Augmentation of intrarenal angiotensin II levels in uninephrectomized aldosterone/salt-treated hypertensive rats; renoprotective effects of an ultrahigh dose of olmesartan.

Recent studies have suggested that aldosterone plays a role in the pathogenesis of renal injury. In this study, we investigated whether local angiotensin II (Ang II) activity contributes to the progression of renal injury in aldosterone/salt-induced hypertensive rats. Uninephrectomized rats were treated with 1% NaCl in a drinking solution and one of the following combinations for 6 weeks: vehicle (2% ethanol, s.c.; n=9), aldosterone (0.75 mug/h, s.c.; n=8), aldosterone+Ang II type 1 receptor blocker olmesartan (10 mg/kg/day, p.o.; n=8), or aldosterone+olmesartan (100 mg/kg/day, p.o.; n=9). Aldosterone/salt-treated hypertensive rats exhibited severe proteinuria and renal injury characterized by glomerular sclerosis and tubulointerstitial fibrosis. Aldosterone/salt-induced renal injury was associated with augmented expression of angiotensin converting enzyme and Ang II levels in the renal cortex and medullary tissues. Renal cortical and medullary mRNA expression of transforming growth factor-beta (TGF-beta) and connective tissue growth factor (CTGF) as well as the collagen contents were increased in aldosterone/salt-treated hypertensive rats. Treatment with olmesartan (10 or 100 mg/kg/day) had no effect on blood pressure but attenuated proteinuria in a dose-dependent manner. Olmesartan at 10 mg/kg/day tended to decrease renal cortical and medullary Ang II levels, TGF-beta and CTGF expression, and collagen contents; however, these changes were not significant. On the other hand, an ultrahigh dose of olmesartan (100 mg/kg/day) significantly decreased these values and ameliorated renal injury. These data suggest that augmented local Ang II activity contributes, at least partially, to the progression of aldosterone/salt-dependent renal injury.     

Superovulation-induced transient hyperprolactinemia in human in vitro fertilization and embryo transfer

To examine the effects of transient hyperprolactinemia on in vitro fertilization and embryo transfer, 61 cycles in 50 euprolactinemic ovulatory women with irreparable tubal diseases were stimulated with clomiphene (CC) alone or CC and human menopausal gonadotropin followed by human chorionic gonadotropin (hCG). Serum prolactin (PRL) increased after hCG administration with peak values of 45.4 +/- 4.2 ng/ml on the day of laparoscopic oocyte aspiration. The highest serum estradiol (E2) concentration was found on the day before PRL peak and serum progesterone (P) began to increase after hCG injection concomitant with the PRL rise. The group having 50 ng/ml or more of PRL (34 cycles) had significantly higher levels of E2 during preovulatory and early luteal phase compared to those of the group having less than 50 ng/ml of PRL (27 cycles) but there was no significant difference between the P levels in the two groups. In the higher PRL group 72 (62.1%) of 116 collected oocytes were fertilized and 6 (20.0%) conceived. In the lower PRL group 45 oocytes (58.4%) of 77 were fertilized and 3 (12.5%) became pregnant. These data suggest that elevated serum PRL concentrations may have no effect on fertilization of oocytes in vitro or embryonic development.     

ENDOSCOPIC SUBMUCOSAL DISSECTION FOR RECURRENT GASTRIC TUMORS

Endoscopic resection has been accepted as the standard treatment for intramucosal gastric tumors of differentiated type. However, the indication was limited to small tumors to achieve en bloc resection and prevent local recurrence in cases of conventional endoscopic mucosal resection (EMR) such as the strip biopsy and the cap technique. To avoid multi‐fragmental resection, we have developed endoscopic submucosal dissection (ESD) as a new endoscopic resection technique. ESD is a remarkable technique, because we make it possible to remove the lesions en bloc regardless of size, shape, coexisting ulcer, and location. However, it is difficult or impossible to resect recurrent tumors en bloc in conventional EMR owing to hard fibrosis, and some patients need laparotomy. Using ESD, we can dissect the submucosal layer as we directly look at the submucosa, and remove the lesion safely and reliably even in cases of hard fibrosis. The key to treatment of recurrent tumors in ESD are as follows: (i) using enough submucosal injection solution (we use a mixture of Glyceol and 1% 1900 kDa hyaluronic acid preparation); (ii) incising the mucosa without fibrosis; (iii) understanding characteristics of various cutting devices, and changing other devices in difficult situations. In these ways we can remove the majority of the recurrent tumors en bloc. Hence, we consider that ESD is a very effective treatment which achieves excellent en bloc and complete resection rates and enables patients with intramucosal gastric tumors to a recurrent‐free survival even in recurrent tumors.     

Preventive effects of intermittent administration of human parathyroid hormone on steroid-induced osteopenia in rats

The purpose of this study was to determine the preventive effect of intermittent administration of human parathyroid hormone (h-PTH) on bone change in steroid-treated rats; this was done by histomorphometric and biochemical analysis. Seven-month-old female Wistar rats were divided into four groups; in-each of the four groups one subgroup was treated for 4 weeks and one for 8 weeks. The groups consisted of: untreated controls, a steroid group (receiving prednisolone), a steroid + PTH group (predniso-lone and h-PTH administered simultaneously), and a steroid + PTH vehicle group. Prednisolone (2.5 mg/kg) and h-PTH (1–34) (6.0 μg/kg) were administered six times a week during the experimental period. At necropsy, bilateral tibiae were collected: one was used for preparing undecalcified sections after Villanueva bone staining, and the other for decalcified tartrate-resistant acid phosphatase (TRAP) stained sections. Biochemical analysis showed that steroids increased urinary calcium at the 8th week; however, such bone metabolic markers as serum 1,25-(OH)₂D and urinary deoxypyridinoline did not change in any treatment group. Histomorphometrically, steroid-induced osteopenia was established at the 8th week by inhibition of both bone formation and bone resorption. The simultaneous intermittent administration of PTH plus steroid, however, increased both bone formation and bone resorption, resulting in increases in bone volume beginning at 4 weeks. These results suggest that the simultaneous intermittent administration of PTH with steroid prevents steroid-induced low-turnover osteopenia by stimulating bone turnover.     

Distribution characteristics of immunosuppressants FK506 and cyclosporin A in the blood compartment

Using two representative immunosuppressants, FK506 (FK) and cyclosporin A (CyA), of which the mechanism of pharmacological action is the same although there is a great difference in the pharmacological intensity, the distribution characteristics were studied in both in vivo and in vitro experiments using rat, dog, and human blood. Blood samples were fractionated by means of sedimentation in Ficoll-Paque®, and the drug contents in the diluted plasma fraction, erythrocyte fraction, and lymphocyte fraction were measured by an HPLC method. FK distributes to the lymphocyte fraction to a level about three times greater than that of CyA, while CyA distributes to the erythrocyte fraction to a level ten times that of FK. The distribution pattern of these fractions was independent of the drug concentration and species after correcting the drug concentration in each fraction with the blood drug concentration. The uptakes of FK and CyA in the isolated lymphocytes obtained from the rat spleen and human peripheral blood were also studied. The amount of FK taken up by the spleen lymphocytes is five times greater than that of CyA. In the case of the uptake study using human peripheral blood lymphocytes, the concentration of FK in the lymphocyte is 100-fold higher than that of CyA. This difference in the lymphocyte level between the two immunosuppressants is thought to be one of the reasons why FK is more potent than CyA, a difference of about 100-fold in the in vitro pharmacological study and about tenfold in the in vivo organ transplantation experiments.     

Central sympathoinhibitory action of a direct-acting vasodilator, budralazine, in anesthetized rats

Previous data on budralazine, 1-[2-(1,3-dimethyl-2-butenylidene)-hydrazino]-phthalazine, has indicated that it is a direct-acting vasodilating agent that does not produce marked tachycardia. The present study was undertaken to elucidate what effects may be seen on the central sympathetic nerve activity when budralazine is given systemically to rats. Budralazine (0.5, 1.0 and 5.0 mg/kg, i.v.) produced a dose-dependent reduction of mean arterial pressure. At doses of 0.5 and 1.0 mg/kg, budralazine induced bradycardia accompanied with a decrease in cardiac sympathetic nerve activity. Preganglionic adrenal sympathetic nerve activity was also reduced by budralazine (1.0 mg/kg, i.v.). A dose of 0.5 mg/kg of budralazine neither influenced carotid sinus nerve activity nor augmented aortic depressor nerve activity. On the contrary, a high dose of budralazine (5.0 mg/kg) produced simultaneous increases in the heart rate and cardiac sympathetic nerve activity along with a marked suppression of aortic depressor nerve activity. Plasma norepinephrine and epinephrine concentrations were also increased at a dose of 5.0 mg/kg. These findings suggest that budralazine doses of 0.5 and 1.0 mg/kg may reduce the sympathetic outflow that is mediated via central sympathoinhibitory action. Baroreceptor-mediated tachycardia occurred after high dose budralazine (5.0 mg/kg) administration in anesthetized rats.     

Modulation of a motor evoked response to transcranial magnetic stimulation by the activity level of the first dorsal interosseous muscle in humans when grasping a stationary object with different grip widths

A relation between corticospinal excitability and background voluntary muscular activity was investigated at low and high transcranial magnetic stimulation (TMS) intensities while grasping a stationary object with different widths (2 and 8 cm) using a precision grip. The muscle activity was recorded from the first dorsal interosseous muscle. Regression analysis revealed that there was a linear relation between the motor evoked potential (MEP) and background muscular activity for both grip widths at each of the TMS intensities. At the low TMS intensity, the slope of the regression lines was similar for the 2 and 8 cm grip widths. It was, however, different when the TMS intensity was high. The results suggested that sensitivity modulation of bias level (input) facilitation occurred with wider grip width. The results of this study would reflect to quantitative aspects of the relation between the synaptic drive to the motoneuron pool and the resulting efferent activity characterized, i.e. input-output relations of the human corticospinal pathway dependent on the occasion demand.