Computer simulation of the synchronization of the sinoatrial central cell in response to periodic stimulation of the vagus nerve

The effect of periodic stimulation of the vagus nerve on the activity of the central cell of the sinoatrial node has been simulated. The regions of synchronization and desynchronization have been revealed, and the phase shift at different stimulation frequencies has been estimated. The positive chronotropic effect has been shown to occur at some frequencies of stimulation.     

Function of myocardial alpha-adrenoceptors

Myocardial α-adrenoceptors are similar to vascular α-adrenoceptors; therefore the drugs which are used to study myocardial α-adrenoceptors can affect the heart indirectly by acting on vascular α-adrenoceptors. High concentrations of α-adrenoceptor stimulant and α-adrenoceptor blocking drugs can exert cardiac effects that do not result from action on α-adrenoceptors; therefore relatively low concentrations of these drugs must be used to obtain specific effects.An α-adrenoceptor mediated positive inotropic effect has been observed in relatively slow beating isolated heart preparations; it is not associated with shortening of the duration of systole or an increase in myocardial cyclic AMP concentration and is probably accompanied by an increase in Ca²⁺ influx. Usually α-adrenoceptor stimulation has no effect on heart rate.Myocardial α-adrenoceptor mediated ventricular arrhythmias have been caused in animals by high concentrations of catecholamines, and a transient increase in α-adrenoceptor concentration has been found in ischemic myocardium. We do not know how myocardial α-adrenoceptor stimulation causes arrhythmias. In isolated heart preparations low concentrations of epinephrine and norepinephrine prolong refractory period and action potential duration by α-adrenoceptor stimulation, and higher concentrations of the catecholamines shorten refractory period and action potential duration by α-adrenoceptor stimulation. In isolated specialized conducting fibers low concentrations of catecholamines reduce automaticity by α-adrenoceptor stimulation and higher concentrations increase automaticity by β-adrenoceptor stimulation. In partially depolorized ventricle preparations α-adrenoceptor stimulation has been reported both to depress and to restore electrical and mechanical activity. Clearly, much remains to be done before we understand α-adrenoceptor mediated cardiac effects.     

Ca2+ participation in vasodilator reactions

Stimulation of alpha-adrenoceptors was simulated by intraarterial injection of 0.6 mmol CaCl2 in acute experiments on resting muscles of the dog hind leg. It has been demonstrated that alpha-adrenergic stimulation of metabolism in skeletal muscles has a vasodilative effect in the muscle-supplying vessels. It has been also shown that imitation of alpha-adrenergic stimulation effect by intraarterial injection of CaCl2 causes Ca- and alpha-adrenergic-dependent vasodilative reactions. It is suggested that disturbance of vasodilative effects caused by alpha-adrenergic stimulation in the effector tissues, counteracting the direct constrictive alpha-adrenoceptor effect in the smooth muscle cells of the vessel wall, can lead to systemic impairment of the vascular tone.     

Stimulated cytokine production correlates in umbilical arterial and venous blood at delivery

BACKGROUND: Umbilical venous blood is easy to obtain after delivery, and thus has been commonly used in many studies for cytokine analysis. Our aim was to evaluate whether or not induced cytokine production differs after stimulation in umbilical artery and vein whole blood samples, using two different stimulation protocols. The effect of such stimulation on fetal and maternal blood was also evaluated. METHODS: Blood samples from umbilical artery (UA) and vein (UV), and from the mother were collected from 23 women after delivery at term. Concentrations of cytokines (IL-4, IFN-gamma, IL-6 and TNF-alpha) were measured in plasma and whole blood after PMA/ConA and PMA/ionomycin stimulation. RESULTS: Both in maternal and in fetal samples, cytokine concentrations in unstimulated plasma samples were lower than in stimulated samples, except for IL-4 after PMA/ConA stimulation. UA and UV showed similar, average cytokine levels after stimulation and the correlations were high (r=0.68-0.95). Cytokine concentrations were clearly higher in umbilical blood than in maternal blood after stimulation, but not in plasma. Correlations between maternal and umbilical samples after stimulation were generally low (r<0.41). IFN-gamma was not detectable in unstimulated plasma samples. The production of IL-4 and IFN-gamma was more intense after PMA/ionomycin stimulation than after PMA/ConA stimulation. INTERPRETATION OF THE RESULTS: Concentrations of the cytokines examined are similar in blood from the UA and UV. For IL-4 and IFN-gamma, the stimulant used has a significant effect on the level of cytokine expression, and interestingly, the effect is more pronounced on the fetal than on the maternal side.     

Cerebral responses of healthy humans to rhythmic transcranial magnetic stimulation of different intensities

The effect of rhythmic transcranial magnetic stimulation (rTMS) of different intensities (single superthreshold rTMS more intense than 1.2 T and subthreshold one with an intensity of 70–80% of the motor threshold) of sagittal premotor cortical areas on the human functional activity was estimated in eight volunteers on the basis of combined EEG, neuropsychological, and hemodynamic examinations. The objectives of the study included the selection of the frequency of activating stimulation and revision of the objective EEG criteria of rTMS efficiency. It has been demonstrated that analysis of the EEG response to photostimulation at different frequencies is efficient in selecting the rTMS frequency. The EEG coherence is one of the most informative characteristics of the rTMS effect on central neurodynamics. The functional effects of stimulation (activating or inhibitory) have been shown to depend on the initial level of intercentral coherent relationships It has been found that rTMS of the sagittal premotor cortex causes definite changes in the functional activity of a healthy brain different from those caused by placebo. These changes are greater in the left hemisphere (in the form of intrahemispheric changes in coherence and depend on the stimulation intensity (superor subthreshold) and the initial state. The vascular factor has been shown to play an important role in the formation of cerebral responses to rTMS.     

Inhibition of transient lower esophageal sphincter relaxations by electrical acupoint stimulation

Acupuncture has been shown to modulate visceral sensation and function. Traditionally, stimulation at the Neiguan (pericardial meridian) has been used to treat upper gastrointestinal symptoms. Some of the effects of acupuncture may be mediated through release of endogenous opioids and are reversed by naloxone. Gastric distension is the major trigger for transient lower esophageal sphincter (LES) relaxations (TLESRs). The aim of this study was to investigate the effect of electric stimulation at the Neiguan and naloxone on the TLESRs. In 14 healthy volunteers, electrical acupoint stimulation was applied at the Neiguan and a sham point on the hip in randomized order on the same day. In 12 healthy volunteers, the effects of naloxone (80 microg/kg iv bolus injection) and saline on electrical acupoint stimulation were compared on separate days at least 1 wk apart. Esophageal motility was measured during distension of the proximal stomach with 500 ml of air using a barostat balloon. Electric acupoint stimulation at the Neiguan decreased the rate of TLESRs by approximately 40% from a median of 6/h to 3.5/h (P < 0.02). Acupoint stimulation had no effect on basal LES pressure, the residual LES pressure during TLESRs, the duration of TLESRs, or gastrointestinal symptoms of fullness, bloating, discomfort, or nausea. The effect of acupoint stimulation was not inhibited by naloxone. Electric acupoint stimulation at the Neiguan significantly inhibits the frequency of TLESRs in response to gastric distention in healthy subjects. This effect does not appear to be mediated through mu-opioid receptors.     

The basis for EDTA-stimulation of methemoglobin reduction in hemolysates of human erythrocytes.

We have studied the stimulation by EDTA of methemoglobin reduction in hemolysates of human erythrocytes. The EDTA effect has been shown not to be the result of an allosteric interaction of EDTA with hemoglobin or the result of a photochemical reduction. The effect does not appear to be due to a direct interaction of free EDTA with either of the catalytic components of the erythrocyte methemoglobin reduction system. The EDTA stimulation seen in hemolysates is due to the formation of an iron-EDTA complex, which transfers electrons from the reductase to methemoglobin.     

Species variations in the relaxation of tail arteries to electrical stimulation

Relaxation in response to electrical stimulation has been studied in isolated tail arteries from rats, cats and pigs. Electrical stimulation elicited contractile responses in unstimulated strips, but caused frequency-dependent relaxations in tail arteries from all species studied, following contractile responses by various agents. The order of susceptibility to the relaxant effect of electrical stimulation in arteries from all three species was pig greater than cat greater than rat. Relaxations to electrical stimulation were unaffected by prior treatment of arteries with atropine, propranolol, tetrodotoxin, indomethacin, ouabain, pyrilamine and chemical denervation with 6-hydroxy-dopamine, but were prevented, dose-dependently, by cimetidine and aminophylline (antagonists of histamine H2-receptor and adenosine P1-receptor, respectively). The results suggest that relaxation of tail arteries from the rat, cat and pig in response to electrical stimulation is modulated by histamine and adenosine.     

PACAP regulates immediate catecholamine release from adrenal chromaffin cells in an activity-dependent manner through a protein kinase C-dependent pathway

Adrenal medullary chromaffin cells are a major peripheral output of the sympathetic nervous system. Catecholamine release from these cells is driven by synaptic excitation from the innervating splanchnic nerve. Acetylcholine has long been shown to be the primary transmitter at the splanchnic-chromaffin synapse, acting through ionotropic nicotinic acetylcholine receptors to elicit action potential-dependent secretion from the chromaffin cells. This cholinergic stimulation has been shown to desensitize under sustained stimulation, yet catecholamine release persists under this same condition. Recent evidence supports synaptic chromaffin cell stimulation through alternate transmitters. One candidate is pituitary adenylate cyclase activating peptide (PACAP), a peptide transmitter present in the adrenal medulla shown to have an excitatory effect on chromaffin cell secretion. In this study we utilize native neuronal stimulation of adrenal chromaffin cells in situ and amperometric catecholamine detection to demonstrate that PACAP specifically elicits catecholamine release under elevated splanchnic firing. Further data reveal that the immediate PACAP-evoked stimulation involves a phospholipase C and protein kinase C-dependant pathway to facilitate calcium influx through a Ni²⁺ and mibefradil-sensitive calcium conductance that results in catecholamine release. These data demonstrate that PACAP acts as a primary secretagogue at the sympatho-adrenal synapse under the stress response.     

DISTRIBUTION OF RIBOSOMAL MATERIAL IN INCUBATED AND ELECTRICALLY STIMULATED CEREBRAL SLICES

Abstract— The distribution of ribosomal fractions has been examined in fresh cerebral cortex tissue and in slices maintained in vitro both with and without electrical stimulation. The electrical stimulation used was of a type that has previously been shown to diminish amino acid incorporation into protein.
Membrane-bound and free fractions were obtained and the ratio of their RNA contents were, for the control tissue 3, and for the electrically stimulated tissue 1 , 8. Electrical stimulation was found to decrease the Mg²⁺ binding affinity of the free. fraction but was without effect on the bound fraction. Stimulation was also found to increase the leakage of soluble protein and RNA from the tissue and its accumulation in the incubation medium.     

Role of the vagus nerve in mechanisms of the modulation of afferent duodenal effects]

The electrostimulation of vagal nerves, the effect of naloxone and atropine on duodenal afferentation by registering evoked potential (EP) at cortex on direct electrostimulation of duodenum have been studied in acute experiments on cats. It has been established that the stimulation of afferent portion of vagal nerves causes the effect of deprivation of EP, whereas the stimulation with certain intensity of efferent portion of vagal nerves intensifies the duodenal afferentation. The effect of afferentation easeness (relief) has been blocked by the application of naloxone 10-20 microgram on duodenal bulbus, but not on it's i. v. injection and without effect on local application of atropine. It is concluded that the role of vagal nerves on the modulation of duodenal nociception is due to the activation of opiate terminals of the efferent vagal nerve portions.     

Effects of oligonucleotide length and atomic composition on stimulation of the ATPase activity of translation initiation factor elF4A.

Eukaryotic translation initiation factor 4A (elF4A) has been proposed to use the energy of ATP hydrolysis to remove RNA structure in the 5' untranslated region (UTR) of mRNAs, helping the 43S ribosomal complex bind to an mRNA and scan to find the 5'-most AUG initiator codon. We have examined the effect of changing the atomic composition and length of single-stranded oligonucleotides on binding to elF4A and on stimulation of its ATPase activity once bound. Substitution of 2'-OH groups with 2'-H or 2'-OCH3 groups reduces ATPase stimulation at least 100-fold, to background levels, without significantly affecting oligonucleotide affinity. These effects suggest that 2'-OH groups participate in an elF4A conformational change that occurs subsequent to oligonucleotide binding and is required for ATPase stimulation. Replacing nonbridging oxygen atoms in phosphodiester linkages with sulfur atoms to make phosphorothioate linkages has no significant effect on stimulation, while substantially increasing affinity. Extending the length of an RNA oligonucleotide from 4 to approximately 15 nt gradually increases oligonucleotide affinity and ATPase stimulation. Consistent with this observation, the increase in affinity and stimulation provided by phosphorothioate linkages and 2'-OH groups is proportional to the number of these groups present within larger oligonucleotides. Further, changing the position of blocks of phosphorothioate linkages or 2'-OH groups within a larger oligonucleotide does not affect affinity and has only a small effect on stimulation. These observations suggest that numerous interactions between the oligonucleotide and elF4A contribute individually to binding and ATPase stimulation. Nevertheless, significant stimulation is observed with as few as four RNA residues. These properties may allow elF4A to operate within regions of 5' UTRs containing only short stretches of exposed single-stranded RNA. As stimulation increases when longer stretches of single-stranded RNA are available, it is possible that the accessibility of single-stranded RNA in a 5' UTR influences translation efficiency.     

Effect of thyroid status on alpha- and beta-catecholamine responsiveness of hamster adipocytes

It has been suggested that part of the increased beta-catecholamine responsiveness in hyperthyroid animals is due to a decrease in alpha-catecholamine action. The present results indicate that neither hyperthyroidism nor hypothyroidism altered the alpha 2-adrenergic inhibition of adenylate cyclase or the alpha 1-adrenergic stimulation of phosphatidylinositol turnover in adipocytes from the white adipose tissue of hamsters. No effect of hyperthyroidism was found on the Kd for binding of [3H]dihydroergocryptine or the number of binding sites in membranes prepared from hamster adipocyte tissue. The stimulation of cyclic AMP due to beta-catecholamines was enhanced in adipocytes from hyperthyroid hamsters, as was lipolysis. However, in adipocytes from hyperthyroid hamsters the maximal stimulation of cyclic AMP due to isoproterenol, ACTH or epinephrine plus yohimbine, as seen in the presence of adenosine deaminase and theophylline, was less than in adipocytes from euthyroid hamsters. The activation of adenylate cyclase by isoproterenol was the same in membranes from hyperthyroid as compared to those from euthyroid hamsters in the absence or presence of guanine nucleotides. These data suggest that thyroid status has little effect on alpha-catecholamine action by enhances the activation of lipolysis by beta-catecholamine agonists.     

Mechanism of the anabolic action of phytoecdisteroids in mammals

In experiments with white mice it has been established that phytoecdisteroides turkesteron, ecdisteron and 2-desoxy-alpha-ecdison in the dose of 5 mg on 1 kg of body mass stimulate the protein synthesis. Using the model of protein synthesis from mice liver it has been shown that the action of phytoecdisteroides is connected with the rise of poliribosome functional activity and rate increase of protein macromolecules formation. Preliminary administration of actinomycin D does not prevent the effect of protein synthesis stimulation. It has been concluded that the anabolic effect of phytoecdisteroides in mammals organism is connected not with induction of RNA synthesis but with the acceleration of translocation processes.     

The Effect of 2-thiouracil on the Growth of Cells in the Root

Observations have been made with either intact seedling rootsor segments of roots of Pea (Vicia faba Meteor) and Maize (Zeamais American yellow horsetooth). Thiouracil, uracil and oroticacid were employed—mostly in concentrations ca. I-5 x10^-3 M. With intact roots, two effects of thiouracil must be distinguished:the first, an immediate stimulation on length increase, andthe second (shown with high con-centration), a marked inhibitionwhich in the conditions of the present series of experimentsbecomes well defined after about I2 hours. A change in growth-rateimmediately after a treatment is applied may be taken as aneffect on cell expansion. When a second delayed effect is observed,and particularly when it is different from an initial effect,this may be taken as an effect on division. Accordingly theeffects observed with the intact root suggest that thiouracilmay have a marked inhibiting effect on division and an equallymarked stimulating effect on expansion. With the intact root the final strong inhibition is partiallyrelieved when uracil is supplied simultaneously. When suppliedalone at the same concentration uracil itself has a slightlyinhibiting effect. Uracil, while having no stimulating effecton division, nevertheless mitigates the strong inhibiting effectthat thiouracil has on this process. It is probable that thouracil exerts a stimulating effect asa result of incorporation into RNA. The fact that in the intactroot uracil may reverse the effect suggests as much. The positionwith segments is markedly different from that with intact roots.In the latter case the stimulation is reversed by uracil, withthe isolated segment it is not. With 2.0-4.0 mm pea segmentsa non-reversible stimulation with thiouracil is observed. With1.0-3.0 mm segments, in which thiouracil alone has no effect,the two compounds together give a marked stimulation. In thissystem when thiouracil alone is available, a stimulation inthe basal tissue is compensated by an inhibition in the apical.When uracil is simultaneously applied the inhibition is removedand some of the stimulation due to the thiouracil persists.The inhibition in the youngest tissue may be interpreted inthe same terms as the stimulation that is due to a prolongationof the period of growth. A discussion is given of the interpretation of the experimentalresults. Thiou-racil affects not only the time but also therate of extension, and for the influence on rate no interpretationcan at present be offered.     

The response of chloride transport to cyclic AMP, calcium and hypotonic shock in normal and cystic fibrosis fibroblasts

It has widely been established that Cl- transport is defective in cystic fibrosis fibroblasts. In the present study, the effect of elevation of intracellular concentration of cyclic AMP and calcium on the efflux of Cl- from human fibroblasts has been investigated. Cyclic AMP analogs (8-bromo cAMP and dibutyryl cAMP) and a beta agonist (isoproterenol) induced only a weak stimulation (5-10%) of Cl- efflux. Conversely, elevation of cytoplasmic calcium concentration produced by addition of the Ca2+ ionophore A23187 in the efflux medium, did not affect Cl- efflux. Our data indicate that the response of Cl- efflux to elevation of cAMP and calcium is similar in normal and cystic fibrosis fibroblasts. Exposure to hypotonic medium induced a significant stimulation of Cl- efflux in fibroblasts from both normal and cystic fibrosis individuals. Substitution of Cl- in the medium by gluconate and the subsequent addition of furosemide did not inhibit the effect of hypotonicity, indicating the involvement of a conductive pathway for Cl- transport, which was insensitive to oligomicin C.     

Effect of Dexamethasone on Rat Respiratory Pathways

It has been shown that a short-term application (10–15 min) of dexamethasone at a concentration of 1.0 µg/ml decreases the muscular contraction amplitude of the trachea and large bronchi to 76.2 ± 3.5% and increases the dilatational effect of histamine (1.0 µg/ml) to 47.4 ± 8.1% at stimulation of pre- and postganglionic nerve fibers. Atropine eliminates completely the effect of dexamethasone on the respiratory tract preparation at the stimulation of pre- and postganglionic nerve fibers. The ganglioblocker decreases the dilatational effect at a simultaneous application of atropine and dexamethasone from 47.4 ± 8.1 to 67.2 ± 5.3%. It is concluded that the dexamethasone effect is due to its action on tracheobronchial epithelial receptors and that this effect is mediated by intramural ganglionic neurons.     

The in vitro effects of Triton WR-1339 on lipid synthesis by bone cells.

Triton WR-1339, administered parenterally, has long been known to be a potent hyperlipemic agent. In vitro lipid biosynthesis is stimulated in liver and brain preparations from animals injected with Triton. Only in a perfused isolated liver system has an in vitro effect of Triton on lipid synthesis been demonstrated. In the present study, lipid biosynthesis has been shown to increase in bone, a third organ system, under the influence of in vitro Triton WR-133. This stimulation affects most major lipid classes. Triton similarly stimulates lipid synthesis in tissue cultures of bone cells. This is the first report of an effect of Triton on lipid synthesis (1) in bone and (2) in any tissue culture system.     

Effects of cyclic nucleotide dependent protein kinases on the endoplasmic reticulum Ca2+ pump of bovine pulmonary artery

This paper describes the stimulation by cyclic nucleotide dependent protein kinases on the Ca2+ uptake by isolated endoplasmic reticulum (ER) vesicles from the bovine main pulmonary artery. This ER fraction has previously been shown to be highly enriched in phospholamban, a protein kinase substrate that has been well characterized in cardiac sarcoplasmic reticulum (SR), where its phosphorylation is accompanied by an increased rate of Ca2+ uptake. As previously observed for the phosphorylation of phospholamban, the stimulation of the rate of Ca uptake was as high with cGMP dependent protein kinase as with cAMP dependent protein kinase. The effect of phosphorylation of the ER membranes from smooth muscle on the Ca2+ uptake was smaller than that seen in cardiac SR, and it was only observed if albumin was included during the isolation of the membranes. This relatively small effect is probably not due to a lower ratio of phospholamban to Ca2(+)-transport enzyme in the ER membranes as compared to cardiac SR. Several alternative explanations are discussed.     

Angiotensin II potentiates responses of the rabbit basilar artery to adrenergic nerve stimulation

Angiotensin II has little contractile effect on the isolated rabbit basilar artery; however, it markedly potentiates contractile responses to adrenergic nerve stimulation. This is not a post-synaptic effect of angiotensin, as responses to exogenous norepinephrine are not altered. Angiotensin increases stimulation-evoked release of norepinephrine, and this effect probably accounts for the increased response to adrenergic nerve stimulation. Since sympathetic stimulation may protect the cerebral circulation from hypertensive damage, increased responsiveness to adrenergic nerve activity produced by angiotensin may have a beneficial effect.