Biomedical subjects

S Takeo

Publications and source records attributed to S Takeo.

At least 37 records · Page 2Linked to original sources

PubMed2000

Age-specific effects of noradrenergic alpha-2 agonist clonidine on the development of amygdaloid kindling in developing rats.

The effects of clonidine on the development of amygdaloid kindling were studied in rats of various ages (14, 21, 28 and 70 postnatal days). Administration of clonidine (0.2, 0.5 mg/kg i.p.) caused a significant retardation of kindling development in the 28-day-old rats as well as in the adult rats, whereas, in the 14-day-old rats, the development of kindling was significantly facilitated by clonidine. No significant effect of clonidine was observed in the 21-day-old rats. These results indicate that in rats the effects of clonidine on the development of amygdaloid kindling vary during development.

Adrenergic alpha-Agonists↗

PubMed2000

Cytoprotective mechanism of heat shock protein 70 against hypoxia/reoxygenation injury.

The role of heat shock protein 70 (HSP70) in the cytoprotection against hypoxia/reoxygenation injury was examined. Adult rat cardiomyocytes were isolated, subjected to hyperthermia at 42 degrees C for 15 min (heat shock treatment), and then incubated at 37 degrees C for 3 to 24 h (HSP production process). Heat shock treatment increased HSP70 production (80-260% increase); the peak increase was seen after 9 h of HSP production process. Thereafter, the cells were subjected to 120-min hypoxia and 15-min reoxygenation. Heat shock treatment increased the survival of the cells subjected to hypoxia/reoxygenation (1.5-2.5-fold); the maximal cytoprotection was observed after 12 h of HSP production process. Heat shock treatment increased HSP70 content in the nucleus when cells were subjected to 12 h of HSP production process. To examine the role of HSP70 accumulation in the nuclear fraction, the activity of poly(ADP-ribose) synthetase (PARS), which functions in the nucleus and consumes high-energy phosphates excessively in the reoxygenated state, were measured in the cells with heat shock and 12 h of HSP production process. Heat shock treatment attenuated the hypoxia/reoxygenation-induced increase in the PARS activity (50% decrease). Treatment of the cells with 3-aminobenzamide, an inhibitor of PARS, exerted the effects similar to those of heat shock treatment. These results suggest that attenuation of the PARS activity in the nucleus may play an important role in the cytoprotective effect of HSP70 on hypoxia/reoxygenation injury.

Animals↗

PubMed2000

A role of PKC in the improvement of energy metabolism in preconditioned heart.

OBJECTIVE: A possible link between activation of PKC and improvement of energy metabolism during reperfusion in ischemic preconditioning hearts was examined. METHODS: Isolated perfused rat hearts were preconditioned by 5-min ischemia and 5-min reperfusion in the presence and absence of a PKC inhibitor polymyxin B (50 microM) and then subjected to 40-min sustained ischemia and subsequent 30-min reperfusion. In another set of experiments, the hearts pretreated with and without a PKC activator PMA (15 pmol/5 min) were subjected to the sustained ischemia and reperfusion. Myocardial high-energy phosphates, glycolytic intermediates and mitochondrial oxygen consumption capacity were determined at appropriate experimental sequences. RESULTS: Preconditioning enhanced the recovery of cardiac function such as left ventricular developed pressure, heart rate and rate-pressure product of the reperfused heart, suppressed the release of creatine kinase, enhanced the reperfusion-induced restoration of myocardial high-energy phosphates, attenuated the reperfusion-induced accumulation in glucose 6-phosphate and fructose 6-phosphate contents, abolished the ischemia-induced increase in tissue lactate content and prevented the ischemia-induced decrease in mitochondrial oxygen consumption capacity. Treatment of the perfused heart with PMA mimicked the effects of preconditioning on post-ischemic contractile function, enzyme release, levels of myocardial energy store, glycolytic intermediates and lactate, and mitochondrial function. Polymyxin B-treatment abolished the preconditioning-induced recovery of post-ischemic contractile function, the suppression of the release of CK, the restoration of myocardial energy store, and the preservation of mitochondrial function, whereas it did not cancel the improvement of glycolytic intermediate levels and the reduction in tissue lactate accumulation. Post-ischemic contractile function was closely related to restoration of high-energy phosphates and mitochondrial oxygen consumption capacity in all hearts subjected to ischemia/reperfusion. CONCLUSION: The results suggest that activation of PKC and preservation of mitochondrial function are closely linked with each other in the preconditioned heart, which may lead to the improvement of post-ischemic contractile function.

Animals↗

PubMed2000

Contribution of sodium channel and sodium/hydrogen exchanger to sodium accumulation in the ischemic myocardium.

Contribution of sodium channels and sodium/hydrogen exchangers (NHEs) to sodium accumulation during ischemia in the ischemic/reperfused heart was examined. Ischemia increased the myocardial sodium. Reperfusion elicited a further increase in the myocardial sodium, which was associated with little recovery of the left ventricular developed pressure (LVDP) of the perfused heart. Treatment with tetrodotoxin or dimethylamirolide (DMA) dose-dependently attenuated the ischemia- and reperfusion-induced increase in myocardial sodium and enhanced the post-ischemic recovery of the LVDP. There was an inverse relationship between the increase in myocardial sodium during ischemia and the post-ischemic recovery of the LVDP.The myocardial sodium accumulation during ischemia is mainly attributed to sodium influx through sodium channels and NHEs.

Amiloride↗

PubMed2000

Attenuation of changes in sarcoplasmic reticular gene expression in cardiac hypertrophy by propranolol and verapamil.

The effects of propranolol and verapamil on contractile dysfunction, subcellular remodeling and changes in gene expression in cardiac hypertrophy due to pressure overload were examined. Rats were subjected to banding of the abdominal aorta and then treated with either propranolol (10 mg/kg daily), verapamil (5 mg/kg daily) or vehicle for 8 weeks after the surgery. Depression of the left ventricular function in the hypertrophied heart was associated with decreases in myofibrillar and myosin Ca2+ ATPase activities as well as Ca2+-pump and Ca2+-release activities of the sarcoplasmic reticulum (SR). The level of alpha-myosin heavy chain (alpha-MHC) mRNA was decreased while that of beta-MHC mRNA was increased in the pressure-overloaded heart. The level of SR Ca2+-pump ATPase (SERCA2) mRNA and protein content for SERCA2 were decreased in the pressure overloaded heart. Treatment of the hypertrophied animals with propranolol or verapamil resulted in preservation of the left ventricular function and prevention of the subcellular alterations. Shift in the alpha- and beta-MHC mRNA levels and changes in the expression in SERCA2 mRNA level and protein content were also attenuated by these treatments. The results suggest that blockade of beta-adrenoceptors or voltage-dependent calcium channels normalizes the cardiac gene expression, prevents subcellular remodeling and thus attenuates heart dysfunction in rats with cardiac hypertrophy. Furthermore, both cardiac beta-adrenoceptors and L-type Ca2+-channels may be involved in the genesis of cardiac hypertrophy due to pressure overload.

Adenosine Triphosphatases↗

PubMed2000

Preservation of mitochondrial function by diazoxide during sustained ischaemia in the rat heart.

1. A possible mechanism for the action of the K(ATP) channel opener diazoxide on the improvement of energy metabolism of ischaemic/reperfused hearts was examined. 2. Isolated, perfused rat hearts were subjected to 40 min ischaemia followed by 60 min reperfusion. Diazoxide at concentrations of 3 to 30 microM was present in the perfusion buffer for the last 15 min of pre-ischaemia. 3. Treatment of the perfused heart with diazoxide enhanced the post-ischaemic recovery of rate-pressure product, attenuated the post-ischaemic rise in left ventricular end-diastolic pressure, and suppressed the release of creatine kinase and purine nucleosides and bases from the reperfused heart. Treatment of the heart with diazoxide also restored myocardial ATP and creatine phosphate and attenuated the decrease in mitochondrial oxygen consumption rate after reperfusion. This attenuation was maintained at the end of ischaemia as well as at the end of reperfusion. 4. In another set of experiments, myocardial skinned bundles were incubated for 30 min under hypoxic conditions in the presence and absence of diazoxide, and then the mitochondrial oxygen consumption rate was determined. Hypoxia induced a decrease in the mitochondrial oxygen consumption rate of the skinned bundles to approximately 40% of the pre-hypoxic value. In contrast, treatment of the bundles with 30 microM diazoxide preserved the normal mitochondrial oxygen consumption rate during hypoxia. This effect was abolished concentration-dependently by the combined treatment with either the K(ATP) channel blocker glibenclamide or 5-hydroxydecanoate. 5. These results suggest that diazoxide is capable of attenuating ischaemia/reperfusion injury of isolated perfused hearts due to preservation of mitochondrial function during ischaemia.

Adenosine Triphosphate↗

PubMed2000

Effect of neutral endopeptidase inhibitor on endogenous atrial natriuretic peptide as a paracrine factor in cultured cardiac fibroblasts.

1. Cardiac remodelling is a fundamental response to hypertension, myocardial infarction and chronic heart failure, and involves cardiac fibroblast proliferation and production of extracellular matrix components such as collagen. The present study was performed to examine the role of endogenous atrial natriuretic peptide (ANP) as a possible paracrine factor for cardiac fibroblasts, and to examine the effects of three neutral endopeptidase (NEP) inhibitors, thiorphan, phosphoramidon and ONO-BB-039-02 (ONO-BB) on endogenous ANP-induced changes in collagen synthesis by cultured neonatal rat cardiac fibroblasts. 2. Each NEP inhibitor singly had no significant effect on collagen synthesis by cardiac fibroblasts, except for maximum concentration (10(-3) M) of thiorphan. 3. Exogenous ANP inhibited collagen synthesis in a concentration-dependent manner (10(-8) - 10(-6) M). Thiorphan (10(-4) and 10(-3) M) and phosphoramidon (10(-5) and 10(-4) M) enhanced the ANP (10(-7) M)-induced decrease in collagen synthesis. ONO-BB (10(-5) and 10(-4) M) slightly enhanced the ANP-induced decrease in collagen synthesis. 4. Myocyte-conditioned medium (MC-CM), as well as exogenous ANP, inhibited collagen synthesis dose-dependently. The decrease in collagen synthesis at 100% MC-CM was augmented by thiorphan (10(-3) M), phosphoramidon (10(-4) M) and ONO-BB (10(-4) M). 5. HS-142-1, a natriuretic peptide receptor antagonist, significantly reduced the MC-CM plus thiorphan- and MC-CM plus ONO-BB-induced decrease in collagen synthesis, by 92 and 62%, respectively and showed a tendency to attenuate the MC-CM plus phosphoramidon-induced decrease in collagen synthesis by 40%. 6. Our observations suggested that endogenous ANP released from cardiomyocytes inhibited collagen synthesis as a paracrine factor and that NEP inhibitors enhanced the activity of this peptide in cardiac fibroblasts.

Animals↗

PubMed2000

The effects of a novel cyclohexane dicarboximide derivative, ST-6, on hypoxia/reoxygenation injury in perfused rat heart.

The present study was undertaken to test if some cyclohexane dicarboximide derivatives may have a cardioprotective effect against hypoxia/reoxygenation injury. Isolated rat hearts were subjected to 20-min of hypoxia followed by 45-min reoxygenation, and their recovery of post-hypoxic cardiac contractile function was examined. Treatment with agents was carried out from 3 min after the onset of hypoxia to the end of hypoxia (17 min during hypoxia). Among the 17 compounds, 2-[4-[4-(4-chlorophenyl)-4-hydroxy-1-piperidinyl]butyl]hexahydro-1H-i soindol-1,3(2H)-dione (ST-6) showed a significant enhancement of post-hypoxic contractile force. This was associated with attenuation of the releases of creatine kinase and purine nucleosides and bases from the perfused heart. Hypoxia-induced increase in myocardial sodium and decrease in potassium ion content was suppressed by ST-6 treatment. The results suggest that ST-6 is capable of protecting the heart against hypoxia/reoxygenation injury possibly through a mechanism by which sodium overload during hypoxia is suppressed.

Animals↗

PubMed2000

Role of cardiac renin-angiotensin system in sarcoplasmic reticulum function and gene expression in the ischemic-reperfused heart.

The aim of this study was to explore the possible participation of cardiac renin-angiotensin system (RAS) in the ischemia-reperfusion induced changes in heart function as well as Ca2+-handling activities and gene expression of cardiac sarcoplasmic reticulum (SR) proteins. The isolated rat hearts, treated for 10 min without and with 30 microM captopril or 100 microM losartan, were subjected to 30 min ischemia followed by reperfusion for 60 min and processed for the measurement of SR function and gene expression. Attenuated recovery of the left ventricular developed pressure (LVDP) upon reperfusion of the ischemic heart was accompanied by a marked reduction in SR Ca2+-pump ATPase, Ca2+-uptake and Ca2+-release activities. Northern blot analysis revealed that mRNA levels for SR Ca2+-handling proteins such as Ca2+-pump ATPase (SERCA2a), ryanodine receptor, calsequestrin and phospholamban were decreased in the ischemia-reperfused heart as compared with the non-ischemic control. Treatment with captopril improved the recovery of LVDP as well as SR Ca2+-pump ATPase and Ca2+-uptake activities in the postischemic hearts but had no effect on changes in Ca2+-release activity due to ischemic-reperfusion. Losartan neither affected the changes in contractile function nor modified alterations in SR Ca2+-handling activities. The ischemia-reperfusion induced decrease in mRNA levels for SR Ca2+-handling proteins were not affected by treatment with captopril or losartan. The results suggest that the improvement of cardiac function in the ischemic-reperfused heart by captopril is associated with the preservation of SR Ca2+-pump activities; however, it is unlikely that this action of captopril is mediated through the modification of cardiac RAS. Furthermore, cardiac RAS does not appear to contribute towards the ischemia-reperfusion induced changes in gene expression for SR Ca2+-handling proteins.

Animals↗

PubMed1999

Relationship between myocardial cation content and injury in reperfused rat hearts treated with cation channel blockers.

A role for K+ and Ca2+ channel blockers in cardiac contractile dysfunction and myocardial ionic imbalance was examined in isolated rat hearts with 35-min ischemia and 60-min reperfusion. The K+ channel blockers glibenclamide (1-30 microM) and sematilide (1-30 microM), Ca2+ channel blockers diltiazem (0.1-3 microM) and nicardipine (0.03-1 microM) and fast Na+ channel blocker tetrodotoxin (0.01-0.3 microM) were delivered for the last 3-min pre-ischemia. Ischemia-induced increase in Na+ content was attenuated by diltiazem and tetrodotoxin at all concentrations employed and by nicardipine at 0.3 microM, whereas the ischemia-induced loss of K+ was suppressed partially by glibenclamide and sematilide and almost completely by the two drugs in combination. Left ventricular developed pressure of untreated hearts did not recover upon reperfusion, which was associated with increases in myocardial Na+ and Ca2+ contents and decreases in K+ and Mg2+ contents. Glibenclamide and sematilide neither enhanced the post-ischemic recovery of left ventricular developed pressure nor affected cation changes during reperfusion. Diltiazem enhanced the recovery of left ventricular developed pressure and attenuated imbalance of the myocardial Na+ during ischemia and of all myocardial cations examined during reperfusion. The effects of nicardipine on these parameters were small. Tetrodotoxin enhanced the recovery of left ventricular developed pressure and reversed the imbalance of all myocardial cations examined during reperfusion in a concentration-dependent manner. The results suggest that blockade of transmembrane flux of K+ during ischemia plays a minor role in the improvement of post-ischemic contractile recovery, rather blockade of transmembrane flux of Na+ attenuates the ischemia and reperfusion injury.

Animals↗

PubMed1999

Microsphere embolism-induced elevation of nerve growth factor level and appearance of nerve growth factor immunoreactivity in activated T-lymphocytes in the rat brain.

Changes in nerve growth factor (NGF) level and type of cells producing NGF were investigated in the rat brain after sustained cerebral embolism. The NGF level was determined by a two-site enzyme immunoassay specific for NGF. The cerebral cortex, striatum, and hippocampus of the embolized hemisphere maximally contained 2.4-, 2.4-, and 1.7-times higher NGF levels than the corresponding regions of the nonembolized hemisphere. A significant increase was transiently observed for 1 week in the cerebral cortex and striatum, whereas the increase was longer lasting, at least of 4 weeks' duration, in the hippocampus. To examine the localization of NGF-like immunoreactivity (NGF-LI), we used a newly developed anti-NGF peptide antiserum that specifically recognized a 30-kDa molecule(s) in the hippocampal extracts or in NGF cDNA-transfected cells, suggesting that the antibody predominantly reacted with the putative NGF precursor protein(s). NGF-LI, which was localized in neurons of the normal or non-embolized hemisphere, was reduced, and on the embolized side new signals emerged in small non-neuronal cells having a round shape. These included cells with common leukocyte antigen CD45 and T-lymphocyte antigen CD3, which did not appear in the normal or non-embolized hemisphere. NGF-LI and CD3 were colocalized in a substantial number of the cells, suggesting that some activated T-lymphocytes produce NGF for neuronal regeneration after sustained cerebral embolism.

Animals↗

PubMed1999

Role of energy metabolism in the preconditioned heart--a possible contribution of mitochondria.

A brief period of ischemia and reperfusion has been shown to protect the myocardium against subsequent sustained ischemia and reperfusion injury, which is called "preconditioning". A great number of investigators have explored the mechanisms underlying this preconditioning-induced cardioprotection. This article dealt with possible mechanisms of energy metabolism and mitochondrial activity for preconditioning-induced cardioprotection. Particularly, the contribution of energy metabolites produced during a brief period of ischemia and reperfusion injury, as well as mitochondrial function that is modified by changes in mitochondrial ATPase activity, opening of mitochondrial ATP-dependent potassium channels and production of free radicals in mitochondria, to ischemic preconditioning is discussed.

Adenosine↗

PubMed1999

Cardioprotective effects of YM934, an ATP-sensitive potassium channel opener, on stunned myocardium in anesthetized dogs.

The effects of YM934 [2-(3,4-dihydro-2,2-dimethyl-6-nitro-2H-1,4-benzoxazin-4-yl) pyridine N-oxide], an adenosine triphosphate (ATP)-sensitive potassium channel opener, on stunned myocardium were examined. Forty eight anesthetized dogs were subjected to 15 min of left anterior descending (LAD) coronary artery occlusion followed by 3 hours of reperfusion. To elucidate the possible contribution of the cardioprotective property of YM934 to stunned myocardium, a nonhypotensive dose of YM934 was directly injected into the LAD coronary artery before the ischemic insults. Intracoronary artery infusion (i.c.) of YM934 (0.1 microg/kg/min) produced a marked improvement in post-ischemic regional contractile dysfunction. The effects were not associated with improvement of hemodynamics, including regional myocardial blood flow during ischemia, heart rate and mean arterial blood pressure. The anatomic areas at risk expressed as a percentage of the left ventricle and regional myocardial blood flow were not significantly different between groups. The cardioprotective effect of YM934 was completely blocked by pretreatment with an ATP-sensitive potassium channel blocker, glibenclamide (1.0 mg/kg i.v. bolus). These results suggest that YM934 exerts cardioprotective effect on stunned myocardium through opening myocardial ATP-sensitive potassium channels.

Adenosine Triphosphate↗

PubMed1999

Improvement of exercise capacity of rats with chronic heart failure by long-term treatment with trandolapril.

1. The effects of long-term treatment with trandolapril, an angiotensin I-converting enzyme inhibitor, on exercise capacity of rats with chronic heart failure (CHF) following coronary artery ligation were examined. CHF was developed by 8 weeks after the coronary artery ligation. 2. The running time of rats with CHF in the treadmill test was shortened to approximately 65% of that of sham-operated rats (16.3+/-1.2 vs. 25.1+/-1.6 min, n = 7; P<0.05). ATP, creatine phosphate (CP), and lactate contents of the gracilis muscle of rats with CHF were similar to those of sham-operated rats before running. After running, ATP and CP were decreased and lactate was increased in both rats with CHF and sham-operated rats. There were no significant differences in the levels of energy metabolites between rats with CHF and sham-operated rats. The rates of decrease in ATP and CP and rate of increase in lactate in the gracilis muscle of rats with CHF during exercise were greater than those of sham operated rats (2.5, 2.0 and 1.5 fold high, respectively), suggesting wastage of energy during exercise in the animals with CHF. 3. Myofibrillar Ca2+ -stimulated ATPase (Ca-ATPase) activity of skeletal muscle of rats with CHF was increased over that of the sham-operated control (62.03+/-1.88 vs. 52.34+/-1.19 micromol Pi mg(-1) protein h(-1) n = 7; P<0.05). The compositions of myosin heavy chain (MHC) isoforms of gracilis muscle were altered by CHF; decreases in MHC types I and IIb and an increase in MHC type IIa were found (P<0.05). 4. Rats with CHF were treated with 1 mg kg(-1) day(-1) trandolapril from the 2nd to 8th week after surgery. Treatment with trandolapril prolonged the running time, reversed the rates of decrease in ATP and CP and the rate of increase in lactate, and restored the Ca-ATPase activity (51.11+/-0.56 micromol Pi mg(-1) protein h(-1), n = 7; P<0.05) and composition ratio of MHC isoforms in the gracilis muscle. 5. The results suggest that long-term trandolapril treatment of rats with CHF may restore their ability to utilize energy without wastage and thus improve exercise capacity.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1999

Reduction by ATP-sensitive potassium channel opener, YM934, of experimental myocardial infarct size in anesthetized dogs.

The present study was undertaken to examine whether the ATP-sensitive potassium channel opener, YM934, would be effective in reducing infarct size in a model of myocardial infarction in anesthetized dogs. For this purpose the effects of nifedipine, a calcium channel blocker, and hydralazine, a vasodilator with unknown mechanisms, were also investigated for comparison. Severe, irreversible myocardial injury was produced by a 90-min occlusion of the proximal left anterior descending coronary artery followed by 5 h of reperfusion. Infusion of YM934 (0.1 microg/kg/min i.c.) during the last 15 min of pre-ischemia reduced the myocardial infarct size and attenuated the release of creatine kinase MB eluted from the hearts without alteration in hemodynamic parameters including regional myocardial blood flow. In contrast, the other vasodilators, hydralazine and nifedipine, did not reduce myocardial infarct size under the same coronary vasodilatory conditions. These observations indicate that intracoronary YM934 is cardioprotective and that this effect is independent of alterations in regional myocardial blood flow.

Animals↗

PubMed1999

Involvement of adenosine receptor, potassium channel and protein kinase C in hypoxic preconditioning of isolated cardiomyocytes of adult rat.

A possible mechanism for hypoxic preconditioning of adult rat cardiomyocytes was pharmacologically investigated. Isolated cardiomyocytes in all experimental groups were incubated for 120 min under hypoxic conditions followed by 15-min reoxygenation (sustained H/R). Sustained H/R decreased rod-shaped cells. Exposure of the cardiomyocytes to 20-min of hypoxia/30-min reoxygenation (hypoxic preconditioning) attenuated the sustained H/R-induced decrease in rod-shaped cells. The effects of hypoxic preconditioning were abolished by treatment with the protein kinase C (PKC) inhibitor polymyxin B, but abolished by neither the adenosine A1/A2-antagonist sulfophenyl theophylline (SPT) nor the ATP-sensitive potassium channel (K(ATP) channel) blocker glibenclamide. In another series of experiments, cardiomyocytes were incubated without hypoxic preconditioning in the presence of either the PKC activator PMA, adenosine or K(ATP)-channel opener nicorandil and then subjected to sustained H/R. Treatment of the cells with PMA, adenosine or nicorandil mimicked the effects of hypoxic preconditioning. The effects of treatment with adenosine and nicorandil were abolished by polymyxin B treatment. Combined treatment with both SPT and glibenclamide abolished the effects of hypoxic preconditioning, whereas it failed to abolish PMA-induced cytoprotection. These results suggest that the activation of PKC in hypoxic preconditioned cardiomyocytes coupled independently with stimulation of adenosine receptor or opening of K(ATP) channel, either of which is fully enough to exert the cytoprotective effects.

Animals↗

PubMed1999

Role of an ATP-sensitive potassium channel opener, YM934, in mitochondrial energy production in ischemic/reperfused heart.

We examined a possible mechanism of action of an ATP-sensitive potassium (K(ATP)) channel opener, YM934, for the improvement of energy metabolism in hearts subjected to 35-min ischemia and 60-min reperfusion. The treatment with 30 nM YM934 for the final 15 min of preischemia enhanced postischemic recovery of left ventricular developed pressure, attenuated the postischemic rise in left ventricular end-diastolic pressure, and suppressed the release of creatine kinase and ATP metabolites during reperfusion. The treatment also restored myocardial ATP and creatine phosphate contents and attenuated the decrease in mitochondrial oxygen consumption rate during reperfusion. The higher mitochondrial function was also seen in YM934-treated hearts at the end of ischemia. In another set of experiments, myocardial skinned bundles were incubated for 30 min under hypoxic conditions in the presence and absence of YM934, and then mitochondrial oxygen consumption rate was determined. Hypoxia decreased the mitochondrial oxygen consumption rate of skinned bundles to approximately 40% of the prehypoxic value. In contrast, the treatment of skinned bundles with 30 nM YM934 preserved the mitochondrial oxygen consumption rate during hypoxia. The effect of YM934 on the hypoxic skinned bundles was abolished by combined treatment with either the K(ATP) channel blocker glyburide or the mitochondrial K(ATP) channel blocker 5-hydroxydecanoate in a concentration-dependent manner. The results suggest that YM934 is capable of attenuating ischemia/reperfusion injury of isolated perfused hearts due to preservation of mitochondrial function during ischemia, probably through opening of mitochondrial K(ATP) channels.

Adenosine Triphosphate↗

PubMed1999

Characterization of positive inotropic effect of colforsin daropate [correction of dapropate] hydrochloride, a water-soluble forskolin derivative, in isolated adult rat cardiomyocytes.

The present study was undertaken to characterize the positive inotropic action of colforsin daropate [corrected] hydrochloride (NKH477), a novel water-soluble forskolin derivative, on isolated cardiomyocytes of adult rats. Simultaneous measurements of cellular contraction and intracellular calcium concentration ([Ca2+]i) were carried out. The effects of isoprenaline and ouabain on these parameters were also determined for comparison. The contraction and maximum [Ca2+]i of NKH477-, isoprenaline-, or ouabain-treated cells were increased concentration dependently. Peak shortening of NKH477-treated cells was positively correlated with the shortening velocity and inversely with the time to peak shortening. Maximum, but not minimum, [Ca2+]i in NKH477-treated cells was correlated with the rate of increase in [Ca2+]i and inversely with the time to maximum [Ca2+]i. Similar results were obtained with isoprenaline. In contrast, ouabain increased both maximum and minimum [Ca2+]i. Treatment with either NKH477 or isoprenaline increased cellular cAMP content, but treatment with ouabain did not. These results suggest that the positive inotropic action of NKH477 is associated with an increase in [Ca2+]i and acceleration of its kinetics.

Animals↗