Inhibitory Action Of Norepinephrine Research Articles

Potential action on the central nervous system of neroli oil extracted from Citrus aurantium

The essential oil from C. aurantium has been widely studied due to its potential anxiolytic action on several receptors in the Central Nervous System (CNS). Although it presents variations in its phytochemical composition depending on its origin, we can highlight that many compounds remain present, such as linalool that demonstrated antagonistic activity on glutamatergic receptors, possible inhibitory action of noradrenaline and serotonin receptors, besides the ability to activate GABA receptors in association with some flavonoids present in the oil. It is globally known that the underlying pathology called anxiety influences worldwide as an antecedent of conflicting psychological and physical disorders, which are associated with various neuronal disorders. In this regard, the oil extracted from C. aurantium flowers shows a potential therapeutic application for the treatment of anxiety disorders. However, more studies are needed to elucidate its complete role on the CNS and to verify and prove its safety and efficacy profile.

Adrenergic receptors inhibit TRPV1 activity in the dorsal root ganglion neurons of rats.

Transient receptor potential vanilloid type 1 (TRPV1) is a polymodal receptor channel that responds to multiple types of stimuli, such as heat, acid, mechanical pressure and some vanilloids. Capsaicin is the most commonly used vanilloid to stimulate TRPV1. TRPV1 channels are expressed in dorsal root ganglion neurons that extend to Aδ- and C-fibers and have a role in the transduction of noxious inputs to the skin into the electrical signals of the sensory nerve. Although noradrenergic nervous systems, including the descending antinociceptive system and the sympathetic nervous system, are known to modulate pain sensation, the functional association between TRPV1 and noradrenaline in primary sensory neurons has rarely been examined. In the present study, we examined the effects of noradrenaline on capsaicin-evoked currents in cultured dorsal root ganglion neurons of the rat by the whole-cell voltage clamp method. Noradrenaline at concentrations higher than 0.1 pM significantly reduced the amplitudes of the inward capsaicin currents recorded at –60 mV holding potential. This inhibitory action was reversed by either yohimbine (an α2 antagonist, 10 nM) or propranolol (a β antagonist, 10 nM). The α2 agonists, clonidine (1 pM) and dexmedetomidine (1 pM) inhibited capsaicin currents, and yohimbine (1 nM) reversed the effects of clonidine. The inhibitory action of noradrenaline was not seen in the neurons pretreated with pertussis toxin (100 μg/ml for 24 h) and the neurons dialyzed intracellularly with guanosine 5’- [β-thio] diphosphate (GDPβS, 200 μM), the catalytic subunit of protein kinase A (250 U/ml) or okadaic acid (1 μM). These results suggest that noradrenaline directly acts on dorsal root ganglion neurons to inhibit the activity of TRPV1 depending on the activation of α2-adrenoceptors followed by the inhibition of the adenylate cyclase/cAMP/protein kinase A pathway.

The involvement of norepinephrine in pain modulation in the nucleus accumbens of morphine-dependent rats

Opioids are effective analgesics used clinically for both acute and chronic pain management. However, repeated opioid treatment can induce serious side effects such as nausea, vomiting, drowsiness, respiratory depression, euphoria, dependence, hyperalgesia, and tolerance. The mechanism of noxious information transmission in the central nervous system following dependence is still not clear. Norepinephrine (NE), an important neurotransmitter, participates both in the process of opioid dependence and also pain modulation in the central nervous system. In this study, we examined the role of NE on the evoked discharges of pain-excitation neurons (PENs) and pain-inhibition neurons (PINs) in the nucleus accumbens (NAc) of rats, following the development of morphine dependence. Our results revealed that NE inhibited the evoked discharges of PENs and attenuated the inhibition of PINs, while phentolamine enhanced the evoked discharges of PENs and facilitated the inhibition of PINs. These results indicate that the inhibitory action of NE on pain modulation acts via alpha adrenoceptors in the NAc of morphine-dependent rats.

The hydroosmotic response of frog urinary bladder to serosal hypertonicity is dependent on adenylate cyclase for its maintenance and affected by [Cl−]ochanges

The role of adenylate cyclase (AC) in the maintenance of the hydroosmotic response to serosal hypertonicity (SH) in anuran urinary bladder is disputed. In this study, norepinephrine (NE) significantly reversed the hydroosmotic response of Rana temporaria bladders in hypertonic medium (330 mosmol/kgH2O). The reversal was inhibited by yohimbine but was unaffected by prazosin and propranolol, indicating that NE action was mediated via alpha2-adrenergic receptors. Preincubation of bladders with indomethacin did not interfere with the inhibitory action of NE, contraindicating a role for prostaglandins. The SH hydroosmotic response was abolished in the presence of 5-n-ethyl-N-isopropyl amiloride (EIPA), but the antidiuretic hormone (ADH) hydroosmotic response was not. EIPA inhibits Na+/H+, known to be activated by cell shrinkage. An investigation of the anionic requirement of the SH hydroosmotic response revealed that replacement of bath Cl- with the nonpermeable anion gluconate reversibly abolished this response. In contrast, the hydroosmotic response to ADH was unaffected by Cl- removal; however, when Cl- was absent, it was no longer augmented in hypertonic bath. The SH response was inhibited by the Cl- channel blocker 5-nitro-2-(3-phenylpropylamino)benzoate but not by the Na/K/2Cl inhibitor bumetanide. Our results show that not only the onset but also the maintenance of the SH hydroosmotic response is dependent on AC activity and does not differ in this respect to the ADH hydroosmotic response. The effect of modifying extracellular Cl- concentration, suggests that this anion, possibly functionally linked with Na+/H+ activity, may be involved in invoking the SH hydroosmotic response in anuran urinary bladder.

Immunostaining of cholinergic pontomesencephalic neurons for α 1 versus α 2 adrenergic receptors suggests different sleep–wake state activities and roles

Cholinergic neurons of the pontomesencephalic tegmentum play a critical role in paradoxical sleep, when, according to single unit recording of ‘possibly’ cholinergic neurons, they fire maximally. The profile of activity of the cholinergic neurons may be determined by noradrenergic locus coeruleus neurons that are active during waking and silent during paradoxical sleep. Indeed, a permissive role of the noradrenergic neurons in paradoxical sleep has been proposed based upon an inhibitory action of noradrenaline through α 2 adrenergic receptors on the cholinergic cells. Yet some ‘possibly’ cholinergic neurons are purportedly maximally active during waking and excited by noradrenaline through α 1 receptors. In the present study, we examined by fluorescent dual-immunostaining in the laterodorsal and pedunculopontine tegmental nuclei of the rat whether choline acetyltransferase-immunopositive neurons are stained for α 2A or α 1A adrenergic receptors. For comparison, we examined immunostaining for these receptors on tyrosine hydroxylase-immunopositive locus coeruleus neurons, which are known to bear α 2A autoreceptors. Whereas virtually all the noradrenergic neurons were labeled for the α 2A and none for the α 1A, approximately half the cholinergic neurons were labeled for the α 2A and one third for the α 1A adrenergic receptors in adjacent sections. These results suggest that different groups of cholinergic neurons bear α 2 versus α 1 adrenergic receptors and would accordingly have different sleep–wake state activities and roles. The α 2-bearing group would be inhibited by noradrenaline during waking to become disinhibited and maximally active while promoting paradoxical sleep, whereas the α 1-bearing group would be excited by noradrenaline during waking to become maximally active while promoting features of that state.

Neurotransmitter release mechanisms in sympathetic neurons: past, present, and future perspectives.

In 1969, Paton and Vizi described the inhibitory actions of noradrenaline on acetylcholine release from the innervation of the guinea-pig ileum longitudinal muscle. They concluded "that acetylcholine output by the nervous networks of the longitudinal strip is under the normal control of the sympathetic by a species of presynaptic inhibition mediated by <==> receptors". This work was carried out in the Pharmacology Department at Oxford University. Clearly, a period in the 'Dreaming Spires' of Oxford sufficiently inspired Sylvester to take up a life long career in scientific research. He has published more than 300 papers on a wide range of topics but clearly has a strong interest in neurotransmitter release mechanisms and recently, non-synaptic interactions between neurons. It seems fitting therefore to write a brief review on the continuing studies on neurotransmitter release mechanisms in sympathetic neurons in a volume honoring the now distinguished Professor Vizi.

Norepinephrine regulation of growth hormone release from goldfish pituitary cells. I. Involvement of alpha2 adrenoreceptor and interactions with dopamine and salmon gonadotropin-releasing hormone.

Adrenergic regulation of growth hormone (GH) release in the goldfish was examined in vitro using dispersed goldfish pituitary cells under column perifusion. Norepinephrine and epinephrine suppressed basal GH release from goldfish pituitary cells in a reversible and dose-dependent manner. At high doses, a transient rebound of GH release was observed after termination of norepinephrine and epinephrine treatment. In this study, the dose-dependence of adrenergic inhibition on basal GH release was mimicked by the alpha2 agonists clonidine and UK14304. Basal GH secretion, however, was not affected by the beta agonist isoproterenol and alpha1 agonist methoxamine. In addition, the inhibitory actions of norepinephrine and clonidine on basal GH release were blocked by the alpha2 antagonists yohimbine and RX821002. The beta antagonist propranolol and alpha1 antagonists prasozin and benoxathian were not effective in this respect. Salmon gonadotropin-releasing hormone (sGnRH) and dopamine, two known GH-releasing factors in fish, stimulated GH release from goldfish pituitary cells and their GH-releasing actions were inhibited by simultaneous treatment with norepinephrine. Furthermore, the GH rebound after norepinephrine treatment was significantly enhanced by prior exposure to sGnRH and this effect was not observed with dopamine treatment. These results, taken together, suggest that in the goldfish adrenergic input at the pituitary level inhibit basal GH release through activation of alpha2 adrenoreceptors. This alpha2 inhibitory influence may interact with dopaminergic and GnRH input to regulate GH secretion from goldfish pituitary cells. The 'post-inhibition' GH rebound after NE treatment and its sensitivity to sGnRH potentiation may also represent a novel mechanism for GH regulation in fish.

α2A-adrenergic receptors in the rat nucleus locus coeruleus: subcellular localization in catecholaminergic dendrites, astrocytes, and presynaptic axon terminals

To define the anatomic substrates subserving the inhibitory actions of α 2-adrenergic receptors ( α 2-ARs) in the locus coeruleus (LC), we used dual-label immunoelectron microscopy with antibodies directed against the A-subtype of α 2-AR ( α 2A-AR) and the catecholamine-synthesizing enzyme tyrosine hydroxylase (TH). Of the profiles containing peroxidase labeling for α 2A-AR ( α 2A-AR-IR) in the LC ( n=735), most were dendrites (∼50%), glial processes (∼30%), and axon terminals (∼15%). α 2A-AR-IR was also observed in unmyelinated axons and perikarya. Within dendrites, α 2A-AR-IR was associated with nonsynaptic regions of the plasma membrane and subsurface cisternae. Approximately 60% of dendrites with α 2A-AR-IR were dually labeled for TH. Fifty percent of the axon terminals contacting α 2A-AR-immunoreactive dendrites formed asymmetric (excitatory) synaptic contacts. Axon terminals with α 2A-AR-IR were not dually labeled for TH and generally formed asymmetric synapses with TH-immunoreactive dendrites that contained or lacked α 2A-AR-IR. Astrocytic processes exhibiting α 2A-AR-IR were closely apposed to TH-labeled dendrites. These results extend previous ultrastructural observations of α 2A-ARs in the LC and suggest that the inhibitory actions of norepinephrine and epinephrine in this region may be mediated by postsynaptic α 2A-ARs on catecholaminergic dendrites and presynaptic α 2A-ARs on excitatory inputs to catecholaminergic dendrites. In addition, the localization of α 2A-AR-IR in astrocytic processes apposed to TH-immunoreactive dendrites suggests a role for α 2A-ARs in functional interactions between catecholaminergic dendrites and neighboring astrocytes.

In Vivo Mutation of the α2A-Adrenergic Receptor by Homologous Recombination Reveals the Role of This Receptor Subtype in Multiple Physiological Processes

α2-Adrenergic receptors (α2ARs) are broadly associated with inhibitory actions of norepinephrine and epinephrine. Studies with drugs designed as α2AR agonists and antagonists have shown that α2ARs participate in a wide range of central nervous system activities, including central regulation of blood pressure, sedation and analgesia, control of affect, and modulation of pituitary hormone release. In the periphery, α2ARs inhibit neurotransmitter release from peripheral nervous system neuronal terminals, inhibit insulin secretion by pancreatic β cells, and participate in the regulation of water and electrolyte balance in the kidney. The α2ARs that elicit these varied responses represent a structural and functional family of receptor subtypes defined by pharmacological measurements and molecular cloning. Interest of studies has been to establish a mouse line that expressed a mutant α2AAR receptor with selectively altered signal transduction capabilities. Studies have shown that mutation of the highly conserved aspartate residue at position 79 in the α2AAR to asparagine (D79N) results in a receptor that is uncoupled from a single signaling pathway. In this purpose the two-step “hit and run” gene-targeting approach is successfully used in mouse embryonic stem cells to establish a mouse line with this D79N α2AAR mutation. Such studies reveal that the α2AAR subtype has a role central to several of the clinically desirable effects of α2AR agonists, suggesting that these functions cannot be separated by administering subtype-specific drugs. Null mutation of the α2BAR subtype has revealed that this subtype mediates the increase in blood pressure immediately following α2AR agonist administration. Thus, drugs that are selective for the α2AAR subtype relative to the α2BAR subtype may hold promise as improved antihypertensive agents. Sedative side effects might be eliminated if high-affinity partial agonists are developed, especially if higher receptor occupancy is needed to evoke sedation in contrast to hypotension.

Excitatory and inhibitory actions of norepinephrine on the Ba2+ current through L-type Ca2+ channels of smooth muscle cells of guinea-pig vas deferens.

The effect of norepinephrine (NE) was examined on the whole-cell Ba2+ current through L-type Ca2+ channels of freshly isolated smooth muscle cells of guinea-pig vas deferens. The magnitude of maximum Ba2+ current [1Ba(max)] varied in different cells, although the capacitance of the cell membrane was similar (approximately 50 pF). Application of dbcAMP augmented 1Ba(max) by 37%, which was canceled by Rp-cAMPs, while PMA decreased the current by 32%, which was canceled by staurosporine. NE increased 1Ba(max) of the cells which originally showed relatively small 1Ba(max), and decreased the current of the cells which showed larger 1Ba(max). In the presence of phentolamine, NE increased 1Ba(max), and this effect was remarkable in cells showed smaller 1Ba(max). In the presence of propranolol, NE decreased 1Ba(max). The excitatory beta-adrenoceptor activation was canceled by Rp-cAMPs, and the inhibitory alpha-adrenoceptor effect was canceled by staurosporine. It is suggested that NE shows dual (excitatory and inhibitory) actions on the L-type Ca2+ channels of smooth muscle of guinea-pig vas deferens. The excitatory beta-adrenoceptor action mediated through cAMP/PKA is predominant in cells with lower density of the Ca2+ channels, while inhibitory alpha-adrenoceptor action mediated through PKC is predominant in cells with higher channel density.

Voltage-dependent noradrenergic modulation of omega-conotoxin-sensitive Ca2+ channels in human neuroblastoma IMR32 cells.

High-threshold (HVA) Ca2+ channels of human neuroblastoma IMR32 cells were effectively inhibited by noradrenaline. At potentials between -20 mV and +10 mV, micromolar concentrations of noradrenaline induced a 50%-70% depression of HVA Ba2+ currents and a prolongation of their activation kinetics. Both effects were relieved at more positive voltages or by applying strong conditioning pre-pulses (facilitation). Facilitation restored the rapid activation of HVA channels and recruited about 80% of the noradrenaline-inhibited channels at rest. Re-inhibition of Ca2+ channels after facilitation was slow (tau r 36-45 ms) and voltage-independent between -30 mV and -90 mV. The inhibitory action of noradrenaline was dose-dependent (IC50 = 84 nM), mediated by alpha 2-adrenergic receptors and selective for omega-conotoxin-sensitive Ca2+ channels, which represent the majority of HVA channels expressed by IMR32 cells. The action of noradrenaline was mimicked by intracellular applications of GTP[gamma S] and prevented by GDP[beta S] or by pre-incubation with pertussis toxin. The time course of noradrenaline inhibition measured during fast application (onset) and wash-out (offset) of the drug were independent of saturating agonist concentrations (10-50 microM) and developed with mean time constants of 0.56 s (tau on) and 3.6 s (tau off) respectively. The data could be simulated by a kinetic model in which a G protein is assumed to modify directly the voltage-dependent gating of Ca2+ channels. Noradrenaline-modified channels are mostly inhibited at rest and can be recruited in a steep voltage-dependent manner with increasing voltages.

Inhibitory action of norepinephrine on sodium transport in vascular smooth muscle cells in culture.

Cultured vascular smooth muscle cells from porcine aortas incubated in Na+ -free medium rapidly release their intracellular Na+ contents (Nai) (23 +/- 4% of baseline after 60 min incubation, mean +/- SEM of 18 experiments). Total Nai release was inhibited by 35-40% after addition of ouabain and by 60-70% after addition of ouabain + bumetanide. Norepinephrine inhibited ouabain and bumetanide-sensitives Na+ efflux with an IC50 of about 10(-9)-10(-8) M. Addition of the alpha-adrenergic agonist phenylephrine (10 microM) to the cells mimicked the inhibitory action of norepinephrine on Nai release. Conversely, the beta-adrenergic agonist isoproterenol was without effect on Nai release. Simultaneous addition of 10 microM norepinephrine and the alpha-adrenergic antagonist phentolamine prevented any effect of norepinephrine on the rate of Nai decline. In A-10 cultured vascular smooth muscle cells, the alpha-adrenergic agonist phenylephrine (10 microM) inhibited 40.0 +/- 8.1% of ouabain-sensitive Rb+ influx and 70.7 +/- 6.9% of bumetanide-sensitive Rb+ influx (mean +/- SEM of three experiments). 50% inhibition of bumetanide-sensitive Rb+ influx was obtained with about 5 x 10(-7) M of phenylephrine. Our results show that in vascular smooth muscle cells a [Na+, K+, Cl-]-cotransport system is able to catalyze outward Na+ movements (in Na+ -free media) of a similar order of magnitude to those of the Na+, K+ pump and that alpha-adrenergic stimulation markedly inhibits Na+ efflux (and Rb+ influx) through these two transport systems.

Pharmacological identification of the α‐adrenergic receptor type which inhibits the β‐adrenergic activated adenylate cyclase system in cultured astrocytes

The adrenergic agonist norepinephrine can exert its influence on cell function by activating both alpha- and beta-adrenergic receptors. In astrocytes, the alpha-adrenergic receptor activity of norepinephrine is known to inhibit the cyclic AMP response elicited by its action at beta-adrenergic receptors. Pharmacological studies were conducted to identify the subtype of alpha-adrenergic receptor which mediates this inhibitory action. The alpha 2-adrenergic antagonist yohimbine potentiated the cyclic AMP response elicited by norepinephrine, whereas the alpha 1-adrenergic antagonist prazosin did not affect the response. The alpha 2-adrenergic agonist clonidine inhibited the cyclic AMP response elicited by the beta-adrenergic agonist isoproterenol and this inhibition could be blocked by yohimbine but not by prazosin. In contrast, the alpha 1-adrenergic agonist phenylephrine did not inhibit the cyclic AMP response to isoproterenol. These studies indicate that the inhibitory action of norepinephrine is mediated by its action at alpha 2-adrenergic receptors.

Electrophysiological effects of locally applied noradrenergic agents at cerebellar Purkinje neurons: receptor specificity

We have investigated the receptor subtype(s) mediating the noradrenergic inhibition of cerebellar Purkinje cell spontaneous firing rate using local application of specific agonists and antagonists, in situ, via pressure microejection. Extracellular action potentials were recorded from Purkinje neurons in anesthetized Fischer 344 rats. Timolol, a β-receptor antagonist, did not affect norepinephrine (NE)-induced inhibition in 9 of 12 cells studied. Phentolamine, a α-receptor antagonist, blocked the effect of NE in 8 of 11 cells. To further determine the subtype of α-receptor involved, the effects of the α 1-antagonist prazosin and α 2-antagonists idazoxan and yohimbine were examined. While prazosin had no effect on NE-mediated inhibition, both idazoxan and yohimbine blocked NE effects. Idazoxan was also successful in blocking phencyclidine (PCP), an indirect noradrenergic agonist. The inhibitory action of NE upon Purkinje cell firing rate was mimicked by the selective α 2-agonist clonidine; whis action of clonidine was blocked by idazoxan but not by timolol or prazosin. In addition, the α 1-adrenergic agonist phenylephrine and the β-adrenergic agonist isoproterenol inhibited Purkinje cell firing rate. Phenylephrine effects were blocked by prazosin but not by timolol or idazoxan. Isoproterenol-induced inhibition was blocked by timolol but not phentolamine. Taken together, these studies suggest that both α and β-receptors alter Purkinje cell firing rate; the depressat action of locally applied NE, however, seems to be mediated primarily via an α 2-adrenergic receptor.

Evidence for a receptor mediated action of norepinephrine distinct from alpha- and beta-adrenoceptors.

The mode of action of (-) norepinephrine (NE) and UK-14,304-18 has been investigated using the cholinergically-evoked 'twitch' response of the electrically stimulated guinea-pig ileum. St 587 and benextramine were employed as antagonists. St 587 acted as a competitive antagonist toward UK-14,304-18, yielding an apparent pA2 value of 7.3. In contrast, St 587 failed to act competitively toward NE. Similarly, benextramine (1 X 10(-5) mol/l) blocked the inhibitory responses to UK-14,304-18 but was considerably less active toward NE. Remaining responses to NE after benextramine were not antagonized by St 587, even at a concentration of 3 X 10(-5) mol/l. It is postulated that NE acts to inhibit the 'twitch' response be evoking two different receptor-mediated events: 1. agonism at the alpha 2-adrenoceptor and 2. agonism at a site which is distinct from the alpha- and beta-subtypes. In the concentrations studied, UK-14,304-18, St 587 and benextramine are postulated to lack affinity for the proposed site. The effect of NE and UK-14,304-18 was also investigated on the contractile responses to exogenously applied histamine. These experiments were done in the presence of muscarinic cholinergic and adrenoceptor blockade. NE inhibited responses to histamine but UK-14,304-18 was inactive. Furthermore, the inhibitory action of NE was stereoselective with the (-) form being 25 times more potent than the (+) enantiomer. These findings suggest the presence of a receptor site for NE which is distinct from cholinergic mechanisms and established alpha and beta-adrenoceptors.

Inhibition of α2-adrenergic agonists on AVP-induced cAMP accumulation in isolated collecting tubule of the rat kidney

A microradioimmunoassay for cAMP was developed in order to analyse the effects of α-adrenergic agonists on vasopressin (AVP)-induced cAMP cell accumulation in single pieces of microdissected medullary (MCT) and cortical (CCT) rat collecting tubules. Under the experimental conditions chosen (4 min of incubation in the presence of a phosphodiesterase inhibitor), no cAMP could be detected either in the bathing solution or in non-stimulating samples of tubule. In MCT, 10 −6 M AVP stimulated cAMP generation up to 128.3 ± 9.0 (SEM) fmoles per mm of tubule per 4 min, N = 11. The response was dose-dependent with a K A value below 10 −10 M AVP. The addition of norepinephrine (NE) (10 −5 M in the presence of propranolol) suppressed the larger part of the response to AVP (from 92% with 2 × 10 −11 M AVP to 76% with 10 −6 MAVP); the addition of 10 −7 M NE still reduced by 59% the MCT response to 10 −10 M AVP (26.2 ± 5.9 vs. 64.0 ± 6.4 fmoles/mm, N = 3). In CCT, 10 −5 M NE reduced by 84% the cAMP generation induced by 10 −10 M AVP (8.8 ± 2.0 vs. 54.2 ± 3.5 fmoles/mm, N = 3). This inhibitory action of NE against the AVP effect in CCT was mimicked by 10 −7 M clonidine; in MCT it was suppressed by phentolamine and yohimbine, but not by prazosin, suggesting that α 2-adrenoreceptors are involved. On the other hand, the addition of the α-agonists to the incubation solution produced no inhibition of the cAMP cell accumulations induced by glucagon, calcitonin and isoproterenol in CCT, or glucagon in MCT, an observation demonstrating that α 2-adrenergic agonists selectively inhibit vasopressin-dependent cAMP generation by these nephron segments.

An unlikely role for cyclic AMP in the mediation of the excitatory and inhibitory effects of noradrenaline on transmission in the olfactory cortex

Simultaneous measurements have been made of the actions of noradrenaline and other agonists, alone and in the presence of appropriate antagonists, on synaptic transmission and cyclic AMP levels in the rat olfactory cortex. The possible role of cyclic AMP as an obligatory mediator of the excitatory and inhibitory actions of noradrenaline is discussed.

Negative control of norepinephrine on the thyroid cyclic AMP system

Negative control on the thyroid cyclic AMP system has been studied. The increase of cyclic AMP levels induced by TSH in dog thyroid slices and its consequent secretion were inhibited by norepinephrine. This effect was different from the previously described activation of cyclic AMP disposal by acetylcholine: it was not calcium-dependent, was observed in the presence of isobutyl methylxanthine and was not inhibited by atropine. The inhibitory action of norepinephrine was abolished by phentolamine but not by l-propranolol. Clonidine and epinephrine also markedly inhibited the elevation of cyclic AMP levels, but phenylephrine did not. The inhibitory effect of norepinephrine and clonidine was abolished by yohimbine but not by prazosin. These results suggest that the effect of adrenergic agents on dog thyroid follicular cells is mediated by α 2-receptors. Similar results were obtained on dog thyroid adenylate cyclase activity: norepinephrine diminished the activation of adenylate cyclase induced by TSH, in a sodium-dependent process. This inhibition was abolished by phentolamine and yohimbine, but not by l-propranolol and prazosin. This shows that the negative α 2-adrenergic effect bears directly on adenylate cyclase.

Prejunctional inhibition mediated via alpha 2-adrenoceptors in excitatory transmission of canine small intestine.

Noradrenaline(NA) inhibited the contractile responses of longitudinal and circular muscles of canine small intestine to field stimulation (20 Hz, 1 ms, supramaximal voltage for 5 s). The purpose of this study was to see if NA-induced inhibitory action is mediated via alpha 1- or alpha 2-receptors and whether the inhibitory action involved prostaglandins. In both muscle layers the alpha 2-agonist, clonidine inhibited the contractile response to field stimulation more potently than did the alpha 1-agonists phenylephrine or methoxamine. It is suggested that NA-mediated prejunctional inhibition is mediated via alpha 2-receptors. Yohimbine, an alpha 2-adrenoceptor blocking drug antagonized NA-induced prejunctional inhibition, while E-643, an alpha 1-blocker, did not affect the inhibition. These results suggest that the inhibitory action of NA is mediated via alpha 2-receptors in both muscle layers. Indomethacin, an inhibitor of prostaglandin synthesis, did not affect NA-induced prejunctional inhibition in circular muscle, while augmenting it in longitudinal muscle. It is thought that NA-induced prejunctional inhibition is not mediated via prostaglandin release.

HOMOGENEOUS AND NON‐HOMOGENEOUS DISTRIBUTION OF INHIBITORY AND EXCITATORY ADRENOCEPTORS IN THE LONGITUDINAL MUSCLE OF THE GUINEA‐PIG ILEUM

1 The effects of adrenoceptor agonists and antagonists on spontaneous and evoked membrane activities of longitudinal muscle cells from different parts of the guinea-pig ileum were observed, using microelectrode methods.2 Isoprenaline inhibited the generation of spikes in cells in the terminal (0-3 cm from the ileocaecal valve) and proximal (more than 50 cm from the ileocaecal valve) regions of the ileum, with no change on the membrane potential and ionic conductance of the membrane. These actions of isoprenaline were abolished by propranolol.3 Noradrenaline and phenylephrine depolarized the membrane and increased both the spike frequency and ionic conductance of cell membranes of the terminal ileum, whereas noradrenaline and clonidine hyperpolarized the membrane, increased the ionic conductance of the membrane and inhibited the spontaneously generated spikes from cells of the proximal ileum. The excitatory effect of phenylephrine in the cells of the proximal ileum and the inhibitory effect of clonidine on cells of the terminal ileum were less pronounced.4 The excitatory actions of noradrenaline or phenylephrine were antagonized by prazosin and phentolamine, but not by yohimbine, whereas the inhibitory actions of noradrenaline or clonidine were antagonized by yohimbine and phentolamine but not by prazosin.5 The cholinergic e.j.ps evoked by field stimulation to the tissue were not affected by isoprenaline or phenyleprine but were inhibited by noradrenaline and clonidine, in both the terminal and proximal regions of the ileum. These actions of noradrenaline and clonidine were antagonized by yohimbine but not by prazosin.6 The results indicate that in the myenteric plexus and longitudinal muscle tissues of the guinea-pig ileum there are prejunctional inhibitory (alpha(2)), postjunctional inhibitory (alpha(2) and beta) and postjunctional excitatory (alpha(1)) adrenoceptors. The homogeneous distributions of prejunctional alpha(2)- and postjunctional beta-adrenoceptors in the ileum are responsible for inhibitions of cholinergic excitatory junction potentials (e.j.ps) and spontaneous spike activities, respectively. The density of distribution of the postjunctional alpha(1)-adrenoceptors is higher in the terminal than in the proximal regions, and these distributions are reversed in the case of the postjunctional alpha(2)-adrenoceptors. The postjunctional alpha(1)-adrenoceptors are probably responsible for the membrane depolarization and alpha(2)-adrenoceptors for the hyperpolarization induced by catecholamines.