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C Schöfl

Publications and source records attributed to C Schöfl.

At least 19 recordsLinked to original sources
PubMed2006

Predicting impaired glucose metabolism in women with polycystic ovary syndrome by decision tree modelling.

AIMS/HYPOTHESIS: Polycystic ovary syndrome (PCOS) is a risk factor of type 2 diabetes. Screening for impaired glucose metabolism (IGM) with an OGTT has been recommended, but this is relatively time-consuming and inconvenient. Thus, a strategy that could minimise the need for an OGTT would be beneficial. MATERIALS AND METHODS: Consecutive PCOS patients (n=118) with fasting glucose <6.1 mmol/l were included in the study. Parameters derived from medical history, clinical examination and fasting blood samples were assessed by decision tree modelling for their ability to discriminate women with IGM (2-h OGTT value >/=7.8 mmol/l) from those with NGT. RESULTS: According to the OGTT results, 93 PCOS women had NGT and 25 had IGM. The best decision tree consisted of HOMA-IR, the proinsulin:insulin ratio, proinsulin, 17-OH progesterone and the ratio of luteinising hormone:follicle-stimulating hormone. This tree identified 69 women with NGT. The remaining 49 women included all women with IGM (100% sensitivity, 74% specificity to detect IGM). Pruning this tree to three levels still identified 53 women with NGT (100% sensitivity, 57% specificity to detect IGM). Restricting the data matrix used for tree modelling to medical history and clinical parameters produced a tree using BMI, waist circumference and WHR. Pruning this tree to two levels separated 27 women with NGT (100% sensitivity, 29% specificity to detect IGM). The validity of both trees was tested by a leave-10%-out cross-validation. CONCLUSIONS/INTERPRETATION: Decision trees are useful tools for separating PCOS women with NGT from those with IGM. They can be used for stratifying the metabolic screening of PCOS women, whereby the number of OGTTs can be markedly reduced.

Adult↗
PubMed2006

Glucagon suppression of ghrelin secretion is exerted at hypothalamus-pituitary level.

CONTEXT: The mechanisms underlying the well-known glucagon-induced satiety effect are unclear. Recently, we showed that glucagon induces a remarkable decrease in the orexigenic hormone ghrelin that might be responsible for this effect. OBJECTIVE: The objective of this study was to evaluate the putative role of the hypothalamic pituitary axis in glucagon's suppressive effect on ghrelin secretion. DESIGN, SUBJECTS, AND METHODS: Prospectively, we studied the endocrine and metabolic responses to im glucagon administration in 22 patients (16 males; age, 21-68 yr; body mass index, 28.1 +/- 1.1 kg/m(2)) with a known hypothalamic-pituitary lesion and at least one pituitary hormone deficiency. Control experiments were performed in 27 healthy subjects (15 males; age, 19-65 yr; body mass index, 25.5 +/- 0.9 kg/m(2)). RESULTS: The suppression of ghrelin by glucagon measured as area under the curve(240 min) was significantly greater in controls when compared with patients (P < 0.01). Although there was a significant decrease in ghrelin in controls (P < 0.001), ghrelin was almost unchanged in patients (P = 0.359). Changes in glucagon, glucose, and insulin levels were comparable between both groups. CONCLUSIONS: We show that the hypothalamic-pituitary axis plays an essential role in the suppression of ghrelin induced by im glucagon administration. Glucagon significantly decreases ghrelin levels in healthy subjects. However, in the absence of an intact hypothalamic-pituitary axis, this effect was abolished. The mechanisms responsible for our observation are unlikely to include changes in glucose or insulin levels.

Adult↗
PubMed2005

Wnt-5a has tumor suppressor activity in thyroid carcinoma.

Stabilization of beta-catenin by inhibition of its phosphorylation is characteristic of an activation of the canonical Wnt/beta-catenin signaling pathway and is associated with various human carcinomas. It contrasts to an as yet incompletely characterized action of an alternative noncanonical Wnt signaling pathway on neoplastic transformation. The aim of the present study was to test the effects of a member of the noncanonical Wnt signaling pathway, Wnt-5a, in primary thyroid carcinomas and in thyroid carcinoma cell lines. Compared to normal tissue Wnt-5a mRNA expression was clearly increased in thyroid carcinomas. Immunohistochemically, a bell-shaped response was observed with low to undetectable levels in normal tissue and in anaplastic tumors whereas differentiated thyroid carcinomas showed strong positive immunostaining for Wnt-5a. Transfection of Wnt-5a in a thyroid tumor cell line FTC-133 was able to reduce proliferation, migration, invasiveness and clonogenicity in these cells. These effects of Wnt-5a are associated with membranous beta-catenin translocation and c-myc oncogene suppression and are mediated through an increase in intracellular Ca(2+) release, which via CaMKII pathways promotes beta-catenin phosphorylation. Specific inhibition of beta-catenin phosphorylation by W-7, a calmodulin inhibitor, or by KN-93, a CaMKII inhibitor, supports these findings whereas PKC inhibitors were without effect. This interaction occurs downstream of GSK-3 beta as no Wnt-5a effect was seen on the Ser(9) phosphorylation of GSK-3 beta. Our data are compatible with the hypothesis that Wnt-5a serves as an antagonist to the canonical Wnt-signaling pathway with tumor suppressor activity in differentiated thyroid carcinomas.

Cell Division↗
PubMed2005

Precision of intracellular calcium spike timing in primary rat hepatocytes.

Extracellular stimuli are often encoded in the frequency, amplitude and duration of spikes in the intracellular concentration of calcium ([Ca2+]i). However, the timing of individual [Ca2+]i-spikes in relation to the dynamics of an extracellular stimulus is still an open question. To address this question, we use a systems biology approach combining experimental and theoretical methods. Using computer simulations, we predict that more naturalistic pulsed stimuli generate precisely-timed [Ca2+]i-spikes in contrast to the application of constant stimuli of the same dose. These computational results are confirmed experimentally in single primary rat hepatocytes upon alpha1-adrenergic stimulation. Hormonal signalling in analogy to neuronal signalling thus has the potential to make use of temporal coding on the level of single cells. The [Ca2+]i-signalling cascade provides a first example for increasing the information capacity of an intracellular regulatory signal beyond the known coding mechanisms of amplitude (AM) and frequency modulation (FM).

Algorithms↗
PubMed2001

Noise enhanced hormonal signal transduction through intracellular calcium oscillations.

In a wide range of non-linear dynamical systems, noise may enhance the detection of weak deterministic input signals. Here, we demonstrate this phenomenon for transmembrane signaling in a hormonal model system of intracellular Ca(2+) oscillations. Adding Gaussian noise to a subthreshold extracellular pulsatile stimulus increased the sensitivity in the dose-response relation of the Ca(2+) oscillations compared to the same noise signal added as a constant mean level. These findings may have important physiological consequences for the operation of hormonal and other physiological signal transduction systems close to the threshold level.

Calcium↗
PubMed2001

[Reversible blindness caused by an invasive prolactinoma].

HISTORY: A 40-year-old man presented with severe headache, nausea and acute blindness. A CT-scan of the skull revealed a huge tumor along the basis of the skull. The patient was referred to our clinic for diagnostic and therapeutic evaluation. INVESTIGATIONS: MRT showed a large right-sided paramedian tumour displacing the brain stem with signs of increased intracranial pressure. Routine laboratory tests were normal except a normochromic anaemia. Endocrine tests demonstrated partial hypopituitarism with alteration of the somatotropic, gonadotropic and corticotropic axis and moderate hyperprolactinaemia. TREATMENT AND COURSE: On the day of admission a transnasal biopsy was taken. The preliminary histopathological diagnosis was a low differentiated carcinoma. Because of this diagnosis and because of the infiltrative tumour growth an operation was not performed but emergency irradiation was begun and dopamine agonist therapy was started because of hyperprolactinaemia. Several days later the final microscopic diagnosis of the transnasal biopsy specimen was reported to be an invasive prolactinoma. Under dopamine agonist therapy prolactin levels rose to a maximum of 6460 ng/ml to decline thereafter to normal values, and the visual disturbances recovered. After 5 weeks of therapy considerable shrinkage of the tumor was demonstrated by MRT. CONCLUSION: The differential diagnosis of acute visual deterioration caused by a large tumour along the basis of the skull includes an invasive prolactinoma. The diagnosis is made by demonstrating grossly elevated prolactin levels. To avoid falsely low prolactin measurements, caused by a hook-effect in the prolactin assay, serum dilution is mandatory in the diagnostic work-up. In the case of a prolactinoma medical treatment with dopamine receptor agonists is the therapy of choice because it causes rapid tumour shrinkage and symptomatic improvement in most patients, so that irradition of the tumour is not indicated. As dopamine agonist therapy is rapidly effective and well tolerated, it should be started even in case of doubt to lose no time until final diagnosis.

Acute Disease↗
PubMed2000

[A young woman with neurofibromatosis 1 (Recklinghausen disease), abdominal tumor and hypertension].

HISTORY AND ADMISSION FINDINGS: A 38-year-old woman, known to have type 1 neurofibromatosis (NF1; von Recklinghausen's disease) and recurrence of a malignant haemangiopericytoma in the lower abdomen developed hypertension. She also had headaches and marked perspiration. Physical examination revealed tachycardia and paleness of the distal digits, in addition to multiple neurofibromas and café-au-lait spots. INVESTIGATIONS: A tumour was found in the region of the right adrenal gland, in addition to the known haemangiopericytoma. The levels of epinephrine and dopamine were elevated, suggesting an orthotopic phaeochromocytoma as the cause of the hypertension. Mutation analysis confirmed the neurofibromatosis by demonstrating a splice mutation of the NF1 gene in exon 8. She also was found to have emphysema of the right upper and middle lobes of the lung. TREATMENT AND COURSE: Because of the extensive local changes the recurrent haemangiopericytoma was only partially resected. At the same time a right adrenalectomy was performed without complication. However, the patient's postoperative recovery was slow, but she was now normotensive. Planned radiotherapy was omitted because of her poor general state. Instead she was given weekly palliative chemotherapy with adriamycin, with little improvement. She died several weeks later from the malignancy. CONCLUSION: This case emphasizes that in a patient with NF1 a phaeochromocytoma must be considered as a possible cause of hypertension. It is likely that the patient's emphysema was associated with the NF1, while the haemangiopericytoma was presumably unconnected with the NF1.

Abdominal Neoplasms↗
PubMed2000

Tolbutamide and diazoxide modulate phospholipase C-linked Ca(2+) signaling and insulin secretion in beta-cells.

Arginine vasopressin (AVP), bombesin, and ACh increase cytosolic free Ca(2+) and potentiate glucose-induced insulin release by activating receptors linked to phospholipase C (PLC). We examined whether tolbutamide and diazoxide, which close or open ATP-sensitive K(+) channels (K(ATP) channels), respectively, interact with PLC-linked Ca(2+) signals in HIT-T15 and mouse beta-cells and with PLC-linked insulin secretion from HIT-T15 cells. In the presence of glucose, the PLC-linked Ca(2+) signals were enhanced by tolbutamide (3-300 microM) and inhibited by diazoxide (10-100 microM). The effects of tolbutamide and diazoxide on PLC-linked Ca(2+) signaling were mimicked by BAY K 8644 and nifedipine, an activator and inhibitor of L-type voltage-sensitive Ca(2+) channels, respectively. Neither tolbutamide nor diazoxide affected PLC-linked mobilization of internal Ca(2+) or store-operated Ca(2+) influx through non-L-type Ca(2+) channels. In the absence of glucose, PLC-linked Ca(2+) signals were diminished or abolished; this effect could be partly antagonized by tolbutamide. In the presence of glucose, tolbutamide potentiated and diazoxide inhibited AVP- or bombesin-induced insulin secretion from HIT-T15 cells. Nifedipine (10 microM) blocked both the potentiating and inhibitory actions of tolbutamide and diazoxide on AVP-induced insulin release, respectively. In glucose-free medium, AVP-induced insulin release was reduced but was again potentiated by tolbutamide, whereas diazoxide caused no further inhibition. Thus tolbutamide and diazoxide regulate both PLC-linked Ca(2+) signaling and insulin secretion from pancreatic beta-cells by modulating K(ATP) channels, thereby determining voltage-sensitive Ca(2+) influx.

Animals↗
PubMed2000

Energetic requirement of carbachol-induced Ca2+ signaling in single mouse beta-cells.

Insulin secretion is under multifactorial control by glucose and neurohumoral factors like acetylcholine (ACH), which activate the Ca2+/phospholipase C signaling pathway. All insulin secretagogues elevate cytosolic free Ca2+ ([Ca2+]i) that is central to the stimulation of insulin secretion. The actions of ACH on [Ca2+]i are glucose dependent but the metabolic steps involved are only partly understood. Here we have characterized the metabolic steps by which glucose exerts its synergistic effects on ACH-linked Ca2+-signals. [Ca2+]i was measured in single fura-2 loaded beta-cells. The ACH analog carbachol (3 microM) caused rise in [Ca2+]i that was strongly dependent on the extracellular glucose concentration ranging from 0-10 mM. Iodoacetate, which blocks glycolysis, thereby preventing the generation of NADH and ATP from glucose metabolism, and rotenone or antimycin, which inhibit complex 1 and 2 of the mitochondrial respiratory chain, respectively, inhibited in glucose (6 mM) the carbachol-induced Ca2+ signal to a similar extent as glucose deprivation. This demonstrates that glucose metabolism and generation of ATP through oxidative phosphorylation of energy rich substrates like NADH and FADH2 are required for carbachol-induced Ca2+ signals. While sodium arsenate, which prevents net glycolytic production of ATP without inhibiting glycolysis, had no significant effect on the carbachol-induced Ca2+-signal, the mitochondrial pyruvate transport inhibitor alpha-cyano-4-hydroxycinnamate and the Krebs cycle inhibitor monofluoroacetate strongly suppressed the rise in [Ca2+]i elicited by carbachol. While pyruvate was ineffective, methyl pyruvate, a membrane-permeant pyruvate analog, and alpha-ketoisocaproate in combination with glutamine, which are both substrates for mitochondrial ATP production, could restore the carbachol-induced Ca2+ signal in glucose-free medium. These data demonstrate for the first time that Krebs cycle metabolism of glucose and ATP formation through oxidative phosphorylation is critical for the glucose dependency of ACH-linked Ca2+-signals in mouse beta-cells, and they suggest that mitochondrial metabolism plays a key role in the interactive regulation of beta-cells by neurohumoral factors activating the Ca2+/phospholipase C signaling pathway.

Adenosine Triphosphate↗
PubMed1999

Regulation of cytosolic free calcium concentration by extracellular nucleotides in human hepatocytes.

The effects of extracellular ATP and other nucleotides on the cytosolic free Ca2+ concentration ([Ca2+]i) have been studied in single primary human hepatocytes and in human Hep G2 and HuH-7 hepatoma cells. ATP, adenosine 5'-O-(3-thiotriphosphate) (ATPgammaS), and UTP caused a concentration-dependent biphasic increase in [Ca2+]i with an initial peak followed by a small sustained plateau in most cells. In some cells, however, repetitive Ca2+ transients were observed. The rank order of potency was ATP >/= UTP > ATPgammaS, and complete cross-desensitization of the Ca2+ responses occurred between ATP and UTP. The initial transient peak in [Ca2+]i was resistant to extracellular Ca2+ depletion, which demonstrates mobilization of internal Ca2+ by inositol 1,4,5-trisphosphate whose formation was enhanced by ATP and UTP. In contrast, the sustained plateau phase required influx of external Ca2+. Ca2+ influx occurs most likely through a capacitative Ca2+ entry mechanism, which was shown to exist in these cells by experiments performed with thapsigargin. On the molecular level, specific mRNA coding for the human P2Y1, P2Y2, P2Y4, and P2Y6 receptors could be detected by RT-PCR in Hep G2 and HuH-7 cells. However, ADP and UDP, which are agonists for P2Y1 and P2Y6 receptors, respectively, caused no changes in [Ca2+]i, demonstrating that these receptors are not expressed at a functional level. Likewise, alpha,beta-methylene-ATP, beta,gamma-methylene-ATP, AMP, and adenosine were inactive in elevating [Ca2+]i, suggesting that the ATP-induced increase in [Ca2+]i was not caused by activation of P2X or P1 receptors. Thus, on the basis of the pharmacological profile of the nucleotide-induced Ca2+-responses, extracellular ATP and UTP increase [Ca2+]i by activating P2Y2 and possibly P2Y4 receptors coupled to the Ca2+-phosphatidylinositol signaling cascade in human hepatocytes. This suggests that extracellular nucleotides from various sources may contribute to the regulation of human liver cell functions.

Adenosine Triphosphate↗
PubMed1999

Ca2+/calmodulin inhibition and phospholipase C-linked Ca2+ Signaling in clonal beta-cells.

Neurotransmitters and hormones, such as arginine vasopressin (AVP) and bombesin, evoke frequency-modulated repetitive Ca2+ transients in insulin-secreting HIT-T15 cells by binding to receptors linked to phospholipase C (PLC). The role of calmodulin (CaM)-dependent mechanisms in the generation of PLC-linked Ca2+ transients was investigated by use of the naphthalenesulfonamide CaM antagonists W-7 and W-13 and their dechlorinated control analogs W-5 and W-12. W-7 (10-30 microM) and W-13 (30-100 microM), but not W-5 (100 microM) and W-12 (300 microM), reversibly inhibited the AVP- and bombesin-induced Ca2+ transients. As the generation of PLC-linked Ca2+ transients requires mobilization of internal Ca2+ and Ca2+ influx through voltage-sensitive (VSCC) and -insensitive (VICC) Ca2+ channels, the effects of the W compounds on these processes were further investigated. First, W-7 dose dependently diminished K+ (45 mM)-induced Ca2+ signals (IC50, approximately 25 microM), and W-13 (100 microM) reduced the K+ (45 mM)-induced [Ca2+]i rise by about 40-60%, whereas W-5 (100 microM) and W-12 (300 microM) had no effect. In addition, W-7 (100 microM) inhibited whole cell Ca2+ currents in mouse beta-cells by about 60%. Second, pretreatment of cells (5 min) with W-7 (30 microM), but not W-5 (30 microM), inhibited agonist-induced internal Ca2+ mobilization by about 75% in Ca2+-free medium. Neither W-7 (30 microM) nor W-5 (30 microM) affected AVP (100 nM)-stimulated formation of IP3. Third, capacitative Ca2+ influx through VICC activated by thapsigargin (2 microM) in the presence of verapamil (50 microM) was inhibited by W-7 (30 microM) but not by W-5 (30 microM). As all of the W compound effects corresponded well to their reported anticalmodulin activity, a specific anticalmodulin action can be assumed. Thus, Ca2+ via activation of CaM-dependent processes could provide positive feedback on the generation of PLC-linked Ca2+ transients in HIT-T15 cells. This appears to involve CaM-dependent regulation of both mobilization of internal Ca2+ and Ca2+ influx through VSCC and VICC.

Animals↗
PubMed1998

Hepatoma with severe non-islet cell tumor hypoglycemia.

We report a 22-yr-old male patient with chronic hepatitis B and a large, well differentiated hepatoma who developed episodes of symptomatic fasting hypoglycemia, which were caused by paraneoplastic secretion of unprocessed "big" insulin-like growth factor-II. Initially, the patient presented with normal liver function, which deteriorated during the clinical course. Therapeutic attempts to reduce tumor mass failed and the patient subsequently died because of metastases of the hepatoma. The pathophysiology of non-islet cell tumor hypoglycemia, differential diagnosis, and therapeutic options are discussed.

Adult↗
PubMed1998

Coding of time-varying hormonal signals in intracellular calcium spike trains.

In a variety of cell types extracellular hormonal stimuli varying in time are transfered across the cell membrane into repetitive spikes of the intracellular calcium concentration ([Ca2+]i). Distinct temporal patterns of [Ca2+]i spikes are capable of regulating the function and structure of target cells. Here, we investigate the ability of transmembrane signaling to encode time-varying hormonal stimulations (bandlimited Gaussian white noise) in a model of receptor-controlled [Ca2+]i oscillations. The encoding of hormonal signals in [Ca2+]i spike trains is quantified by using an information-theoretic approach allowing to estimate the hormonal stimulus from [Ca2+]i spike trains. Our results suggest that intracellular [Ca2+]i spike trains convey faithful information on temporal variations of extracellular hormonal concentrations at scales of 30-200 sec, corresponding to cut-off frequencies between 5 and 30 mHz of the random hormonal stimulation.

Animals↗
PubMed1998

Coarse-grained entropy rates quantify fast Ca2+ dynamics modulated by pharmacological stimulation.

Calcium (Ca2+) is an ubiquitous intracellular messenger which regulates cellular processes, such as secretion, contraction, and cell proliferation. A variety of cell types respond to hormonal stimuli with periodic oscillations of the intracellular free Ca2+ concentration ([Ca2+]i) which can be modulated in their frequency in a dose-dependent manner. The period of these well-studied oscillations varies normally between 30 sec and a couple of minutes. Here we study [Ca2+]i oscillations in clonal beta cells (hamster insulin secreting cells, HIT) under pharmacological stimulation. Besides the well-known high-amplitude low frequency oscillations we try to analyze for the first time low-amplitude high frequency oscillations of [Ca2+]i under pharmacological stimulation which have not been explored in experimental approaches to date. Using coarse-grained entropy rates computed from information-theoretic functionals we demonstrate differences in temporal complexity of the fast low-amplitude [Ca2+]i dynamics corresponding to different phases of pharmacological stimulation which are additional to the well-known dose-dependent pattern of low-frequency high amplitude [Ca2+]i dynamics.

Algorithms↗
PubMed1997

Impairment of ATP-induced Ca2+ -signalling in human thyroid cancer cells.

Extracellular nucleotides like ATP that activate the Ca2+ -phosphatidylinositol (PI) signalling pathway have been suggested to participate in the regulation of normal human thyroid function. We examined, whether P2y-purinergic receptors are expressed on human thyroid cancer cells and whether post-receptor Ca2+ signalling is altered by malignant transformation. Extracellular ATP caused a biphasic increase in cytosolic free Ca2+ ([Ca2+]i) in normal human thyrocytes and in human follicular (FTC) and papillary (PTC) thyroid carcinoma cells. In FTC and PTC cell lines the dose-response curves for ATP-induced changes in [Ca2+]i were shifted to the right when compared with normal thyrocytes, whereas in undifferentiated thyroid carcinoma (UTC) cells even high concentrations of ATP (500 microM) failed to stimulate a rise in [Ca2+]i. By contrast, ATP stimulated inositol 1,4,5-trisphosphate (IP3) formation and capacitative Ca2+ entry was operational as judged by thapsigargin in normal thyrocytes and all thyroid cancer cells. Thus, P2y-purinergic receptors are expressed on thyroid tumor cells independent of degree of differentiation. In UTC cells, however, impairment in the Ca2+ -phosphatidylinositol (PI) signalling cascade occurs distal to the formation of IP3 and proximal to the activation of capacitative Ca2+ entry. Disturbed ATP-induced Ca2+ -signalling and alterations in the Ca2+ -PI signalling cascade may contribute to decreased expression or loss of specific thyroid functions in thyroid cancer cells.

Adenosine Triphosphate↗
PubMed1997

Twenty-four-hour rhythms of plasma catecholamines and their relation to cardiovascular parameters in healthy young men.

Diurnal and ultradian rhythms of plasma norepinephrine and epinephrine and their role in the regulation of cardiovascular parameters were investigated over 24 h of recumbency in a group of five men. Catecholamines were measured at 10 min intervals, and blood pressure and heart rate were recorded continuously. Norepinephrine and epinephrine rapidly fluctuated in each subject, with no obvious diurnal rhythm. Spectral analysis suggested two ultradian rhythms with periods of around 12 h and 50-100 min for both catecholamines. The pulse detection programs PULSAR and CLUSTER revealed 20-30 pulses/24 h for norepinephrine and epinephrine, with a significant correlation between the two rhythms (r = 0.63-0.80, P < 0.001). Neither the frequency nor the amplitude of these rapid fluctuations differed between day and night. Arousal in the morning caused a small increase in plasma catecholamines and getting out of bed a large increase. Thus changes in posture and activity are the main influences on the diurnal variations of plasma catecholamines reported previously, while the ultradian rhythms of sympathoadrenomedullary activity appear to be of intrinsic origin. Blood pressure and heart rate exhibited a diurnal rhythm with a nightly decrease. Arousal and rising from bed increased blood pressure and heart rate significantly. Although the amplitude of the rapid fluctuations of plasma catecholamines at times exceeded those caused by postural changes in the morning, when both plasma norepinephrine and epinephrine levels correlated highly with all cardiovascular parameters, correlations were not significant during recumbency. Thus the intrinsic ultradian fluctuations of plasma catecholamines appear not to be involved in the control of cardiovascular parameters during recumbency, and the increase in blood pressure and heart rate in the morning appears to be controlled by direct sympathetic neural input to the heart and vasculature in response to changes in activity and posture rather than by an endogenous surge of plasma catecholamines.

Adult↗
PubMed1996

Generation of repetitive Ca2+ transients by bombesin requires intracellular release and influx of Ca2+ through voltage-dependent and voltage independent channels in single HIT cells.

In the present study, the bombesin-induced changes in cytosolic free Ca2+ ([Ca2+]i) were investigated in single Fura-2 loaded SV-40 transformed hamster beta-cells (HIT). Bombesin (50-500 pM) caused frequency-modulated repetitive Ca2+ transients. The average frequency of the Ca2+ transients induced by bombesin (200 pM) was 0.58 +/- 0.02 min-1 (n = 121 cells). High concentrations of bombesin (> or = 2 nM) triggered a large initial Ca2+ transient followed by a sustained plateau or by a decrease to basal levels. In Ca(2+)- free medium, bombesin caused only one or two Ca2+ transients and withdrawal of extracellular Ca2+ abolished the Ca2+ transients. The voltage-dependent Ca2+ channel (VDCC) blockers, verapamil (50 microM) and nifedipine (10 microM), reduced amplitude and frequency of the Ca2+ transients and stopped the Ca2+ transients in some cells. Thapsigargin caused a sustained rise in [Ca2+]i in the presence of extracellular Ca2+ while in its absence the rise in [Ca2+]i was transient. Verapamil (50 microM) inhibited the thapsigargin-induced increase in [Ca2+]i by about 50%. Depletion of intracellular Ca2+ stores by repetitive stimulation with increasing concentrations of bombesin or thapsigargin in Ca(2+)-free medium caused an agonist-independent increase in [Ca2+]i when extracellular Ca2+ was restored, which was larger than in control cells that had been incubated in Ca(2+)-free medium for the same period of time. This rise in [Ca2+]i and the thapsigargin-induced increase in [Ca2+]i were only partly inhibited by VDCC-blockers. Thus, depletion of the agonist-sensitive Ca2+ pool enhances Ca2+ influx through VDCC and voltage-independent Ca2+ channels (VICC). In conclusion, the bombesin-induced Ca2+ response in single HIT cells is periodic in nature with frequency-modulated repetitive Ca2+ transients. Intracellular Ca2+ is mobilized during each Ca2+ transient, but Ca2+ influx through VDCC and VICC is required for maintaining the sustained nature of the Ca2+ response. Ca2+ influx in whole or part is activated by a capacitative Ca2+ entry mechanism.

Animals↗