Yoshio Nishida

A novel anti-diabetic drug, miglitol, markedly reduces myocardial infarct size in rabbits

We examined whether N‐hydroxyethyl‐1‐deoxynojirimycin (miglitol), a new human anti‐diabetic drug with effects to inhibit α‐1,6‐glucosidase glycogen debranching enzyme and reduce the glycogenolytic rate as well as to inhibit α‐1,4‐glucosidase, could reduce infarct size in the rabbit heart. Rabbits were subjected to 30‐min coronary occlusion followed by 48‐h reperfusion. The infarct size as a percentage of area at risk was not reduced by pre‐ischaemic treatment with 1 mg kg−1 miglitol (42.7±4.0%, n=10) compared with the saline control group (41.7±2.3%, n=10). However, it was significantly and dose‐dependently reduced by pre‐ischaemic treatment with 5 or 10 mg kg−1 of miglitol (25.7±4.5%, n=10, and 14.6±2.4%, n=10, respectively) without altering the blood pressure, heart rate or blood glucose level. However, there was no evidence of an infarct‐size reducing effect after pre‐reperfusion treatment with 10 mg kg−1 of miglitol (35.0±3.0%, n=10). Another 40 rabbits given 1, 5 and 10 mg kg−1 of miglitol or saline before ischaemia (n=10 in each) were sacrificed at 30 min of ischaemia for biochemical analysis. Miglitol preserved significantly the glycogen content, and attenuated significantly the lactate accumulation in a dose dependent manner in the ischaemic region at 30 min of ischaemia. Pre‐ischaemic treatment, but not pre‐reperfusion treatment, with miglitol markedly reduced the myocardial infarct size, independently of blood pressure and heart rate. A dose‐dependent effect of miglitol on infarct size, glycogenolysis and lactate formation suggests that the mechanism may be related to the inhibition of glycogenolysis. Thus, miglitol may be beneficial for coronary heart disease as well as diabetes mellitus.

Assessment of area at risk and efficacy of treatment in patients with acute coronary syndrome using99mTc tetrofosmin imaging in humans

The determination of the myocardium at risk before intervention and the change in that region after intervention constitute a promising measurement tool for the assessment of acute therapy. A new99mTc labeled myocardial blood flow tracer,99mTc tetrofosmin, is expected to enable the evaluation of myocardium at risk because of the absence of redistribution. This preliminary study was performed in 9 patients with acute coronary syndrome (4 unstable angina and 5 acute myocardial infarction) to investigate whether recovery of perfusion by tetrofosmin imaging parallels mechanical improvement. Tetrofosmin imaging was performed acutely and 3–30 days later. Visual analysis of defect severity was assessed in both studies. Segments with improvement in perfusion were accompanied by significant wall motion recovery compared with normal and unimproved segments (Δ WMI: normal segments 0.40±0.67, improved segments 1.79±0.68, unimproved segments −0.15±0.16, p< 0.01 for improved segments compared with other groups), suggesting the efficacy of this tracer for the assessment of the acute therapy. These data suggest that99mTc tetrofosmin imaging is a useful method for the assessment of the myocardial area at risk and the efficacy of acute therapy in acute myocardial infarction and unstable angina.

Modulation of cardiac interstitial noradrenaline levels through KATP channels during ischemic preconditioning in rabbits: comparison of the effect of anesthesia between pentobarbital and ketamine + xylazine

SummaryIn rabbits, both the stimulation of α1-adrenoceptors and ischemic preconditioning (PC) reduce infarct size. One candidate for the mechanism of PC is noradrenaline (NA), which stimulates α1-adrenoceptors in the myocardium during PC. Opening of the KATP channel is considered to be another candidate for PC, since a KATP channel blocker, glibenclamide, blocks the infarct size-reducing effect of the PC of 5-min ischemia and 5-min reperfusion in rabbits anesthetized with ketamine + xylazine. However, in rabbits anesthetized with pentobarbital, the infarct size-reducing effect of PC was not blocked by glibenclamide. The effect of glibenclamide on the PC effect thus differs depending on the anesthesia used. Therefore, we speculated that the increase in cardiac interstitial NA levels induced by PC may be modified by the anesthesia used, thus regulating the effect of glibenclamide on the PC effect. In open-chest Japanese white male rabbits anesthetized with pentobarbital or ketamine + xylazine, myocardial interstitial NA levels were measured before and during the PC of 5-min ischemia and 5-min reperfusion in the presence or absence of the KATP channel blocker, glibenclamide (0.3mg/kg, i.v.), using a microdialysis technique. The NA levels were measured using high-performance liquid chromatography coupled with electrochemical detection. The PC of 5-min ischemia and 5-min reperfusion significantly elevated the interstitial NA level. This increase in the NA level was not blocked by glibenclamide under anesthesia with pentobarbital. Under anesthesia with ketamine + xylazine, the PC did not cause an increase in the myocardial interstitial NA level in either the absence or the presence of glibenclamide. In conclusion, PC elevates the myocardial interstitial NA level, and this elevation is not mediated through the opening of the KATP channel under anesthesia with pentobarbital. Under anesthesia with ketamine + xylazine, PC does not cause an increase in the myocardial interstitial NA level. This may explain the discrepancy in the blocking effect of glibenclamide on the infarct size-reducing effect of PC between anesthesia with pentobarbital and ketamine + xylazine.

Role of protein kinase C in the reduction of infarct size by N-methyl-1-deoxynojirimycin, an α-1,6-glucosidase inhibitor

Preischaemic treatment with N‐methyl‐1‐deoxynojirimycin (MOR‐14), an α‐1,6‐glucosidase inhibitor, attenuates glycogenolysis and lactate accumulation during ischaemia and markedly reduces infarct size in rabbit hearts. In the present study, we have investigated whether protein kinase C (PKC), a principal mediator of ischaemic preconditioning, is also involved in the cardioprotective effect of MOR‐14. To assess the effect of PKC inhibition on infarct size in MOR‐14‐treated hearts, 38 rabbits were subjected to 30 min of ischaemia followed by 48 h of reperfusion. Infarct size, as a per cent of area at risk, was significantly smaller in rabbits administered 100 mg kg−1 of MOR‐14 10 min before ischaemia (17±2%, n=10), than in a control group (46±5%, n=10). This beneficial effect of MOR‐14 was abolished when 5 mg kg−1 of chelerythrine, a PKC inhibitor, was given 10 min prior to MOR‐14 injection (39±4%, n=10), although chelerythrine alone did not alter infarct size (43±4%, n=8). Further, chelerythrine had no effect on MOR‐14‐induced attenuation of glycogen breakdown and lactate accumulation in hearts excised at 30 min of ischaemia. Immunoblot analysis of PKC in homogenates of Langendorff‐perfused rabbit hearts revealed that MOR‐14 significantly increased levels of PKC‐ε in the particulate fraction at 20 and 30 min of ischaemia and in the cytosolic fraction at 30 min of ischaemia. Taken as a whole, our data suggest that PKC acts downstream of the inhibition of glycogenolysis by MOR‐14 to reduce infarct size. Thus, activation of PKC is a more direct mediator of the cardioprotection afforded by MOR‐14 than is inhibition of glycogenolysis.

Identification of asynergic but viable myocardium in patients with chronic coronary artery disease by gated blood pool scintigraphy during isosorbide dinitrate and low-dose dobutamine infusion: Comparison with thallium-201 scintigraphy with reinjection

To evaluate the ability of low-dose dobutamine and isosorbite dinitrate (ISDN) gated blood pool scintigraphy (GBPS) and thallium SPECT with reinjection to identify viability in asynergic myocardium, both procedures were performed in 38 consecutive patients with chronic coronary artery disease and left ventricular dysfunction. Twenty-two of the 38 patients with successful revascularization were analyzed. GBPS was performed at the baseline and during continuous infusion of low dose dobutamine (5 μg/kg/min) and ISDN (2 μg/kg/min). Cine mode GBPS wall motion was scored from normal (0) to dyskinesis (4) semiquantitatively. Forty-seven of 110 segments with severe asynergy at the baseline were analyzed. Viability determined by GBPS was defined as wall motion score improvement by more than 1 grade. Thallium viability was defined as the segment with redistribution or fill in with severe initial perfusion defect. GBPS was 76.7% sensitive and 70.6% specific for predicting post vascularization wall motion improvement (p < 0.005). Of 47 segments with severe asynergy, concordance of judgement was obtained in 40 segments (85.1 %), and reversibility was correctly diagnosed in 34 of 40 patients (85.0%), but thallium with reinjection correctly identified tissue viability in 6 of 7 segments with discordance between 2 studies.These data suggest that most cases of reversible asynergy (hibernating myocardium) respond to ISDN and dobutamine, suggesting the possibility of predicting improvement by revascularization, although some underestimation of tissue viability remained to be resolved. Thallium with reinjection is superior to low-dose dobutamine + ISDN GBPS for the assessment of myocardial viability.

N-Methyl-1-deoxynojirimycin (MOR-14), an α-glucosidase inhibitor, markedly improves postischemic left ventricular dysfunction

Abstract We examined whether pharmacological inhibition of glycogenolysis by N-methyl-1-deoxynojirimycin (MOR-14), a new compound which reduces the glycogenolytic rate by inhibiting the α-1,6-glucosidase activity of the glycogen-debranching enzyme, can protect the heart against postischemic left ventricular dysfunction. The hearts of male Sprague-Dawley rats were excised, and perfused on a Langendorff apparatus with Krebs-Henseleit solution with a gas mixture of 95% O2 and 5% CO2. The hearts were paced at 320 beats/min except during the ischemia. Left ventricular developed pressure (LVDP, mmHg), ±dP/dt (mmHg/s), and coronary flow (ml/min) were continuously monitored. All hearts were perfused for a total of 120 min including a 30-min preischemic period followed by a 30-min episode of global ischemia and 60 min reperfusion, with or without 0.5 or 2 mM of MOR-14 during the 30-min preischemic period or the first 30 min of reperfusion. In another series of experiments, the myocardial content of glycogen and lactate was measured during the 30-min episode of ischemia in groups treated with and without 2 mM of MOR-14. Preischemic but not postischemic treatment with MOR-14 significantly improved LVDP and ±dP/dt without altering coronary flow during reperfusion in a dose-dependent manner. MOR-14 significantly preserved the glycogen content and significantly attenuated the lactate accumulation during the 30-min episode of ischemia. Preischemic treatment with MOR-14 is protective against postischemic left ventricular dysfunction through the inhibition of glycogenolysis in the isolated rat heart.