Kex2 family endoprotease furin is expressed specifically in pit-region parietal cells of the rat gastric mucosa. (73/4793)

The proprotein-processing endoprotease furin is localized in the gastric epithelial cells of the pit region in the rat gastric gland. The gastric pit is composed of several cell types, including gastric surface mucosal (GSM) cells and parietal cells. Furin converts many growth- or differentiation-related proproteins to their active forms. We examined identification of furin-positive cells by immunostaining of rat gastric mucosa and regulators of the furin expression by measuring the furin promoter activity by luciferase assay. Furin-positive cells were stained for H(+)-K(+)-ATPase, indicating that they are parietal cells. Furin-positive parietal cells were not stained for transforming growth factor-alpha (TGF-alpha) but were surrounded by TGF-alpha-positive GSM cells. In contrast, parietal cells below the proliferative zone were positive for TGF-alpha but not for furin. Furin-positive parietal cells expressed a high level of epidermal growth factor receptor (EGFR). TGF-alpha stimulated the furin promoter activity highly in a mouse GSM cell line GSM06. Thus we suggest that the parietal cells of the pit region have furin-mediated functions that can be stimulated by EGFR signaling.  (+info)

The influence of phentolamine on the hyperglycaemic and lipolytic effects of ammonia in sheep. (74/4793)

Intravenous infusion over 30 min of ammonium chloride [10-1 g/kg b.w.] caused a significant increase of blood glucose and free fatty acids levels, and a similar effect was observed with adrenaline. Phentolamine [1 mg/kg b.w.] abolished the hyperglycaemic action of ammonium chloride but only slightly diminished the lipolytic effect. It is concluded that the ammonium ion influences carbohydrate metabolism chiefly by way of catecholamines and stimulation of alpha-adrenergic receptors, while tissue lipids are mobilized by ammonia by another route, possibley directly.  (+info)

Electrophysiological effects of flecainide and propafenone on atrial fibrillation cycle and relation with arrhythmia termination. (75/4793)

OBJECTIVES: (1) To investigate the electrophysiological effects of flecainide and propafenone during atrial fibrillation, and their relation to arrhythmia termination; (2) to investigate the effects of isoprenaline on atrial fibrillation in basal conditions and during treatment with class 1C drugs to evaluate the role of adrenergic stimulation on proarrhythmic events occurring during this treatment. DESIGN: Prospective, single centre study. SETTING: University hospital. METHODS: 10 patients with lone paroxysmal atrial fibrillation underwent an electrophysiological study. The dynamic behaviour of MFF (the mean of 100 consecutive atrial fibrillation intervals) was evaluated at two atrial sites after induction of atrial fibrillation either at baseline or after class 1C drug administration (flecainide or propafenone 2 mg/kg). The effects of isoprenaline on MFF and RR interval were also investigated both under basal conditions and during class 1C drug treatment. RESULTS: After induction of atrial fibrillation, mean (SD) MFF shortened with time, and was further shortened by isoprenaline infusion (177 (22) v 162 (16) v 144 (11) ms, p < 0.05). The administration of class 1C drugs reversed this trend and significantly increased the MFF to an average of 295 (49) ms, leading to conversion to sinus rhythm within 10 minutes in all patients. Atrial fibrillation was then reinduced on class 1C drugs: isoprenaline shortened the MFF and RR interval with a trend to AV synchronisation (223 (43) v 269 (49) ms for the MFF, 347 (55) v 509 (92) ms for the RR, p < 0.05); 1:1 sustained AV conduction occurred in two patients, at 187 and 222 beats/min respectively. One of these patients underwent electrical cardioversion because of haemodynamic collapse. CONCLUSIONS: Class 1C drugs are effective at restoring sinus rhythm by increasing the MFF to a much greater extent than observed in self terminating atrial fibrillation episodes, and reversing the spontaneous atrial fibrillation behaviour (progressive shortening of MFF and self perpetuation of atrial fibrillation). MFF prolongation with 1:1 conduction at fast ventricular rates may lead to synchronisation during adrenergic stimulation, with a very short ventricular cycle; hence it is advisable to keep the patients at rest after acute class 1C drug loading or to consider pharmacological modulation of AV conduction for patients who are prone to a fast ventricular response.  (+info)

Effect of raised plasma beta endorphin concentrations on peripheral pain and angina thresholds in patients with stable angina. (76/4793)

OBJECTIVE: To determine whether changes in plasma concentrations of beta endorphins alter angina threshold and peripheral pain threshold in patients with stable angina. DESIGN: Latin square design comparison of angina thresholds by exercise treadmill test and peripheral pain thresholds using a radiant heat source in eight patients with stable angina under control conditions, after stimulation of pituitary beta endorphin release by ketoconazole, after suppression of pituitary beta endorphin release by dexamethasone, and after blockade of opioid receptors by intravenous naloxone. RESULTS: An approximately fivefold increase in circulating concentrations of beta endorphins was found after administration of ketoconazole (mean (SEM): 13.9 (1.2) v 73.8 (6.2) pg/ml; p < 0.05), which was associated with an increase in peripheral pain threshold to a radiant heat source (time to onset of pain perception 72 (19) v 123 (40) seconds; p < 0.05), but no significant difference in angina threshold. A reduction in circulating concentrations of beta endorphins after pretreatment with dexamethasone was statistically non-significant (13.9 (1.2) v 9.0 (1.5) pg/ml; NS) and was not associated with any change in either peripheral pain or angina thresholds. No effects were seen after blockade of opioid receptors by previous administration of intravenous naloxone. CONCLUSIONS: Increased plasma concentrations of beta endorphins alter peripheral pain threshold but not angina threshold in patients with stable angina pectoris.  (+info)

Home inotrope treatment for intractable heart failure following heart transplantation. (77/4793)

A 49 year old man developed intractable heart failure three years after undergoing heart transplantation. Coronary angiography showed no evidence of graft vascular disease. An initial cardiac biopsy identified one episode of rejection which responded to augmented immunosuppressive treatment. The patient became inotrope dependent and has now survived at home for 22 months using an ambulatory delivery system for intravenous adrenaline (epinephrine), without significant complications. There has been a noticeable improvement in symptoms and left ventricular systolic performance, both clinically and as seen through echocardiographic and radiographic examination. This improvement was substantiated by the results of cardiac catheterisation, which showed a return to normal left ventricular filling pressure and cardiac output. The case is noteworthy because this treatment has allowed a patient who otherwise would have been hospital bound to return to the community. With the current shortage of organs, he would have been unlikely to receive a second transplant. The clinical features and outcome, and social, medicolegal, and financial issues are discussed.  (+info)

Calcimimetic compound NPS R-568 stimulates calcitonin secretion but selectively targets parathyroid gland Ca(2+) receptor in rats. (78/4793)

N-(3-[2-Chlorophenyl]propyl)-(R)-alpha-methyl-3-methoxybenzylamine (NPS R-568) is an orally active compound that activates Ca(2+) receptors on parathyroid cells and rapidly suppresses plasma levels of parathyroid hormone (PTH) and Ca(2+) (ED(50), 1 and 10 mg/kg, respectively). We now show that increased calcitonin secretion contributes to NPS R-568-induced hypocalcemia. In parathyroidectomized thyroid-intact rats in which normocalcemia was restored by PTH infusion, NPS R-568 rapidly reduced plasma Ca(2+) levels, indicating that decreased PTH secretion was not solely responsible for the hypocalcemia seen in normal animals. NPS R-568 decreased plasma Ca(2+) levels in thyroidectomized parathyroid-intact rats, but the rate of onset of hypocalcemia was slower than in controls. In contrast, NPS R-568 had no effect on plasma Ca(2+) levels in PTH-infused, thyroparathyroidectomized rats, providing evidence that increased calcitonin secretion caused the hypocalcemia in PTH-infused parathyroidectomized rats. NPS R-568 rapidly increased plasma calcitonin levels to a peak at 10 to 20 min after oral dosing (ED(50) 40 mg/kg). NPS R-568 did not affect the rate of disappearance of (45)Ca from blood, indicating that hypocalcemia resulted from decreased influx of Ca(2+) into the circulation and not from increased efflux. This suggests that NPS R-568-induced hypocalcemia resulted solely from reduced efflux of Ca(2+) from bone after increased calcitonin and reduced PTH secretion. Thus, NPS R-568 causes hypocalcemia by activating Ca(2+) receptors on C cells and parathyroid cells; however, NPS R-568 is about 40 times more potent in reducing PTH levels than in increasing calcitonin levels.  (+info)

Zinc stimulates DNA synthesis during its antiapoptotic action independently with increments of an antiapoptotic protein, Bcl-2, in porcine kidney LLC-PK(1) cells. (79/4793)

Cadmium, an environmental pollutant, caused nephroptosis that was inhibitable by zinc. The mechanism of the antiapoptotic action of zinc is poorly understood. In this study, we found the stimulation of DNA synthesis, as assessed by bromodeoxyuridine incorporation, during prevention by zinc of apoptosis, suggesting that the proliferactive nature of zinc contributes to its inhibition of apoptosis. This finding was consistent with the result that the cells driven by dialyzed fetal bovine serum were resistant to apoptotic stimuli of cadmium. Furthermore, zinc activated the expression of endogenous Bcl-2 proteins. However, overexpression of Bcl-2 proteins by transfection did not facilitate zinc-mediated DNA synthesis. Thus, one possible role of zinc in the prevention of apoptosis is to promote DNA synthesis independently with activation of antiapoptotic proteins Bcl-2.  (+info)

CaM kinase II-dependent mobilization of secretory granules underlies acetylcholine-induced stimulation of exocytosis in mouse pancreatic B-cells. (80/4793)

1. Measurements of cell capacitance were used to investigate the mechanisms by which acetylcholine (ACh) stimulates Ca2+-induced exocytosis in single insulin-secreting mouse pancreatic B-cells. 2. ACh (250 microM) increased exocytotic responses elicited by voltage-clamp depolarizations 2.3-fold. This effect was mediated by activation of muscarinic receptors and dependent on elevation of the cytoplasmic Ca2+ concentration ([Ca2+]i) attributable to mobilization of Ca2+ from intracellular stores. The latter action involved interference with the buffering of [Ca2+]i and the time constant (tau) for the recovery of [Ca2+]i following a voltage-clamp depolarization increased 5-fold. As a result, Ca2+ was present at concentrations sufficient to promote the replenishment of the readily releasable pool of granules (RRP; > 0.2 microM) for much longer periods in the presence than in the absence of the agonist. 3. The effect of Ca2+ on exocytosis was mediated by activation of CaM kinase II, but not protein kinase C, and involved both an increased size of the RRP from 40 to 140 granules and a decrease in tau for the refilling of the RRP from 31 to 19 s. 4. Collectively, the effects of ACh on the RRP and tau result in a > 10-fold stimulation of the rate at which granules are supplied for release.  (+info)