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Biomedical subjects

Y Koretsune

Publications and source records attributed to Y Koretsune.

At least 37 records · Page 2Linked to original sources
PubMed1995

Pharmacological effects of concomitant administration of beta-adrenoceptor blocker and agonist in normal subjects: characterization by heart rate response to exercise. Effects of beta-blocker combined with beta-agonist.

The effects of a combination regimen of metoprolol and beta 1-adrenoceptor agonist denopamine on resting and exercise heart rate have been studied in 10 normal volunteers. Maximal ramp upright bicycle exercise was performed three times at 1-week intervals. Two hours before each exercise test, 5 mg metoprolol plus 20 mg denopamine, 5 mg metoprolol plus a denopamine placebo, or two placebos were orally administered in a double-blind fashion. During exercise after placebo administration, heart rate increased in parallel with the exercise intensity. Compared to the placebo values, resting heart rate was significantly decreased by an average of 10 beats.min-1 by 5 mg metoprolol, whereas it was not altered by the combination regimen. During exercise, however, both the combination regimen and metoprolol alone showed a significant negative chronotropic effect, decreasing peak exercise heart rate by an average of 14 and 21 beats.min-1, respectively. Peak oxygen uptake was also significantly decreased by both regimens. We conclude that concomitant administration of 5 mg metoprolol and 20 mg denopamine exerts an effective beta-adrenoceptor blocking action during exercise but a minimal effect at rest in normal subjects. The combination regimen appears to have a favourable pharmacological profile for beta-adrenoceptor blocker therapy in patients with chronic heart failure.

Adrenergic beta-Agonists↗
PubMed1995

High prevalence of atrial fibrosis in patients with dilated cardiomyopathy.

OBJECTIVES: We examined the extent of fibrotic changes in the left atrium of cardiomyopathic human hearts and investigated the relation of mechanical overload caused by left ventricular dysfunction to fibrosis of the left atrium. BACKGROUND: Left atrial dysfunction in dilated cardiomyopathy may contribute to progression of heart failure. In contrast to fibrosis of the left ventricle, atrial fibrosis has not been extensively studied in cardiomyopathic hearts. METHODS: The extent of fibrosis in the left atrium and left ventricle was determined by an automatic image analyzer in 38 autopsied hearts obtained from 9 patients who died of noncardiac illness (control group), 16 patients with dilated cardiomyopathy, 6 patients with hypertrophic cardiomyopathy with features mimicking dilated cardiomyopathy and 7 patients with a previous myocardial infarction. Transverse sections were obtained at the upper margins of the foramen ovale and left auricle in the left atrium and the median level of the left ventricle. RESULTS: There were no significant differences in extent of left atrial dilation, left ventricular dysfunction or duration of illness among the three groups with cardiac disease. Percent area of left atrial fibrosis (mean +/- SD) was significantly greater in the specimens from patients with dilated cardiomyopathy (13.1 +/- 6.1%, p < 0.01) and hypertrophic cardiomyopathy mimicking dilated cardiomyopathy (26.5 +/- 9.5%, p < 0.01) than in those from patients with an old myocardial infarction (3.8 +/- 1.1%). Percent area of left ventricular fibrosis in hearts from patients with dilated cardiomyopathy (12.9 +/- 8.6%) was significantly smaller than that in hearts from patients with hypertrophic cardiomyopathy mimicking dilated cardiomyopathy (35.8 +/- 11.9%, p < 0.01) and a previous myocardial infarction (38.4 +/- 8.0%, p < 0.01). Percent area of atrial fibrosis was significantly correlated with left ventricular ejection fraction in the group with a previous myocardial infarction but not in the other groups. CONCLUSIONS: There was a high degree of fibrotic change in the left atrium in the groups with dilated cardiomyopathy and hypertrophic cardiomyopathy mimicking dilated cardiomyopathy. Our findings suggest that atrial fibrosis in these patients may not have been related to mechanical overload of the left atrium but to some other, still unknown mechanisms.

Adult↗
PubMed1994

Progressive decreases in coronary vein flow during reperfusion in acute myocardial infarction: clinical documentation of the no reflow phenomenon after successful thrombolysis.

OBJECTIVES: This study was undertaken to examine the effects of coronary flow dynamics after thrombolysis on infarct size limitation. BACKGROUND: It has been commonly accepted that early thrombolysis does not necessarily salvage infarcted myocardium. Plausible causes for myocardial necrosis include such factors as elapsed time to reperfusion, residual stenosis, collateral vessels, hemodynamic loads, preconditioning and reperfusion injury. Recently, the no reflow phenomenon has been elucidated to be associated with infarct extension in clinical studies employing contrast echocardiography or thallium scintigraphy. METHODS: Nineteen patients with early reperfusion in acute anterior myocardial infarction and comparable clinical background were studied. The patients were classified into two groups on the basis of pattern of thermodilution measurements of great cardiac vein flow after reperfusion: group A, 9 patients with a progressive decrease in great cardiac vein flow during the 1st 24 h of the onset of infarction; and group B, 10 patients without this observation. Left ventricular ejection fraction and thallium perfusion defect were compared between the two groups at follow-up. RESULTS: There were no significant differences in systemic hemodynamic variables between groups A and B, and neither group had recurrent ischemic events suggesting reocclusion or restenosis during the study. In group A, both great cardiac vein flow (mean +/- SD 44 +/- 17% reduction) and oxygen extraction (38 +/- 15% reduction) were progressively decreased after the onset of reperfusion. Compared with group B, this group showed a lower left ventricular ejection fraction (36 +/- 7% vs. 63 +/- 15%, p < 0.01) and a larger thallium-201 defect severity index (1,091 +/- 366 U vs. 247 +/- 261 U, p < 0.01) at follow-up. Although other patient characteristics were comparable between the two groups, antecedent angina occurred in 90% of group B patients in contrast to only 33% of group A patients. CONCLUSIONS: Salvage of myocardium from infarction by successful thrombolysis was not observed in the patients demonstrating progressive decreases in great cardiac vein flow (group A). In those patients, inadequate myocardial reperfusion on a microvascular basis might be associated with a much larger myocardial infarction. Antecedent angina may protect against a progressive decrease in coronary flow and may have beneficial effects on infarct size limitation.

Adult↗
PubMed1994

Prognosis of patients with severe congestive heart failure referred to the cardiac transplant program. Osaka University Cardiac Transplant Program.

In any program for cardiac transplantation, appropriate recipient selection is critically important. The purpose of this study is to evaluate the prognosis of 42 patients with severe cardiac dysfunction who were referred to the Patient Referral Committee of the Osaka University Cardiac Transplant Program from August 1990 to July 1993. All of the patient profiles and clinical data were presented and discussed in the Committee Conference. The Committee classified the patients into three groups according to the following criteria: Class A; 14 patients judged to have a medical indication for heart transplantation, Class B; 7 patients with possible indications which required reevaluation for a definite indication after further intensive medical treatments, and Class C; 21 patients who did not have indications for heart transplantation or who required further clinical examinations and/or medical treatments before a final judgment. Twelve of the 14 Class A patients had a history of NYHA functional class IV and ejection fractions were 25% or less in all of the patients but one (18.5 +/- 1.7%). Six patients in Class A had a history of ventricular tachycardia. The one-year survival rate of Class A patients was 60%, and only 28% survived for 28 months. One patient underwent successful heart transplantation in the United States. If we assume that this patient would have died within a year without heart transplantation, the estimated one-year survival rate would fall to 48%, which is comparable to the survival rate of patients who have been accepted for transplant, but are being treated medically, in Western countries.(ABSTRACT TRUNCATED AT 250 WORDS)

Actuarial Analysis↗
PubMed1992

Relation between glycolysis and calcium homeostasis in postischemic myocardium.

This study examined the hypothesis that glycolysis is required for functional recovery of the myocardium during reperfusion by facilitating restoration of calcium homeostasis. [Ca2+]i was measured in isolated perfused rabbit hearts by using the Ca2+ indicator 1,2-bis(2-amino-5-fluorophenoxy)ethane-N,N,N',N'-tetraacetic acid (5F-BAPTA) and 19F nuclear magnetic resonance spectroscopy. In nonischemic control hearts, inhibition of glycolysis with iodoacetate did not alter [Ca2+]i. In hearts subjected to 20 minutes of global zero-flow ischemia, [Ca2+]i increased from 260 +/- 80 nM before ischemia to 556 +/- 44 nM after 15 minutes of ischemia (p less than 0.05). After reperfusion with 5 mM pyruvate as a carbon substrate, [Ca2+]i increased further in hearts with intact glycolysis to 851 +/- 134 nM (p less than 0.05 versus ischemia) during the first 10 minutes of reperfusion, before returning to preischemic levels. In contrast, inhibition of glycolysis during the reperfusion period resulted in persistent severe calcium overload ([Ca2+]i, 1,380 +/- 260 nM after 15 minutes of reperfusion, p less than 0.02 versus intact glycolysis group). Furthermore, despite the presence of pyruvate and oxygen, inhibition of glycolysis during early reperfusion resulted in greater impairment of functional recovery (rate/pressure product, 3,722 +/- 738 mm Hg/min) than did reperfusion with pyruvate and intact glycolysis (rate/pressure product, 9,851 +/- 590 mm Hg/min, p less than 0.01). Inhibition of glycolysis during early reperfusion was also associated with a marked increase in left ventricular end-diastolic pressure during reperfusion (41 +/- 5 mm Hg) compared with hearts with intact glycolysis (16 +/- 2 mm Hg, p less than 0.01). The detrimental effects of glycolytic inhibition during early reperfusion were, however, prevented by initial reperfusion with a low calcium solution ([Ca]o, 0.63 mM for 30 minutes, then 2.50 mM for 30 minutes). In these hearts, the rate/pressure product after 60 minutes of reperfusion was 12,492 +/- 1,561 mm Hg/min (p less than 0.01 versus initial reflow with [Ca]o of 2.50 mM). These findings indicate that the functional impairment observed in postischemic myocardium is related to cellular Ca2+ overload. Glycolysis appears to play an important role in restoration of Ca2+ homeostasis and recovery of function of postischemic myocardium.

Animals↗
PubMed1991

Detrimental effects of beta-adrenergic stimulation on beta-adrenoceptors and microtubules in the heart.

Increased plasma catecholamines - in particular, excessive beta-adrenoceptor activation in chronic heart failure - may easily desensitize the beta-adrenoceptors as well as the postreceptor signal transductions. Since these detrimental changes in the failing heart could be reversible, administration of low-dose beta-blocker, which minimizes the negative inotropic effects, may be effective in attenuating the harmful effects of sympathetic nerve activation. Beta-adrenoceptor stimulation may also produce microtubule disruptions of the cell either through direct action or through an increase in heart rate. Treatment with beta-blockers could attenuate Ca overload by slowing the heart rate and may be useful as a protection from the structural disintegration of the cell. Thus, to clarify the underlying mechanisms of beta-blocker therapy for chronic heart failure, we have to consider not only to the functional aspects but also to the structural changes of the cells.

Adrenergic beta-Antagonists↗
PubMed1991

Alterations of intracellular calcium homeostasis and myocardial energetics in acute adriamycin-induced heart failure.

To elucidate the mechanism of acute contractile failure induced by adriamycin, the intracellular concentrations of free calcium ([Ca2+]i) and energy-related phosphate compounds were determined in isolated ferret hearts. The time-averaged [Ca2+]i was measured at 10 min resolution using fluorine nuclear magnetic resonance (NMR) spectroscopy and the NMR-sensitive Ca2+ indicator 5F-BAPTA. [Ca2+]i significantly increased from a control of 381 +/- 66 nM (mean +/- SEM, N = 5) to 789 +/- 171 nM during 30 min of perfusion with adriamycin (30 mg/L), and remained elevated for at least 30 min after washout. The isovolumic LV pressure decreased to 80.7 +/- 8.9% of control (N = 12, p less than 0.05) and did not recover after washout. Intramyocardial contents of energy-related phosphates were determined by phosphorus NMR spectroscopy in seven other hearts. No significant change in myocardial energy metabolism was observed during adriamycin exposure and after washout; inorganic phosphate did not increase, and phosphocreatine and ATP did not decrease. These results indicate that Ca overload induced by adriamycin is associated with acute contractile failure. Adriamycin has been reported to inhibit Na-Ca exchange and to affect the gating of Ca2+ release channels in sarcoplasmic reticulum. Whatever the cause of the calcium overload, the fact that dysfunction persists as an aftereffect of adriamycin is consistent with the hypothesis that calcium overload, in the absence of ischemia, can leave behind long-lasting contractile dysfunction.

Adenosine Triphosphate↗
PubMed1991

Role of oxygen-derived free radicals in myocardial edema and ischemia in coronary microvascular embolization.

BACKGROUND: Oxygen-derived free radicals are thought to injure the ischemic heart during coronary microvascular embolization. METHODS AND RESULTS: To test this idea, microspheres (15 microns in diameter) were repetitively administered into the left anterior descending coronary artery to cause microvascular embolization in dogs. Myocardial contractile and metabolic dysfunctions were significantly attenuated after treatments with recombinant human superoxide dismutase, an acyl derivative of ascorbic acid (CV3611, 2-O-octadecylascorbic acid), and xanthine oxidase inhibitor (allopurinol). The free radical scavengers and inhibitor enhanced the coronary hyperemic flow response during embolization, and the total number of microspheres causing maximal embolization was increased by these drugs. When 8-phenyltheophylline was additionally administered with superoxide dismutase, these beneficial effects were abolished, indicating that coronary effects of these drugs may be due to increased release of adenosine during coronary microvascular embolization. CONCLUSIONS: We conclude that oxygen radicals worsen the ischemic injury in coronary microembolization.

Allopurinol↗
PubMed1991

Mechanism of early ischemic contractile failure. Inexcitability, metabolite accumulation, or vascular collapse?

The basis of early ischemic contractile failure was investigated in perfused ferret hearts at 27 degrees C. Isovolumic left ventricular developed pressure fell by more than 50% within 30 seconds of the onset of total global ischemia and reached zero by 5 minutes. Monophasic action potential recordings revealed no decrease in excitability during this period. Phosphorus nuclear magnetic resonance spectra obtained at 30-second resolution showed no significant changes in inorganic phosphate or phosphocreatine during the first 30 seconds of ischemia. Intracellular pH (pHi) and ATP changed even more slowly; therefore, none of these metabolites could account for the rapid fall in force. To gauge the contribution of intravascular pressure, we compared ordinary aortic flow occlusion with tissue-level ischemia induced by massive coronary microembolization at the level of the precapillary arterioles. Functional depression developed significantly more slowly in the microembolized hearts, despite accumulation of inorganic phosphate and protons comparable with that in ordinary ischemia. After microembolization, the time course of functional depression reflected much more closely the concomitant inorganic phosphate and pHi changes. Thus, our results provide novel evidence supporting the importance of vascular collapse in the mechanism of early ischemic contractile failure.

Animals↗
PubMed1991

Glycolytic inhibition and calcium overload as consequences of exogenously generated free radicals in rabbit hearts.

Free radicals have been implicated in the pathogenesis of reperfusion injury, but it is unclear how they exert their deleterious effects on cellular metabolism. Several lines of indirect evidence suggest that free radicals elevate intracellular Ca2+ concentration ([Ca2+]i) and inhibit glycolysis as part of their mechanism of injury. We tested these ideas directly in hearts subjected to hydroxyl radicals produced by the Fenton and Haber-Weiss reactions. Nuclear magnetic resonance spectra were obtained from Langendorff-perfused rabbit hearts before, during, and after 4 min of perfusion with H2O2 (0.75 mM) and Fe(3+)-chelate (0.1 mM). Isovolumic left ventricular pressure exhibited progressive functional deterioration and contracture after exposure to H2O2 + Fe3+. Phosphorus nuclear magnetic resonance (NMR) spectra revealed partial ATP depletion and sugar phosphate accumulation indicative of glycolytic inhibition. To measure [Ca2+]i, fluorine NMR spectra were acquired in a separate group of hearts loaded with the Ca2+ indicator 5F-BAPTA [5,5'-difluoro derivative of 1,2-bis-(o-aminophenoxy)ethane- N,N,N',N'-tetraacetic acid]. Mean time-averaged [Ca2+]i increased from 347 +/- 14 nM in control to 1,026 +/- 295 nM 4 min after free radical generation (means +/- SEM, n = 7), and remained elevated thereafter. We conclude that free radicals induce clear-cut, specific derangements of cellular metabolism in the form of glycolytic inhibition and calcium overload. The observed increase in [Ca2+]i suggests that the deleterious effects of free radicals are at least partially mediated by secondary changes in cellular calcium homeostasis.

Adenosine Triphosphate↗
PubMed1991

Pathophysiology and pathogenesis of contractile failure in stunned myocardium.

To investigate excitation-contraction coupling in stunned myocardium, intracellular free calcium concentration [( Ca2+]i) was measured before and after ischemia in perfused hearts using gated 19F NMR and the Ca2+ indicator 5F-BAPTA. Maximal Ca(2+)-activated force was also measured in parallel experiments. Stunned myocardium was created by reperfusion after 15 min global ischemia at 37 degrees C in isolated ferret hearts. In stunned myocardium, peak [Ca2+]i was paradoxically higher than that in control, but maximal Ca(2+)-activated pressure was lower in stunned hearts. These results indicate that contractile failure in stunned myocardium is due to a decrease in the myofilament sensitivity to Ca2+ as well as to a decrease in maximal Ca(2+)-activated force; failure of activator Ca2+ delivery cannot be implicated. The role of intracellular calcium overload in the pathogenesis of stunned myocardium was also investigated. Time-averaged 19F NMR measurements directly revealed the increase in [Ca2+]i during ischemia and in the early phase of reperfusion. The strategies to prevent Ca overload during reperfusion with modified reperfusate succeeded in preserving contractile function. Transient Ca overload without ischemia induced by different causes, i.e., high [Ca]0 perfusion, ventricular fibrillation or treatment with adriamycin, also produced contractile dysfunction that outlasted the interventions themselves. Thus, we propose that transient Ca overload during ischemia and early reperfusion initiates long-lasting contractile dysfunction in stunned myocardium.

Animals↗
PubMed1990

Mechanism of ischemic contracture in ferret hearts: relative roles of [Ca2+]i elevation and ATP depletion.

When coronary perfusion is interrupted, the diastolic force generated by the myocardium first falls but eventually increases. The delayed rise in force, ischemic contracture, has been attributed either to ATP depletion or to elevation of the intracellular free calcium concentration ([Ca2+]i). To distinguish between these possibilities, we measured [Ca2+]i and ATP concentration [( ATP]) in ferret hearts using nuclear magnetic resonance (NMR) spectroscopy. Mean time-average [Ca2+]i and [ATP] equaled 0.25 microM and 2.7 mumol/g wet wt, respectively, under control perfusion conditions. [Ca2+]i increased and [ATP] fell during total global ischemia. Although [Ca2+]i exceeded the usual systolic levels of 1.7 microM within 20-25 min of ischemia and reached a steady level between 2 and 3 microM by 30-35 min, force only began to rise after 40 min. In contrast, the time required for [ATP] to fall to less than 10% of control levels coincided closely with the onset of contracture. Ischemia in the presence of iodoacetate, an inhibitor of glycolysis, led to a precipitous fall in [ATP] and a concomitant rise in force, both of which preceded any elevation of [Ca2+]i. Thus changes in [Ca2+]i are neither sufficient nor necessary for the initiation of ischemic contracture. We conclude that ATP depletion is primary and that the rise in resting force reflects the formation of rigor cross bridges.

Adenosine Triphosphate↗
PubMed1990

Recovery of contractility and pHi during respiratory acidosis in ferret hearts: role of Na(+)-H+ exchange.

During acute respiratory acidosis, cardiac contractile pressure first drops but then recovers substantially. We investigated the mechanism of this response in isovolumic perfused ferret hearts. Developed pressure (DP) and its first derivative (dP/dt) were measured before, during, and after hypercapnia induced by equilibrating the perfusate with 15% CO2, rather than the 5% CO2 used in control. Intramyocardial pH (pHi) was measured by phosphorus nuclear magnetic resonance (NMR) spectroscopy. After the onset of hypercapnia (1-2 min), DP and +dP/dt reached minimal mean values of 37 +/- 2 and 39 +/- 3% of control, respectively. This early decline in myocardial contactility was followed by a partial recovery such that DP and +dP/dt had returned to 66 +/- 6 and 62 +/- 4% of control, respectively, by 14 min of hypercapnia. pHi fell from 7.17 +/- 0.01 in control to 6.88 +/- 0.11 after approximately 2 min of hypercapnia. Thereafter, pHi recovered linearly with a mean slope of 0.011 +/- 0.003 pH U/min. Ethylisopropylamiloride (10(-6) M), a blocker of Na(+)-H+ exchange, prevented the recovery of pHi during hypercapnia and attenuated the recovery of contractility by 40%. We conclude that the recovery of contractility during respiratory acidosis at least partially reflects an underlying recovery of pHi mediated by Na(+)-H+ exchange.

Acidosis, Respiratory↗
PubMed1990

Relative roles of Ca2(+)-dependent and Ca2(+)-independent mechanisms in hypoxic contractile dysfunction.

Contractile function is known to be impaired during hypoxia or metabolic inhibition, but the relative importance of activator Ca2+ deficiency compared with the accumulation of depressant metabolites remains controversial. To distinguish between these possibilities, we used nuclear magnetic resonance (NMR) spectroscopy to measure the most likely mediators--intracellular [Ca2+] [( Ca2+]i), inorganic phosphate concentration [( Pi]), and pH--before and during hypoxia in perfused ferret hearts. Ca2+ transients were quantified by gated fluorine-19 NMR spectroscopy. Left ventricular developed pressure decreased to steady-state levels approximately 60% of control values after 20 minutes of hypoxic perfusion (induced by equilibrating the perfusate with 10% O2-90% N2). With hypoxia, phosphorus NMR revealed an increase in [Pi] and a mild intracellular acidosis. Both [Pi] and intracellular pH correlate well with the extent of decline of developed pressure in each heart, but multiple regression analysis points to the changes in [Pi] as the dominant influence. In contrast, [Ca2+]i at end diastole was not influenced by hypoxia, whereas the peak systolic values were paradoxically increased. The ratio of Ca2+ transient amplitude in hypoxia to that in control had no correlation with percent of developed pressure. These findings indicate that contractile failure during relatively mild, steady-state hypoxia is not due to a critical failure of any of the mechanisms that regulate cytoplasmic activator Ca2+. Instead, the accumulation of Pi (and to a lesser degree, H+) mediates hypoxic contractile dysfunction.

Animals↗