Impact of RyR2 potentiation on myocardial function

This perspective attempts to shed light on an old and not yet solved controversy in cardiac physiology, i.e., the impact of increasing ryanodine receptor (RyR)2 open probability on myocardial function. Based on an already proven myocyte model, it was shown that increasing RyR2 open probability results in a purely short-lived increase in Ca2+ transient amplitude, and, therefore, it does not increase cardiac contractility. However, potentiation of RyR2 activity permanently enhances fractional Ca2+ release, shifting the intracellular Ca2+ transient versus sarcoplasmic reticulum (SR) Ca2+ content curve to a new state of higher efficiency. This would allow the heart to maintain a given contractility despite a decrease in SR Ca2+ content, to enhance contractility if SR Ca2+ content is simultaneously preserved or to successfully counteract the effects of a negative inotropic intervention. New & Noteworthy Increasing ryanodine receptor (RyR)2 open probability does not increase cardiac contractility. However, RyR2 potentiation shifts the intracellular Ca2+ transient-sarcoplasmic reticulum (SR) Ca2+ content relationship toward an enhanced efficiency state, which may contribute to a positive inotropic effect, preserve contractility despite decreased SR Ca2+ content, or successfully counteract the effects of a negative inotropic actionCentro de Investigaciones Cardiovasculare

Impact of RyR2 potentiation on myocardial function

This perspective attempts to shed light on an old and not yet solved controversy in cardiac physiology, i.e., the impact of increasing ryanodine receptor (RyR)2 open probability on myocardial function. Based on an already proven myocyte model, it was shown that increasing RyR2 open probability results in a purely short-lived increase in Ca2+ transient amplitude, and, therefore, it does not increase cardiac contractility. However, potentiation of RyR2 activity permanently enhances fractional Ca2+ release, shifting the intracellular Ca2+ transient versus sarcoplasmic reticulum (SR) Ca2+ content curve to a new state of higher efficiency. This would allow the heart to maintain a given contractility despite a decrease in SR Ca2+ content, to enhance contractility if SR Ca2+ content is simultaneously preserved or to successfully counteract the effects of a negative inotropic intervention. New & Noteworthy Increasing ryanodine receptor (RyR)2 open probability does not increase cardiac contractility. However, RyR2 potentiation shifts the intracellular Ca2+ transient-sarcoplasmic reticulum (SR) Ca2+ content relationship toward an enhanced efficiency state, which may contribute to a positive inotropic effect, preserve contractility despite decreased SR Ca2+ content, or successfully counteract the effects of a negative inotropic actionCentro de Investigaciones Cardiovasculare

CaMKII-dependent responses to ischemia and reperfusion challenges in the heart

Ischemic heart disease is a leading cause of death, and there is considerable imperative to identify effective therapeutic interventions. Cardiomyocyte Ca2+ overload is a major cause of ischemia and reperfusion injury, initiating a cascade of events culminating in cardiomyocyte death, myocardial dysfunction, and occurrence of lethal arrhythmias. Responsive to fluctuations in intracellular Ca2+, Ca2+/calmodulin-dependent protein kinase II (CaMKII) has emerged as an enticing therapeutic target in the management of ischemic heart injury. CaMKII is activated early in ischemia and to a greater extent in the first few minutes of reperfusion, at a time when reperfusion arrhythmias are particularly prominent. CaMKII phosphorylates and upregulates many of the key proteins involved in intracellular Na+ and Ca2+ loading in ischemia and reperfusion. Experimentally, selective inhibition of CaMKII activity reduces cardiomyocyte death and arrhythmic incidence post-ischemia. New evidence is emerging that CaMKII actions in ischemia and reperfusion involve specific splice variant targeted actions, selective and localized post-translational modifications, and organelle-directed substrate interactions. A more complete mechanistic understanding of CaMKII mode of action in ischemia and reperfusion is required to optimize intervention opportunities. This review summarizes the current experimentally derived understanding of CaMKII participation in mediating the pathophysiology of the heart in ischemia and in reperfusion, and highlights priority future research directions.Centro de Investigaciones Cardiovasculare

Na+-Ca2+ exchange function underlying contraction frequency inotropy in the rat myocardium

In most mammalian species, an increase in stimulation frequency (ISF) produces an increase in contractility (treppe phenomenon), which results from larger Ca2+ transients at higher frequencies, due to an increase in sarcoplasmic reticulum Ca2+ load and release. The present study attempts to elucidate the contribution of the Na+-Ca2+ exchanger (NCX) to this phenomenon. Isolated cat ventricular myocytes, loaded with [Ca2+]i- and [Na+]i-sensitive probes, were used to determine whether the contribution of the NCX to the positive inotropic effect of ISF is due to an increase in Ca2+ influx (reverse mode) and/or a decrease in Ca2+ efflux (forward mode) via the NCX, due to frequency-induced [Na+]i elevation, or whether it was due to the reduced time for the NCX to extrude Ca2+. The results showed that the positive intropic effect produced by ISF was temporally dissociated from the increase in [Na+]i and was not modified by KB-R7943 (1 or 5 μM), a specific blocker of the reverse mode of the NCX. Whereas the ISF from 10 to 30 beats min-1 (bpm) did not affect the forward mode of the NCX (assessed by the time to half-relaxation of the caffeine-induced Ca2+ transient), the ISF to 50 bpm produced a significant reduction of the activity of the forward mode of the NCX, which occurred in association with an increase in [Na+]i (from 4.33 ± 0.40 to 7.25 ± 0.50 mM). However, both changes became significant well after the maximal positive inotropic effect had been reached. In contrast, the positive inotropic effect produced by ISF from 10 to 50 bpm was associated with an increase in diastolic [Ca2+]i, which occurred in spite of a significant increase in the relaxation rate and at a time at which no increases in [Na+]i were detected. The contribution of the NCX to stimulus frequency inotropy would therefore depend on a decrease in NCX-mediated Ca2+ efflux due to the reduced diastolic interval between beats and not on [Na+]i-dependent mechanisms.Facultad de Ciencias MédicasCentro de Investigaciones Cardiovasculare

Rested-state contractions and rest potentiation in spontaneously hypertensive rats

To gain further insight into the excitation-contraction coupling mechanisms in hypertrophy, we studied rested-state contractions, rest decay curves, and rest potentiation under different experimental conditions using papillary muscles of spontaneously hypertensive rats (SHR) and age-matched normotensive Wistar and Wistar-Kyoto (WKY) rats. Under constant stimulation at 1.1 Hz, contractility and relaxation were not significantly different in hypertensive when compared with normotensive animals. Rested-state contraction (the first beat after a rest interval of 15 minutes) increased to 159.2 ± 23% and 123.5 ± 7.5% of prerest values in Wistar and WKY rats, respectively, whereas in SHR it did not differ from prerest values (92.8 ± 9.8%). Ryanodine, used to preferentially inhibit sarcoplasmic reticulum function, eliminated the differences in rested-state contractions observed between hypertensive and normotensive rats. Maximal rest potentiation (the first beat after a rest interval of 1 minute) was also significantly higher in Wistar and WKY rats than in SHR. These differences persisted at low extracellular Na⁺, when Ca2+ efflux via the Na⁺-Ca2+ exchanger was inhibited. Rest decay curves (the decay in contractility from maximal rest potentiation to rested-state contraction) showed a similar pattern in the three rat strains. The results suggest that the altered inotropic responses of the SHR arise from an alteration in calcium handling by the sarcoplasmic reticulum. Experiments on saponin-skinned trabeculae indicated that fractional calcium release induced by caffeine was significantly reduced in the SHR. We conclude that the altered inotropic response observed in SHR may reflect a diminished release of calcium from the sarcoplasmic reticulum.Facultad de Ciencias MédicasCentro de Investigaciones Cardiovasculare

A Cross-Country Empirical Analysis of Determinants of Clean Development Mechanism (CDM) Projects

The CDM seems to play a significant role in international GHG reduction activities. Yet, a few emerging countries have hosted majority of CDM projects whereas most LDCs have not hosted CDM projects at all. Given the current distributional imbalance, this study aims to identify determinants of CDM project hosting based on an empirical analysis using the tobit model. On the basis of the literature review, this study focuses on two factors, namely the host countries’ qualities of business environment and scientific level. As a result, this study finds the significance of business environment for both bilateral and unilateral CDM projects. Likewise, the significance of scientific and technical level is confirmed especially for unilateral CDM projects. Finally, this article suggests that eligible host countries should focus exclusively on the improvement of controllable determinants such as business environment to attract CDM investors. In addition, it is likely to be better for eligible host countries with low GHG emissions to develop CDM projects unilaterally using programmatic CDM due to their lower economic attractiveness

CaMKII-dependent responses to ischemia and reperfusion challenges in the heart

Ischemic heart disease is a leading cause of death, and there is considerable imperative to identify effective therapeutic interventions. Cardiomyocyte Ca2+ overload is a major cause of ischemia and reperfusion injury, initiating a cascade of events culminating in cardiomyocyte death, myocardial dysfunction, and occurrence of lethal arrhythmias. Responsive to fluctuations in intracellular Ca2+, Ca2+/calmodulin-dependent protein kinase II (CaMKII) has emerged as an enticing therapeutic target in the management of ischemic heart injury. CaMKII is activated early in ischemia and to a greater extent in the first few minutes of reperfusion, at a time when reperfusion arrhythmias are particularly prominent. CaMKII phosphorylates and upregulates many of the key proteins involved in intracellular Na+ and Ca2+ loading in ischemia and reperfusion. Experimentally, selective inhibition of CaMKII activity reduces cardiomyocyte death and arrhythmic incidence post-ischemia. New evidence is emerging that CaMKII actions in ischemia and reperfusion involve specific splice variant targeted actions, selective and localized post-translational modifications, and organelle-directed substrate interactions. A more complete mechanistic understanding of CaMKII mode of action in ischemia and reperfusion is required to optimize intervention opportunities. This review summarizes the current experimentally derived understanding of CaMKII participation in mediating the pathophysiology of the heart in ischemia and in reperfusion, and highlights priority future research directions.Centro de Investigaciones Cardiovasculare

Rol del oxido nitrico (NO) sobre el efecto inotropico negativo asociado con el estrés hipertónico

En diferentes situaciones patológicas como estados de deshidratación severa, hiperglucemia, hiperlipidemia y diabetes, los cardiomiocitos sufren encogimiento osmótico y éste se asocia con un efecto inotrópico negativo (EIN). En un trabajo previo demostramos que el hinchamiento hipotónico promueve la liberación de Óxido Nítrico (NO) y que éste aportaría soporte contráctil. El objetivo de este estudio es evaluar si el estrés hipertónico (SH) también promueve la liberación de NO y de ser así, examinar su impacto sobre la contractilidad.Facultad de Ciencias Médica

Rol del oxido nitrico (NO) sobre el efecto inotropico negativo asociado con el estrés hipertónico

En diferentes situaciones patológicas como estados de deshidratación severa, hiperglucemia, hiperlipidemia y diabetes, los cardiomiocitos sufren encogimiento osmótico y éste se asocia con un efecto inotrópico negativo (EIN). En un trabajo previo demostramos que el hinchamiento hipotónico promueve la liberación de Óxido Nítrico (NO) y que éste aportaría soporte contráctil. El objetivo de este estudio es evaluar si el estrés hipertónico (SH) también promueve la liberación de NO y de ser así, examinar su impacto sobre la contractilidad.Facultad de Ciencias Médica

Rol del oxido nitrico (NO) sobre el efecto inotropico negativo asociado con el estrés hipertónico

En diferentes situaciones patológicas como estados de deshidratación severa, hiperglucemia, hiperlipidemia y diabetes, los cardiomiocitos sufren encogimiento osmótico y éste se asocia con un efecto inotrópico negativo (EIN). En un trabajo previo demostramos que el hinchamiento hipotónico promueve la liberación de Óxido Nítrico (NO) y que éste aportaría soporte contráctil. El objetivo de este estudio es evaluar si el estrés hipertónico (SH) también promueve la liberación de NO y de ser así, examinar su impacto sobre la contractilidad.Facultad de Ciencias Médica