Sodium dependence of the inotropic effect of a reduction in extracellular potassium concentration

Summary The positive inotropic effect of a reduction of [K⁺]_e from 5.9 mM to 1.2 mM or less depends on the extracellular concentration of sodium. The increase in contractility is greatly reduced or prevented if [Na⁺]_e has been diminished from 140 mM to 70 mM (with the addition of sucrose).A reduction of [K⁺]_e to 1.2 mM leads to an increase in membrane resting potential (MRP) by an average of 16 mV (from –71 mV to –87 mV) and to a diminution of the overshoot by 7 mV, both changes not being influenced by a reduction of [Na⁺]_e.The increase in the rate of depolarization is relatively small (6%) indicating that the sodium-carrying system in guinea-pig ventricular muscle is almost completely activated at a MRP not far from –70 mV.The sodium-dependence of the inotropic effect caused by a reduction of [K⁺]_e points to the significance of the impairment of the sodium pump by the reduction of [K⁺]_e in the production of the inotropic effect. The mechanism of the inotropic effect is assumed to consist of an increase in calcium influx through an increased sodium/calcium exchange as a consequence of a rise in [Na⁺]_i.The duration of the AP of guinea-pig papillary muscle is dependent on the relation [Ca²⁺]_e/[Na⁺]_e ². A diminution of [Na⁺]_e to 50%, therefore, does not alter the length of the plateau phase of the AP (at 30% repolarization) provided that [Ca²⁺]_e has been reduced simultaneously to one fourth.The duration of the plateau of the AP is shortened by an average of 22 msec in response to a reduction of [K⁺]_e to 1.2 mM. This shortening of the plateau is the only alteration in the electrical behaviour of the cardiac cell which is correlated with the positive inotropic effect of the reduction of [K⁺]_e, since it occurs only with [Na⁺]_e of 140 mM but not with 70 mM. Considering the antagonism between calcium and sodium in regard to their effects upon AP duration, the shortening of the plateau is assumed to be indicative of a reduction of slow sodium inward current as a result of an increase in calcium influx.Supported by the Deutsche Forschungsgemeinschaft.     

Report and Recommendations of the Workshop of the European Centre for the Validation of Alternative Methods for Drug-Induced Cardiotoxicity

Cardiotoxicity is among the leading reasons for drug attrition and is therefore a core subject in non-clinical and clinical safety testing of new drugs. European Centre for the Validation of Alternative Methods held in March 2008 a workshop on “Alternative Methods for Drug-induced Cardiotoxicity” in order to promote acceptance of alternative methods reducing, refining or replacing the use of laboratory animals in this field. This review reports the outcome of the workshop. The participants identified the major clinical manifestations, which are sensitive to conventional drugs, to be arrhythmias, contractility toxicity, ischaemia toxicity, secondary cardiotoxicity and valve toxicity. They gave an overview of the current use of alternative tests in cardiac safety assessments. Moreover, they elaborated on new cardiotoxicological endpoints for which alternative tests can have an impact and provided recommendations on how to cover them.     

Postnatal Left Ventricular Contractility in Very Low Birth Weight Infants

The objective of the study was to evaluate postnatal changes in left ventricular (LV) contractility in very low birth weight (VLBW) infants. An echocardiographic study comparing 18 VLBW infants without significant complications and 16 normal term infants was carried out at the Neonatal Intensive Care Unit in Akita University Medical Hospital, Japan. The echocardiographic examinations were performed within 6 hours of birth and on day 5. We obtained the relations between rate-corrected mean velocity of circumferential fiber shortening (mVcfc) and end-systolic wall stress (ESS), which were calculated from two-dimensional LV short-axis views to compensate for the distorted LV shape, and we compared these relations statistically. In both VLBW and term infants there were inverse linear correlations between mVcfc and ESS for each study period (p < 0.05). The regression line of VLBW infants had a lower y-intercept and a steeper slope than that of term infants at 6 hours of age but almost corresponded on day 5. It is concluded that the left ventricle of VLBW infants adapts to postnatal hemodynamic alterations with low contractility but operates with a contractile state similar to that of term infants on day 5.     

高钙对烧伤早期豚鼠离体心脏固有收缩性的影响

为了探讨烧伤早期心肌固有收缩力降低的机制,本实验观察了35％体表面积Ⅲ度烧伤后8小时,灌流豚鼠离体心脏对高钙溶液(含Cacl_2 3.2mmol/L台氏液)的反应及对Ca~(2+)的消耗量。结果表明,烧伤组在高钙液灌流情况下,左心室内压的±dp/dtmax、心室肌细胞动作电位幅度,最大去极化速率.复极化50％的时程缩短程度均低于对照组(P<0.05);对常钙或高钙灌流液中Ca~(2+)的交换量,烧伤组也显著低于对照组(P<0.01)。提示烧伤早期心肌细胞对Ca~(2+)的摄取、利用,心肌细胞电位对Ca~(2+)的反应均低于正常,这可能是此期心肌固有收缩性和舒张功能显著降低的重要原因之一。     

Effects of uridine triphosphate on contractility,cyclic nucleotide levels and membrane potential in the isolated frog ventricle

A study has been made of the effects of uridine 5-triphosphate (UTP) on the isolated frog ventricle. Preparations were superfused with solutions containing different concentrations of UTP, and changes in contractility, cyclic nucleotide levels and membrane potential were measured. UTP produced a long lasting increase in isometric twitch tension, which was unaffected by adrenergic receptor antagonists (propranolol and phentolamine). The levels of adenosine 3,5-cyclic monophosphate (cyclic AMP) and guanosine 3,5-cyclic monophosphate (cyclic GMP) were measured at different times during exposure of the ventricle to 10^–4 M UTP. The increase in the force of contraction was found to be accompanied by a rise in intracellular cyclic AMP. Cyclic GMP levels were seen to fall initially, but then to increase later, as both twitch and cyclic AMP started to decline. UTP also produced marked changes in the shape of the action potential; its duration and positive overshoot were both increased. The effects of UTP on twitch tension, cyclic nucleotide levels and action potential parameters were all dose-related. The change in contractility was found to be linearly related to (a) the ratio of the amount of cyclic AMP: cyclic GMP present in the fibres, and (b) to the increase in duration of the action potential. These results suggest that cyclic AMP, cyclic GMP and the availability of Ca²⁺ may all be involved in mediating the response to UTP.     

Weakness of whole muscles in mice deficient in Cu, Zn superoxide dismutase is not explained by defects at the level of the contractile apparatus

Mice deficient in Cu,Zn superoxide dismutase (Sod1^−/− mice) demonstrate elevated oxidative stress associated with rapid age-related declines in muscle mass and force. The decline in mass for muscles of Sod1^−/− mice is explained by a loss of muscle fibers, but the mechanism underlying the weakness is not clear. We hypothesized that the reduced maximum isometric force (F_o) normalized by cross-sectional area (specific F_o) for whole muscles of Sod1^−/− compared with wild-type (WT) mice is due to decreased specific F_o of individual fibers. Force generation was measured for permeabilized fibers from muscles of Sod1^−/− and WT mice at 8 and 20 months of age. WT mice were also studied at 28 months to determine whether any deficits observed for fibers from Sod1^−/− mice were similar to those observed in old WT mice. No effects of genotype were observed for F_o or specific F_o at either 8 or 20 months, and no age-associated decrease in specific F_o was observed for fibers from Sod1^−/− mice, whereas specific F_o for fibers of WT mice decreased by 20 % by 28 months. Oxidative stress has also been associated with decreased maximum velocity of shortening (V_max), and we found a 10 % lower V_max for fibers from Sod1^−/−compared with WT mice at 20 months. We conclude that the low specific F_o of muscles of Sod1^−/− mice is not explained by damage to contractile proteins. Moreover, the properties of fibers of Sod1^−/− mice do not recapitulate those observed with aging in WT animals.     

Resynchronization and Strain Recovery Following Reimplantation of Anomalous Coronary Artery: A Tissue Doppler and Three-dimensional Echocardiographic Study

Resynchronization may play a significant role in recovery following surgical reimplantation of anomalous left coronary artery from the pulmonary artery (ALCAPA). Three-dimensional echocardiography and tissue Doppler may quantify this recovery. A 6-week-old infant presented with signs of congestive heart failure due to ALCAPA. Two-dimensional echocardiography showed a severely dilated left ventricular (LV) cardiomyopathy and the presence of ALCAPA was confirmed by catheterization. Three-dimensional echocardiography and tissue Doppler imaging showed severe abnormalities of systolic and diastolic synchrony and decreased contractility with a left ventricular ejection fraction (LVEF) of 13%. The infant underwent surgical coronary reimplantation and was discharged 5 weeks later with an LVEF of 54%. Serial quantitative assessment showed resynchronization and normalization of global LV function following reimplantation. However, segmental contractility improved significantly but remained depressed at discharge. The immediate recovery observed following reimplantation of anomalous coronary may be largely due to resynchronization.     

Nitric oxide, myocardial failure and septic shock

Septic shock is a major cause of hospital deaths despite modern intensive therapy. Profound hypotension is caused by a collapse of regulatory mechanisms. Recent advances have established that bacterial products and the host inflammatory response together generate uncontrolled production of nitric oxide throughout the vasculature, accounting for this vasodilatation. Progressive heart failure is a further manifestation of established septic shock. Emerging research suggests that overproduction of nitric oxide within the myocardium likewise leads to loss of normal myocardial function. The possibility exists that exciting future therapies will be able to selectively inhibit the overproduction of nitric oxide and aid recovery from this frequently lethal condition.