Forskolin- and diacylglycerol-like potentiation of isoproterenol-induced positive inotropic effect in guinea pig papillary muscles by the musk component,musclide

Musclide (ML) is a glycerol-rich mixed component extracted from musk, a dried secretion from the preputial follicle of musk deer, Moschus moschiferus Linn. ML (50 μg/mL) that caused no direct inotropic effect potentiated isoproterenol (Isp)-induced positive inotropic effect in isolated guinea pig papillary muscles. This cardiotonic action has been attributed to β-adrenergic potentiation. The mechanisms were further investigated using pertussis toxin (IAP), cholera toxin (CTX), forskolin (FK) and dioctanoylglycerol (DOG). IAP pretreatment (50 μg/kg, i.p., the 3rd day before tissue isolation) and/or DOG (200 μM, preliminarily applied for 5 min) increased the maximal response of the concentration-response curve for isoproterenol. CTX pretreatment (0.1 μM, for 3 h) increased the affinity. ML (50 μg/mL) or FK (82.9 nM) preliminarily applied for 5 min caused increases in both the maximal response and affinity. The extent of potentiation produced by ML or DOG was not changed in normal muscles or IAP-pretreated muscles. The extent of potentiation by ML was greater in CTX-pretreated muscles than in normal ones. ML or DOG, when combined with FK, caused only the increase in the maximal response. These results suggest that the potentiation mechanisms of ML are partially FK (adenylate cyclase activator)-like and partially DOG (protein kinase C activator)-like.     

A case of gallbladder adenoma with wide base]

A 65-year-old man was referred for a gallbladder elevated lesion. Abdominal US showed a hypoechoic tumor with wide base at the gallbladder body. The maximum velocity of the gallbladder wall blood flow was 20 cm/s. The outermost hyperechoic layer was irregular, but not disrupted on EUS images. We diagnosed the lesion as gallbladder carcinoma with the depth of subserosa. Cholecystectomy was performed and the tumor was diagnosed as tubular adenoma of the gallbladder. The p53 immumostaining was negative. A gallbladder adenoma with wide base is rare, here we report this case with the several considerations.     

Preventive effect of post-ischemic reperfusion injury by terminal Nicorandil-Mg cardioplegia]

In this study, we evaluated the postischemic myocardial tissue blood flow, specific enzymes, and functional recovery infused with a Nicorandil vasodilator-magnesium solution (Nico.: 8 mg/L, Mg: 20 mEq/L) given just prior to reperfusion (Terminal Cardioplegia, TCP). 27 patients undergoing valve replacement were divided into two groups; the hearts of group non-TCP (nTCP) (n = 15) were reperfused after ischemia without TCP, and in the other hearts of group TCP (n = 12), TCP was given for 2 min prior to reperfusion. During the reperfusion period, myocardial tissue blood flow (TBF) on the anterior wall of left ventricle were monitored by a laser blood flow-meter. Thereafter, serum CK-MB levels, MM3/MM1 values by CK-MM subbands (MM1, MM2, MM3) levels and LVSWI were measured until 24 hours after surgery. At 5 and 10 min of reperfusion, Group TCP had a significantly greater TBF than Group nTCP (5 min; G-TCP: 69.9 +/- 19.0 ml/100 g.min, G-nTCP: 47.5 +/- 20.9, p less than 0.05, 10 min; G-TCP: 74.9 +/- 22.8, G-nTCP: 56.1 +/- 23.4, p less than 0.05). At 3 hrs after surgery, an increase of MM3/MM1 values was significantly suppressed in Group TCP compared to Group nTCP (G-TCP: 2.6 +/- 0.6, G-nTCP: 3.4 +/- 1.0, p less than 0.05). Also, Group TCP had better recovery of LVSWI. These results indicate that the TCP might reduce the postischemic reperfusion injury by the improvement of myocardial TBF and metabolism.     

Phosphonate O-deethylation of [4-(4-bromo-2-cyano-phenylcarbamoyl) benzyl]-phosphonic acid diethyl ester, a lipoprotein lipase-promoting agent, catalyzed by cytochrome P450 2C8 and 3A4 in human liver microsomes.

NO-1886 ([4-(4-bromo-2-cyano-phenylcarbamoyl) benzyl]-phosphonic acid diethyl ester) increases lipoprotein lipase activity, resulting in a reduction in plasma triglycerides and an increase in high-density lipoprotein cholesterol. The metabolism of NO-1886 in human liver was investigated in the present study. Ester cleavage of NO-1886 from diethyl phosphonate to monoethyl phosphonate was the major metabolic pathway catalyzed by cytochrome P450. In addition, the minor metabolic pathway in human liver was the hydrolysis of the amide bond of NO-1886 by a specific cytosolic esterase. Eadie-Hofstee plots of phosphonate O-deethylation of NO-1886 in human liver microsomes showed a biphasic curve, indicating low- and high-K(m) components. Inhibition experiments with chemical inhibitors and antibodies against various cytochrome P450 isoforms suggested the involvement of CYP2C8 and CYP3A in the phosphonate O-deethylation. Recombinant CYP3A4 and CYP2C8 expressed in baculovirus-infected insect cells and human lymphoblastoid cells exhibited a high activity for phosphonate O-deethylation of NO-1886. The recombinant cytochrome P450 enzymes indicated that CYP2C8 and CYP3A4 were responsible for the low- and high-K(m) components in human liver microsomes, respectively. The selectivity of CYP2C8 in catalyzing phosphonate O-deethylation indicates that coadministration of drugs that are metabolized by the same enzyme requires careful consideration.     

The effects of coronary revascularization in patients with severe left ventricular dysfunction

To evaluate the operative risk of coronary diseased patients who had severe left ventricular dysfunction, we retrospectively reviewed the cases of 798 patients who had received A-C bypass surgery at Juntendo University between Jan. 1984 and Dec. 1989. The patients with severe left ventricular dysfunction (Ejection Fraction less than 30%) (Group-A, n = 9) were compared with the patients with moderately impaired left ventricular function (E.F. 30%-40%) (Group-B, n = 28) and normal left ventricular function (E.F. greater than or equal to 50%) (Group C, n = 34). The mean E.F. were 21.56 +/- 3.72% in Group-A, 34.28 +/- 3.17% in Group-B, 64.19 +/- 12.02% in Group-C. There were no differences between the 3 groups with regard to Cardiac Index, LVEDP, number of diseased vessels, number of grafts, aortic cross clamp time and cardio-pulmonary bypass time. The percentages of patient who needed catecholamines support in postoperatively were 77.8% in Group-A, 46.4% in Group-B and 61.8% in Group-C. There were no operative and hospital deaths in each of the 3 Groups, whereas 2 patients of Group-A died later of noncardiac disease. We propose that patients with severe left ventricular dysfunction (15 less than or equal to EF, less than 30%) benefit from CABG surgery with low risk, and that each left ventricular E.F., Cardiac Index or LVEDP alone were less significant predictors of operative results as measured by preoperative left ventricular function.     

Evidence for the involvement of a pulmonary first-pass effect via carboxylesterase in the disposition of a propranolol ester derivative after intravenous administration

The disposition kinetics of O-butyryl propranolol (butyryl-PL), a model compound containing an ester moiety, after intravenous administration was compared with that of PL in rats and beagle dogs. Rats showed only 30% conversion of butyryl-PL to PL up to 2 h after dosing, whereas dogs showed nearly complete conversion within 10 min after administration. The CL(total) of butyryl-PL in rats was 5.8 l/h/kg and that in dogs was 65.6 +/- 18.6 l/h/kg, both of which were greater than hepatic blood flow. The in vivo conversion from butyryl-PL to PL in the rat could be explained on the basis of the hydrolysis characteristics in the liver and blood. The in vitro hydrolysis data and the in vivo data after intra-arterial administration clearly demonstrated that the extremely high CL(total) of butyryl-PL in dogs was dependent on first-pass hydrolysis in the lung in addition to hydrolysis at a blood flow-limited rate in the liver and kidney. The availability of butyryl-PL after passage through the lung was 50%. Furthermore, the isoform of carboxylesterase involved in the pulmonary hydrolysis of butyryl-PL in the dog was identified as D1, a CES-1 group enzyme. However, butyryl-PL was not recognized as a substrate by CES-1 family carboxylesterases, which are present at high levels in the rat lung (RH-1) and kidney (RL-1). These findings indicate that extrahepatic metabolism, especially in the lung, is important in the disposition of drugs containing an ester moiety after intravenous administration and that the substrate specificity of carboxylesterase isozyme distinguishes from others.