Hiroyuki Koshiyama

Central galanin stimulates pituitary prolactin secretion in rats: Possible involvement of hypothalamic vasoactive intestinal polypeptide

The effect of galanin, a newly identified neuropeptide, on pituitary prolactin (PRL) secretion was examined in the rat. Intracerebroventricular (i.c.v.) injection of all 5 doses of galanin (0.4, 1, 2, 5 and 10 micrograms/rat) raised plasma PRL levels in urethane-anesthetized rats. Galanin injection (2 micrograms/rat, i.c.v.) also increased plasma PRL levels in conscious rats. The intermediate dose of galanin (2 micrograms/rat, i.c.v.) produced a greater response in plasma PRL levels than either smaller or larger doses of galanin. Intravenous injection of galanin did not affect plasma PRL levels. Passive immunization with specific anti-vasoactive intestinal polypeptide (VIP) rabbit serum suppressed plasma PRL response to galanin (2 micrograms/rat, i.c.v.) in anesthetized rats. These findings indicate that central galanin has a stimulatory role in pituitary PRL secretion via the hypothalamus in the rat and that VIP may be involved in rat PRL release induced by galanin.

Galanin stimulates growth hormone (GH) secretion via GH-releasing factor (GRF) in conscious rats

The possibility of a role of hypothalamic growth hormone (GH)-releasing factor (GRF) in GH secretion induced by centrally administered galanin was investigated in freely moving male rats. Intracerebroventricular (i.c.v.) injection of synthetic galanin (0.4 or 2 micrograms/rat) elicited a dose-related increase in plasma GH in these conscious rats. Pretreatment with rabbit antiserum specific for rat GRF significantly inhibited the plasma GH increase induced by i.c.v. injection of galanin (2 micrograms/rat). These findings suggest that galanin-induced GH secretion in the rat is mediated at least in part by hypothalamic GRF.

Renal Expression of Two ‘Thyroid-Specific’ Genes: Thyrotropin Receptor and Thyroglobulin

Numerous renal abnormalities accompany thyroid disease, most of which have been ascribed to the effects of thyroid hormone on renal metabolism. In the present report, we investigate the renal expression of the nominally thyroid-specific proteins, thyroid-stimulating hormone (TSH) receptor (TSHR) and thyroglobulin (Tg), as potential links between renal and thyroid function. The expression of TSHR has been identified in several extrathyroidal tissues, but its presence in the kidney remains controversial. We have used reverse-transcriptase polymerase chain reaction and DNA sequencing to demonstrate the presence of TSHR transcript in human and mouse kidney, in a primary culture of human kidney, and in a green monkey kidney epithelioid cell line. Furthermore, human kidney cells responded to TSH with a 2.5- fold increase in intracellular cyclic adenosine monophosphate, suggesting the presence of functional TSHR protein. Comparison of renal expression of TSHR in a bovine growth hormone transgenic mouse model of progressive glomerulosclerosis with control mice suggested increased TSHR transcript in the renal cortex of transgenic animals. TSHR transcript was also detected in mouse mesangial cells in vitro which responded to TSH with significant increases in the formation of three-dimensional hillhocks. Polymerase chain reaction also confirmed the presence of Tg transcript in human and mouse kidneys and in mouse mesangial cells, but no effect of either TSH or cyclic adenosine monophosphate on Tg transcript levels could be discerned. Immunofluorescent staining with a monoclonal anti-Tg antibody identified positive staining in the cytoplasm of mesangial cells. These data suggest that the kidney is capable of expressing the thyroid-specific genes, TSHR and Tg, which could conceivably mediate effects of thyroid disease in the kidney.

Case of adrenocorticotropic hormone-independent macronodular adrenal hyperplasia with possible adrenal hypersensitivity to angiotensin II.

With increasing case reports, it has been indicated that some cases with adrenocorticotropic hormone (ACTH)-independent macronodular adrenal hyperplasia (AIMAH) show abnormal responses in cortisol to various stimulation tests. Here we report a case of AIMAH that showed an aberrant response to angiotensin II via AT1 receptor in cortisol hypersecretion. A 53-yr-old man was admitted to our division seeking further examinations for the possible diagnosis of Cushings syndrome. He had hypertension, diabetes mellitus, and physical stigmata, such as moon face and central obesity. His plasma ACTH level was undetectable, and plasma cortisol level was high. Plasma cortisol showed no normal diurnal rhythm and was not suppressed after the administration of 8 mg of dexamethasone. Abdominal computed tomography demonstrated nodular enlargement of bilateral adrenal glands. He was diagnosed with Cushings syndrome owing to AIMAH. An injection of arginine vasopressin (AVP) increased plasma cortisol and aldosterone levels, whereas ACTH remained undetectable. After 4 h in an upright position, plasma cortisol and aldosterone levels were increased. Pretreatment with candesartan, angiotensin II receptor AT1 antagonist, blocked the increase in plasma cortisol level. These results suggested a possibility of adrenal hypersensitivity to angiotensin II and AVP in cortisol secretion. Bilateral laparoscopic adrenalectomy was performed. The histological findings of the specimen were compatible with AIMAH. In summary, we have made the first report on a case of AIMAH with possible hypersensitivity to angiotensin II.

Effect of calcium channel blocker amlodipine on the intimal-medial thickness of carotid arterial wall in type 2 diabetes.

Although several reports have suggested that calcium channel blockers may inhibit progression of atherosclerosis in animals, it is still controversial whether they have any clinically significant antiatherogenic action in humans. The measurement of intimal-medial thickness (IMT) of the common carotid artery by B-mode ultrasound technique has been recognized as a powerful and noninvasive method to evaluate early atherosclerotic lesions. We investigated the effect of treatment with amlodipine, a powerful calcium channel blocker, on IMT. Twenty-two hypertensive patients with type 2 diabetes were enrolled in a prospective open study. An amlodipine group (amlodipine, 5 mg; n = 11) and a control group receiving angiotensin-converting enzyme inhibitors (n = 11) were studied before and 6 months after treatment. Amlodipine treatment caused a significant decrease in IMT compared with control (-0.052 +/- 0.017 vs. 0.011 +/- 0.021 mm; p < 0.05). Although the exact mechanisms remain to be elucidated, our preliminary result suggests that amlodipine has an antiatherogenic action in type 2 diabetes.

Metastatic renal cell carcinoma to the pituitary gland presenting with hypopituitarism

A 57-year-old man with pituitary metastasis from renal cell carcinoma is reported. He underwent right nephrectomy and total pancreatectomy for renal cell carcinoma and its pancreatic metastasis, respectively. Imaging studies showed an intrasellar mass lesion. The examination revealed panhypopituitarism, diabetes insipidus and bitemporal hemianospia. Metastatic renal cell carcinoma was diagnosed by the biopsy of the pituitary tumor. Metastatic renal cell carcinoma to the pituitary gland, which is extremely rare, appears to have unique features of presenting with hypopituitarism and visual disturbance more frequently than other metastatic pituitary tumors.

Pitavastatin decreases the expression of endothelial lipase both in vitro and in vivo.

AIMS In addition to their cholesterol-lowering effect, statins increase high-density lipoprotein cholesterol (HDL-C) levels. Endothelial lipase (EL) is a regulator of plasma HDL-C levels. In the present study, the effects of statins on EL expression were investigated. METHODS AND RESULTS The 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor pitavastatin suppressed basal and cytokine-treated EL expression in endothelial cells. Concomitant treatment with mevalonate or geranylgeranyl pyrophosphate completely reversed the inhibitory effect of pitavastatin, suggesting that geranylgeranylated proteins are involved in the inhibition of EL expression by statins. Inhibition of RhoA activity by overexpression of a dominant-negative mutant of RhoA or a Rho kinase inhibitor decreased EL levels. Pitavastatin reduced phospholipase activities of endothelial cells, and concomitant treatment with mevalonate reversed its inhibitory effect. Pitavastatin reduced RhoA activity and EL expression in mouse tissues. Furthermore, plasma EL concentrations in human subjects were measured by enzyme-linked immunosorbent assays. Plasma EL levels were negatively associated with plasma HDL levels in 237 patients with cardiovascular diseases, and pitavastatin treatment reduced plasma EL levels and increased HDL-C levels in 48 patients with hypercholesterolaemia. CONCLUSION These findings suggest that statins can reduce EL expression in vitro and in vivo via inhibition of RhoA activity. The inhibition of EL expression in the vessel wall may contribute to the anti-atherogenic effects of statins.

Comparison of effects of amlodipine and angiotensin receptor blockers on the intima–media thickness of carotid arterial wall (AAA study: Amlodipine vs. ARB in atherosclerosis study)

Although there have been increasing reports, which suggest that angiotensin receptor blockers (ARBs) may have anti-atherogenic actions, most of them are performed in vitro and there are a few reports about anti-atherogenic action in vivo. Especially, in humans, there have been no reports about effect of ARBs on atheroslocerosis. On the other hand, there have been several reports, including ours, which indicate that amlodipine, a calcium channel blocker, has a unique property to cause a reduction in the intima-media thickness (IMT) of common carotid artery, which is established to be an indicator of early atherosclerotic lesion, in humans. The present study investigated which of amlodipine and/or ARBs might have more profound effect on IMT progression. The study included 104 hypertensive patients with type 2 diabetes. They were divided into the two groups: the amlodipine group (n=58), who received amlodipine (2.5-5mg/day) and the ARB group (n=46), who received losartan (25-50mg/day), candesartan (4-8 mg/day), valsaratan (40-80 mg/day) or telmisartan (20-40 mg/day). IMT changes were examined during an average of 56.9 weeks. The amlodipine group showed a significant decrease in IMT compared to the ARB group (-0.046 [S.E. 0.161] mm vs. 0.080 [S.E. 0.255] mm, P<0.05). These results suggest that amlodipine has an inhibitory effect on early atherosclerotic process, and that ARBs do not have any effect on it in hypertensive patients with type 2 diabetes.

Relationship Between Carotid Intima-Media Thickness and Silent Cerebral Infarction in Japanese Subjects With Type 2 Diabetes

OBJECTIVE We examined the relationship between intima-media thickness of common carotid artery (CCA-IMT) and silent cerebral infarction (SCI) with the magnetic resonance imaging (MRI) study in Japanese subjects with type 2 diabetes. RESEARCH DESIGN AND METHODS The brain MRI study and the carotid ultrasonography were performed in a total of 217 consecutive Japanese subjects with type 2 diabetes. Various risk factors for SCI were examined using multiple logistic analyses. RESULTS The SCI was found in 60.4% of the diabetic subjects. In the diabetic subjects, age, systolic blood pressure (SBP), pulse wave velocity, and CCA-IMT were significantly higher in the subjects with SCI than in those without it. Multiple logistic analyses indicated that age, SBP, and CCA-IMT were significant and independent risk factors of SCI in the diabetic subjects. CONCLUSIONS CCA-IMT, but not pulse wave velocity, was independently associated with SCI in Japanese subjects with type 2 diabetes.

Possible link of pioglitazone with bladder cancer in Japanese patients with type 2 diabetes

We retrospectively examined the frequency of bladder cancer in Japanese patients with type 2 diabetes in relation to use of pioglitazone. Among a total of 663 patients identified to be taking pioglitazone, 9 had bladder cancer (1.36%). Overall the hazard ratio of 1.75 [95% CI: 0.89-3.45] for pioglitazone for bladder cancer was not significant. However the prevalence of bladder cancer was 2.10% in patients taking pioglitazone for less than 24 months which was significant increased (HR 2.73 [95% CI: 1.11-6.72]).