Possible involvement of IGF-1 receptor and IGF-binding protein in insulin-induced enhancement of noradrenaline response in diabetic rat aorta

1. We investigated the mechanisms underlying the changes in vascular contractile responsiveness induced by chronic treatment with insulin in controls and established streptozotocin (STZ)-induced diabetic rats. 2. The aortic contractile response to noradrenaline (NA) showed no significant difference between controls and diabetics, but it was significantly greater in insulin-treated diabetic rats than in the other groups. To investigate the mechanism, we examined the changes in NA-induced contractility following treatment with insulin and insulin-like growth factor-1 (IGF-1) in organ-cultured control and diabetic aortas. 3. The contractile response to NA in organ-cultured diabetic rat aortas treated with insulin (500 ng ml-1, 16 h) or IGF-1 (20 ng ml-1, 16 h) was significantly greater than the corresponding values for (a) diabetic rat aortas cultured in serum-free medium, and (b) control aortas incubated with insulin or IGF-1. Incubating control aortas with insulin or IGF-1 had no significant effect on the contraction induced by NA. 4. The expressions of the IGF-1 receptor mRNA and protein were increased in STZ-induced diabetic aortas and further increased in insulin-treated diabetics. The mRNA expressions of IGF-binding protein (IGFBP)-2 and IGFBP-3 were normal in diabetic aortas. In contrast, those of IGFBP-4 and IGFBP-5 were significantly decreased in diabetic aortas, and not restored by insulin treatment. 5. These results suggest that the insulin deficiency and chronic hyperinsulinemia in diabetes upregulate the IGF-1 receptor and downregulate IGFBP-4 and IGFBP-5 in the aorta. This may be a major cause of the increased vascular contractility induced by insulin administration and by hyperinsulinemia in established diabetes, resulting in hypertension.     

Characterization of beta 3-adrenoceptor-mediated relaxation in rat abdominal aorta smooth muscle

The present study was carried out to characterize beta-adrenoceptor subtypes mediating relaxation of rat abdominal aorta smooth muscle. (-)-Isoprenaline and a nonconventional beta(3)-adrenoceptor agonist, (+/-)-[4-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]-1,3-dihydro-2H-benzimidazol-2-one] hydrochloride ((+/-)-CGP12177A), induced concentration-dependent relaxation of (-)-phenylephrine (0.3 microM) preconstricted spiral preparations. Pretreatment with a combination of (+/-)-2-hydroxy-5-[2-[[2-hydroxy-3-[4-[1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl]phenoxy]propyl]amino]ethoxy]-benzamide methanesulfonate (CGP20712A, a selective beta(1)-adrenoceptor antagonist) and (+/-)-1-[2,3-(dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[(1-methylethyl)amino]-2-butanol hydrochloride (ICI-118,5511, a selective beta(2)-adrenoceptor antagonist) (0.1 microM for each) produced a 14-fold rightward shift of the concentration-response curve for (-)-isoprenaline; however, the relaxation in response to (+/-)-CGP12177A was unaffected by the blockade of beta(1)- and beta(2)-adrenoceptors. In the presence of CGP20712A and ICI-118,551 (0.1 microM for each), the concentration-response curves for (-)-isoprenaline and (+/-)-CGP12177A were shifted to the right by a nonselective beta(1)-, beta(2)- and beta(3)-adrenoceptor antagonist, (+/-)-bupranolol (3 and 10 microM). These results clearly suggest that beta(3)-adrenoceptors are involved in beta-adrenoceptor-mediated relaxation of rat abdominal aorta smooth muscle.     

Dependency of temporary threshold shift of vibratory sensation in fingertip on 1/3 octave-band hand-arm vibration exposure period

Objectives  To investigate the dependency of temporary threshold shift of vibratoty sensation (TTS_v) in fingertip on hand-arm vibration exposure period. Methods  Six healthy students were instructed to grip a vibrating or nonvibrating handle in the experimental room. The gripping force was 40 N. The vibratory sensation threshold at 125 Hz was measured before and after the exposure in the exposed middle fingertip. The exposure vibration was vertical and the 1/3 octave-band vibration with had a central frequency of 200 Hz and an intensity of 39.2 m/s². The exposure periods were 8, 15, 30, 60, 120, 240 and 600 s. TTS_v,t was evaluated as the difference in vibratory sensation threshold between immediately before and t seconds after the exposure. Results  TTS_v recovered exponentially as in several previous studies and its use enabled us to estimate the time constant and TTS_v,0. TTS_v,0 with vibration exposure was significantly larger than that without it. The regression analysis of the relationship between vibration exposure period (T) and TTS_v,0 (T) for each subject confirmed the good fit of the equation TTS_v,0(T)=B₀+B₁ ^*Log₁₀(T), where B₀ and B₁ are the calculated constants (adjusted R²=0.56–0.87). The time constants did not show such a clear dose effect relationship of exposure period as TTS_v,0. Conclusion  The dependency of TTS_v,0 on vibration exposure period was asymptotically proportional to the logarithm of gripping period. To more quantitatively confirm the relationship of the time constants for recovering time course of TTS_v, it may be necessary to improve the measurement method for TTS_v.     

Critical roles of platelets in lipopolysaccharide-induced lethality: effects of glycyrrhizin and possible strategy for acute respiratory distress syndrome

Within a few minutes of an intravenous injection of a lipopolysaccharide (LPS) into mice, platelets accumulate, largely in the lung. At higher doses, LPS induces rapid shock (within 10 min), leading to death within 1 h. This type of shock differs from so-called endotoxin shock, in which shock signs and death occur several hours or more later. Here, we found that platelet depletion (by a monoclonal anti-platelet antibody) prevented LPS-induced rapid shock, but increased delayed lethality. In Japan, glycyrrhizin (GL), a compound isolated from licorice, is daily and slowly infused intravenously into chronic hepatitis C patients. A single bolus intravenous injection into mice of GL (200 mg/kg or less) shortly before (or simultaneously with) LPS injection reduced the pulmonary platelet accumulation and the severity of the rapid shock, and prevented death in both the early and later periods. GL itself, at 400 mg/kg, produced no detectable abnormalities in the appearance or activity of mice. Intraperitoneal injection of aspirin or dexamethasone had only marginal effects on LPS-induced platelet responses and lethality. These results suggest that platelets play important roles in the development of both the rapid and delayed types of shock induced by LPS. Although the mechanism by which GL suppresses platelet responses and delayed lethality remains to be clarified, GL might provide a strategy for alleviating the acute respiratory distress syndrome seen in sepsis. Our results may also support the proposal by Cinatl et al. [Cinatl J, Morgenstern B, Bauer G, Chandra P, Ravenau H, Doerr HW. Glycyrrhizin, an active component of liquorice roots, and replication of SARS-associated coronavirus. Lancet 2003; 361: 2045-6.] that GL may be an effective drug against severe acute respiratory syndrome.     

Scale for assessing interests of Japanese elderly people in their daily life

OBJECTIVE: Programs to support independent living for elderly people are generally designed taking into account physical and psychological conditions. The interests of individuals are diverse even when the physical conditions are the same. Interests in daily life are important factors for adequate planning of the programs for independent living. The purpose of this study was to examine an evaluation structure of interests of Japanese elderly people in their daily life. METHODS: Focus group interviews were conducted to collect items for interests in daily life by several researchers targeting activity groups of elderly people. Eighteen items were extracted from a total of 50 following the principles: (1) Items with similar meanings are brought together; (2) Items which might have big differences in meaning depending on the subject were excluded; and (3) Items which were double barreled were excluded. The questionnaire 18 items were designed to give a 4-point Likart scale for answers from "very important" to "not important at all". The survey was conducted in 20 municipalities all over Japan in 2000. From residents aged 65 years and over, 6,094 individuals were selected randomly as the study population. RESULTS: Of 5,565 participants, 4,527 individuals answered all 18 items. "To have a good time with the family" was the favorite answer (54.8%), rated as "very important". Four factors (eigenvalue > 1) were extracted by applying principal component analysis: "to live with good communication", "to achieve one's purpose", "to live socially", and "to live comfortably". "To live with good communication" showed the highest score and "To live socially" showed the lowest score. CONCLUSION: With this scale, we could precisely determine the diversity of interests of Japanese elderly people in their daily life. We suggest that this scale might be useful not only to analyze the interests of individuals, but also to plan programs in terms of quality of life or independent living in late life.     

Correlation between vasoconstrictor roles and mRNA expression of alpha1-adrenoceptor subtypes in blood vessels of genetically engineered mice

We examined the contribution of each alpha(1)-adrenoceptor (AR) subtype in noradrenaline (NAd)-evoked contraction in the thoracic aortas and mesenteric arteries of mice. Compared with the concentration-response curves (CRCs) for NAd in the thoracic aortas of wild-type (WT) mice, the CRCs of mutant mice showed a significantly lower sensitivity. The pD(2) value in rank order is as follows: WT mice (8.21) > alpha(1B)-adrenoceptor knockout (alpha(1B)-KO) (7.77) > alpha(1D)-AR knockout (alpha(1D)-KO) (6.44) > alpha(1B)- and alpha(1D)-AR double knockout (alpha(1BD)-KO) (5.15). In the mesenteric artery, CRCs for NAd did not differ significantly between either WT (6.52) and alpha(1B)-KO mice (7.12) or alpha(1D)-KO (6.19) and alpha(1BD)-KO (6.29) mice. However, the CRC maximum responses to NAd in alpha(1D)- and alpha(1BD)-KO mice were significantly lower than those in WT and alpha(1B)-KO mice. Except in the thoracic aortas of alpha(1BD)-KO mice, the competitive antagonist prazosin inhibited the contraction response to NAd with high affinity. However, prazosin produced shallow Schild slopes in the vessels of mice lacking the alpha(1D)-AR gene. In the thoracic aorta, pA(2) values in WT mice for KMD-3213 and BMY7378 were 8.25 and 8.46, respectively, and in alpha(1B)-KO mice they were 8.49 and 9.13, respectively. In the mesenteric artery, pA(2) values in WT mice for KMD-3213 and BMY7378 were 8.34 and 7.47, respectively, and in alpha(1B)-KO mice they were 8.11 and 7.82, respectively. These pharmacological findings were in fairly good agreement with findings from comparison of CRCs, with the exception of the mesenteric arteries of WT and alpha(1B)-KO mice, which showed low affinities to BMY7378. We performed a quantitative analysis of the mRNA expression of each alpha(1)-AR subtype in these vessels in order to examine the correlation between mRNA expression level and the predominance of each alpha(1)-AR subtype in mediating vascular contraction. The rank order of each alpha(1)-AR subtype in terms of its vasoconstrictor role was in fairly good agreement with the level of expression of mRNA of each subtype, that is, alpha(1D)-AR > alpha(1B)-AR > alpha(1A)-AR in the thoracic aorta and alpha(1D)-AR > alpha(1A)-AR > alpha(1B)-AR in the mesenteric artery. No dramatic compensatory change of alpha(1)-AR subtype in mutant mice was observed in pharmacological or quantitative mRNA expression analysis.     

Surgical indications and microsurgical anatomy of the transchoroidal fissure approach for lesions in and around the ambient cistern

OBJECTIVE: Opening the temporal part of the choroidal fissure (CF) makes it possible to expose the crural cistern, the ambient cistern, and the medial temporal lobe. We examined the microsurgical anatomy and the surgical indications for use of the trans-CF approach. METHODS: The microsurgical anatomy encountered in the trans-CF approach for lesions in and around the ambient cistern was studied in three cadavers. On the basis of these cadaveric studies, the trans-CF approach was used during surgery in three live patients with such lesions. RESULTS: The angiographic "plexal point," which indicates the entrance of the anterior choroidal artery as it enters the temporal horn of the lateral ventricle, was thought to be a key anatomic landmark of the trans-CF approach. A cortical incision for entry into the temporal horn should be made in the inferior temporal gyrus to minimize the potential damage to the optic radiations and to the speech centers. After the CF is opened posteriorly to the plexal point between the tenia fimbria and the choroid plexus, the posterior cerebral artery (PCA) in the ambient cistern can be observed with minimal caudal retraction of the hippocampus. In this study, surgical procedures using the trans-CF approach were successfully performed on patients with high-positioned P2 aneurysms whose PCA ran close to the plexal point or higher, whose medial temporal arteriovenous malformations were fed mainly by the PCA, and whose tentorial hiatus meningiomas protruded into the temporal horn through the CF, with no resulting postoperative visual or memory disturbances. CONCLUSION: The trans-CF approach is especially useful in surgery for lesions in and around the ambient cistern.     

Mild to severe lithium-induced nephropathy models and urine N-acetyl-beta-D-glucosaminidase in rats

Long-term treatment with lithium induces functional and/or structural disturbances in the kidneys. However, no procedure has been established for the early diagnosis of lithium intoxication. In this study, we prepared mild to severe lithium-induced nephropathy rat models and examined the usefulness of urine N-acetyl-beta-D-glucosaminidase (NAG) for the early diagnosis of lithium-induced renal insufficiency. Lithium was administered by repeated intraperitoneal injection (1, 2 and 4 mEq/kg/day for 10 days). We also measured the plasma creatinine and paraaminohippuric acid (PAH) clearance, and observed renal histological changes. Lithium pretreatment elevated the plasma creatinine level and decreased PAH clearance in a dose-dependent manner. The NAG level in the lithium 4 mEq/kg group was very high. The levels in the lithium 1 mEq/kg and 2 mEq/kg groups were almost the same and were higher than the control group. A histological examination of the kidney revealed glomerular congestion and/or atrophy and tubular expansion in all of the groups except the control group. These histological changes were dose-dependent. In conclusion, urine NAG may be useful in the early diagnosis of renal side effects caused by lithium therapy. When the urine NAG level becomes high in a patient taking lithium for bipolar disorder, the physician may need to consider lithium-induced renal insufficiency.