1,25-Dihydroxyvitamin D3 enhances the effect of refeeding on steady state preproinsulin messenger ribonucleic acid levels in rats

To elucidate the regulatory mechanism of vitamin D action on insulin biosynthesis and secretion, we examined preproinsulin (ppI) mRNA levels in the pancreas of normal rats, vitamin D-deficient rats, and rats supplemented with 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] or calcium (Ca) for 3 days. The ppI mRNA levels determined by dot blot analysis in vitamin D-deficient, 1,25-(OH)2D3-replete, and Ca-replete rats were 39.1%, 68.7%, and 66.7%, respectively, of values in normal rats. These results concur with previously reported levels of insulin secretion in the perfused rat pancreas. The reduced level of ppI mRNA should lead to a decrease in insulin biosynthesis and, thus, impair insulin secretion in vitamin D-deficient rats. The observed partial recovery of ppI mRNA levels through supplementation of 1,25-(OH)2D3 or Ca may be one mechanism by which insulin secretion is restored in rats after 1,25-(OH)2D3 or Ca repletion. We examined further the time course of ppI mRNA accumulation in rats after a single administration of 1,25-(OH)2D3. When fasting was continued for an additional 24-h period after an overnight fast, ppI mRNA levels were not changed significantly in either vitamin D-deficient or replete rats. However, in the rats that were pair-fed after overnight fasting, ppI mRNA levels in 1,25-(OH)2D3-replete rats increased at 8 and 24 h, whereas ppI mRNA in vitamin D-deficient rats increased only at 24 h. Moreover, the increment at 24 h was significantly larger in 1,25-(OH)2D3-replete rats than in vitamin D-deficient rats. We conclude that 1,25-(OH)2D3 enhances steady state levels of ppI mRNA only under conditions of refeeding and during feeding.     

Effect of antisomatostatin gamma-globulin on gastrin release in rats

In order to determine the mechanism of endogenous gastric somatostatin in the regulation of gastrin release, antisomatostatin rabbit gamma-globulin was administered in vivo and in vitro in the rat. First, in rats anesthetized by chloral hydrate, intravenous injection of 1 ml antisomatostatin rabbit gamma-globulin had no significant effect on plasma gastrin levels. Second, basal gastrin release from the isolated perfused rat stomach was not affected by the administration of antisomatostatin rabbit gamma-globulin (1:99 and 1:1 dilutions). Third, the addition of antisomatostatin rabbit gamma-globulin (1:99) to incubated rat antral mucosa, however, significantly increased the basal gastrin release. From these results, it is concluded that antral somatostatin exerts its inhibitory effect on basal gastrin release mainly not through the circulation but via paracrine pathways.     

Effect of benidipine hydrochloride, a long-acting T-type calcium channel blocker, on blood pressure and renal function in hypertensive patients with diabetes mellitus. Analysis after switching from cilnidipine to benidipine

BACKGROUND: Calcium channel blockers are commonly used to treat hypertension, and are known to generally act on the L-type calcium channel. Recent studies have shown, however, that some calcium channel blockers also block other calcium channel subtypes, including N- and T-type channels. Cilnidipine (CAS 132203-70-4) is an L- and N-type calcium channel blocker, and benidipine hydrochloride (benidipine, CAS 91599-74-5) is known to inhibit the T-type as well as L- and N-type calcium channels. In this study, effects of switching from cilnidipine to benidipine on blood pressure (BP) lowering and renal functions were investigated in order to clarify the physiological properties of the T-type calcium channel. METHODS AND RESULTS: Forty hypertensive patients with diabetes and poor BP control despite receiving cilnidipine were selected, and the changes in BP and urine protein (UP) scores were investigated retrospectively after switching from cilnidipine to benidipine for more than 3 months. BP (systolic/diastolic) significantly decreased from 155.8 +/- 13.7 mmHg/76.5 +/- 13.3 mmHg to 145.9 +/- 17.0 mmHg/71.4 +/- 13.7 mmHg after benidipine treatment, and this effect was stably maintained for one year. UP also significantly decreased from 1.29 to 0.67 in the mean score. The decrease in UP may be explained by a mechanism other than BP lowering effect. CONCLUSION: These results demonstrate that benidipine has a more potent antihypertensive effect than cilnidipine and also a renoprotective effect, indicating the high usefulness of benidipine in hypertensive patients with diabetes. T-type calcium channel blockade was suggested to be possibly involved in the enoprotective effect of benidipine.     

Enhanced neuronal damage after ischemic insults in mice lacking Kir6.2-containing ATP-sensitive K+ channels

Adenosine triphosphate (ATP)-sensitive potassium (KATP) channels, incorporating Kir6.x and sulfonylurea receptor subunits, are weak inward rectifiers that are thought to play a role in neuronal protection from ischemic insults. However, the involvement of Kir6.2-containing KATP channel in hippocampus and neocortex has not been tested directly. To delineate the physiological roles of Kir6.2 channels in the CNS, we used knockout (KO) mice that do not express Kir6.2. Immunocytochemical staining demonstrated that Kir6.2 protein was expressed robustly in hippocampal neurons of the wild-type (WT) mice and absent in the KO. To examine neuronal sensitivity to metabolic stress in vitro, and to ischemia in vivo, we 1) exposed hippocampal slices to transient oxygen and glucose deprivation (OGD) and 2) produced focal cerebral ischemia by middle cerebral artery occlusion (MCAO). Both slice and whole animal studies showed that neurons from the KO mice were severely damaged after anoxia or ischemia, whereas few injured neurons were observed in the WT, suggesting that Kir6.2 channels are necessary to protect neurons from ischemic insults. Membrane potential recordings from the WT CA1 pyramidal neurons showed a biphasic response to OGD; a brief hyperpolarization was followed by a small depolarization during OGD, with complete recovery within 30 min after returning to normoxic conditions. By contrast, CA1 pyramidal neurons from the KO mice were irreversibly depolarized by OGD exposure, without any preceding hyperpolarization. These data suggest that expression of Kir6.2 channels prevents prolonged depolarization of neurons resulting from acute hypoxic or ischemic insults, and thus protects these central neurons from the injury.     

Involvement of Exoc3l, a protein structurally related to the exocyst subunit Sec6, in insulin secretion

The exocyst is an octameric complex involved in docking or tethering of secretory vesicles to fusion sites of the plasma membrane. Sec6 is the core subunit of the exocyst complex. Here we identify an isoform of Sec6, deposited as Exocyst complex component 3-like (Exoc3l) in the database, by in silico screening using rat Sec6 as a probe. The amino acid sequence of Exoc3l has 31% identity and 53% similarity with that of Sec6. RT-PCR analysis reveals that Exoc3l is expressed in insulin-secreting MIN6 cells as well as in various tissues including pancreatic islets and brain. In co-immunoprecipitation experiments, Exoc3l was found to interact with Sec5, Sec8, and Sec10, all of which are binding partners of Sec6 in the exocyst complex. Furthermore, overexpression of a deletion mutant of Exoc3l in MIN6 cells suppressed glucose-stimulated secretion. These results suggest that Exoc3l is involved in regulated exocytosis of insulin granules.     

Progress in the management of ST-segment elevation myocardial infarction during economic transition in Poland between 1992 and 2006

Implementation of new therapeutic strategies is intended to decrease morbidity and mortality in patients with acute coronary syndromes (ACS). The aim of this study is to evaluate progress in the treatment of ST-segment elevation myocardial infarction (STEMI) in 1992-2006 based on data from Polish National ACS Registry. A total of 881 STEMI patients in 1992-1996 and 889 in 2005-2006 were enrolled. The use of reperfusion therapy resulted in marked reduction in in-hospital and post-discharge mortality with the best results achieved in the invasive arm. Low invasive approach rate in high-risk patients resulted in no reduction in global mortality.     

Irritable bowel syndrome in the elderly

Irritable bowel syndrome (IBS) is a very common gastrointestinal disorder. The prevalence of IBS is about 10-15% of the general population. Epidemiological studies suggested that the prevalence of IBS decreased with age, but IBS remains an important gastrointestinal illness in the aged. But there has been very few research examining on IBS in elderly. Whether advancing age impacts on IBS is largely unknown and how the disorder manifest in the elderly remains unclear. Aging is connected with an increasing prevalence of many chronic neurological difficulties, cardiovascular diseases and mental disabilities. The management of the IBS needs to take the age-related issues into account in elderly. Clinical therapeutic trials should be undertaken in elderly people to ascertain treatment.