Nitric oxide (NO) is a cotransmitter of inhibitory motor neurons of the enteric nervous system. This study examined the effect of 7-nitroindazole (7-NI), an inhibitor of neuronal NO synthase (NOS), ...on intestinal peristalsis and muscle activity and compared 7-NI with N(G)-nitro-L-arginine methyl ester (L-NAME), a nonselective inhibitor of NOS isoforms. Peristalsis in isolated segments of the guinea pig small intestine was triggered by a perfusion-induced rise of the intraluminal pressure. While L-NAME (10-300 micromol/l) lowered the peristaltic pressure threshold (PPT) at which propulsive muscle contractions were elicited, 7-NI (10-300 micromol/l) caused a concentration-related increase in PPT. L-Arginine (1-3 mmol/l) failed to reverse peristaltic motor depression evoked by 7-NI but annulled the L-NAME-evoked stimulation of peristalsis. Drugs which stimulated peristalsis, such as L-NAME, naloxone, apamin and suramin plus pyridoxal phosphate-6-azophenyl-2'-4'-disulphonic acid counteracted the inhibitory effect of submaximally effective concentrations of 7-NI on peristalsis. 7-NI (100-300 micromol/l) inhibited circular muscle contractions evoked by cholecystokinin octapeptide, the NK(1) receptor agonist GR-73,632 and indomethacin whereas L-NAME (100-300 micromol/l) failed to inhibit any drug-evoked contraction. These data show that 7-NI, unlike L-NAME, inhibits circular muscle contractions of the gut and depresses intestinal peristalsis. It is concluded that the inhibitory motor action of 7-NI is unrelated to inhibition of neuronal NOS and arises from depression of smooth muscle activity.
The tachykinins substance P and neurokinin A are excitatory cotransmitters of cholinergic enteric neurons, their actions being mediated by NK
1, NK
2 and NK
3 receptors. This study examined which of ...these receptors are part of the neural circuitry of peristalsis. Peristaltic propulsion in luminally perfused segments of the guinea-pig isolated ileum was elicited by a rise of the intraluminal pressure. The pressure threshold at which peristaltic contractions were triggered was used to quantify drug effects on peristalsis, inhibition of peristalsis being reflected by an increase in the pressure threshold. The NK
1, NK
2 and NK
3 receptor antagonists SR-140 333, SR-48 968 and SR-142 801 (each at 0.1 μM), respectively, had little effect on peristaltic activity as long as cholinergic transmission was left intact. However, both the NK
1 and NK
2 receptor antagonist (each at 0.1 μM) abolished peristalsis after cholinergic transmission via muscarinic receptors had been blocked by atropine (1 μM) and peristalsis rescued by naloxone (0.5 μM). When cholinergic transmission via nicotinic receptors was suppressed by hexamethonium (100 μM) and peristalsis restored by naloxone (0.5 μM), only the NK
2 receptor antagonist (0.1 μM) was able to attenuate peristaltic performance as deduced from a rise of the peristaltic pressure threshold by 106%. The NK
3 receptor antagonist (0.1 μM) lacked a major influence on peristalsis under any experimental condition. It is concluded that tachykinins acting via NK
1 and NK
2 receptors sustain intestinal peristalsis when cholinergic neuroneuronal and neuromuscular transmission via muscarinic receptors has been suppressed. NK
2 receptors help maintaining peristalsis once cholinergic neuroneuronal transmission via nicotinic receptors has been blocked, whereas NK
3 receptors play little role in the neural pathways of peristalsis.
•Cutting forces are only affected by feed rate and not by spindle speed.•Due to the friction based heat generation temperatures increase with drilling time.•Cutting forces are higher in case of ...animal bone vs. biomechanical test materials.•Bone anisotropy has negligible effect on the resulting cutting forces.•Tool tip geometry affects difference in forces between radial and axial drilling.
The research presented in this paper investigated the effects of spindle speed and feed rate on the resultant cutting forces (thrust force and torque) and temperatures while drilling SawBones® biomechanical test materials and cadaveric cortical bone (bovine and porcine femur) specimens. It also investigated cortical bone anisotropy on the cutting forces, when drilling in axial and radial directions. The cutting forces are only affected by the feed rate, whereas the cutting temperature in contrast is affected by both spindle speed and feed rate. The temperature distribution indicates friction as the primary heat source, which is caused by the rubbing of the tool margins and the already cut chips over the borehole wall. Cutting forces were considerably higher when drilling animal cortical bone, in comparison to cortical test material. Drilling direction, and therewith anisotropy, appears to have a negligible effect on the cutting forces. The results suggest that this can be attributed to the osteons being cut at an angle rather than in purely axial or radial direction, as a result of a twist drill's point angle.
Interlayer burr formation during drilling of stacks is a widespread issue in the aerospace industry. The minimisation of the interlayer burr would contribute to significant time and cost savings, as ...it would allow for clamping, drilling and fastening to be carried out without any intermediate deburring that requires separating the layers. This paper reports about a not-before observed phenomenon associated with the relationship between interlayer gap width and burr height when drilling aluminium-aluminium stacks with the presence of sealant at the interface. Initial experiments of the research were conducted to determine the interlayer gap widths in relation to a range of clamping forces, followed by drilling experiments to assess how the interlayer gap width affects the interlayer burr formation process and burr height. Although the presence of an interlayer gap results in larger burrs being formed, it allows upwards-travelling chips to enter the gap and erode away the newly formed burr. Larger interlayer gap widths were found to yield a more pronounced abrasion of the interlayer burrs, often leading to their complete removal; in some cases, this abrasion even resulted in a noticeable rounding of the borehole edges. This phenomenon was found to strongly affect the interlayer borehole quality and, thus, makes this research highly significant to the aerospace industry, where the quality of the borehole at the stack interface is of major interest.
The mechanisms that regulate the strength of synaptic transmission and intrinsic neuronal excitability are well characterized; however, the mechanisms that promote disease-causing neural network ...dysfunction are poorly defined. We generated mice with targeted neuron type-specific expression of a gain-of-function variant of the neurotransmitter receptor for glycine (GlyR) that is found in hippocampectomies from patients with temporal lobe epilepsy. In this mouse model, targeted expression of gain-of-function GlyR in terminals of glutamatergic cells or in parvalbumin-positive interneurons persistently altered neural network excitability. The increased network excitability associated with gain-of-function GlyR expression in glutamatergic neurons resulted in recurrent epileptiform discharge, which provoked cognitive dysfunction and memory deficits without affecting bidirectional synaptic plasticity. In contrast, decreased network excitability due to gain-of-function GlyR expression in parvalbumin-positive interneurons resulted in an anxiety phenotype, but did not affect cognitive performance or discriminative associative memory. Our animal model unveils neuron type-specific effects on cognition, formation of discriminative associative memory, and emotional behavior in vivo. Furthermore, our data identify a presynaptic disease-causing molecular mechanism that impairs homeostatic regulation of neural network excitability and triggers neuropsychiatric symptoms.
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