Electrophysiological evidence for the autoregulation of β-cell secretion by insulin

Electrophysiological studies of cultured rat pancreatic β-cells using intracellular microelectrodes show that exogenous insulin over the range of 0.1–10.0 μg/ml inhibits the electrical activity due to 27.8 mM glucose in a dose-related manner. This inhibitory effect is manifested by a mean increase of the membrane potential from about ?20 to ?30 mV and inhibition of the manner of cells impaled showing spike activity from 60 to less than 10%. The inhibitory influence of insulin is rapid occuring within 5 min for the highest level used. The results provide evidence for a negative feedback role of insulin in regulating its own release.     

Electrophysiological evidence for the autoregulation of beta-cell secretion by insulin.

Electrophysiological studies of cultured rat pancreatic beta-cells using intracellular microelectrodes show that exogenous insulin over the range of 0.1 -- 10.0 microng/ml inhibits the electrical activity due to 27.8 mM glucose in a dose-related manner. This inhibitory effect is manifested by a mean increase of the membrane potential from about --20 to --30 mV and inhibition of the number of cells impaled showing spike activity from 60 to less than 10%. The inhibitory influence of insulin is rapid occurring within 5 min for the highest level used. The results provide evidence for a negative feedback role of insulin in regulating its own release.     

Analysis of the regulation of noradrenaline secretion by autoadrenoreceptors and stimulation frequency

A mathematical model is presented which quantitatively describes the value of secreted mediator to each subsequent impulse in the series of presynaptic impulses. The model is constructed with the account taken of the role of presynaptic adrenoreceptors regulating noradrenaline secretion. An analysis of the model shows that the observed decrease and further stabilization of presynaptic responses in the series of presynaptic impulses observed in neurophysiological experiments can be connected with the work of alpha- and beta-autoadrenoreceptors. The increase of impulsation frequency affects the sensitivity of these receptors, which brings about an increase of concentration of secreted to each subsequent impulse mediator in the synaptic slit in the series of presynaptic impulses and stabilization of secretion at a higher level.     

RAW264.7 cells lack prostaglandin-dependent autoregulation of tumor necrosis factor-alpha secretion

Studies of the response of RAW264.7 cells (RAW) to lipopolysaccharide (LPS) were carried out to determine why these cells do not demonstrate the prostaglandin (PG)-dependent autocrine regulation of tumor necrosis factor-alpha (TNF-alpha) secretion observed in primary resident peritoneal macrophages (RPMs). The major cyclooxygenase (COX) product of LPS-stimulated RAW was PGD2, with lesser amounts of PGE2. LPS-treated RAW produced PGs more slowly and reached their maximal PG synthetic rate later than did LPS-treated RPMs, as a result of lower constitutive COX-1 expression and a slower rate of COX-2 induction. Cytosolic phospholipase A2 and levels of free arachidonic acid were similar in RAW and RPMs. In contrast to RPMs, LPS-treated RAW produced high quantities of TNF-alpha, which were not altered in the presence of COX inhibitors. This failure of endogenous PGs to suppress TNF-alpha secretion was explained by the absence of the prostaglandin D2 receptor and the low levels of PGE2 produced during the first 2 h of the LPS response. These studies demonstrate that autocrine regulation of TNF-alpha secretion in response to LPS is greatly facilitated by a COX-1-mediated rapid accumulation of PGs as well by a correspondence between the PGs produced and the receptors expressed by the cells.     

A dynamic model of renal blood flow autoregulation

To test whether a mathematical model combining dynamic models of the tubuloglomerular feedback (TGF) mechanism and the myogenic mechanism was sufficient to explain dynamic autoregulation of renal blood flow, we compared model simulations with experimental data. To assess the dynamic characteristics of renal autoregulation, a broad band perturbation of the arterial pressure was employed in both the simulations and the experiments. Renal blood flow and tubular pressure were used as response variables in the comparison. To better approximate the situationin vivo where as large number of individual nephrons act in parallel, each simulation was performed with 125 parallel versions of the model. The key parameters of the 125 versions of the model were chosen randomly within the physiological range. None of the constituent models, i.e., the TGF and the myogenic, could alone reproduce the experimental observations. However, in combination they reproduced most of the features of the various transfer functions calculated from the experimental data. The major discrepancy was the presence of a bimodal distribution of the admittance phase in the simulations. This is not consistent with most of the experimental data, which shows a unimodal curve for the admittance phase. The ability of the model to reproduce the experimental data supports the hypothesis that dynamic autoregulation of renal blood flow is due to the combined action of TGF and the myogenic response.     

Effect of stimulation of alpha and beta presynaptic adrenoceptors on the liberation of noradrenaline produced by electric stimulation in rabbit carotid sinus]

The experiments carried out on the isolated carotid sinus in the rabbit demonstrated that alpha and beta adrenoceptors are capable of detecting the circulating catecholamines and the catecholamines of the synaptic cleft in order to modulate the release of noradrenaline from the sympathetic nerve endings in response to a potential action.     

A model approach to in situ coronary autoregulation

Pressure and flow waveforms were recorded at the entrance of the circumflex coronary artery in anaesthetized dogs during artificial constriction and release of the aorta which caused noticeable variations in the coronary perfusion pressure. The beat-to-beat mean diastolic flow resulting from the autoregulation of the coronary bed in response to the pressure changes was analysed on the basis of a simple model. Flow variations were interpreted as the result of an active mechanism, triggered by the pressure changes and affecting the elastic behaviour of the vessels. The timing and the main characteristics of this response mechanism, after constrictions of varying duration, were evaluated and are discussed. The predicted variations in vessel distensibility and cross-sectional area were compared with data quoted in the literature, showing that the results of this procedure are compatible with those of in vitro measurements on isolated microvessels.     

Metabolic model of autoregulation in the Circle of Willis

The Circle of Willis (CoW) is a ringlike structure of blood vessels found at the base of the brain. Its main function is to distribute oxygen-rich arterial blood to the cerebral mass. In a previous study, a one-dimensional (1D) model of the CoW was created to simulate a series of possible clinical scenarios such as occlusions in afferent arteries, absent or stringlike circulus vessels, or arterial infarctions (Moorhead et al., 2004, Comput. Methods Biomech. Biomed. Eng., 7(3), pp. 121-130). The model captured cerebral haemodynamic autoregulation by using a proportional-integral-derivative (PID) controller to modify efferent artery resistances. Although some good results and correlations were achieved, the model was too simple to capture all the transient dynamics of autoregulation. Hence a more physiologically accurate model has been created that additionally includes the oxygen dynamics that drive the autoregulatory response. Results very closely match accepted physiological response and limited clinical data. In addition, a set of boundary conditions and geometry is presented for which the autoregulated system cannot provide sufficient perfusion, representing a condition with increased risk of stroke and highlighting the importance of modeling the haemodynamics of the CoW. The system model created is computationally simple so it can be used to identify at-risk cerebral arterial geometries and conditions prior to surgery or other clinical procedures.     

An autoregulation model in the system of squid axonal channels

A model that describes the interactions in the system of squid axon channels is proposed. The variables of the model are channel concentration and membrane voltage. The model represents the simplest mathematical formulation of the data on axon membrane, its components, and their role in the generation and propagation of action potential.     

Pharmacological identification of the major subtypes of adrenoceptors involved in the canine external carotid vasoconstrictor effects of adrenaline and noradrenaline.

This study investigated the potential effects of adrenaline and noradrenaline on the external carotid blood flow of vagosympathectomised dogs and the receptor mechanisms involved. One minute (1 min) intracarotid infusions of adrenaline and noradrenaline produced dose-dependent decreases in external carotid blood flow without changes in blood pressure or heart rate. These responses, which remained unaffected after saline, were: (i) mimicked by the adrenoceptor agonists, phenylephrine (alpha1) and BHT933 (6-Ethyl-5,6,7,8-tetrahydro-4H-oxazolo [4,5-d] azepin-2-amine dihydrochloride; alpha2); (ii) abolished after phentolamine (2000 microg/kg) unmasking a vasodilator component (subsequently blocked by propranolol; 1000 microg/kg); and (iii) partly blocked by rauwolscine (30 and 100 microg/kg), and subsequently abolished by prazosin (100 microg/kg). Accordingly, rauwolscine (100 and 300 microg/kg) markedly blocked the responses to BHT933 without affecting those to phenylephrine; likewise, prazosin (100 microg/kg) markedly blocked the responses to phenylephrine without affecting those to BHT933. These results show that both alpha1- and alpha2-adrenoceptors mediate vasoconstriction within the canine external carotid circulation. Moreover, after blockade of alpha1/alpha2-adrenoceptors, both adrenaline and noradrenaline exhibit a beta-adrenoceptor-mediated vasodilator component.     

Maintaining a memory by transcriptional autoregulation

One of the key features of cellular differentiation programs is stability. Although differentiation is reversible in principle, many components of the gene batteries induced upon terminal differentiation are maintained throughout a cell's life. For example, muscle cells continuously express the myosin gene, and GABAergic neurons continuously express genes for GABA synthesis and transport. Maintaining gene expression patterns in the nervous system is a particular challenge given the non-renewing nature and therefore extensive life span of many neuronal cell types.     

Studies on the mechanism of inhibition of glucose-stimulated insulin secretion by noradrenaline in rat islets of Langerhans.

Noradrenaline (norepinephrine) was shown to be a potent inhibitor of glucose-induced insulin release from rat pancreatic islets, with half-maximal inhibition of the secretory response to 20 mM-glucose occurring at approx. 0.3 microM, and complete suppression of the response occurring at 4 microM-noradrenaline. Inhibition of insulin secretion by noradrenaline was antagonized by the alpha 2-adrenergic antagonist yohimbine (half maximally effective dose approximately 1 microM), but was largely unaffected by the alpha 1-adrenergic antagonist prazosin at concentrations up to 50 microM, suggesting that the response was mediated by alpha 2-adrenergic receptors. Noradrenaline significantly reduced the extent of 45Ca2+ accumulation in glucose-stimulated islets, although as much as 5 microM-noradrenaline was required for 50% inhibition of this response. The ability of noradrenaline to inhibit islet-cell 45Ca2+ uptake was totally abolished in media containing 1 mM-dibutyryl cyclic AMP, suggesting that the response may have been secondary to lowering of islet cyclic AMP. Under these conditions, however, noradrenaline was still able to inhibit insulin secretion maximally. The data suggest that the site(s) at which noradrenaline acts to mediate inhibition of insulin secretion in rat islets lies distal to both islet-cell cyclic AMP accumulation and Ca2+ uptake.     

Role of alpha and beta adrenoceptors on the salivary secretion in the mandibular gland of the rabbit

The stimulation of the superior cervical ganglion increased the salivary flow rate (about five-fold) in all 35 rabbits studied but two. The administration of alpha or beta adrenoceptor blocking drugs was unable to eliminate the positive effect of the sympathetic stimulation on the salivary flow, though the flow rate fell about 50% with the administration of each of the blockers. According to these results both types of receptors may be involved in the secretory response of this gland. Nevertheless it seems that the beta-adrenoceptors play a more important role in the secretory response and the alpha-adrenoceptors in the motor one.