Tohru Nakai

Effects of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors on mitochondrial respiration in ischaemic dog hearts.

1 Effects of 3‐hydroxy‐3‐methylglutaryl coenzyme A (HMG‐CoA) reductase inhibitors, pravastatin and simvastatin, on the myocardial level of coenzyme Q10, and on mitochrondrial respiration were examined in dogs 2 Either vehicle (control), pravastatin (4 mg kg−1day−1), or simvastatin (2 mg kg−1day−1) was administered orally for 3 weeks. First, the myocardial tissue level of coenzyme Q10 was determined in the 3 groups. Second, ischaemia was induced by ligating the left anterior descending coronary artery (LAD) in anaesthetized open chest dogs, pretreated with the inhibitors. After 30 min of ischaemia, nonischaemic and ischaemic myocardium were removed from the left circumflex and LAD regions, respectively, and immediately used for isolation of mitochondria. The mitochondrial respiration was determined by polarography, with glutamate and succinate used as substrates 3 Simvastatin significantly decreased the myocardial level of coenzyme Q10, but pravastatin did not 4 Ischaemia decreased the mitochondrial respiratory control index (RCI) in both groups. Significant differences in RCI between nonischaemic and ischaemic myocardium were observed in the control and simvastatin‐treated groups 5 Only in the simvastatin‐treated group did ischaemia significantly decrease the ADP/O ratio, determined with succinate 6 The present results indicate that simvastatin but not pravastatin may cause worsening of the myocardial mitochondrial respiration during ischaemia, probably because of reduction of the myocardial coenzyme Q10 level.

Effects of Bibr-277, an angiotensin Ii type 1 receptor antagonist, on stunned myocardium in dogs

BackgroundAngiotensin converting enzyme inhibitors can protect the myocardium from ischaemic damage. We examined the effect of BIBR-277, an angiotensin II receptor type 1 antagonist, on myocardial stunning in dogs. MethodsPentobarbital-anaesthetized open-chest dogs were subjected to 20 min ligation of the left anterior descending coronary artery, followed by reperfusion for 60 mm. Saline or 0.3, 1 or 3 mg/kg body weight BIBR-277 was injected intravenously 10 min before coronary ligation. The myocardial contractile function was measured by ultrasonometry. The tissue levels of energy metabolites in the 60 min reperfused heart were determined. ResultsMyocardial contractile function assessed in terms of percentage segment-shortening in the saline-treated group decreased during ischaemia and returned towards the pre-ischaemic level during reperfusion but incompletely (myocardial stunning). A significant and dose-dependent improvement in the percentage segment-shortening during reperfusion was observed in the BIBR-277-treated groups. The levels of ATP, ADP and AMP in the reperfused heart were not modified by BIBR-277 treatment compared with those in the saline-treated group. ConclusionBIBR-277 ameliorates the myocardial contractile dysfunction during reperfusion after ischaemia, although it did not bring about any improvement in the high-energy phosphate levels in the reperfused heart.

Influence of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors on mitochondrial respiration in rat liver during ischemia.

Effects of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, pravastatin and simvastatin, on mitochondrial respiration in ischemic rat liver were examined. Either vehicle, pravastatin (2 or 4 mg/kg per day), or simvastatin (1 or 2 mg/kg per day) was orally administered for 3 weeks. Liver ischemia was induced by cessation of the systemic circulation for 60 min. Liver mitochondria were isolated and the respiration was determined by polarography using glutamate and succinate as substrates. In the vehicle-treated group, ischemia drcreased ZO3, respiratory control index (RCI: QO3/QO4), and ADP/O ratio. Pretreatments with pravastatin and simvastatin enhanced the decreases in QO3 measured with either glutamate or succinate, and in ADP/O ratio measured with succinate. Because of decreasing QO4, HMG-CoA reductase inhibitors did not modify the changes in RCI due to ischemia. There were no significant differences in respiratory indices between pravastatin- and simvastatin-treated groups. In conclusion, HMG-CoA reductase inhibitors may enhance respiratory impairment of liver mitochondria under pathophysiological conditions, such as ischemia.

Acute effect of simultaneous administration of tryptophan and ethanol on serotonin metabolites in the locus coeruleus in rats

Using the microdialysis method, we investigated whether the levels of serotonin (5-hydroxytryptamine, 5-HT) and its metabolites, 5-hydroxyindoleacetic acid (5-HIAA) and 5-hydroxytryptophol (5-HTPL), in the locus coeruleus are influenced by tryptophan alone or simultaneous administration of tryptophan and ethanol. Tryptophan (50 mg/kg, i.p.) led to a significant increase in the levels of 5-HIAA, but not 5-HT in the locus coeruleus. However, ethanol (1.25 g/kg) had no effect on the levels of 5-HT and its metabolites. Combined administration of tryptophan and ethanol caused very marked increases in 5-HIAA and 5-HTPL levels in the locus coeruleus. A time lag in the increased 5-HIAA levels between tryptophan alone and tryptophan plus ethanol was observed. Moreover, 5-HIAA levels in the locus coeruleus induced by tryptophan were abolished by microinjection of 5,7-dihydroxytryptamine (150 microg/4 microl) into the dorsal raphe nucleus. Judging from the present results, the serotonergic afferents to the locus coeruleus may originate for about 20-30% from cell bodies located in the dorsal raphe nucleus. Teeth-chattering was significantly detected in the tryptophan plus ethanol-treated rats when compared with the tryptophan-treated rats, but not in the saline-treated controls. These results may suggest that the increased levels of 5-HIAA and 5-HTPL in the locus coeruleus induced by tryptophan are potentiated by ethanol, and that these levels are partly responsible for behavioral activation.

Physiological Role and Localization of the New Ouabain Receptor Protein (31.5 KD) from Cat Cardiac Muscles, Using The Monoclonal AB Against the Protein

Role and localization of the new ouabain receptor protein (31.5 kD) were studied by using its monoclonal AB. The protein may be a key protein in the E-C coupling process in the cat cardiac muscle.

Energy Ameliorants: A New Category of Antianginal Drugs

Depletion of adenosine triphosphate (ATP) caused by ischemia may cause myocardial contractile dysfunction during ischemia and reperfusion. We speculate that loss of adenine nucleotides during ischemia may occur from the adenosin diphosphate (ADP) store near the contractile elements. We have tested several agents as candidates for energy ameliorants to fill ADP stores with ADP: (1) adenine nucleotide precursors, such as adenosine, inosine, 5-amino-4-imidazole carboxamide riboside (AICAr), and a nucleoside/nucleotide mixture (OG-VI); (2) membrane-permeable adenine nucleotide analogues, such as 8-bromo-5′-adenosine monophosphate (8-bromo-AMP) and N 6, 2′ 3′-tributyryl-5′ -adenosine monophosphate (tributyryl-AMP); and (3) liposome-entrapped ADP. Pentobarbital-anesthetized dogs were subjected to 20-min ligation of the left-anterior descending coronary artery, followed by reperfusion for 30 min. Saline or an energy ameliorant was infused at O. lmlkg−1min−1 from the left femoral vein throughout the experiment. Prepared liposome-entrapped ADP was intracoronarily infused at 0.5 ml body−1 min−1. The myocardial contractile function was measured by ultrasonometry and assessed by percentage (%) segment shortening. The level of ATP was determined in the 30min-reperfused heart. During ischemia, % segment shortening decreased in all groups. Reperfusion recovered the % segment shortening to a certain extent depending on the energy ameliorants used. A significant improvement in the % segment shortening during reperfusion was observed in the OG-VI-, 8-bromo-AMP-, and AICAr-infused groups. Liposome-entrapped ADP also enhanced the % segment shortening recovery during reperfusion. In the OG-VI- and 8-bromo-AMP-infused groups, the level of ATP in the reperfused heart was significantly higher than that in the saline-infused group. This result indicates that some agents can act as energy ameliorants to improve the ability of the heart to recover from ischemia and reperfusion.

Effects of BIBR-277, an Angiotensin-II Type-1 Receptor Antagonist, on Ischemic Myocardial Stunning in Dogs

BIBR-277, an angiotensin-II type-1 receptor antagonist, improved the recovery of contractile function of the stunned myocardium. Enalapril also lessened the contractile dysfunction during reperfusion in the stunned myocardium. These drugs may act to reduce ischemic damage by removing the systemic and coronary vasoconstrictive effects of angiotensin II.