To examine whether cytosolic acetyl-CoA hydrolase in rat liver is involved in regulation of cholesterol biosynthesis, we investigated the alteration of the enzyme activity under conditions of stimulation (cholestyramine treatment) and suppression [cholesterol feeding, a potent competitive inhibitor of microsomal 3-hydroxy-3-methylglutaryl-CoA reductase (CS 514) treatment, and a hypolipidemic drug [alpha-(p-chlorophenoxy)isobutyric acid, CPIB] injection) of cholesterol biosynthesis. The enzyme activity in rat liver increased significantly in the early diabetic, cholesterol-fed, CS 514-, and CPIB-treated groups, but no change in its activity was observed in chronic diabetic groups. Cholestyramine treatment to cholesterol-fed rats made the enzyme activity return to the initial level. When chronic diabetic rats were given a cholesterol diet or treated with CS 514 or CPIB, the activity increased significantly. Inhibition of cholesterol biosynthesis caused by these treatments induced increase in the enzyme activity with increase in the enzyme protein, judging from results obtained by enzyme-linked immunosorbent assay. These results suggest that this enzyme has a physiological role in maintenance of the equilibrium between the cytosolic acetyl-CoA concentration and CoA-SH pool for cholesterol metabolism.

This study was a prospective, randomized, open, blinded endpoint study to assess the effects of angiotensin II type 1 receptor blocker, losartan, compared with calcium channel blocker, amlodipine, on left ventricular (LV) diastolic function and atherosclerosis of the carotid artery in Japanese patients with mild-to-moderate hypertension, LV hypertrophy, diastolic dysfunction and preserved systolic function. Fifty-seven patients were randomly assigned to losartan-or amlodipine-based treatment groups and were followed up for 18 months. Blood pressure was similarly reduced by both regimens. Losartan shortened the transmitral E-wave deceleration time, and amlodipine reduced LV mass index; however, there was no significant difference in the percent changes of these indices between the two groups. Mean carotid intima-media thickness (mean IMT) as well as plaque score significantly increased in the amlodipine-based regimen (pre: 1.05 ± 0.26 mm, follow-up: 1.23 ± 0.33 mm, P¼0.0015), but not in the losartan-based regimen (pre: 1.08 ± 0.35 mm, follow-up: 1.16 ± 0.52 mm, P¼non-significant). The percent increase in mean IMT in the amlodipine-based regimen tended to be large compared with the losartan-based regimen (amlodipine: 19.8 ± 23.7%, losartan: 6.9 ± 23.3%, P¼0.06). Under similar reduction of blood pressure, losartan is likely effective in protecting the progression of atherosclerosis of the carotid artery compared with amlodipine. Losartan may improve LV diastolic function, and amlodipine may attenuate LV hypertrophy; however, this study cannot make consecutive remarks about the superiority of either treatment regimen in the effects on cardiac function and geometry. This study has been registered at

A 28-year-old man with acute myocardial infarction after carbon monoxide poisoning is reported. He had chest pain after the exposure to carbon monoxide. The electrocardiogram, serum enzymes, and technetium-99m pyrophosphate scintigrams showed anterior myocardial infarction. The coronary angiogram, which was performed one month after the onset, showed no visible atherosclerotic lesion. As to the cause of myocardial infarction, it is assumed that carbon monoxide reduced the oxygen supply to the myocardium and might induce coronary artery spasm with or without accompanying coronary thrombosis.

Cold labile extramitochondrial acetyl-CoA hydrolase (dimeric form) purified from rat liver was activated by various nucleoside triphosphates and inhibited by various nucleoside diphosphates. Activation of acetyl-CoA hydrolase by ATP was inhibited by a low concentration of ADP (Ki congruent to 6.8 microM) or a high concentration of AMP (Ki congruent to 2.3 mM). ADP and AMP were competitive inhibitors of ATP. A Scatchard plot of the binding of ATP to acetyl-CoA hydrolase (dimer) at room temperature gave a value of 25 microM for the dissociation constant with at least 2 binding sites/mol of dimer. Cold-treated monomeric enzyme also associated with ATP-agarose, suggesting that the monomeric form of the enzyme also has a nucleotide binding site(s), probably at least 1 binding site/mol of monomer. Phenylglyoxal or 2,3-butanedione, both of which modify arginyl residues of protein, inactivated acetyl-CoA hydrolase. ATP (an activator) greatly protected acetyl-CoA hydrolase from inactivation by these reagents, while ADP (an inhibitor) greatly (a substratelike, competitive inhibitor), and CoASH (a product) were less effective. However, addition of ADP plus valeryl-CoA (or CoASH) effectively prevented the inactivation by 2,3-butanedione, but that is not the case for phenylglyoxal. These results suggest that one or more arginyl residues are involved in the nucleotide binding site of extramitochondrial acetyl-CoA hydrolase and that their nucleotide binding sites locate near the substrate binding site.

When Donryu male albino rats were given diet containing 0.06% 3′–methyl‐4‐dimethyl‐ aminoazobenzene (3′–Me‐DAB) for 20 weeks, the activity of cytosolic acetyl‐CoA hydrolase in their livers decreased to about one‐third the initial level in week 2, returned to the control level in week 7, and then decreased again to about one‐tenth of the control in week 20. These changes in enzyme activity were parallel with changes in the amount of enzyme protein determined by ELISA. In 3′–Me‐DAB‐resistant rats, however, the enzyme activity and enzyme protein remained within the normal range during administration of 3′–Me‐DAB‐containing diet for 20 weeks and no tumors were detectable macroscopically. Interestingly, the biphasic change in this enzyme activity was inversely associated with the well known change of γ‐glutamyltranspeptidase activity during azo‐dye‐induced hepatocarcinogenesis.