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At least 343 records · Page 19Linked to original sources
PubMed1998

Effects of epinastine hydrochloride on cholinergic neuro-effector transmission in canine tracheal smooth muscle.

We determined the effects of epinastine hydrochloride, an anti-asthmatic drug, on cholinergic neuro-effector transmission in canine trachea. Isometric tension of tracheal strips was measured in the presence of indomethacin and propranolol. Epinastine (10(-6) M) significantly suppressed the contraction evoked by electrical field stimulation, but had no effect on the acetylcholine-evoked contraction. An L-type Ca2+ channel blocker, nicardipine, did not suppress the electrical field stimulation-induced smooth muscle contraction and did not alter the inhibitory effect of epinastine. An N-type Ca2+ channel blocker, omega-conotoxin, suppressed the electrical field stimulation-induced contraction in a dose-dependent manner, and in a subthreshold/intermediate concentration abolished the inhibitory effect of epinastine. These findings indicate that epinastine exerts prejunctional inhibitory effects on airway smooth muscle of dogs, presumably by inhibiting acetylcholine release from vagal nerve terminals, and suggest that this effect is mediated by N-type Ca2+ channels.

Animals↗
PubMed2000

Rank-order inhibition by omega-conotoxins in human and animal autonomic nerve preparations.

The inhibitory effects of the omega-conotoxins GVIA, MVIIA and MVIIC on electrically-evoked, tetrodotoxin (10(-7) M)-sensitive, autonomic nerve activity were studied using human, rat or guinea-pig vas deferens and intestinal tissues. In each preparation from each species, nM concentrations of omega-conotoxins GVIA and MVIIA prevented the neuronally-mediated contractions, whereas omega-conotoxin MVIIC was either markedly less potent (IC(50)'s 1.4 or 2.9 log units more than for omega-conotoxin GVIA in guinea-pig ileum and rat vas deferens, respectively) or was without significant activity (human vas deferens, human Taenia coli) when tested at similar concentrations. In contrast the differences in potency between omega-conotoxins GVIA and MVIIC were considerably less when assayed directly on Ca(2+) channel currents evoked from rat superior cervical ganglion neurons in culture (approximately 0.1 log unit difference) and from a stable cell line expressing rat alpha(1B), alpha(2)delta, beta(1b) Ca(2+) channel subunits (approximately 0.9 log unit). These different rank-orders of inhibitory activity of the conotoxins support the suggestion that there are pharmacologically distinct N-type Ca(2+) channels in the peripheral nervous system, and that this tissue-dependent difference is seen in man.

Animals↗
PubMed1985

Ultrastructure of vesicourethral innervation. III. Axoaxonal synapses between postganglionic cholinergic axons and probably SIF-cell derived processes in the feline lissosphincter.

Ultrastructurally nonspecialized axoaxonal-type synapses between postganglionic cholinergic axons innervating the lissosphincter and apposed probably SIF-cell derived neuronal processes are described. These processes were considered as the peripheral extraganglionic counterparts of those belonging to type I SIF cell interneurons, described in many mammalian peripheral autonomic ganglia. On this basis, the herein reported cholinergic/probably SIF-cell derived axoaxonal-type synapses are proposed as an auxiliary mechanism of prejunctional catecholaminergic inhibition of the normally excitatory cholinergic (postganglionic parasympathetic) neuroeffector transmission in the feline lissosphincter.

Animals↗
PubMed2000

Voltage-gated calcium channels in autonomic neuroeffector transmission.

Calcium influx through voltage-gated calcium channels (VGCCs) is required for neurotransmitter release. Recent research has characterised several pharmacologically and electrophysiologically distinct VGCC subtypes, some of which are involved in neurotransmitter release. Transmitter release from autonomic neurons can be coupled to calcium entry through N-, P/Q- and/or R-type VGCCs; the precise combination of VGCC subtypes appears to vary according to the neurotransmitter, tissue and species. L-type channels rarely appear to be important in autonomic neurotransmitter release. There does not appear to be a general rule regarding the nature of the VGCCs coupled to release of a particular transmitter in different tissues or species. Release of the same neurotransmitter from different populations of neurons often reveals a different pattern of involvement of VGCCs. Transmitters released from the same population of neurons are sometimes coupled to calcium influx through different VGCC subtypes. However, release of transmitters thought to be co-localised within vesicles is coupled to calcium influx through the same VGCCs. The role of VGCC subtypes in transmitter release can be altered by mode of nerve stimulation. Different VGCC subtypes may be coupled to transmitter release at low versus high electrical stimulation frequencies, or in response to potassium depolarization or chemical stimulation. In certain disease processes, voltage-gated calcium channels on autonomic neurons can be targeted; for example antibodies to P/Q-type VGCCs in Lambert-Eaton myasthenic syndrome downregulate VGCCs, thereby inhibiting autonomic neuroeffector transmission.

Animals↗
PubMed1999

Characterization of postjunctional alpha-adrenoceptors in the pithed mouse.

The adrenoceptor subtypes responsible for the pressor response to alpha1- and alpha2-adrenoceptor agonists have not yet been established, although gene knockout experiments in the mouse have provided evidence for a role of the alpha1B- and alpha2B-adrenoceptor. We have evaluated the blood pressure response to selective activation of postjunctional alpha1- and alpha2-adrenoceptors in the pithed mouse. The pressor response to phenylephrine was sensitive to blockade by terazosin, a selective alpha1-adrenoceptor antagonist, but insensitive to rauwolscine, an antagonist at alpha2-adrenoceptors. Phentolamine, a nonselective alpha-adrenoceptor antagonist, blocked the response to either phenylephrine or the selective alpha2-adrenoceptor agonist B-HT 933, whereas rauwolscine blocked only B-HT 933. A dose of terazosin effective against phenylephrine had no effect on B-HT 933; however, the B-HT 933 response was antagonized when the terazosin dose was increased tenfold. A high dose of doxazosin, an alpha1-adrenoceptor antagonist having no affinity for the alpha2B adrenoceptor, blocked the response to phenylephrine but not B-HT 933. Comparison of the potencies of these antagonists against the pressor response to phenylephrine with their affinities for recombinant alpha1-adrenoceptor subtypes suggests that this response is mediated by either alpha1B- or alpha1D-adrenoceptors. The alpha2B-adrenoceptor subtype is likely to take part in the response to B-HT 933. The ability of certain quinazoline alpha1-adrenoceptor antagonists to block the alpha2B adrenoceptor may contribute to their activity as antihypertensive agents.

3T3 Cells↗
PubMed2001

Lack of evidence for peripheral alpha(1)- adrenoceptor blockade during long-term treatment of heart failure with carvedilol.

OBJECTIVES: The purpose of this study was to determine whether carvedilol's alpha(1)-adrenoceptor antagonism persists during long-term therapy of patients with congestive heart failure (CHF). BACKGROUND: Carvedilol and metoprolol differ in that carvedilol also antagonizes beta(2)- and alpha(1)-adrenoceptors. We hypothesized that in contrast to metoprolol, carvedilol would increase calf vascular conductance (CVC), blunt neurally mediated vasoconstriction and attenuate neuroeffector transfer function gain. METHODS: We randomized 36 patients with CHF (age 55 +/- 1 years, ejection fraction 19 +/- 1%, means +/- SE) to either drug. Blood pressure (BP), heart rate, muscle sympathetic nerve activity (MSNA) and CVC were assessed before and after four months of treatment. The variability of BP and MSNA was determined using fast Fourier transformation. RESULTS: Paired data were obtained in 23 (carvedilol, 13; metoprolol, 10) subjects. Both beta-blockers decreased heart rate, but neither affected mean BP or CVC (carvedilol: 0.016 +/- 0.002 to 0.018 +/- 0.003 U; metoprolol: 0.020 +/- 0.002 to 0.020 +/- 0.004 U). Isometric handgrip exercise (30% of maximum) increased heart rate, mean BP and MSNA. The calf vasoconstrictor response to handgrip exercise was not affected by carvedilol (from 16 +/- 6 resistance U to 25 +/- 10 resistance U, NS). The gain of the transfer of oscillations in MSNA into BP under resting conditions was not attenuated by carvedilol. CONCLUSIONS: Carvedilol did not increase CVC, blunt the calf vasoconstrictor response to handgrip or attenuate the gain of the neuroeffector transfer function, indicating the absence of functionally important peripheral alpha(1)-adrenoceptor antagonism during long-term treatment of CHF.

Adrenergic Fibers↗
PubMed1998

Prejunctional alpha2-adrenoceptors and peroxide-induced potentiation of norepinephrine release from the bovine iris.

Peroxides can enhance field-stimulated [3H]norepinephrine ([3H]NE) release in isolated irides from several mammalian species. In the present study, we investigated the role of prejunctional alpha2-adrenoceptors in peroxide-induced potentiation of sympathetic neurotransmission in bovine isolated irides. Isolated hemi-irides were incubated in a Krebs buffered-solution containing [3H]NE and prepared for studies of neurotransmitter release using the superfusion method. Alpha2-adrenoceptor agonists, oxymetazoline, UK-14304 and clonidine inhibited field-stimulated [3H]NE overflow without affecting basal tritium efflux. Pretreatment of tissues with H2O2 (300 microM) had no effect on inhibition of evoked [3H]NE release caused by the alpha2-adrenergic agonists. However, H2O2 (300 microM) caused significant (P < 0.01) leftward shifts of excitatory concentration-response curves to yohimbine (10 nM-1 microM). In contrast, yohimbine (1 microM) did not prevent the enhancement of evoked [3H]NE overflow induced by H2O2 (300 microM). In conclusion, excitatory effects of peroxides on sympathetic neurotransmission in bovine irides are not mediated by prejunctional alpha2-adrenoceptors.

Adrenergic Fibers↗
PubMed1997

Depressant effects of hypoxia and hypoglycaemia on neuro-effector transmission of guinea-pig intestine studied in vitro with a pharmacological model.

1. Since intermittent ischaemia may play an important role in the aetiology of Inflammatory Bowel Disease, particularly Crohn's Disease, a pharmacological model of neuronal ischaemia was applied to guinea-pig isolated intestinal preparations to mimic the acute effects of reduced blood flow on intestinal motility. 2. Neuro-effector transmission and smooth muscle performance were examined in myenteric plexus-longitudinal muscle preparations of guinea-pig ileum exposed to sodium cyanide (NaCN), in order to inhibit oxidative phosphorylation, or to iodoacetic acid (IAA), to block glycolysis. Comparisons were made with the effects due to simple deprivation of oxygen or glucose. 3. Depression of cholinergic neuro-effector transmission induced by hypoxia or NaCN (effective concentration range 0.1-3 mM), given as separate treatments, singly or repetitively over 60-90 min, were apparent within 30 s and were reversible. The maximum inhibition was 90% and the IC50 for NaCN was 0.3 mM. A conspicuous component of these inhibitions was prejunctional. 4. Non-cholinergic neuro-effector contractions were inhibited by up to 90% by anoxia or NaCN but recovery was incomplete and slower than with cholinergic contractions. 5. Glucose-free solutions also caused a reversible failure of cholinergic neuro-effector transmission but of slower onset. In contrast, IAA (0.06-1 mM) abolished contractions irreversibly, apparently by a direct depressant effect on smooth muscle contraction. Unlike NaCN, IAA caused an initial potentiation of electrically-induced contractions, partly by a prejunctional potentiation of cholinergic neuro-effector transmission. 6. It is concluded that a disruption of intestinal activity in pathological conditions associated with intestinal ischaemia may result from disturbances in the function of enteric neurones.

Animals↗
PubMed1998

Pharmacological evidence for the presence of a peripheral postjunctional D2-like dopamine receptor in rabbit splenic artery.

1. This study was designed to investigate the involvement of postjunctional D2-like receptors in a rabbit vasculature model used to evaluate the D1-like agonist activity. Dopamine, epinine and (-)-DP-5,6-ADTN, three mixed D1/D2-like agonists, fenoldopam and SKF 82958, two selective D1-like agonists and SKF 89124, a selective D2-like agonist, were administered cumulatively in precontracted and alpha/beta-blocked rabbit splenic artery rings in order to evaluate their D1-like-mediated vasorelaxant activity before and after pretreatment with the selective D2-like antagonist YM 09151-2 (1 nM). 2. Dopamine (pD2=6.35+/-0.09), epinine (pD2=6.73+/-0.13), (-)-DP-5,6-ADTN (pD2=7.56+/-0.09) and SKF 82958 (pD2=8.55+/-0.10) reversed completely the U46619-induced contracture whereas SKF 89124 was inactive up to 10 microM and fenoldopam acted like a partial agonist (pD2=8.31+/-0.09, alpha=0.62). The selective D2-like dopamine receptor antagonist YM 09151-2 (1 nM) significantly (P<0.05) potentiated the vasorelaxant activity of dopamine (pD2=7.01+/-0.07), epinine (pD2=7.14+/-0.08), (-)-DP-5,6-ADTN (pD2=8.19+/-0.09) and SKF 89124 (40% relaxation at 10 microM), whereas it did not alter the effects of fenoldopam (pD2=8.40+/-0.09, alpha=0.68) and SKF 82958 (pD2=8.58+/-0.08). 3. The D2-like antagonist YM 09151-2 induced the same degree of effect with all the substances tested in both endothelium-denuded and endothelium-intact preparations. 4. The selective D2-like dopamine receptor agonist SKF 89124 did not produce any intrinsic effect on the splenic artery, but was able to produce a rightward shift of the forskolin-induced relaxation. 5. The results of these experiments support the existence of a non-endothelial postjunctional D2-like dopamine receptor counteracting the D1-like-mediated vasodilatation in rabbit splenic artery, probably by the inhibition of adenylate cyclase.

Animals↗
PubMed1998

Different receptors for angiotensin II at pre- and postjunctional level of the canine mesenteric and pulmonary arteries.

1. This investigation was undertaken to compare pre- and postjunctional receptors involved in the responses of the canine mesenteric and pulmonary arteries to angiotensin II. 2. In the mesenteric artery, angiotensin II caused an enhancement of tritium overflow evoked by electrical stimulation (EC30% = 5 nM), the maximal effect representing an increase by about 45%. Postjunctionally, angiotensin II caused concentration-dependent contractions (pD2 = 8.57). Saralasin antagonized both pre- and postjunctional effects of angiotensin II, but it was more potent at post- than at prejunctional level (pA2 of 9.51 and 8.15, respectively), while losartan antagonized exclusively the postjunctional effects of angiotensin II (pA = 8.15). PD123319 had no antagonist effect either pre- or postjunctionally. 3. In the pulmonary artery, angiotensin II also caused an enhancement of the electrically-evoked tritium overflow (EC30% = 1.54 nM), its maximal effect increasing tritium overflow by about 80%. Postjunctionally, angiotensin II caused contractile responses (pD2 = 8.52). As in the mesenteric artery, saralasin antagonized angiotensin II effects at both pre- and postjunctional level and it was more potent postjunctionally (pA2 of 9.58 and 8.10, respectively). Losartan antagonized only the postjunctional effects of angiotensin II (pA2 = 7.96) and PD123319 was ineffective. 4. It is concluded that in both vessels: (1) pre- and postjunctional receptors belong to a different subtype, since they are differently antagonized by the same antagonists; (2) postjunctional receptors belong to AT1 subtype, since they are blocked by losartan but not by AT2 antagonists; (3) prejunctional receptors apparently belong to neither AT1 or AT2 subtype since they are blocked by neither AT1 nor AT2 antagonists.

Angiotensin II↗
PubMed1999

Heterogeneity of prejunctional NPY receptor-mediated inhibition of cardiac neurotransmission.

Neuropeptide Y (NPY) has been proposed as the candidate inhibitory peptide mediating interactions between sympathetic and vagal neurotransmission in several species, including man. Here, we have defined the NPY receptors involved in modulation of cardiac autonomic neurotransmission using receptor-selective agonists and antagonists in the rabbit and guinea-pig isolated right atria. In isolated atrial preparations, sympathetically-mediated tachycardia (ST; with atropine 1 microM) or vagally-mediated bradycardia (VB; with propranolol 0.1-1 microM) in response to electrical field stimulation (EFS, 1-4 pulses) were tested 0-30 min after incubation with single concentrations of vehicle, NPY (0.01-10 microM), the Y2 receptor agonist N-Acetyl-[Leu28,31]NPY(24-36) (termed N-A[L]NPY(24-36)) or the Y1 receptor agonist [Leu31,Pro34]NPY (LP). The effect of NPY on the concentration-chronotropic response curves to isoprenaline and bethanechol were also assessed. Guinea-pig atria: NPY and N-A[L]NPY(24-36) caused concentration-dependent inhibition of VB and ST to EFS. Both peptides caused maximal inhibition of VB and ST within 10 min incubation and this remained constant. LP caused a concentration-dependent, transient inhibition of ST which was antagonized by the Y1-receptor antagonist GR231118 (0.3 microM), with apparent competitive kinetics. Rabbit atria: NPY (1 or 10 microM) had no effect on VB at any time point, but both NPY and LP caused a transient (approximately 10 min) inhibition of sympathetic tachycardia. This inhibition could be prevented by 0.3 microM GR231118. N-A[L]NPY(24-36) had no effect on ST. NPY had no effect on the response to beta-adrenoceptor stimulation by isoprenaline nor muscarinic-receptor stimulation by bethanechol in either species. Thus, in the guinea-pig, NPY causes a stable inhibition of both VB and ST to EFS via Y2 receptors and transient inhibition of ST via Y1 receptors. In contrast in the rabbit, NPY has no effect on the cardiac vagus and prejunctional inhibition of ST is transient and mediated by a Y1-like receptor (rather than Y2). Therefore it would be surprising if NPY plays a functional role in modulation of cardiac neurotransmission in the rabbit.

Animals↗
PubMed1999

Development of peripheral autonomic synapses: neurotransmitter receptors, neuroeffector associations and neural influences.

1. The functional innervation of autonomic target tissues occurs early during development, at a time when both the nerves and post-synaptic target tissues are still differentiating. 2. Physiological responses appear soon after the arrival of the first fibres when uptake and release mechanisms within the nerves are already functional. Initial responses differ from those in the mature animal, both in the form and, frequently, in the subtypes of receptors involved. 3. Results of a number of studies suggest that the initial expression of neurotransmitter receptors during development is largely independent of neural influences. Changes recorded in neurotransmitter receptor expression during development appear to be similarly independent of neural influences. 4. While signal transduction pathways coupling adrenergic neurotransmitter receptors to effector responses appear to develop independently of the nerves, the efficient coupling of muscarinic receptors often requires the action of the neurotransmitter, acetylcholine. 5. During the period of synapse formation, the neural plexus continues to expand. While developing varicosities can release the neurotransmitter, the capacity for neurotransmitter retention appears to be restricted. Developmental changes in the neurotransmitters that produce functional responses, while well known in the sweat glands, may also be seen in more subtle forms in other target tissues. 6. Ultrastructural studies suggest that close physical associations between the membranes of the release sites of the developing nerves and the target cells may form early during development when physiological responses are still immature. These close associations could enable more specific reciprocal interactions between nerves and target cells involving known and novel growth factors, neuropeptides and cytokines important in shaping the mature synaptic characteristics.

Animals↗