonist orciprenaline (at 10(-7) and 10(-6) mol/L) increased the amplitude of the Ca2+ transient in both groups; however, the extent of potentiation was less in diabetic compared with control cardiomyocytes. Orciprenaline decreased the duration of the transient to the same extent in both groups. 4. The alpha-adrenoceptor agonist phenylephrine (at 10(-7) and 10(-6) mol/L) had no effect on the Ca2+ transient in control myocytes but caused a significant concentration-dependent increase in its amplitude in diabetic cardiomyocytes. Phenylephrine had no effect on the time course of the transient in either group. 5. These results demonstrate differential effects of insulin-dependent diabetes on the responsiveness of cardiomyocytes to alpha- and beta-adrenoceptor stimulation. The heightened response to alpha-adrenoceptor stimulation observed in diabetic cardiomyocytes may partly compensate for the diminished myocardial beta-adrenoceptor response.

Acute effects of taurine on intracellular calcium in normal and diabetic cardiac myocytes.

The present study investigated the acute effects of taurine on intracellular Ca2+ ([Ca2+]i) in normal and diabetic cardiac myocytes. [Ca2+]i was monitored using fura-2 in single myocytes isolated from control or streptozotocin-treated rats and paced at frequencies between 0.33 Hz and 2.0 Hz in the absence or presence of 20 mM taurine. Increasing stimulus frequency resulted in significant increases in resting and peak [Ca2+]i, and amplitude of the Ca2+ transient in both control and diabetic myocytes. The amplitude of the Ca2+ transient and the extent of its increase with increasing frequency was, however, significantly lower in the diabetic myocytes. Taurine significantly increased resting [Ca2+]i, peak [Ca2+]i, and the amplitude of the Ca2+ transient in both control and diabetic myocytes at all stimulus frequencies examined. The degree of potentiation of the Ca2+ transient decreased with increasing stimulus frequency in control cells but not in diabetic cells. In the absence of taurine the decay of the Ca2+ transient was significantly slower in diabetic than control myocytes. Taurine was without significant effect on the time course of the Ca2+ transient decay in control cells, however, in diabetic cells it significantly accelerated the rate of decay. The data demonstrate directly that taurine is able to increase [Ca2+]i and the amplitude of the Ca2+ transient in both normal and diabetic cardiac myocytes. In addition several of the effects of taurine appeared to be more pronounced in diabetic than control cells.

Amrinone and energy output of rabbit papillary muscles.

We studied the effects of amrinone (300 micrograms X ml-1) on the mechanical and energetic outputs of nonfailing rabbit papillary muscles at 27 degrees C using a myothermic technique. Amrinone was found to markedly stimulate the basal (i.e., nonbeating) metabolism. In mechanical experiments, at a 0.5-Hz stimulus rate, amrinone increased the rate of stress development and peak active stress but shortened the time to peak stress and the contractile duration. The linear relationship between total (active + passive) stress and heat production was altered by amrinone such that there was a 68% increase in the activation heat component (intercept) and an 11% increase in the energy cost per unit stress development (slope). In afterloaded isotonic experiments amrinone increased the capacity of papillary muscles to accomplish external work (W) by approximately 50% on average; however, this effect was associated with an increased total energy usage per beat (ET) such that the overall mechanical efficiency (W/ET X 100%) was not significantly altered at any load level. We conclude that amrinone greatly increases calcium delivery to the myofilaments and slightly increases the cost of stress development. These effects are examined in the light of amrinone's postulated mode of action, and possible reasons for the clinical observation of a decrease in myocardial oxygen consumption after amrinone administration are considered.

Effects of the antibiotic ionophore X-537A on contractility and ionic exchange in rabbit ventricular myocardium.

The effects of the ionophore X-537A on mechanical function and on ionic exchange were studied in the isolated, arterially perfused rabbit interventricular septum. X-537A produced an initial positive inotropic response which was, however, transient in this preparation and appeared to be dependent on an effect of the ionophore on catecholamines. The positive inotropy gave way to a progressive decline in force development which was unrelated to the action of catecholamines and was not accompanied by the development of contracture. Isotope uptake experiments revealed that coincident with this decline in force development there was a continuous net loss of tissue K+ and a net gain of Na+. X-537A (5 micronM) perfused for 20 minutes resulted in a net K+ loss of 50.2 +/- 4.6 mmol/kg dry weight and a net Na+ gain of 74.0 +/- 4.5 mmol/kg dry weight. Isotope washout experiments confirmed that the entire net loss of K+ could be accounted for by increased K+ efflux. X-537A did not alter Na+ efflux nor did it have any detectable effect on 45Ca exchange of the perfused septum in which the ability to detect net movements is at a level of approximately +/- 550 micron mol/kg dry weight. On removal of the ionophore the decline in force development ceased and reversed to near control levels and the progressive ionic changes ceased. However, despite the near total recovery of contractile function the Na+ and K+ levels remained at values little different from those reached at the termination of X-537A perfusion. In addition, after removal of the ionophore, we found that K+ exchange rate remained significantly less than control and, furthermore, a kinetic inhomogeneity of tissue K+ was observed. The results emphasize a dissociation between cellular Na+ and K+ content and function following the ionic perturbations induced by the ionophore.

Effects of caffeine on Ca-activated force production in skinned cardiac and skeletal muscle fibres of the rat.

Skinned fibres prepared by mechanical and/or chemical means from cardiac and skeletal muscles of the rat were activated in solutions strongly buffered for Ca2+ (with 50 mM EGTA) in the absence or presence of caffeine 5-40 mM. In all preparations caffeine was found to reversibly shift the relation between steady-state force and free [Ca2+] toward lower free [Ca2+] in a dose dependent manner. This increase in apparent Ca2+ sensitivity was not antagonized by procaine and was the same, within each muscle type, irrespective of the manner in which the skinned fibre was prepared, and consequently the degree to which it retained cellular membranes. The effect was more pronounced in cardiac and slow-twitch than in fast-twitch, myofibrillar preparations. At equivalent concentrations theophylline mimicked this effect of caffeine in all preparations, however, addition of exogenous cyclic AMP neither mimicked nor modified, in any way, the effect. Maximum Ca2+ -activated force production was not affected by caffeine below 20 mM but was depressed by concentrations of 20 mM and above. The increase in apparent Ca2+ sensitivity produced by caffeine can not be the result of a mobilization of some cellular store of Ca2+ but must arise from a direct effect of caffeine on the myofilaments which leads to a change in the apparent affinity constant of the force controlling sites for Ca2+.

Energy expenditure of longitudinal smooth muscle of rabbit urinary bladder.

Heat production, oxygen consumption, and lactate production of longitudinal smooth muscle from rabbit urinary bladder has been measured at 27 degrees C. In isometric contractions (initiated by 1-Hz electrical stimulation) ranging in duration from 2 to 300 s, total energy expenditure correlated linearly with the force-time integral. For any given force-time integral oxygen consumption could account for only approximately 60% of the total energy measured as heat production. A substantial contribution of aerobic lactate production to the total energy flux was observed. This lactate production was also linearly correlated with force-time integral and was of sufficient magnitude to account for the discrepancy between total energy expenditure determined as heat production and oxygen consumption. The suprabasal rate of energy expenditure during the maintenance of force was approximately 2.6 mW/g and remained constant throughout contractions of up to 5-min duration, suggesting that in this muscle there is no change in the energetic cost of force maintenance with increasing duration of contraction. The rate of energy expenditure during the initial period of force development was, however, about twofold greater than that during subsequent force maintenance, indicating that there is an extra energy cost associated with the activation of contraction and development of force above that required for force maintenance.

Fluorometric studies of recovery metabolism of rat fast- and slow-twitch muscles.

Recovery metabolism of fast-twitch extensor digitorum longus (EDL) and slow-twitch soleus (SOL) muscles of the rat has been investigated using fluorometric monitoring of reduction of nicotinamide adenine dinucleotide (NAD). In both EDL and SOL, groups of twitch contractions produced a decrease in fluorescence (oxidation of NADH) which returned to the resting base line after contraction ceased. These responses proceeded more quickly in EDL than SOL and were abolished by anoxia. A 1-s tetanus of SOL produced an initial reduction which could be abolished with iodoacetate followed by a prolonged oxidation which could be blocked by anoxia. The fluorescence of EDL was decreased immediately following a 1-s tetanus but then rapidly increased well beyond the resting level of reduction and persisted throughout the recovery period. This reduction was largely depressed by iodoacetate. The results indicate marked differences in the recovery metabolism of these muscles, consistent with predominantly mitochondrial oxidative activity in the slow-twitch muscles and predominantly glycolytic activity in the fast-twitch muscles.