Effects of anthocyanidin derivative (HK-008) on relaxation in rat perfused mesenterial bed.

Anthocyanins, which are responsible for a variety of bright colors (including red, blue, and purple) in fruits, vegetables, and flowers, are consumed as dietary polyphenols. Anthocyanin-containing fruits are thought to decrease coronary heart disease and are used in anti-diabetic preparations. Diabetes is associated with a variety of cardiovascular complications that may be mediated by endothelial dysfunction, and so this study was designed mainly to characterize the influence of a synthesized anthocyanidin derivative (HK-008) over acetylcholine (ACh)-induced relaxation in mesenteric arterial beds isolated from rats. In a glucose-tolerance test in intact rats, HK-008 (30 mg/kg) reduced the glucose level as effectively as the same dose of glibenclamide. The aortic relaxation induced by pinacidil (an ATP-sensitive potassium channel opener) was greatly inhibited by glibenclamide (10 microM), and also significantly inhibited by HK-008 (10 microM). Interestingly, the ACh-induced relaxation in the perfused, preconstricted mesenteric arterial bed was significantly enhanced by HK-008 (10 microM), and this enhancement was significantly attenuated by indomethacin (10 microM). The ACh-induced mesenteric relaxation was impaired by an increase in oxidative stress, viz. superoxide-generating treatment [xanthine oxidase (XO; 0.1 U/ml) plus hypoxanthine (HX; 10 microM)]. However, this impairment was strongly suppressed by HK-008 (10 microM). These results suggest that HK-008 increases endothelium-induced relaxation by suppressing oxidative stress or modulating prostanoids signaling. This compound may therefore be useful against certain cardiovascular disorders.     

Significance of the hepatic mitochondrial redox state in the development of posttraumatic jaundice

The effect of the hepatic energy status on the development of posttraumatic jaundice (PTJ) was studied to clarify the mechanism of PTJ. Fifty-four patients with severe torso injury who were expected to develop PTJ on admission with an average Injury Severity Score of 27 were selected for this study. They were retrospectively divided into three groups according to their maximum bilirubin concentration by day 10: group H, 12 patients with marked elevation of serum bilirubin (>8 g/dl); group L, 23 with mild bilirubinemia (2–8 g/dl); and group N, 19 with no bilirubinemia (<2 g/dl). Group H patients, in whom trauma-related shock was severe and prolonged, developed severe hyperbilirubinemia, and their arterial ketone body ratio (AKBR), which reflects the hepatic mitochondrial redox state and is closely correlated to its energy production, was significantly lower throughout the first week. In contrast, the AKBR increased to an above normal level, indicating enhanced energy production in groups N and L. The serum direct/total bilirubin was also higher in group H. The abnormal hepatic energy metabolism is considered to have reduced the excretion of conjugated bilirubin from the hepatocytes into the bile canaliculi, which is a process that has to proceed against the bilirubin concentration gradient. The subsequent diffusion of the accumulated water-soluble conjugated bilirubin in hepatocytes into the blood is thus considered to be one of the causes of PTJ.     

Expression of matrix metalloproteinase matrilysin (mmp-7) was induced by activated ki-ras via ap-1 activation in sw1417 colon cancer cells

The matrix metalloproteinase matrilysin (MMP-7) is a member of the matrix metallo-proteinase gene family, which is believed to play an important role in tumor invasion and metastasis. We have previously found that matrilysin mRNA is specifically expressed in colorectal cancers and adenomas and that its message is localized in the tumor cells themselves. We examined the effects of activated Ki-ras oncogene on the expression of matrilysin in colon cancer cells. We showed that both mRNA and the enzymatic activity of matrilysin were induced by the introduction of activated Ki-ras into SW1417 colon cancer cells. To understand the mechanisms regulating this induction, we analyzed alterations of AP-1 activity induced by activated Ki-ras, using the chloramphenicol acetyltransferase assay. AP-1 activity in SW1417 cells expressing activated Ki-ras was higher than that in control cells. The gel-shift assay also showed higher levels of AP-1 binding protein in SW1417 cells expressing activated Ki-ras than those in control cells. Our results suggest that activated Ki-ras may play a role in inducing expression of matrilysin through an AP-1-dependent pathway in colon cancer cells.     

Differential effects of isoproterenol on the canine atrial action potential in the presence of carbachol or nicorandil

In canine atrial muscles, carbachol and nicorandil hyperpolarized the resting membrane potential and shortened the action potential duration. In the presence of carbachol or nicorandil, isoproterenol further hyperpolarized the resting membrane potential and shortened the action potential duration. Isoproterenol significantly increased the plateau duration in the presence of nicorandil, but further abbreviated it in the presence of carbachol. This increase in the plateau duration by isoproterenol in the presence of nicorandil probably reflects the increase in the slow inward current.     

Noradrenergic function and the dexamethasone suppression test in depression

We measured the plasma free 3-methoxy-4-hydroxyphenylglycol (MHPG) levels and the serum cortisol levels before and after the oral administration of dexamethasone. There was not a significant difference in the plasma free MHPG levels between the patients with major depression and normal subjects. There was a significant positive correlation between the plasma MHPG levels and postdexamethasone cortisol levels in patients with major depression. This indicates that there exists a certain relation between abnormalities of the central noradrenergic systems and hypothalamic-pituitary-adrenal axis in patients with major depression. The mean total scores of the Hamilton Rating Scale for Depression of the first (MHPG less than 5 ng/ml) and third (10 ng/ml less than or equal to MHPG) groups were significantly higher than those of the second (5 less than or equal to MHPG less than 10 ng/ml) group.     

Effects of chronic administration of L-arginine on vasoactive responses induced by endothelin-1 and its plasma level in streptozotocin-induced diabetic rats.

To investigate the mechanism underlying increased endothelin-1 (ET-1) release in diabetic rats, we administered L-arginine chronically to streptozotocin (STZ)-induced diabetic rats. The plasma concentrations of glucose, ET-1 and NOx (NO2- + NO3-) were all significantly raised at 10 weeks after the STZ injection. Chronic administration of L-arginine resulted in a significantly higher plasma NOx concentration and a significantly lower plasma ET-1 level at 10 weeks compared with the untreated diabetic group. ET-1 induced a biphasic vasodilator/vasoconstrictor response in the perfused isolated mesenteric arterial beds from all groups. The vasodilatation was significantly greater in diabetic rats than in age-matched controls. Chronic oral L-arginine administration had no significant effect on the enhanced ET-1-induced vasodilatation seen in the untreated diabetic rats. The vasoconstrictions induced by ET-1 and methoxamine were significantly attenuated in STZ-diabetic rats. The attenuated vasoconstrictor response to ET-1, but not that to methoxamine, was further attenuated by chronic treatment with L-arginine. We conclude that since chronic L-arginine administration not only reduced the increase in plasma ET-1 levels but also further attenuated the ET-1-induced vasoconstriction without affecting the change in vasodilatation, chronic L-arginine administration could be valuable for the treatment of the symptoms of diabetic mellitus related to ET-1.     

Evaluation of cerebral intravascular blood flow by time density curve study of intravenous digital subtraction angiography]

Time density curve (TDC) can be reconstructed from the data of intravenous digital subtraction angiography (IVDSA). We evaluated peak time (PT) and modal transit time (MOTT) of the TDC as the probable indicator of cerebral intravascular blood flow. Cerebral IVDSA and single photon emission CT (SPECT) were performed on 12 patients of ischemic cerebrovascular disease, which consisted of 3 internal carotid artery (ICA) occlusions, one middle cerebral artery (MCA) occlusion, one anterior cerebral artery (ACA) branch occlusion and 7 lacunar infarctions. We classified former 4 patients as occlusion group and latter 8 as reference group. In 3 patients (2 ICA and one MCA occlusions), SPECT study revealed definite hypoaccumulation in the MCA territory of occlusive side. Two regions of interest (ROI) were placed on the territories of right and left middle cerebral arteries in the frontal view of cerebral IVDSA. Digital data processor fitted gamma curve to the TDC of each ROI, and calculated PT and MOTT. The absolute lateralities of PT and MOTT of MCA territory was significantly (p less than 0.05) larger in occlusion group than reference group. Patients with hypoaccumulation in SPECT had significantly (p less than 0.02) larger laterality of MOTT than patients with isoaccumulation. One ICA occluded patient without hypoaccumulation in corresponding MCA territory had relatively small laterality of MOTT similar to the patients of ACA branch occlusion and lacunar infarction. These results suggest that PT and MOTT are possible to detect the laterality of the intravascular blood flow in MCA territories caused by major artery occlusion.(ABSTRACT TRUNCATED AT 250 WORDS)     

Retrograde thrombosis of feeding arteries after removal of arteriovenous malformations

Five cases of retrograde thrombosis of former feeding arteries after removal of an arteriovenous malformation (AVM) are reported. The clinical features of these patients were studied and compared to those of 71 patients without this complication. The following characteristics were found to correlate with retrograde thrombosis: 1) advancing age of the patient; 2) large AVM size; and 3) markedly dilated and elongated feeders. It is suggested that the slow flow in the former feeding arteries that was observed immediately after AVM removal and pathological changes in these vessels due to long-standing hemodynamic stresses contributed to the development of retrograde thrombosis. Neurological manifestations related to retrograde thrombosis were noted in three of the five cases. Although infrequent, this complication should be considered as a serious possibility following removal of an AVM.     

Phorbol ester does not mimic,but antagonizes the alpha-adrenoceptor-mediated positive inotropic effect in the rabbit papillary muscle

Summary The phorbol ester 12-O-tetradecanoyl phorbol-13-acetate (TPA) was used to examine the hypothesis that phosphoinositide turnover is involved in the regulation of myocardial contractility mediated by stimulation of alpha-adrenoceptors in the mammalian cardiac muscle. Exposure of the isolated rabbit papillary muscle electrically driven at a rate of 1 Hz at a temperature of 37°C to TPA in concentrations of 10–1000 nmol/l for 30 min did not affect the basal force of contraction. The concentration-response curve for the positive inotropic effect of (–)-phenylephrine mediated by stimulation of alpha-adrenoceptors in the presence of (±)-bupranolol (100 nmol/1) was shifted to the right and downward by TPA in concentrations of 30–1000 nmol/l, while the effect of (–)-phenylephrine mediated by stimulation of beta-adrenoceptors in the presence of prazosin (100 nmol/l) was not decreased, but slightly enhanced by exposure of the muscle to relatively low concentrations of TPA (10–100 nmol/l). Incubation of the membrane fraction isolated from the rabbit ventricular muscle with TPA in vitro under the same condition as employed in the physiological experiments decreased the specific binding of [³H]prazosin but not that of [³H]CGP-12177, while the non-tumor promoting phorbol ester, PDD, was ineffective. These results indicate that activation of protein kinase C by TPA does not mimic the positive inotropic effect of catecholamines mediated by activation of myocardial alpha-adrenoceptors. on the other hand, the specific interaction of alpha-adrenoceptor-mediated processes with TPA in the rabbit papillary muscle is in line with the view that the facilitation of phosphoinositide turnover and subsequent activation of protein kinase C may play a certain role in the coupling of alpha-adrenoceptor occupation by agonists to the process leading to the positive inotropic action. Send offprint requests to M. Endoh