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At least 127 records · Page 7Linked to original sources
PubMed1992

Mechanism of soman-induced contractions in canine tracheal smooth muscle.

The actions of the irreversible organophosphorus cholinesterase (ChE) inhibitor soman were investigated on canine tracheal smooth muscle in vitro. Concentrations of soman greater than or equal to 1 nM increased the amplitude and decay of contractions elicited by electric field stimulation. The effect on decay showed a marked dependence on stimulation frequency, undergoing a 2.4-fold increase between 3 and 60 Hz. Soman also potentiated tensions due to bath applied acetylcholine (ACh). Little or no potentiation was observed for contractions elicited by carbamylcholine, an agonist that is not hydrolyzed by ChE. Concentration of soman greater than or equal to 3 nM led to the appearance of sustained contractures. These contractures developed with a delayed onset and were well correlated with ChE activity. Alkylation of muscarinic receptors by propylbenzilylcholine mustard antagonized the actions of soman on both spontaneous and electrically-evoked muscle contractions. The results are consistent with a mechanism in which the toxic actions of soman are mediated by accumulation of neurally-released ACh secondary to inhibition of ChE activity. An important factor in this accumulation is suggested to be the buffering effect of the muscarinic receptors on the efflux of ACh from the neuroeffector junction.

Acetylcholine↗
PubMed2002

The role of nerves in asthma.

Asthma is a syndrome characterized by reversible episodes of wheezing, cough, and sensations of chest tightness and breathlessness. These symptoms are secondary to changes in the activity of the nervous system. The mechanisms by which the nervous system is altered such that the symptoms of asthma occur have not yet been elucidated. Airway inflammation associated with asthma may affect neuronal activity at several points along the neural reflex pathway, including the function of the primary afferent (sensory) nerves, integration within the central nervous system, synaptic transmission within autonomic ganglia, and transmission at the level of the postganglionic neuroeffector junction. We provide a brief overview of these interactions and the relevance they may have to asthma.

Animals↗
PubMed1987

Mechanism of alpha blockade for blood pressure control.

The realization that a generalized increase in peripheral vascular resistance was the fundamental hemodynamic abnormality in essential hypertension and that the maintenance of arteriolar tone depended on the continuity of the adrenergic nervous system led to the alpha-adrenoceptor inhibitors being the first substances to receive serious consideration as antihypertensive agents. An agent that inhibited the effect of the adrenergic transmitter at the neuroeffector junction was anticipated to be ideal in inhibiting adrenergic vasoconductor tone. The clinical expectations for these compounds in the treatment of arterial hypertension, however, were not fulfilled. Although they lowered blood pressure, the effect was accompanied by unacceptable side effects such as tachycardia, and tolerance rapidly developed. The realization that transmitter norepinephrine modulates its own release through a prejunctionally located, alpha-adrenoceptor operated control mechanism explained several paradoxical phenomena and suggested exciting therapeutic possibilities. Most important, it provided a plausible if not compelling explanation for the clinical failure of the classic alpha-adrenoceptor inhibitors as antihypertensive agents. Characterization of the prejunctional and postjunctional effects of alpha agonists and antagonists led to the conclusion that prejunctional and postjunctional alpha adrenoceptors differed in receptor structure and led to the identification of prazosin as the first virtually specific alpha-adrenoceptor inhibitor. This was a crucially important step in the development of specific agents to combat adrenergic predominance in essential hypertension. Antihypertensive drugs like prazosin and doxazosin preserve feedback control of transmitter norepinephrine release, and consequently cause minimal reflex activation. They represent an alternative choice for therapy in all grades of hypertension with virtually no contra indicatons to their use.

Adrenergic alpha-Antagonists↗
PubMed1989

Endothelin inhibits presynaptic adrenergic neurotransmission in rat mesenteric artery.

The effect of endothelin(ET) on adrenergic neurotransmission was examined in isolated perfused rat mesenteric arteries. Porcine ET(10(-12) to 10(-10)M) attenuated the pressor response to sympathetic nerve stimulation (NS). It also stimulated the release of prostaglandin E2 (PGE2), but its inhibition of the pressor response to NS was not affected by indomethacin treatment. ET also caused dose-dependent inhibition of [3H]norepinephrine release during NS. Higher doses of ET rather enhanced the pressor response to NS. These results suggest that ET inhibits presynaptic adrenergic neurotransmission without mediation of PGE2, while it potentiates the responsiveness of the postsynaptic alpha-adrenergic receptor. Thus ET appears to act directly on the neuroeffector junction as well as on the peripheral vasculature.

Adrenergic Fibers↗
PubMed1984

Effects of locally generated angiotensin II on noradrenergic transmission in guinea-pig isolated atria.

The extent to which cardiac neuroeffector function may be modulated by angiotensin II (AII) generated locally from angiotensin I (AI) was investigated in guinea-pig spontaneously beating isolated atria radiolabelled with [3H]noradrenaline. AI and AII were equipotent in increasing the rate and force of atrial contractions with a threshold concentration between 0.1 and 1.0 nM. In contrast, AI was approximately twenty times less potent than AII in enhancing the stimulation-induced (S-I) efflux of radioactivity. The actions of AI and AII on rate and force of atrial contractions, as well as those on S-I efflux of radioactivity, were substantially blocked by the AII receptor antagonist saralasin. On the other hand, the converting enzyme inhibitors captopril and MK-422 selectively blocked the actions of AI without affecting those of AII. These results suggest that significant local conversion of AI to AII occurs in guinea-pig isolated atria. This locally generated AII can act on myocardial AII receptors to increase rate and force of atrial contractions, and on AII receptors located on sympathetic nerve terminals to facilitate sympathetic neurotransmission. The lower potency of AI compared to AII in modulating transmitter release, in contrast to the equal potency of the peptides in mediating chronotropic and inotropic responses, may be due to conversion of AI to AII at sites remote from the neuroeffector junction.

Angiotensin I↗
PubMed1984

Comparison of the pharmacological actions of some new 4-aminopyridine derivatives.

The pharmacological actions of 2,4-diaminopyridine (2,4-DAP) and 3-[(dimethylamino)-carbonyl] amino 4-aminopyridine (LF-14) were examined and compared with those of 4-aminopyridine (4-AP) in anaesthetized rats and on isolated rat and guinea-pig tissues. Both compounds were more potent than 4-AP in reversing the neuromuscular block caused by pancuronium bromide. The ED50S of LF-14, 2,4-DAP and 4-AP were 100 micrograms/kg, 140 micrograms/kg and 450 micrograms/kg, respectively. LF-14 and 2,4-DAP were also more potent in their in vitro actions on the neuroeffector junctions in the ileum and the isolated heart. 2,4-DAP and LF-14 either did not facilitate or only slightly facilitated the recovery time from xylazine/ketamine anaesthesia which was used as a test for their central action; 4-AP significantly reduced the recovery time. We therefore conclude that both 2,4-DAP and LF-14 are stronger peripherally acting compounds with less central action, and that they may be possible replacements for 4-AP as antagonists of non-depolarizing muscle relaxants.

Aminopyridines↗
PubMed1988

Clonidine inhibits electrodermal responses by an action on the spinal cord.

Experiments were designed to determine the neural site of action for clonidine inhibition of sympathetic-cholinergic electrodermal responses (EDR) in anesthetized cats. Administration of clonidine (0.3-3.0 micrograms i.a.) directly to the stellate ganglion did not significantly decrease the amplitude of responses evoked by submaximal hypothalamic stimulation but did inhibit hypothalamic-evoked EDR when administered intrathecally at the C6 to T2 spinal levels. Administration of clonidine to the ganglion, however, did depress EDR evoked by the ganglionic stimulant, 1,1-dimethyl-4-phenylpiperazinium iodide (DMPP, 10 micrograms i.a.). Intravenous clonidine (1-30 micrograms) also reduced EDR amplitude evoked by single pulse stimulation of both the pre- and postganglionic sympathetic nerves with responses elicited from both sites depressed to an equal extent. Yohimbine (0.5 mg/kg i.v.) uniformly antagonized clonidine's depression of EDR regardless of the site or mode of activation. These results indicate that clonidine depresses centrally evoked sudomotor responses by activation of alpha 2-adrenoceptors in the spinal cord and to a limited extent by direct action at the neuroeffector junction. Although a possible DMPP-clonidine interaction appears to take place at the level of the sympathetic ganglion, it is unlikely that ganglionic blockade contributes significantly to clonidine inhibition of EDR evoked by electrical activation of the nervous system.

Animals↗
PubMed1991

Regulation of acetylcholine hydrolysis in canine tracheal smooth muscle.

The regulation of acetylcholine (ACh) lifetime by acetylcholinesterase (AChE, EC 3.1.1.7) and butyrylcholinesterase (BuChE, EC 3.1.1.8) was evaluated in vitro in canine tracheal smooth muscle preparations. Selective inhibition of AChE by low concentrations of 1,5-bis(N-allyl-N,N-dimethyl-4-ammoniumphenyl)-pentane-3-one dibromide (BW 284C51) led to increases in the amplitude and half-relaxation time of contractions elicited by electric field stimulation. Maximal responses were observed in the presence of 10(-6) M BW 284C51, where the amplitude and half-relaxation time were increased by 84 and 198%, respectively. Higher concentrations of BW 284C51, on the other hand, depressed the amplitude and shortened the decay of electric field stimulation-induced contractions by a mechanism involving blockade of muscarinic receptors. Selective inhibition of BuChE by tetraisopropylpyrophosphoramide (iso-OMPA) led to monotonic increases in the electric field stimulation amplitude and duration. These alterations were less marked than those observed in the presence of BW 284C51. Co-application of BW 284C51 (10(-5) M) and iso-OMPA (10(-5) M) resulted in a 1330% prolongation in the decay of electric field stimulation-induced contractions and the development of a sustained contracture. Such contractures were not observed with either inhibitor alone at any concentration tested. The results indicate that both hydrolytic enzymes are involved in the regulation of ACh lifetime at the canine tracheal neuroeffector junction with AChE exerting the more prominent role. The finding that BuChE co-regulates ACh lifetime in canine trachealis muscle demonstrates a functional role for this enzyme.

Acetylcholine↗
PubMed1993

Activation of neuropeptide Y1 and neuropeptide Y2 receptors by substituted and truncated neuropeptide Y analogs: identification of signal epitopes.

Neuropeptide Y (NPY-(1-36)) acts on Y1 and Y2 receptors at the sympathetic neuroeffector junction. Various truncated NPY analogs were tested in the isolated guinea-pig caval vein where NPY is a vasoconstrictor (Y1 receptors) and in isolated rat vas deferens, by monitoring the suppression of electrically evoked contractions (Y2 receptors). The aim of this study was to define which parts of the NPY-(1-36) molecule were required to activate these receptors. NPY-(1-36), [Pro34]NPY and [Glu16,Ser18,Ala22,Leu28,31]NPY (ESALL-NPY), the latter being an analog with increased alpha-helicity in the 14-31 region, evoked vasoconstriction with similar potency and efficacy. Cyclic as well as linear NPY analogs having the 4 to 7 N-terminal amino acid residues linked to the 9 to 19 C-terminal residues by an 8-aminooctanoic acid (Aoc) residue were 25-50 times less potent than NPY-(1-36) itself. In the cyclic analogs, a disulfide bond was introduced to bring the N- and C-termini close together. Linear Aoc-2-27-NPY was virtually inactive. The Y1 receptor needs an intact N-terminal end of NPY in order to become fully activated. The requirements for the C-terminus are less stringent, since substitutions in this part of the molecule resulted in fully active analogs. The central portion of the molecule may impose steric constraints on the N- and C-terminal ends, thereby facilitating Y1 receptor activation, but it does not seem to be essential for receptor recognition. NPY-(2-36) and NPY-(5-36) were only slightly less potent than the parent molecule in suppressing electrically evoked twitches in the vas deferens.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1985

Distribution and function of peripheral alpha-adrenoceptors in the cardiovascular system.

alpha-Adrenoceptors may be subdivided based on their anatomical distribution within the synapse. Presynaptic alpha-adrenoceptors are generally of the alpha 2-subtype and modulate neurotransmitter liberation via a negative feedback mechanism. Postsynaptic alpha-adrenoceptors are usually of the alpha 1-subtype and mediate the response of the effector organ. Although this "anatomical" subclassification is generally applicable, many exceptions exist. A more useful classification of alpha-adrenoceptor subtypes is based on a pharmacological characterization in which selective agonists and antagonists are used. Peripheral alpha-adrenoceptors are critical in the regulation of the cardiovascular system. Postsynaptic alpha-adrenoceptors in arteries and veins represent a mixed population of alpha 1/alpha 2-adrenoceptors, with both subtypes mediating vasoconstriction. In the peripheral arterial circulation, postsynaptic vascular alpha 1-adrenoceptors are found in the adrenergic neuroeffector junction, whereas postsynaptic vascular alpha 2-adrenoceptors are located extrajunctionally. In the venous circulation, it appears that alpha 2-adrenoceptors may be predominantly junctional, whereas alpha 1-adrenoceptors may be predominantly extrajunctional. It has been proposed that junctional alpha-adrenoceptors will respond predominantly to norepinephrine liberated from sympathetic neurons, whereas extrajunctional alpha-adrenoceptors likely respond to circulating catecholamines. The functional role of extrajunctional alpha-adrenoceptors may be more important in disease states such as hypertension and congestive heart failure where circulating levels of catecholamines may be high and contribute to the maintenance of elevated vascular resistance. alpha 2-Adrenoceptors are also associated with the intima and may play a role in the release of an endogenous relaxing factor from the endothelium.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Specialized functional pathways are the building blocks of the autonomic nervous system.

The autonomic nervous system supplies each type of target organ via separate pathways which consist of sets of pre- and postganglionic neurones with distinct patterns of reflex activity. This has been firmly established for the lumbar sympathetic nervous system to skin, skeletal muscle and viscera, for the thoracic sympathetic outflow to the head and for several parasympathetic systems. In principle, that was already known by Langley. The specificity of the messages that these pathways transmit from the central nervous system arises from integration within precisely organized pathways in the neuraxis. The messages travel along discrete functional pathways and are transmitted to the target tissues via close neuroeffector junctions. Integration in the periphery occurs within each pathway, both in ganglia and at the level of the effector organs. We still need to understand how the central messages get through without distortion and how they control the diverse functions of the vasculature and viscera.

Animals↗
PubMed1983

Vasoactive intestinal polypeptide-immunoreactive nerves in the kidney.

Nerve fibers immunoreactive for vasoactive intestinal polypeptide (VIP) were demonstrated by immunocytochemistry in the dog and rat kidney. They were seen in association with the renal artery and its branches. In the dog, VIP-immunoreactive fibers were rarely seen close to small blood vessels suggestive of arterioles. The possible existence of neuroeffector junctions between VIP-positive fibers and renin-secreting juxtaglomerular cells requires further investigation. VIP-positive renal nerves, however, might have a vasodilatatory role.

Animals↗
PubMed1986

Effects of morphine in the isolated mouse urinary bladder.

Acute morphine increased the responses to acetylcholine of the isolated mouse urinary bladder. A chronic morphine treatment did not change the responses of the urinary bladder to acetylcholine or ATP. The acute administration of morphine did not modify the contractile response to ATP in the urinary bladders from untreated or chronically morphine treated mice. Methadone and ketocyclazocine decreased the responses to the electrical stimulation of the urinary bladder. These depressant effects were not modified by naloxone. The results suggest the nonexistence of opiate receptors in the mouse urinary bladder and the lack of direct effects of morphine on the neuroeffector junction.

Acetylcholine↗
PubMed1994

Inhibitory effect of prostaglandins on dopamine release from the retina.

1. Prostaglandins have been shown to modulate transmitter release from both central and peripheral neuroeffector junctions. In the present study, we examined the effect of prostaglandins on [3H]-dopamine release from isolated, superfused rabbit retina. 2. Both naturally occurring and synthetic prostaglandins produced concentration-dependent reduction of electrically evoked [3H]-dopamine overflow without affecting basal tracer efflux. The rank order of potencies of the agonists was: sulprostone > 16,16-dimethyl PGE2 > PGE2 >> 11-deoxy-PGE1 > PGF2 alpha. 3. The PGE2-mediated inhibition of field stimulated [3H]-dopamine release was not blocked by the selective EP1-receptor antagonist, AH6809 (5-30 microM). 4. The cyclooxygenase inhibitor, flurbiprofen (3 microM) had no effect on basal or evoked [3H]-dopamine overflow nor did it affect the inhibition caused by PGE2 suggesting that endogenous prostaglandins are not involved in the regulation of dopamine release in the retina. 5. The inhibition of [3H]-dopamine release produced by submaximal concentrations of PGE2, apomorphine and melatonin were not additive indicating that presynaptic PGE2, D2- and melatonin receptors coexist at sites for neurotransmitter release and may share a common mechanism for regulation of dopamine release. 6. We conclude that prostaglandin-induced inhibition of electrically evoked [3H]-dopamine release from the rabbit retina may be mediated by specific prostaglandin receptors of the EP3 subtype.

Animals↗
PubMed1996

Central noradrenergic neurons signal via ATP to elicit vasopressin responses to haemorrhage.

It is now clear that ATP acts as a neurotransmitter in both the peripheral and central nervous systems. In the periphery, purinergic transmission has been best studied at certain sympathetic neuroeffector junctions where ATP, co-localized with noradrenaline, is used to elicit the primary post-junctional response. More recently, several groups have raised the possibility that central catecholaminergic neurons might use ATP in a similar fashion. Accordingly, we now present findings from immediate early gene expression and electrophysiological studies which indicate that ATP, acting through P2 purinoreceptors, is used as a transmitter by caudal brainstem noradrenergic neurons, the A1 group, in their interaction with vasopressinergic neurosecretory cells. Supraoptic nucleus vasopressin cell responses to moderate haemorrhage, known to be generated by the A1 projection, were suppressed by hypothalamic application of the P2 receptor antagonist suramin. However, suramin did not alter vasopressin cell responses to osmotic challenge or severely hypotensive haemorrhage, two stimuli known to excite vasopressin cells independently of the A1 projection. These data are consistent with an identity of action between the A1 input to vasopressin cells and the activation of ATP receptors on vasopressin cells. The use of ATP as a transmitter by other catecholamine neurons in the brain awaits further confirmation, but the present findings suggest that in certain instances the therapeutic manipulation of central catecholamine neuron output might best be achieved with pharmacological agents which target purinergic rather than adrenergic transmission.

Adenosine Triphosphate↗
PubMed1985

Innervation of the late distal nephron: an autoradiographic and ultrastructural study.

A study of the monoaminergic innervation of the cortical distal nephron beyond the thick ascending limb of Henle (TALH) was carried out by surveying nine autoradiograms, from three rats injected with exogenous tritiated norepinephrine, for overlapping of the tubule by accumulations of autoradiographic grains (AAGs). The largest number of the AAGs appeared on the late distal convoluted tubule-connecting tubule (LDCT-CNT) portion and the vast majority of the AAGs were related to the afferent arteriole. The distal convoluted tubule (DCT) and cortical collecting duct (CCD) showed half of their AAGs related to the efferent arterioles and capillary-interstitium although a substantial amount was associated with the afferent arterioles or arteries. Electron microscopy of reembedded autoradiograms demonstrated the presence of neuroeffector junctions with the CNT and CCD at sites of AAG overlap. The presence of adrenoceptors in the late distal nephron suggests the possibility of a local response of the nephron to the action of the adrenergic nerves shown in this study.

Animals↗
PubMed2004

Assessment of O-methylated catecholamine levels in plasma and urine for diagnosis of autonomic disorders.

The term 'metanephrines' is used to indicate the two catechol 3-O-methylated metabolites of epinephrine (E) and norepinephrine (NE): metanephrine and normetanephrine (NMN). The corresponding 3-O-methylated metabolite of dopamine is usually referred to as 3-methoxytyramine rather than 3-methoxydopamine and is not generally considered a "metanephrine". O-Methylation occurs outside the sympathetic neuron and neuroeffector junction. Metanephrines are products of the enzyme catechol-O-methyltransferase (COMT). Subsequent conjugation with sulfate or deamination by monoamine oxidase (MAO) followed by reduction to vanilmandelic acid (VMA) facilitates urinary excretion. For the clinician, measurement of normetanephrine provides an index of norepinephrine released during sympathetic nervous system activity, whereas metanephrine concentration provides an indication of adrenal medullary metabolism of epinephrine prior to its discharge into the circulation. Plasma epinephrine concentration is the preferable index of adrenal medullary epinephrine discharge. Pheochromocytomas, with their protean clinical manifestations, may be diagnostic challenges, but assay of metanephrines, especially plasma metanephrine, can be particularly helpful in diagnosis. These COMT metabolites may also help in elucidation of still undiscovered genetic and acquired disorders of catecholamine metabolism.

Animals↗
PubMed2000

Salivary glands in ixodid ticks: control and mechanism of secretion.

The salivary glands are vital to the biological success of ixodid ticks and the major route for pathogen transmission. Important functions include the absorption of water vapor from unsaturated air by free-living ticks, excretion of excess fluid for blood meal concentration, and the secretion of bioactive protein and lipid compounds during tick feeding. Fluid secretion is controlled by nerves. Dopamine is the neurotransmitter at the neuroeffector junction regulating secretion via adenylate cyclase and an increase in cellular cAMP. Dopamine also affects the release of arachidonic acid which is subsequently converted to prostaglandins. Prostaglandin E(2) (PGE(2)) is secreted at extremely high levels into tick saliva for export to the host where it impacts the host physiology. Additionally, PGE(2) has an autocrine or paracrine role within the salivary gland itself where it interacts with a PGE(2) receptor to induce secretion (exocytosis) of bioactive saliva proteins via a phosphoinositide signalling pathway and an increase in cellular Ca(2+). Regulation of fluid secretion has been extensively studied, but little is known about the mechanism of fluid secretion. Continuing advances in tick salivary gland physiology will be made as key regulatory and secretory gland proteins are purified and/or their genes cloned and sequenced.

Journal Article↗