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T O Neild

Publications and source records attributed to T O Neild.

15 recordsLinked to original sources
PubMed1992

Effects of neuropeptide Y and agonists selective for neuropeptide Y receptor sub-types on arterioles of the guinea-pig small intestine and the rat brain.

1. The actions of neuropeptide Y (NPY) and agonists selective for NPY receptor subtypes were examined on arterioles from the guinea-pig small intestine and the rat pia in order to characterize the receptors mediating the vasoconstrictor and potentiating effects of NPY. 2. A method was developed for measuring the potentiating effects of NPY in situations where it was not possible to obtain a full concentration-response relationship for the vasoconstrictor. NPY, 50 nM, had a greater potentiating effect on the guinea-pig intestinal arterioles than those from the rat pia. 3. NPY and the Y1-selective agonist, NPY[Leu31,Pro34], potentiated the constrictor responses to U46619 in both arterioles and responses to noradrenaline in the guinea-pig arterioles. There was marked desensitization of the potentiating effect, and cross-desensitization between NPY and NPY[Leu31,Pro34]. Both NPY and NPY[Leu31,Pro34] caused constriction of the rat pial arterioles but not of those from the guinea-pig intestine. 4. The Y2-selective agonist PYY(13-36) caused no potentiation or vasoconstriction and did not affect the potentiation by NPY or NPY[Leu31,Pro34]. 5. The potentiating and vasoconstrictor effects of NPY on these arterioles were mediated by Y1 receptors.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1990

Hyperpolarization and relaxation of arterial smooth muscle caused by nitric oxide derived from the endothelium.

Stimulation of the endothelial lining of arteries with acetylcholine results in the release of a diffusible substance that relaxes and hyperpolarizes the underlying smooth muscle. Nitric oxide (NO) has been a candidate for this substance, termed endothelium-derived relaxing factor. But there are several observations that argue against the involvement of NO in acetylcholine-induced hyperpolarization. First, exogenous NO has no effect on the membrane potential of canine mesenteric arteries. Second, although haemoglobin (believed to bind and inactivate NO (refs 11-15)) and methylene blue (which prevents the stimulation of guanylate cyclase) inhibit relaxation, neither has an effect on hyperpolarization. Finally, nitroprusside, thought to generate NO in vascular smooth muscle, relaxes rat aorta without increasing rubidium efflux. Nevertheless, nitrovasodilators, nitroprusside and nitroglycerin cause hyperpolarization in some arteries. NO might therefore be responsible for at least part of the hyperpolarization induced by acetylcholine. We now report that hyperpolarization and relaxation evoked by acetylcholine are reduced by NG-monomethyl-L-arginine, an inhibitor of NO biosynthesis from L-arginine. Thus NO derived from the endothelium can cause hyperpolarization of vascular smooth muscle, which might also contribute to relaxation by closing voltage-dependent calcium channels. Our findings raise the possibility that hyperpolarization might be a component of NO signal transduction in neurons or inflammatory cells.

Acetylcholine↗
PubMed1990

Actions of neuropeptide Y on arterioles of the guinea-pig small intestine are not mediated by smooth muscle depolarization.

Neuropeptide Y was applied to arterioles of the submucosa of the guinea-pig small intestine while arteriole diameter and smooth muscle membrane potential were monitored. Neuropeptide Y (50 nM-1 microM) caused no smooth muscle depolarization, and caused a small constriction in only 15 out of 38 arterioles studied. 50 nM Neuropeptide Y increased the amplitude of constriction caused by noradrenaline or brief trains of nerve stimulation, showing that it potentiated the effects of vasoconstrictors as it does in other arteries. The factor by which the amplitude was increased was greatest for small constrictions. Neuropeptide Y reduced the amplitude of the excitatory junction potential, suggesting that it decreased neurotransmitter release. These results show that the potentiating action of Neuropeptide Y does not depend on smooth muscle depolarization.

Animals↗
PubMed1990

Response of the rat tail artery to prolonged exposure to noradrenaline.

1. The contractions of the rat tail artery in response to noradrenaline applied for 30 min periods were recorded under conditions that potentiate the vascular escape phenomenon (spontaneous partial relaxation in the continued presence of a vasoconstrictor) in smaller arteries. 2. The conditions were elevated temperature (from 32-37 degrees C), 500 nM forskolin and 10 microM 3-isobutyl-1-methyl xanthine. 3. None of these conditions caused any change in the time-course of constriction in response to noradrenaline, or produced any evidence of vascular escape in this large artery.

1-Methyl-3-isobutylxanthine↗
PubMed1990

Vasodilatation of arterioles by acetylcholine released from single neurones in the guinea-pig submucosal plexus.

The nervous control of arterioles in the guinea-pig submucosal plexus was studied. Outside diameters of arterioles were recorded using a video-monitoring system. Changes in arteriolar diameter in response to electrical stimulation of single neurones or ganglia in the plexus were measured. 2. When the arteriole was pre-constricted with the prostaglandin analogue U46619 or with phenylephrine, electrical stimulation (2-20 Hz, 10 s) of a ganglion dilated the blood vessel. This vasodilatation was abolished by tetrodotoxin or by cutting the fine nerve strands running between the ganglion and the arteriole. 3. The vasodilatations caused by ganglionic stimulation were blocked by the muscarinic antagonists atropine, pirenzepine, (11[[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H- pyrido[2,3-b][1,4]benzodiazepine-6-)-one (AFDX-116), 4-diphenylacetoxy-N-methyl-piperidine methiodide (4-DAMP) and hexahydrosilodifenidol (HSDF). IC50 values for the inhibition of nerve-evoked vasodilatation by pirenzepine, AFDX-116 and HSDF were 500 nM, 4 microM and 25 nM respectively. Physostigmine (1 microM) increased the dilatation by 90%. 4. Muscarine dilated all submucosal arterioles; the concentration causing half-maximum effects was 200 nM. Muscarinic vasodilatations were inhibited by pirenzepine, AFDX-116, and HSDF in a competitive manner; dissociation equilibrium constants determined by Schild analyses were 125 nM, 1.3 microM and 4 nM respectively. 5. Gossypol, an irreversible inhibitor of the production of endothelium-derived relaxing factor (EDRF), did not reduce the vasodilatation produced by either ganglionic stimulation or muscarine in submucosal arterioles. 6. Intracellular recordings were made from submucosal neurones and action potentials were elicited by depolarizing current pulses (10 ms duration, 10 Hz/10 s). In seven neurones vasodilatation was associated with intracellularly evoked action potentials; this vasodilatation was blocked by pirenzepine. Cell bodies of reidentified vasodilator neurones were subsequently shown to contain immunoreactive choline acetyltransferase. 7. These results show that cholinergic neurones in the submucosal plexus project to submucosal arterioles and that they release acetylcholine onto muscarinic receptors to produce vasodilatation. The muscarinic receptor activated by nerve-released acetylcholine is the M3 subtype and its location appears to be on the vascular smooth muscle rather than the endothelium.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1978

Slowly-developing depolarization of neurones in the guinea-pig inferior mesenteric ganglion following repetitive stimulation of the preganglionic nerves.

Intracellular recordings were made from cells of the isolated guinea-pig inferior mesenteric ganglion. Stimulation of both hypogastric nerves at 30 Hz for 2 sec caused a slowly developing depolarization (SD) and fall in cell input resistance which reached a peak 10-30 sec after the end of stimulation. The amplitude of the SD was increased in a graded manner if the stimulus voltage was increased. The SD was unaffected by tubocurarine, atropine or guanethidine, but was blocked by removing external Ca. These results suggested that the SD was caused by the release of some substance from a large number of nerve terminals.

Animals↗
PubMed1978

Life time and elementary conductance of the channels mediating the excitatory effects of acetylcholine in Aplysia neurones.

1. The excitatory effects of acetylcholine (ACh) on an identified group of Aplysia neurones have been studied under voltage clamp in an attempt to measure the average life time. tau, of the channels opened by ACh and the elementary current, iel, flowing through these channels. The value of tau was determined both from spectral noise analysis and from current relaxations after voltage steps. Both methods lead to similar values. iel was calculated from the ratio of the variance of the ACh induced noise to the mean ACh induced current. 2. tau is increased by hyperpolarization, or by lowering the temperature. At 12 degrees C, tau = 27 msec AT -80 MV, tau = 17 msec at mV. tau is about 5 times smaller at 21 degrees C than at 12 degrees C. 3. iel increases linearly with hyperpolarization. At -80 mV, in Tris-buffered sea water, the mean value of iel was 0.8 X 10)-12) A at 12 degrees C. At 21 degrees C, this value was multiplied by 1.8. 4. The estimate of the ACh reversal potential Erev obtained by extrapolation of the relation between iel and the membrane potential V was + 30 mV. The estimate obtained from the analysis of the instantaneous current changes produced by voltage steps was + 15 mV. The difference between the two values appears to be due to the development of a K curent activated by the entry of Ca into the cell during the ACh response. This current introduces an error in opposite directions into the two estimates of Erev, which can therefore be assumed to be intermediate between + 15 and + 30 mV. An assumed value of + 20 mV yields an elementary conductance of 8 X 10(-12) omega-1 at 12 degrees C in Tris-buffered sea water. 5. The total ACh induced current measured in steady-state conditions increases more with hyperpolarization than does iel. The difference can be entirely accounted for by the fact that hyperpolarization increases tau. 6. When carbachol or tetramethylammonium is applied instead of ACh, the value of iel is identical to that found with ACh, but tau is slightly shorter (about 75%). 7. Inward ACh induced currents can still be observed in solutions where all Na has been replaced by Cs, Mg, or Ca. 8. iel increases when Na is replaced by Cs; it decreases when Na is replaced by Mg or Ca. In all Na-free solutions, tau is larger than in Na sea water: the lengthening of tau is largest for Ca sea water, smallest for Cs sea water. An interpretation of these changes of gamma is proposed. This interpretation may also account for the voltage sensitivity of gamma in normal sea water. 9. Partial replacement of NaCl by TrisCl strikingly reduces the ACh induced current. gamma is not modified by Tris substitution, and the reduction of the total current is entirely accounted for by a steep decrease of iel. Tris does not seem to affect the pore opening and closing processes, but to block the ACh controlled channel.

Acetylcholine↗
PubMed1978

The mode of action of antagonists of the excitatory response to acetylcholine in Aplysia neurones.

1. The mode of action of various antagonists of acetylcholine (ACh) excitatory effects on Aplysia neurones was studied under voltage clamp. ACh was applied by iontophoresis whereas antagonists were applied in the bath. Tubocurarine and hexamethonium were the most thoroughly studied compounds. 2. The 'elementary current', calculated as the ratio of the variance of the ACh noise to the mean ACh induced current, was not modified by any of the antagonists tested. 3. The evolution of the ACh induced current after a voltage jump, which is normally described by a single exponential, was modified by all the antagonists tested. A common feature of the modified relaxations was the appearance, over a certain concentration range of the antagonist, of two successive and opposite exponential components. 4. The characteristics of the composite relaxations depend on the antagonist. For a given antagonist they vary with membrane potential, ACh concentration, and antagonist concentration. 5. The noise power spectra of the ACh induced current showed changes consistent with those of the relaxations. 6. In the absence of antagonists, the current induced by a steady application of ACh increases linearly with hyperpolarization. In the presence of antagonists, the I-V curve shows a marked curvature, indicating a proportionally larger reduction of the ACh response at more negative membrane potentials. 7. The voltage sensitivity of the blocking action of hexamethonium and decamethonium is noticeably stronger than that of monovalent antagonists. 8. A model is proposed which accounts for the observed effects. It assumes that the antagonists studied bind perferentially to the 'activated' ACh-receptor complex, and convert it to a non-conducting state. Kinetic constants can be calculated for this reaction; e.g. for curare, at 12 degrees C and -80 mV, the dissociation and association constants were estimated at 0.1 sec-1 and 4 X 10(5) M-1 sec-1. 9. Partial replacement of the extracellular Na by Tris modifies the relaxations observed in the presence of hexamethonium. Hexamethonium appears less effective in the presence of Tris, which supports the hypothesis that the binding site of the antagonists is linked to the ionic channel.

Acetylcholine↗
PubMed1978

An analysis of excitatory junctional potentials recorded from arterioles.

1. Arterioles were impaled with two independent micro-electrodes, one to pass current and the other to record membrane potential. 2. When current was injected into one branch of an arteriole, a membrane potential change could be detected either in the same branch or in an adjoining branch indicating that the arteriolar smooth muscle cells were electrically connected. 3. Fine dissection of the arteriolar tree gave short segments of arteriole which appeared to behave electrically as short cables with sealed ends. 4. Analysis of the electrotonic potentials recorded from isolated segments of arterioles allowed a determination of the arteriole cable properties. 5. Using the data from the cable analyses it was concluded that the junctional current underlying an excitatory junction potential has a duration that is brief when compared with that of the potential.

Animals↗