Biomedical subjects

R Ishisu

Publications and source records attributed to R Ishisu.

6 recordsLinked to original sources

PubMed1997

MCI-154, a Ca2+ sensitizer, decreases the oxygen cost of contractility in isolated canine hearts.

An increase in the responsiveness of the contractile machinery to Ca2+ could theoretically enhance the mechanoenergetics of the heart. To clarify this unresolved issue, we studied the effects of MCI-154, a Ca2+ sensitizer, on the mechanoenergetics in terms of the left ventricular contractility index [slope of end-systolic pressure-volume relationship (Emax)] and the relationship between myocardial oxygen consumption (VO2) and left ventricular pressure-volume area in excised cross-circulated canine hearts. MCI-154 increased Emax by 42 +/- 31% (SD), although the slope of the VO2-PVA relationship (an indicator of contractile efficiency) was unchanged by MCI-154. Despite equal increases in Emax, the relative increase in unloaded VO2 (delta VO2/delta Emax) during infusion of MCI-154 was, however, significantly less than that during CaCl2 infusion (0.0016 +/- 0.0018 vs. 0.0059 +/- 0.0054; P < 0.05). By contrast, delta VO2/delta Emax for milrinone was the same as that for CaCl2 (0.0043 +/- 0.0041 vs. 0.0039 +/- 0.0045; P > 0.05). Basal metabolism in KCl-arrested hearts was unchanged by MCI-154, indicating that MCI-154 consumes less energy than CaCl2 for excitation-contraction coupling. These findings suggest that MCI-154 acts energetically as a Ca2+ sensitizer in beating canine whole hearts.

Animals↗

PubMed1996

Changes in calcium transient and left ventricular function during positive inotropic stimulation and myocardial ischemia in indo-1-loaded beating guinea pig heart.

To elucidate the issues such as excitation-contraction coupling and myocardial ischemia, it is necessary to measure intracellular free Ca2+ concentration and mechanical function of hearts perfused via the normal arterial circulation. For this purpose, we simultaneously measured Ca(2+)-dependent indo-1 fluorescence and left ventricular (LV) pressure on a beat-to-beat basis in Langendorff guinea-pig hearts, and investigated the changes in Ca2+ transient and LV function during inotropic stimulation and myocardial ischemia. The indo-1 fluoresence ratio and LV developed pressure increased the perfusate [Ca2+] increased from 1.6 to 3.2 mmol/L, and there was a good correlation between Ca2+ transient and LV contractility. Digoxin (10(-6) mol/L) and milrinone (10(-5) mol/L) increased LV contractility with a concomitant increase in Ca2+ transient, and the relative increase of Ca2+ transient produced by milrinone was much more than that by digoxin. The reduction of coronary perfusion pressure from 80 to 40 mm Hg decreased LV contractility with an increase in indo-1 fluorescence ratio. These results suggest that Ca2+ responsiveness of contractile apparatus declines during inotropic stimulation by milrinone and during myocardial ischemia. Thus, this experimental technique is useful to investigate the interrelation of Ca2- regulation and LV function during a variety of pharmacological and physiologic perturbations.

Animals↗

PubMed1996

Decrease in oxygen cost of contractility during hypocapnic alkalosis in canine hearts.

Ca2+ sensitization of contractile machinery could theoretically enhance the mechanoenergetics of the heart. We studied the effects of alkalosis with Ca2+ sensitization on mechanoenergetics within the framework of the relationships of left ventricular pressure-volume area (PVA; a measure of the total mechanical energy), myocardial oxygen consumption per beat (VO2), and the contractility index [E(max) (slope of end-systolic pressure-volume relation)] in 10 excised, cross-circulated canine hearts. Alkalosis was stably maintained without hypoxia (mean pH 7.66). Alkalosis increased E(max) without changing the slope of the VO2-PVA relation, a reflected contractile efficiency. The incremental ratio of unloaded VO2 to E(max) in alkalosis was significantly lower than that in Ca2+ sensitization (0.0012 +/- 0.0010 vs. 0.0062 +/- 0.0030 ml O2 . mmHg-1 . ml . beat-1 . 100 g LV-2; P < 0.01). Basal metabolism under KCl arrest was unchanged by alkalosis, indicating the decreased energy cost of the excitation-contraction coupling by alkalosis. Compared with the control, alkalosis increased E(max) during the Ca2+ infusion of various concentrations without any further increase in unloaded VO2. Thus we demonstrated a decreased oxygen cost of contractility during alkalosis, presumably due to Ca2+ sensitization.

Alkalosis, Respiratory↗

PubMed1996

Differential effects of EMD-53998 on calcium-pressure relationship in normal and ischemic guinea pig heart.

We investigated the effects of EMD-53998 and digoxin on Ca2+ transients and left ventricular (LV) function in indo 1-loaded Langendorff guinea pig hearts. EMD-53998 (10(-9) to 10(-5) M) and digoxin (10(-10) to 10(-6) M) increased +dP/dt and Ca2+ transients in normal hearts. The relative increase in Ca2+ transients by EMD-53998 was similar to digoxin. At 10(-5) M, EMD-53998 increased LV end-diastolic pressure. Low-flow ischemia decreased +dP/dt by 50%, while indo 1 ratio increased by 10-25%. EMD-53998 (10(-9) to 10(-6) M) effectively restored the depressed +dP/dt with little effect on indo 1 ratio, but at 10(-5) M, it markedly elevated LV end-diastolic pressure and the beneficial effect on contractile dysfunction disappeared. Digoxin (10(-10) to 10(-7) M) failed to improve LV function, but at 10(-6) M, it restored contractile dysfunction with a large increase in indo 1 ratio. The relation between indo 1 ratio and +dP/dt clearly showed that EMD-53998 restored contractile dysfunction by Ca2+ sensitization. These findings suggest that Ca2+ sensitization by EMD-53998 is an advantageous approach for ischemic contractile failure but impairs diastolic function.

Animals↗

PubMed1996

Calcium sensitization in perfused beating guinea pig heart by a positive inotropic agent MCI-154.

We investigated the effects of MCI-154, a positive inotropic agent that increases the myofilament response to Ca++, on Ca++ transients, left ventricular (LV) function and phosphodiesterase (PDE) III activity of guinea pig heart, and compared them with the effects of pimobendan and milrinone. In Langendorff guinea pig hearts loaded with a fluorescent Ca++ probe indo-1, LV pressure and Ca++ transient were measured simultaneously. MCI-154 (10(-10)-10(-6) M) increased LV developed pressure, +dP/dt and -dP/dt with a reduction of LV end-diastolic pressure, although it did not affect coronary flow. The positive inotropic activity of MCI-154 was more potent than that of pimobendan and milrinone; EC50 values (concentrations for increasing +dP/dt by 50% from base line) were 4.31, 41.5 and 294 x 10(-9) M, respectively. The positive inotropic effect of MCI-154 was accompanied by the increase in systolic, diastolic and amplitude of indo-1 fluorescence ratio. The relative increase in Ca++ transients against the increase in LV contractility produced by MCI-154, however, was significantly less than that by increasing perfusate [Ca++], pimobendan or milrinone. MCI-154 (3 x 10(-7)-10(-4) M) inhibited the activity of PDE III isolated from guinea pig LV tissues, but the inhibitory effect of MCI-154 was less than pimobendan and milrinone; IC50 values were 10.1, 3.5 and 2.4 x 10(-6) M, respectively. These findings suggest that MCI-154 exerts a positive inotropic effect mainly through Ca(++)-sensitizing action in intact beating whole hearts.

Animals↗

PubMed1996

Restoration of ischemic contractile failure of indo-1-loaded guinea pig heart by a calcium sensitizer, MCI-154.

We investigated the effect of a new Ca++ sensitizer, MCI-154, which is known to increase myofibrillar Ca++ sensitivity and maximal Ca(++)-activated force, on Ca++ transients and left ventricular (LV) function in indo-1-loaded Langendorff guinea plg hearts subjected to a reduction in coronary perfusion pressure from 80 to 40 mm Hg. During low-flow ischemia, LV contractility decreased by 50%, whereas systolic and diastolic indo-1 fluorescence ratios increased by 10%. The treatment with MCI-154 (10(-10) to 10(-6) M) 15 min after ischemia effectively restored the depressed LV function with little effect on indo-1 ratio. EMD 53998 (10(-9) to 10(-6) M), which also acts on maximal Ca(++)-activated force, restored LV function with a minimal impact on indo-1 ratio, but at 10(-5) M, EMD 53998 caused diastolic dysfunction, and its beneficial effect on systolic function disappeared. The relation between indo-1 ratio and LV contractility showed that MCI-154 and EMD 53998 restored ischemic contractile failure by Ca(++)-sensitizing action. It was noted that the restoration of LV dysfunction by MCI-154 or EMD 53998 was more pronounced than that by pimobendan, which acts primarily on Ca++ sensitivity. In contrast, the phosphodiesterase inhibitor milrinone restored LV function, but it doubled the increase in indo-1 ratio during ischemia. These findings suggest that a decrease in myofilament Ca++ responsiveness may be an important cause of ischemic contractile failure and that the restoration of depressed Ca++ responsiveness by intervention such as MCI-154 may be a promising approach for restoring the depressed function.

Animals↗