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Biomedical subjects

Y Koretsune

Publications and source records attributed to Y Koretsune.

At least 55 records · Page 3Linked to original sources
PubMed1990

Cell calcium, oncogenes, and hypertrophy.

The cellular mechanisms of cardiac hypertrophy remain unclear despite tantalizing clues gleaned from a variety of experimental approaches. Here we examine the hypothesis that an increase in cytosolic free Ca2+ concentration ([Ca2+]i) triggers the expression of proto-oncogenes, which in turn direct the characteristic increase in protein synthesis. New results from perfused ferret hearts are presented demonstrating that [Ca2+]i increases as a direct consequence of an elevation in perfusion pressure. It therefore seems plausible that [Ca2+]i constitutes the crucial link between the initial stimulus for hypertensive hypertrophy (elevated perfusion pressure) and the secondary alterations in gene expression. Nevertheless, further investigation will be required to establish whether changes in [Ca2+]i are necessary or sufficient to stimulate myocardial cell growth.

Animals↗
PubMed1990

Quantification of [Ca2+]i in perfused hearts. Critical evaluation of the 5F-BAPTA and nuclear magnetic resonance method as applied to the study of ischemia and reperfusion.

Calcium has been implicated as a mediator of cell injury in ischemia and reperfusion, but direct measurements of Ca2+ are required to refine this idea. We used nuclear magnetic resonance spectroscopy and the Ca2+ indicator 5F-BAPTA to measure [Ca2+]i in perfused ferret hearts. Several lines of evidence are presented to show that loading with the acetoxymethyl ester of 5F-BAPTA is not significantly complicated by accumulation of partially de-esterified metabolites, compartmentalization into mitochondria, or disproportionate uptake into endothelial cells. During 20 minutes of total global ischemia at 30 degrees C, time-averaged [Ca2+]i increased significantly, reaching peak values roughly three times control at 15-20 minutes. Reperfusion resulted in a persistent elevation of [Ca2+]i during the first 5 minutes, but not afterward. Although the nonlinear response of 5F-BAPTA to [Ca2+] leads to underestimation of the true time-averaged [Ca2+]i, the measured alterations of intracellular Ca2+ homeostasis during ischemia are large compared with the likely errors in quantification. Phosphorus nuclear magnetic resonance spectroscopy of 5F-BAPTA-loaded hearts reveals changes during ischemia similar to those recorded previously in hearts not containing a Ca2+ indicator. Developed pressure recovers to only 50% of control values during reflow, indicating that the presence of 5F-BAPTA in the cytosol does not protect against stunning, at least when the extracellular calcium concentration has been raised to 8 mM. We conclude that 5F-BAPTA provides useful measurements that reveal that time-averaged [Ca2+]i rises during ischemia and returns to control levels soon after reperfusion.

Animals↗
PubMed1990

Excitation-contraction coupling in postischemic myocardium. Does failure of activator Ca2+ transients underlie stunning?

To elucidate the mechanism of contractile dysfunction in postischemic ("stunned") myocardium, time-resolved measurements of intracellular free Ca2+ concentration ([Ca2+]i) were made using gated 19F nuclear magnetic resonance in seven perfused ferret hearts loaded with the fluorinated Ca2+ indicator 5F-BAPTA. Left ventricular developed pressure decreased to 65 +/- 3% (mean +/- SEM) of control after 15 minutes of global ischemia at 37 degrees C. In stunned myocardium, diastolic [Ca2+]i (0.24 +/- 0.03 microM) was not changed from control (0.18 +/- 0.03 microM, p greater than 0.10), but peak [Ca2+]i (1.03 +/- 0.13 microM) was paradoxically higher than that in control (0.61 +/- 0.06 microM, p less than 0.02). The slope of the relation between developed pressure and Ca2+ transient amplitude in stunned myocardium was significantly lower than that in control (p less than 0.05), even after normalization by maximal Ca2(+)-activated pressure. These results indicate that contractile failure in stunned myocardium is due to a decrease in the myofilament sensitivity to Ca2+ as well as to the previously identified decrease in maximal Ca2(+)-activated force; failure of activator Ca2+ delivery cannot be implicated. The increase in the amplitude of Ca2+ transients would require that more ATP be spent in Ca2+ sequestration; thus, decreased efficiency of energy utilization in stunned myocardium would result.

Animals↗
PubMed1989

An increase in myocardial beta-adrenoceptors to compensate for postischaemic dysfunction following coronary micro-embolisation in dogs.

This study examined whether beta-adrenoceptors increase in number during recovery from prolonged myocardial stunning and whether they compensate for lack of physiological response to beta-adrenergic stimulation in this abnormality. The left coronary artery was embolished in anaesthetised dogs with non-labelled microspheres (15 +/- 1 micron; 1.2 X 10(6).kg-1 body weight). Haemodynamic studies were performed before (control) and 24 h and 1 week after embolisation, in the conscious state. Myocardial noradrenaline content, plasma catecholamine concentrations and the density of beta-adrenoceptors (Bmax) were also assessed at three study intervals. At 24 h after embolisation, both systolic and diastolic cardiac function was significantly depressed. The inotropic response to isoprenaline was preserved, but the response to forskolin was markedly depressed. One week after embolisation, resting systolic function was restored to control levels and histological examination showed absence of myocardial necrosis. Although plasma noradrenaline concentration had returned to normal, myocardial noradrenaline content had decreased by 36% and the density of beta-adrenoceptors had increased by 48%. Myocardial relaxation was still impaired and the inotropic response to forskolin was also still depressed, whereas the response to isoprenaline was normal. Moreover, the down regulation of the increased beta-adrenoceptors by isoprenaline infusion for 24 h unmasked the latent systolic dysfunction. These results indicate that the density of beta-adrenoceptors increases during the recovery process from prolonged myocardial stunning and that this increase may compensate, at least in part, for impairment of the inotropic mechanism distal to the beta-adrenoceptors.

Animals↗
PubMed1989

Adenosine-induced hyperemia attenuates myocardial ischemia in coronary microembolization in dogs.

We have recently reported that coronary microembolization sustains myocardial ischemia with hyperemic response of coronary blood flow (CBF) induced by massive release of adenosine from the ischemic myocardium. In this study, we tested the hypothesis that this hyperemic flow caused by released adenosine improves myocardial ischemia. In eight dogs (control), microspheres (5.0 X 10(4)/ml of base-line CBF) were repetitively injected until CBF decreased toward zero, and the changes in CBF, fractional shortening, lactate extraction ratio (LER), and adenosine release were studied. In 15 other dogs, an identical procedure was done with an intracoronary infusion of prazosin (4 micrograms.kg-1.min-1, n = 8) or theophylline (0.1 mg.kg-1.min, n = 7) to elucidate the effect of adenosine, since prazosin inhibits release of adenosine from ischemic myocardium and theophylline blocks adenosine receptors. In 16 other dogs, hemodynamic and metabolic parameters were examined with and without these drugs after a single injection of microspheres (1.0 X 10(5)/ml of base-line CBF). In the control group, CBF increased to 170 +/- (SE) 14% of the base-line CBF at 16-30% of maximal embolization. In contrast, intracoronary infusion of prazosin markedly attenuated adenosine release and hyperemic response and significantly deteriorated both fractional shortening and LER. Theophylline also significantly attenuated the hyperemic response and tended to decrease both fractional shortening and LER. A salutary effect of adenosine release was further confirmed by the improvement of ischemic changes in the same dog after withdrawal of prazosin and theophylline associated with an increase in CBF. Thus we conclude that adenosine released from ischemic myocardium improves ischemia in microembolization through the hyperemic response.

Adenosine↗
PubMed1989

Cell calcium in the pathophysiology of ventricular fibrillation and in the pathogenesis of postarrhythmic contractile dysfunction.

The mechanism of ventricular fibrillation is poorly understood at the cellular level. We explored the role of intracellular free calcium in the pathophysiology and pathogenesis of ventricular fibrillation in perfused ferret hearts loaded with the Ca2+ indicator 5F-BAPTA. Nuclear magnetic resonance spectroscopy was used to measure [Ca2+]i, pH, and high-energy phosphates. During ventricular fibrillation induced by burst pacing, [Ca2+]i rose rapidly and dramatically, exceeding by four times the control within 5 minutes. [Ca2+]i remained markedly elevated throughout 20 minutes of fibrillation, but it returned to control values shortly after defibrillation. In a group of hearts kept isovolumic by a balloon in the left ventricle, acidosis and high-energy phosphate depletion developed despite the maintenance of normal coronary pressure. To distinguish the effects of superimposed ischemia from those of the arrhythmia itself, we lowered left ventricular volume during fibrillation in a second group of hearts. This maneuver decreased wall stress such that fibrillation had no significant adverse effect on intracellular pH, high-energy phosphates, or lactate efflux. [Ca2+]i still increased remarkably despite the absence of ischemic changes. Developed pressure did not recover to control levels after defibrillation in either group; the hearts appeared "stunned." We conclude that intracellular calcium increases as a direct consequence of ventricular fibrillation. The increase in [Ca2+]i may cause the contractile dysfunction observed in postarrhythmic hearts. Its possible role in initiating or maintaining the arrhythmia is less clear.

Animals↗
PubMed1989

Calcium and its role in myocardial cell injury during ischemia and reperfusion.

Direct measurements of intracellular free Ca2+ concentration ([Ca2+]i) were obtained during ischemia and reperfusion in ferret hearts loaded with the Ca2+ indicator, the 5,5'-difluoro derivative of 1,2-bis(o-aminophenoxy)ethane-N,N,N',N',-tetraacetic acid. During 15 minutes of ischemia at 37 degrees C, time-averaged [Ca2+]i increased significantly and decreased rapidly during reperfusion. In contrast to metabolic inhibition in isolated muscle or cells, the increase in [Ca2+]i during true ischemia occurs in the absence of a mechanical contracture. After ischemia, contractile function does not recover completely: the hearts are "stunned." Our results support the hypothesis that an increase in cellular calcium-loading causes dysfunction in the form of myocardial stunning while leaving unresolved the precise mechanism of the calcium-mediated injury.

Animals↗
PubMed1988

Alpha 2-adrenoceptor activity exerts dual control of coronary blood flow in canine coronary artery.

To test the hypothesis that alpha 2-adrenoceptor activity exerts a dual control of coronary blood flow, i.e., vasoconstriction and augmentation of the vasodilatory effect of adenosine, four doses of adenosine were infused into left anterior descending coronary artery before and during alpha 2-adrenoceptor stimulation or attenuation in anesthetized open-chest dogs. During a moderate alpha 2-adrenoceptor attenuation (yohimbine or rauwolscine, ic), which did not alter coronary blood flow (CBF) at the base-line condition, the hyperemic response of CBF to infused adenosine was markedly reduced, whereas during the potent attenuation both base-line CBF and adenosine-induced hyperemic CBF were significantly increased. Inversely, the moderate alpha 2-stimulation (0.03 microgram.kg-1.min-1 norepinephrine with prazosin, ic, or 0.04 microgram.kg-1.min-1 clonidine ic, under propranolol pretreatment) augmented the adenosine-induced coronary vasodilation, but the potent alpha 2-stimulation (0.3 microgram.kg-1.min-1 norepinephrine with prazosin ic, or 0.3 microgram.kg-1.min-1 clonidine ic) reduced both base-line CBF hyperemic CBF. In contrast, alpha 2-adrenoceptor activity did not affect papaverine-induced coronary vasodilation. Moreover, the reactive hyperemic flow after a brief coronary occlusion was reduced significantly during the moderate alpha 2-adrenergic attenuation, but it was augmented during the potent one. These results indicate that the moderate activation of the alpha 2-adrenoceptor augments the hyperemic response of CBF to both exogenous and endogenous adenosine, whereas the potent alpha 2-activation may mask this vasodilatory effect through the coronary vasoconstrictive effect.

Adenosine↗
PubMed1987

A possible model of the anginal syndrome with normal coronary arteriograms: microembolization of canine coronary arteries.

To investigate whether disseminative coronary embolization with microspheres brings about a pathophysiological mimicking of the syndrome of exertional angina with a normal coronary arteriogram, 25 dogs were studied immediately and 2 weeks after the coronary embolization with microspheres 15 micron [2.5 X 10(5) or 5.0 X 10(5)/regional flow (ml/min)] and 25 micron [2.0 X 10(5)/regional flow (ml/min)] in diameter. Two weeks after embolization with the 15-micron microspheres, the resting coronary blood flow recovered to the control (preembolization) level with the absence of myocardial necrosis, but the coronary flow reserve was significantly lower. In ten dogs receiving the larger dose embolization (5 X 10(5)/regional flow (ml/min], lactate production or a marked decrease in lactate extraction was observed during rapid atrial pacing. In five dogs subject to 25-micron microsphere embolization, however, disseminative patchy myocardial necrosis was observed and the coronary flow reserve remained normal. These results indicate that the chronic state after microembolization with a large dose of 15-micron microspheres mimics the syndrome of exertional angina with a normal coronary arteriogram, whereas 25-micron microsphere embolization does not. Thus, the condition of some patients with a normal coronary arteriogram but with reduced coronary flow reserve may be attributable to microcirculatory disturbances in the coronary arterioles or smaller vessels. Moreover, we observed that the coronary flow at the induction of myocardial ischemia by pacing was much less than the reactive hyperemic flow. This discrepancy may be a characteristic feature in this syndrome.

Angina Pectoris↗
PubMed1987

Alpha 1-adrenoceptor activity regulates release of adenosine from the ischemic myocardium in dogs.

The goal of this study was to test the hypothesis that alpha 1-adrenoceptor activity plays a key role in the release of adenosine from the ischemic myocardium. In 51 open-chest dogs, the left anterior descending coronary artery was perfused through an extracorporeal bypass tube from the carotid artery, and adenosine release into the local coronary vein was measured by the radioimmunoassay technique following the reduction of perfusion pressure for 20 minutes under alpha 1-, alpha 2-, and beta-adrenoceptor attenuations. Adenosine and lactate concentrations in the coronary arterial and venous blood sampled from the perfused area were determined, as well as fractional shortening. In the untreated condition, adenosine release was significantly (p less than 0.01) increased from 1.7 +/- 0.8 (SEM) to 8.8 +/- 1.3 nmol/100 g/min, 20 minutes after the onset of hypoperfusion (coronary blood flow: 28 +/- 2 ml/100 g/min) following the initial overshoot release. Neither beta- nor alpha 2-adrenoceptor attenuation affected the increase in adenosine release during hypoperfusion except for the slight attenuation of the overshoot release by beta-attenuation. In contrast, intracoronary infusions of prazosin and phentolamine during coronary hypoperfusion markedly attenuated (p less than 0.01) release of adenosine (1.8 +/- 0.7 nmol/100 g/min at 20 minutes). The extents of decreases in fractional shortening and lactate production were comparable between the untreated and alpha 1-adrenoceptor attenuation.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine↗
PubMed1986

Role of adenosine in hyperemic response of coronary blood flow in microembolization.

To investigate the pathophysiology of acute embolization of small coronary vessels and the role of adenosine in this abnormality, regional coronary blood flow (CBF), coronary vascular resistance, arteriovenous O2 difference, lactate extraction ratio, and adenosine release were studied in 39 anesthetized open-chest dogs after acute coronary embolization with microspheres of three different diameters (15 +/- 1, 94 +/- 8, and 293 +/- 23 microns). In 16 dogs, the left anterior descending coronary artery was embolized by repetitive injections of 15-microns microspheres, up to 4.4 +/- 0.4 X 10(5)/g myocardium; at this point CBF, determined by the electromagnetic flowmeter at the proximal site of the artery, was reduced toward zero. Up to 37% of total embolization, resting CBF increased to 175 +/- 36% of control; thereafter it decreased almost linearly as the extent of embolization was increased. After embolization, coronary arteriovenous O2 difference was significantly (P less than 0.01) decreased with a marked release of adenosine in the coronary vein. Despite a hyperemic flow response of CBF in the embolized area, myocardial ischemia was not prevented; maximal increase in CBF after 100-microns microsphere embolization (141 +/- 11% of control CBF, n = 6) was significantly (P less than 0.05) less than that in 15-micron microsphere embolization, whereas 300-microns microsphere embolization minimally increased CBF (123 +/- 13%, P greater than 0.1; n = 5). Hyperemic flow remained unchanged for at least 3 h when adenosine was persistently released. Theophylline significantly attenuated this response. These results indicate that in embolization with microspheres less than 300 microns in diameter, hyperemic response of coronary blood flow occurs, probably due to the hyperemia of nonoccluded vessels in the adjacent area of ischemic foci to adenosine released from the ischemic myocardium.

Adenosine↗
PubMed1986

Cardiotonic activity of a new inotropic agent, 3,4-dihydro-6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]-2(1H)- quinolinone (OPC-8212), in the dog with and without beta-blocker and Ca++-antagonist pretreatment.

Hemodynamic effects of a new inotropic agent, OPC-8212 (2(1H)-quinolinone derivative) were studied in anesthetized open chest dogs pretreated with propranolol and diltiazem. Three doses (1, 3 and 10 mg/kg) of OPC-8212 were administered intravenously and the net hemodynamic effect (% change) was obtained by subtraction of the effect of the solvent from the gross effect, since the vehicle has a transient, but significant hemodynamic effect. The maximal inotropic effect occurred 3 minutes after administration: LV dP/dt max and cardiac output (CO) increased by 19 +/- 2.5% and 28 +/- 8.5%, respectively, at 3 mg/kg. These cardiotonic effects were dose-dependent, whereas heart rate, peak LV pressure (PLVP) and mean aortic pressure were minimally changed at any dose. Accordingly, systemic vascular resistance (SVR) decreased in a dose-dependent manner although the decrease was much less than that in administration of isoproterenol. The inotropic effect was not blocked by beta-adrenoceptor blockade (propranolol 1 mg/kg), indicating that the cardiotonic action of this agent is not due to beta-adrenergic stimulation. Thus, this agent could reverse beta-blocker-induced heart failure. During infusion of diltiazem (0.1 mg/kg/min following bolus intravenous administration of 0.5 mg/kg), the increases in LV dP/dt max and CO due to OPC-8212 were similar to those in the control study. In contrast to the effects under beta-adrenoceptor blockade, however, decreased PLVP was restored by OPC-8212. Neither chronotropic nor rrhythmogenic effects were observed in the control or with either pharmacological intervention. These results indicate that OPC-8212 has a potent inotropic action with modest vasodilatory effect even with propranolol or diltiazem pretreatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Beneficial effect of OPC-8212 (3,4-dihydro-6-(4-(3,4-dimethoxy benzoyl)-1-piperazinyl)-2(1H)-quinolinone on myocardial oxygen consumption in dogs with ischemic heart failure.

The effect of a new inotropic agent, OPC-8212 (2(1H)-quinolinone derivative), on myocardial oxygen consumption (MVO2) following intravenous administration (1 and 3 mg/kg/min) was studied in normal and ischemic failing hearts in open chest dogs. Ischemic failing heart was obtained by intracoronary injection of 15-micron microspheres and volume loading. OPC-8212 significantly increased LV max dP/dt and decreased mean aortic pressure, whereas heart rate was not altered in both normal and failing hearts. Despite the remarkable positive inotropic effect, this agent did not increase MVO2 in the normal hearts and even decreased MCO2 in the ischemic failing hearts associated with a decrease in LV end-diastolic pressure and hence, LV chamber size. These results indicate that OPC-8212 does not increase myocardial oxygen demand, probably because the increase in MVO2 by positive inotropic effect is offset by a decrease in MVO2 due to a decrease in chamber size. Thus, OPC-8212 may be promising for the treatment of congestive heart failure with reduced coronary flow reserve.

Animals↗
PubMed1986

[Collateral circulation during exercise-induced angina: evaluation by coronary angiography].

The pathophysiological significance of coronary collateral vessels remains controversial, despite previous intensive studies. We performed the multistage supine ergometer stress test for 26 patients with effort angina and collaterals. The changes in the collaterals were observed during each anginal attack by coronary angiography before and after intravenous nitroglycerin. The collaterals of 21 patients disappeared or diminished during exercise-induced angina before nitroglycerin administration, and were unchanged in the remaining five cases. However, the collaterals of all patients after nitroglycerin administration were unchanged or increased during exercise-induced angina. Considering there were no significant changes in pulmonary arterial end-diastolic pressures during angina before and after nitroglycerin administration, a pressure gradient between the donor and recipient coronary arteries was suggested as being related to the patency of the collaterals. These results suggested the following: 1. It is not appropriate to postulate that the collaterals visualized at rest may remain unchanged during exercise-induced angina. 2. It is not reasonable to conclude that exercise accelerates the development of collateral circulation. 3. One favorable effect of nitroglycerin administration is the prevention of exercise-induced ischemia via collateral circulation.

Adult↗
PubMed1985

Comparison of coronary hemodynamic and cardiac metabolic alterations during coronary artery spasm associated with ST segment elevation or depression.

Coronary vasospasms are usually indicated by ST elevation or depression in the electrocardiogram (ECG). To test the hypothesis that ST elevation represents more severe myocardial ischemia than does ST depression, we determined the coronary sinus blood flow (CSBF) and the transcardiac lactate extraction ratio (LER) in 19 selected patients who had focal vasospasms in the left anterior descending artery. In 10 patients, ergonovine (0.11 +/- 0.02 mg, mean +/- SEM) provoked severe (total or subtotal) coronary vasospasm with ST elevation. Under these conditions, CSBF significantly decreased (from 97 +/- 8 ml/min to 79 +/- 5 ml/min, p less than 0.01) with a marked reduction in LER (from 29 +/- 5% to -14 +/- 6%, p less than 0.01). In contrast, 10 vasospastic events with ST depression after ergonovine (0.15 +/- 0.04 mg, NS) were recognized as mild spastic narrowing or severe spasms with well developed collateral circulation. Alteration of CSBF was significant in only a few patients and the overall CSBF response was non-significant (from 106 +/- 12 ml/min to 103 +/- 13 ml/min). The reduction in LER in this group was less pronounced than those in patients with ST elevation (p less than 0.05). These results indicate that coronary vasospasm with ST elevation may be related to the more pronounced reduction in coronary blood flow accompanied by more severe myocardial ischemia. Such observations may support the contention that some ischemic events associated with ST elevation or depression can be interpreted as a continuous spectrum of vasospastic disorders.

Adult↗