Effects of carnitine palmitoyltransferase I inhibitors on hepatic hypertrophy.

We investigated the effect of two types of carnitine palmitoyltransferase I inhibitors, ethyl 2-(6-(4-chlorophenoxy)hexyl)oxirane-2-carboxylate (etomoxir) and (R)-3-carboxy-N,N, N-trimethyl-2-¿[hydroxy(tetradecyloxy)phosphinyl]oxy¿-1-propana minium hydroxide (SDZ CPI 975), on cardiac and hepatic hypertrophy in ddY mice. One-week administration of etomoxir caused cardiac and hepatic hypertrophy, 19% and 22% as a ratio to body weight, respectively. Although 4-week administration of etomoxir caused hepatic hypertrophy, there was no significant change in liver triglyceride content in the first or second week. In cultured HepG(2) cells, etomoxir treatment (1 week) did not cause triglyceride to accumulate. One-week administration of SDZ CPI 975 caused neither cardiac nor hepatic hypertrophy. In vitro, neither drug had selectivity for carnitine palmitoyltransferase I isozymes. These findings suggest that the hepatic hypertrophy following 1- or 2-week treatment with etomoxir is caused by mechanisms different from those responsible for triglyceride accumulation, and that inhibition of carnitine palmitoyltransferase I may not necessarily induce hepatic hypertrophy.

Effects of specific antagonists of angiotensin II receptors and captopril on diabetic nephropathy in mice.

We investigated whether angiotension II was involved with diabetic nephropathy in the mouse model. Twelve days after streptozotocin (STZ) injection, the urinary albumin excretion (UAE) level was increased by 118% of the baseline value. On days 21, 28, 35 and 42 after STZ injection, the UAE levels were significantly increased compared with the level at day 12. A marked elevation of creatinine clearance and diabetic-induced renal hypertrophy were also observed on day 49 after STZ injection. The 35-day treatments of captopril and Dup 753 (angiotensin II type 1 receptor antagonist) significantly attenuated the increment of UAE levels (26.4% on day 14 and 34.6% on day 28). PD123177 (angiotensin II type 2 receptor antagonist) also attenuated the increment of UAE (24.7% on day 14) at the dose of 150 mg/kg. Furthermore, Dup 753 partially prevented diabetic-induced renal hypertrophy. These results suggest that angiotensin II type 2 receptor as well as type 1 receptor may be involved in the development of diabetic nephropathy in the STZ-induced diabetic mice, and these mice are beneficial models of early diabetic nephropathy.

Vasopressor effect of lysophosphatidic acid on spontaneously hypertensive rats and Wistar Kyoto rats.

Intravenous injection of lysophosphatidic acid (LPA, 1-acyl-sn-glycerol-3-phosphate) into conscious, spontaneously hypertensive rats (SHR) promptly elicited hypertension in a dose-dependent manner, its effect being significantly higher than in conscious, age-matched Wistar Kyoto strain rats (WKY). There was, however, no difference between the potencies of LPA in raising the mean blood pressure of SHR and WKY anesthetized with pentobarbital. The releases of norepinephrine, angiotensin II, prostaglandin and leukotriene were found not to be involved in the vasopressor effect of LPA in SHR, although thromboxane seemed to be slightly related to the action of LPA.

Effects of efonidipine hydrochloride (NZ-105), a calcium antagonist, on renal function in conscious spontaneously hypertensive rats.

1. We investigated the effects of short- and long-term administration of efonidipine hydrochloride (NZ-105), 1,4-dihydropyridine derivative, in conscious spontaneously hypertensive rats (SHR). 2. Oral administration of NZ-105 for 12 weeks caused diuretic and natriuretic effects, which were not attenuated during the experimental period. 3. In the short-term experiment for investigating the mechanism of the diuretic effect, intravenous injection of NZ-105 (0.03 mg/kg of body weight) significantly increased the urine volume (UV), renal plasma flow (RPF) and glomerular filtration rate (GFR). The increment rate of UV and RPF was 105.4 +/- 17.8% and 111.7 +/- 72.8%, respectively, which were larger than the increment rate of GFR (38.5 +/- 14.0%). 4. The diuretic or natriuretic effect of NZ-105 was suggested to be due to both the inhibition of sodium reabsorption and, at least in part, the increase of GFR.

Formation of PAF-like compounds by peroxidation of phospholipids from bovine brain.

This short review describes the identification by mass spectrometry of phospholipids having an sn-2-short-chain monocarboxylate, dicarboxylate or omega-hydroxycarboxylate group in a fraction with PAF-like activity from a bovine brain lipid extract. The similar molecular heterogeneities of these unique phospholipids suggest that they are formed via a common mechanism, possibly peroxidation of membrane phosphatidylcholines. This possibility is supported by the finding that these PAF-like compounds were actually formed during peroxidation of synthetic phosphatidylcholines induced by Fe2+/ascorbate/EDTA.

Quantitative analysis of platelet-activating factor in rat brain.

Age-related decrease of the platelet-activating factor (PAF) content in rat brain was shown by a convenient method consisting of solid extraction of lipids with a Sep-Pak C-18 cartridge, lipid separation by HPLC and bioassay on rabbit platelets. This method was sufficiently sensitive to allow measurement of PAF in a single brain, and the recovery of PAF was quite high throughout the procedure.

[Changes of acinar cells in the pancreato-biliary duct ligation with exocrine pancreatic stimulation model in rats; protective effects of a new potent protease inhibitor, ONO3307].

To evaluate the changes of pancreatic acinar cells in the pancreatic duct obstructed animals as well as the protective effects of a new potent protease inhibitor, ONO3307, we measured the serum amylase levels, pancreatic water content, histological changes, lysosomal fragility in in-vitro incubation, cathepsin B distribution in acinar cells, and cathepsin B and amylase output into pancreatic juice after short-termed (3 hrs) pancreatic duct obstruction with caerulein (0.2 micrograms/kg.hr) infusion in rats. Serum amylase levels, pancreatic water content, and lysosomal fragility in duct obstructed with caerulein infused animals were significantly increased compared with the control groups, and remarkable shift of cathepsin B from lysosomal fraction to zymogen fraction was observed in this group. These changes tended to continue 24 hours after removal of duct obstruction. But with infusion of ONO3307, these changes observed in duct-obstructed with caerulein infusion groups were significantly, almost completely attenuated. These results indicate the intimate relationship between the pathogenesis of acute pancreatitis and lysosomes and some known proteases which are inhibited by ONO 3307 and suggest the usefulness of such a kind of protease inhibitor in the treatment of acute pancreatitis.

Identification of sn-2-omega-hydroxycarboxylate-containing phospholipids in a lipid extract from bovine brain.

Phospholipids having both a long-chain acyl (palmitoyl or stearoyl) and a short-chain hydroxycarboxylyl (C3-C9) residue were identified by GC-MS in a fraction with PAF-like activity from a bovine brain lipid extract. The hydroxyl group in the hydroxycarboxylate residue was determined to be at the omega-position by comparison of the mass spectra of the tert-butyl-dimethylsilyl derivatives of these compounds with those of synthetic hydroxybutyrate-containing phosphatidylcholines. The co-existence of short-chain hydroxycarboxylate-, monocarboxylate- and dicarboxylate-containing phospholipids in the bovine brain lipid extract suggested that these compounds were formed by peroxidation of membrane phospholipids, especially phosphatidylcholines.

[Clinical studies on PC-904 in biliary tract diseases (author's transl)].

The clinical effects of PC-904, a new semisynthetic penicillin, were studied in patients with biliary tract diseases, and the results were as follows: 1) PC-904 showed an average peak serum level of 40.7 +/- 11.6 microgram/ml 2 hours after an intravenous drip infusion of 1 g of the agent. The biliary level showed a peak value of 126.5 +/- 85.4 microgram/ml 2 hours to 3 hours after the infusion. 2) Isolated organisms from bile before the treatment were E. coli, Klebsiella, Proteus, Pseudomonas, Enterococcus and Bacteroides. MIC of PC-904 on 18 strains of isolated organisms was almost 6.25 microgram/ml or less. All isolated organisms except one strain of Klebsiella oxytoca disappeared after the treatment. 3) Six patients with cholelithiasis were medicated with PC-904 to prevent post-operative infections. The clinical effects were good in 4, poor in 1 and unknown in 1 case. 4) As to side effects no adverse reactions and allergic reactions were noted. Also no significant abnormalities of laboratory findings were observed.