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The function of presynaptic angiotensin II receptors at postganglionic sympathetic terminal axons under conditions of uninterrupted sympathetic impulse traffic was studied in anesthetized rabbits (alfadolone + alfaxalone). Mean arterial... more
The function of presynaptic angiotensin II receptors at postganglionic sympathetic terminal axons under conditions of uninterrupted sympathetic impulse traffic was studied in anesthetized rabbits (alfadolone + alfaxalone). Mean arterial pressure, postganglionic renal sympathetic firing rate, the arterial plasma noradrenaline concentration, and heart rate were measured before (basal values) and at the end of 4-min infusions of sodium nitroprusside. Angiotensin II (20 or 100 ng kg-1 min-1) caused dose-dependent increases of basal mean arterial pressure and decreases of basal sympathetic nerve activity and heart rate, but did not change the basal plasma noradrenaline concentration. Moreover, it shifted the sympathetic nerve activity-plasma noradrenaline relationship in a manner indicating an increase of the average release of noradrenaline per action potential. Angiotensin II at 100 ng kg-1 min-1 had an additional effect, at any given blood pressure, sympathetic nerve activity and heart rate were lower than in the controls. Captopril (1 mg kg-1 followed by 1 mg kg-1 h-1) caused no change in any parameter. The results demonstrate that exogenous angiotensin II activates release-facilitating receptors at postganglionic sympathetic neurons in rabbits with ongoing sympathetic nerve activity. Endogenous angiotensin II, however, played no role in cardiovascular regulation under the present, acute experimental conditions. Vasopressin, which was studied for comparison, lacked a presynaptic effect on the release of noradrenaline but caused sympathoinhibition by an action on a central component of the baroreflex.
Research Interests: Kidney, Hemodynamics, Blood Pressure, Cardiovascular Pharmacology, Animals, and 12 moreAnesthesia, Heart rate, Norepinephrine, SYNAPSES, Sympathetic Nervous System, Rabbits, Angiotensin II, Captopril, nitroprusside, Cardiovascular medicine and haematology, Pharmacology and pharmaceutical sciences, and In Vitro Techniques
Research Interests: In Vitro, Kidney, Hemodynamics, Blood Pressure, Animals, and 14 moreResuscitation, Corticosterone, Cocaine, Heart, Norepinephrine, Clinical Sciences, Public health systems and services research, Adrenocorticotropic Hormone, Propranolol, Rabbits, Vasodilation, Arterial pressure, hydrocortisone, and In Vitro Techniques
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Perioperative liver injury due to decreased perfusion may be an underlying mechanism behind the development of systemic inflammatory response syndrome. We designed this animal study to assess whether thoracic epidural anesthesia (TEA)... more
Perioperative liver injury due to decreased perfusion may be an underlying mechanism behind the development of systemic inflammatory response syndrome. We designed this animal study to assess whether thoracic epidural anesthesia (TEA) impairs liver oxygenation due to induced hypotension. After ethical approval, 19 anesthetized and acutely instrumented pigs were randomly assigned to 3 groups (control and TEA alone versus TEA plus volume loading). Bupivacaine 0.5% 0.75 mL per segment was injected into the epidural space, aiming for a T5 to T12 block. After baseline values were obtained, measurements were repeated 60 and 120 min after epidural injection. TEA was associated with decreased mean arterial blood pressure but no change in total hepatic blood flow. Oxygen delivery to the liver and oxygen uptake remained unchanged. Liver tissue oxygen partial pressure did not decrease. The plasma indocyanine green disappearance rate remained stable. Volume loading before TEA did not relevantly affect total hepatic blood flow; it even decreased oxygen supply to the liver by hemodilution. We conclude that, despite decreased mean arterial blood pressure, TEA did not affect liver oxygenation. There was no clinically relevant effect of volume loading on total hepatic perfusion.
Research Interests: Catheterization, Liver, Epinephrine, Hemodynamics, Animals, and 15 moreAnesthesia, Norepinephrine, Clinical Sciences, General Anesthesia, Digestive System, Blood Flow, Lactic Acid, Oxygen Consumption, Neurosciences, Portal vein, Oxygenation, Nitroglycerin, Pulmonary Artery, Laparotomy, and Cardiac output
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Presynaptic CB(1) cannabinoid receptors are frequently targets of endogenous cannabinoids (endocannabinoids) released from postsynaptic neurons. It is known that the glutamatergic afferent input to a neuron can trigger endocannabinoid... more
Presynaptic CB(1) cannabinoid receptors are frequently targets of endogenous cannabinoids (endocannabinoids) released from postsynaptic neurons. It is known that the glutamatergic afferent input to a neuron can trigger endocannabinoid production and that the released endocannabinoid can suppress the glutamatergic input. We tested the hypothesis that activation of the glutamatergic input to a neuron leads to an endocannabinoid-mediated suppression of the GABAergic afferent input to the same neuron. Spontaneous postsynaptic currents (sPSCs) were recorded with patch-clamp techniques in Purkinje cells in mouse cerebellar brain slices. Activation of the climbing fiber-mediated glutamatergic input to Purkinje cells led to a suppression of the sPSCs by 34+/-3%. This suppression was mostly due to suppression of GABAergic spontaneous inhibitory postsynaptic current (sIPSCs), because 93% of the sPSCs recorded in Purkinje cells were GABAergic sIPSCs. Blockade of ionotropic, but not metabotropic glutamate receptors, prevented the suppression. The climbing fiber activation led to an increase in calcium concentration in the Purkinje cells, and this increase was necessary for the suppression of sPSCs, because the suppression did not occur when the calcium increase was prevented by BAPTA. No sPSC suppression was observed in the presence of the CB(1) antagonist rimonabant or the diacylglycerol lipase inhibitor orlistat. In a further series of experiments GABAergic sIPSCs were recorded: these sIPSCs were also suppressed after climbing fiber activation, and the suppression was sensitive to the CB(1) antagonist SLV319. Finally, the GABAergic synaptic transmission between molecular layer interneurons and Purkinje cells was directly studied on simultaneously patch-clamped neuron pairs. Climbing fiber activation led to suppression of the interneuron --> Purkinje cell synaptic transmission. The results point to a novel form of endocannabinoid-mediated heterosynaptic plasticity. The endocannabinoid production in a neuron is triggered by its glutamatergic synaptic input and is dependent on an increase in intracellular calcium concentration. The produced endocannabinoid, in turn, suppresses the GABAergic synaptic input to the neuron by activating CB(1) cannabinoid receptors.
Research Interests: Neuroscience, Psychology, Calcium, Cerebrospinal Fluid, Mice, and 15 moreAnimals, Neurons, Potassium Channels, Purkinje Cells, Endocannabinoids, Neurosciences, Interneurons, Reference Value, Patch Clamp, Climbing Fiber, Intracellular Calcium, Purkinje cell, Glutamate Receptor, Retrograde Signaling, and In Vitro Techniques
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Systemically administered cannabinoids elicit marked cardio- vascular effects, and the role of the central and the peripheral nervous system in these effects is not clarified. The aim of this study was to characterize the actions of... more
Systemically administered cannabinoids elicit marked cardio- vascular effects, and the role of the central and the peripheral nervous system in these effects is not clarified. The aim of this study was to characterize the actions of cannabinoids on car- diovascular regulatory centers in conscious rabbits. A catheter for administration of drugs into the cisterna cerebellomedullaris and an electrode for recording renal sympathetic nerve activity were implanted under halothane anesthesia. Experiments were carried out later in conscious animals. Two cannabinoid recep- tor agonists were injected intracisternally: the aminoalkylindole WIN55212-2 (0.1, 1, and 10 m gk g 21) and the bicyclic D9- tetrahydrocannabinol analog CP55940 (0.1, 1, and 10 m gk g21). WIN55212-2 and CP55940 dose dependently increased renal sympathetic nerve activity and the plasma noradrenaline con- centration and also lowered the heart rate. The highest doses of WIN55212-2 and CP55940 increased blood pressure. In con- trast, intracisternal injection of WIN55212-3 (0.1, 1, and 10 mg kg21), an enantiomer of WIN55212-2 with very low affinity for cannabinoid binding sites, had no effects. The CB1 cannabi- noid receptor antagonist SR141716A (0.5 mg kg21, i.v.) atten- uated the effects of intracisternally administered WIN55212-2 (0.1, 1, and 10 m gk g21). The results indicate that cannabinoids, acting directly on cardiovascular regulatory centers, elicit sym- pathoactivation and bradycardia. These effects were likely me- diated by CB1 cannabinoid receptors, because they were elic- ited by two cannabinoid agonists belonging to different chemical classes (WIN55212-2 and CP55940), but not by the inactive enantiomer WIN55212-3, and because they were attenuated by the CB1 cannabinoid receptor antagonist SR141716A.
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It was shown recently that Delta9-tetrahydrocannabinol, like several other drugs eliciting euphoria, stimulates dopaminergic neurons projecting from the ventral tegmental area (VTA) to the nucleus accumbens. The aim of the present work... more
It was shown recently that Delta9-tetrahydrocannabinol, like several other drugs eliciting euphoria, stimulates dopaminergic neurons projecting from the ventral tegmental area (VTA) to the nucleus accumbens. The aim of the present work was to clarify the mechanism of this stimulatory effect. Our hypothesis was that cannabinoids depress the GABAergic inhibition of dopaminergic neurons in the VTA. Electrophysiological properties of VTA neurons in rat coronal midbrain slices were studied with the patch-clamp technique. GABA(A) receptor-mediated inhibitory postsynaptic currents (IPSCs) were evoked by electrical stimulation in the vicinity of the recorded neurons. The amplitude of IPSCs was depressed by the synthetic mixed CB1/CB2 cannabinoid receptor agonist WIN55212-2 (10(-6) and 10(-5) m). The CB1 cannabinoid receptor antagonist SR141716A (10(-6) m) prevented the inhibition produced by WIN55212-2 (10(-5) m). Two observations showed that IPSCs were depressed with a presynaptic mechanis...
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The CB1 cannabinoid receptor is widely distributed in the central and peripheral nervous system. Within the neuron, the CB1 receptor is often localised in axon terminals, and its activation leads to inhibition of transmitter release. The... more
The CB1 cannabinoid receptor is widely distributed in the central and peripheral nervous system. Within the neuron, the CB1 receptor is often localised in axon terminals, and its activation leads to inhibition of transmitter release. The consequence is inhibition of neurotransmission via a presynaptic mechanism. Inhibition of glutamatergic, GABAergic, glycinergic, cholinergic, noradrenergic and serotonergic neurotransmission has been observed in many regions of the central nervous system. In the peripheral nervous system, CB1 receptor-mediated inhibition of adrenergic, cholinergic and sensory neuroeffector transmission has been frequently observed. It is characteristic for the ubiquitous operation of CB1 receptor-mediated presynaptic inhibition that antagonistic components of functional systems (for example, the excitatory and inhibitory inputs of the same neuron) are simultaneously inhibited by cannabinoids. Inhibition of voltage-dependent calcium channels, activation of potassium ...
Research Interests: Neurotransmission, Ion Channels, Cannabinoids, Dopamine, Glutamate, and 12 moreHumans, Animals, Peripheral Nervous System, Central Nervous System, Acetylcholine, Synaptic Transmission, Synaptic Vesicle Recycling, Presynaptic Inhibition, Norepinephrine, Transmitter release, CB 1 receptor, and Gamma-Aminobutyric Acid
The substantia nigra pars reticulata (SNR) belongs to the brain regions with the highest density of CB(1) cannabinoid receptors. Anatomical studies indicate that the great majority of CB(1) receptors in the SNR are localized on terminals... more
The substantia nigra pars reticulata (SNR) belongs to the brain regions with the highest density of CB(1) cannabinoid receptors. Anatomical studies indicate that the great majority of CB(1) receptors in the SNR are localized on terminals of GABAergic axons arriving from the caudate-putamen (striatonigral axons). The aim of the present experiments was to clarify the role of CB(1) receptors on terminals of striatonigral axons. Oblique sagittal slices, including the caudate-putamen and the substantia nigra, were prepared from brains of young mice. Electrical stimulation in the caudate-putamen elicited GABAergic inhibitory postsynaptic currents (IPSCs) in the SNR, which were studied by patch-clamp techniques. The long latency of IPSCs (14+/-1 ms) suggests that striatonigral axons were indeed activated within the caudate-putamen. The synthetic CB(1)/CB(2) cannabinoid receptor agonist WIN55212-2 (R(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazin-yl]-(1-nap...
Research Interests: Neuroscience, Psychology, Immunohistochemistry, Patch-clamp and imaging techniques, Cannabinoids, and 15 moreDopamine, Cerebrospinal Fluid, Mice, Animals, Substantia nigra, Synaptic Transmission, Presynaptic Inhibition, Neural pathways, Bovine Serum Albumin, Ipsc, Neurosciences, Patch Clamp, Ethylene Glycol, Cannabinoid Receptor, and GABAA receptor
Cannabinoids elicit marked cardiovascular responses. It is not clear how peripheral effects on the autonomic nervous system contribute to these responses. The aim of the present study was to characterize the peripheral actions of... more
Cannabinoids elicit marked cardiovascular responses. It is not clear how peripheral effects on the autonomic nervous system contribute to these responses. The aim of the present study was to characterize the peripheral actions of cannabinoids on the autonomic innervation of the heart. Experiments were carried out on pithed rabbits. In the first series of experiments, postganglionic sympathetic cardioaccelerator fibers were stimulated electrically. The synthetic cannabinoid receptor agonists WIN55212-2 (0.005, 0.05, 0.5, and 1.5 mg kg(-1) i.v.) and CP55940 (0.003, 0.03, 0.3, and 1 mg kg(-1) i.v.) dose dependently inhibited the electrically evoked cardioacceleration. The inhibition by WIN55212-2 (0.5 mg kg(-1) i.v.) was prevented by the CB(1) cannabinoid receptor antagonist SR141716A (0.5 mg kg(-1) i.v.). WIN55212-2 (0.5 mg kg(-1) i.v.) did not change the increase in heart rate evoked by injection of isoprenaline. In the second series of experiments, preganglionic vagal fibers were st...
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Research Interests: Cannabinoids, Biological Sciences, Evoked Potentials, Caudate Nucleus, Mice, and 15 moreAnimals, The, Synaptic Transmission, Presynaptic Inhibition, Success Rate, SYNAPSES, Pyrazoles, Membrane Potential, Putamen, Interneurons, Patch Clamp, Piperidines, Cannabinoid Receptor, Medical and Health Sciences, and In Vitro Techniques
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Directionality of information flow through neuronal networks is sustained at cellular level by polarized neurons. However, specific targeting or anchoring motifs responsible for polarized distribution on the neuronal surface have only... more
Directionality of information flow through neuronal networks is sustained at cellular level by polarized neurons. However, specific targeting or anchoring motifs responsible for polarized distribution on the neuronal surface have only been identified for a few neuronal G-protein-coupled receptors (GPCRs). Here, through mutational and pharmacological modifications of the conformational state of two model GPCRs, the axonal CB1R cannabinoid and the somatodendritic SSTR2 somatostatin receptors, we show important conformation-dependent variations in polarized distribution. The underlying mechanisms include lower efficiency of conformation-dependent GPCR endocytosis in axons, compared with dendrites, particularly at moderate activation levels, as well as endocytosis-dependent transcytotic delivery of GPCRs from the somatodendritic domain to distal axonal portions, shown by using compartmentalized microfluidic devices. Kinetic modeling predicted that GPCR distribution polarity is highly re...
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Research Interests: Biological Sciences, Mice, Animals, Synaptic Transmission, Long Term Depression, and 12 moreEnzyme, Synaptic inhibition, Calmodulin, Purkinje Cells, Protein Kinase, Endocannabinoids, Cerebellar Cortex, Interneurons, Intracellular Calcium, Purkinje cell, Phospholipase C, and Medical and Health Sciences
Endocannabinoids released by postsynaptic neurons inhibit neurotransmitter release from presynaptic axon terminals. One typical stimulus of endocannabinoid production is an increase of calcium concentration in postsynaptic neurons. The... more
Endocannabinoids released by postsynaptic neurons inhibit neurotransmitter release from presynaptic axon terminals. One typical stimulus of endocannabinoid production is an increase of calcium concentration in postsynaptic neurons. The aim of the present study was to clarify whether depolarizing GABAergic synaptic input, by increasing calcium concentration in postsynaptic neurons, can trigger endocannabinoid production. Spontaneous GABAergic inhibitory postsynaptic currents (sIPSCs) were recorded in Purkinje cells in mouse cerebellar slices with patch-clamp pipettes containing 151 mM chloride (a usual recording mode). sIPSCs were depolarizing inward currents under this condition. Combined electrophysiological and fluorometric calcium imaging experiments indicated that sIPSCs frequently triggered calcium spikes. After the calcium spikes, a short-term suppression of sIPSCs occurred. This suppression was prevented by the CB(1) cannabinoid receptor antagonist rimonabant and the diacylglycerol lipase inhibitor orlistat, but not changed by URB597, an inhibitor of anandamide degradation. It is, therefore, likely that CB(1) receptors and 2-arachidonoylglycerol were involved. For testing the physiological significance of the above observation, we carried out experiments on brains of 3- to 5-day-old mice. The gramicidin-induced perforated patch-clamp mode was used for preserving the physiological intracellular chloride concentration of the neurons. Depolarizing GABAergic sIPSCs occurred under this condition, but at a very low rate. Rimonabant did not change the frequency of these sIPSCs, arguing against the persistence of an endocannabinoid tone. The results point to a new kind of trigger of endocannabinoid production: depolarizing GABAergic synaptic input can elicit endocannabinoid production in postsynaptic neurons by activating calcium channels. The produced endocannabinoid suppresses GABA release from presynaptic axon terminals.
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Research Interests: In Vitro, Kidney, Hemodynamics, Blood Pressure, Animals, and 14 moreResuscitation, Corticosterone, Cocaine, Heart, Norepinephrine, Clinical Sciences, Public health systems and services research, Adrenocorticotropic Hormone, Propranolol, Rabbits, Vasodilation, Arterial pressure, hydrocortisone, and In Vitro Techniques
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Research Interests: Humans, Hypertension, Blood Pressure, Animals, Presynaptic Inhibition, and 12 moreHT, Transmitter release, Sympathetic Nervous System, Mechanism of action, Imidazoles, Nts, Pharmacology and Therapeutics in Dentistry, Sympathetic nerve activity, Clonidine, Brain stem, Antihypertensive agents, and Pharmacology and pharmaceutical sciences
Research Interests: Neuroscience, Psychology, Electrophysiology, Neurotransmission, Cannabinoids, and 15 moreSubthalamic Nucleus, Glutamate, Mice, Animals, Dendrites, Synaptic Transmission, Neurons, Globus Pallidus, Neural pathways, Pyrazoles, Neurosciences, Patch Clamp, Piperidines, Glutamate Receptor, and Excitatory Postsynaptic Potentials
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Research Interests: Blood Pressure, Animals, Male, Heart rate, Central Nervous System, and 15 moreSynaptic Transmission, Presynaptic Inhibition, Norepinephrine, Rats, Wistar Rats, Sympathetic Nervous System, Pyrazoles, Phenylephrine, Piperidines, Calcium Channel Blockers, Cannabinoid Receptor, Pharmacology and pharmaceutical sciences, Vas Deferens, Neurotransmitter Release, and Arginine Vasopressin
Research Interests: Patch-clamp and imaging techniques, Cannabinoids, Animals, Substantia nigra, Synaptic Transmission, and 11 moreNeurons, Motor System, Rats, Wistar Rats, CB 1 receptor, Patch Clamp, Gamma-Aminobutyric Acid, Cannabinoid Receptor, Excitatory Postsynaptic Potentials, GABAA receptor, and Pharmacology and pharmaceutical sciences
Research Interests: Cannabinoids, Blood Pressure, Animals, Male, Heart rate, and 15 morePresynaptic Inhibition, Norepinephrine, Cardiovascular system, Rats, Wistar Rats, Hypotension, Sympathetic Nervous System, Pyrazoles, Nucleus tractus solitarii, Piperidines, Cannabinoid Receptor, Bradycardia, Brain stem, Mean Arterial Pressure, and Pharmacology and pharmaceutical sciences
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Effects of dynorphin-(1-13), Leu5-enkephalin, D-Ala2,D-Leu5-enkephalin (DADLE), and for comparison bremazocine, on plasma noradrenaline concentration and mean arterial pressure (MAP) were studied in pithed rabbits. In the first series of... more
Effects of dynorphin-(1-13), Leu5-enkephalin, D-Ala2,D-Leu5-enkephalin (DADLE), and for comparison bremazocine, on plasma noradrenaline concentration and mean arterial pressure (MAP) were studied in pithed rabbits. In the first series of experiments, the sympathetic outflow was stimulated electrically via the pithing rod at 2 Hz twice for 3 min each (S1, S2). Drugs were administered before S2. Bremazocine 10 micrograms/kg + 2 micrograms/kg/h and 100 micrograms/kg + 20 micrograms/kg/h, dynorphin 1 and 3 micrograms/kg/min, Leu5-enkephalin 100 micrograms/kg/min and DADLE 10 and 30 micrograms/kg/min all diminished the electrically-evoked increase in plasma noradrenaline and MAP. The effects were antagonized by naloxone. In the second series, an infusion of noradrenaline (2 micrograms/kg/min) was given twice for 3 min each (N1, N2). Drugs were administered before N2. Bremazocine 100 micrograms/kg + 20 micrograms/kg/h slightly enhanced the pressor effect of exogenous noradrenaline, whereas dynorphin 3 micrograms/kg/min, Leu5-enkephalin 100 micrograms/kg/min and DADLE 30 micrograms/kg/min caused no significant change. In the third series, the sympathetic outflow was stimulated continuously at 2 Hz, and the interaction of dynorphin and DADLE was studied. Dynorphin 1 microgram/kg/min and DADLE 10 micrograms/kg/min initially decreased MAP to a similar extent. The effect of DADLE faded with time. When, during continuous infusion of DADLE 10 micrograms/kg/min, and after return of MAP to the pre-DADLE level, dynorphin 1 microgram/kg/min or DADLE 10 micrograms/kg/min was infused additionally, the effect of dynorphin was unchanged, whereas that of DADLE was almost abolished. We conclude that the opioid peptides as well as bremazocine decrease action potential-evoked release of noradrenaline and, secondarily, blood pressure.(ABSTRACT TRUNCATED AT 250 WORDS)
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The function of presynaptic alpha 2-autoreceptors at postganglionic sympathetic neurones under conditions of normal, ongoing sympathetic impulse traffic was studied in anaesthetized rabbits (alfadolone + alfaxalone). Clonidine was used as... more
The function of presynaptic alpha 2-autoreceptors at postganglionic sympathetic neurones under conditions of normal, ongoing sympathetic impulse traffic was studied in anaesthetized rabbits (alfadolone + alfaxalone). Clonidine was used as an alpha 2-adrenoceptor agonist, and yohimbine and rauwolscine were used as antagonists. Mean arterial pressure, postganglionic renal sympathetic firing rate, arterial plasma noradrenaline concentration and heart rate were measured before (basal values) and at the end of 3-min infusions of sodium nitroprusside and phenylephrine, which were given to modulate efferent activity in the sympathetic nervous system through the baroreflex. The nitroprusside- and phenylephrine-induced changes of mean arterial pressure produced the expected changes in sympathetic nerve activity, plasma noradrenaline and heart rate. Clonidine (5 micrograms kg-1 + 0.5 micrograms kg-1 min-1) reduced the basal mean arterial pressure, sympathetic nerve activity and heart rate. It also reduced the nitroprusside-induced increase in the plasma noradrenaline level without changing the nitroprusside-induced increase in sympathetic firing. These results, as well as the mean arterial pressure-sympathetic nerve activity and the sympathetic nerve activity-plasma noradrenaline function curves indicate that clonidine inhibited both sympathetic tone centrally and the average release of noradrenaline per action potential peripherally. Yohimbine (1 mg kg-1 + 0.1 mg kg-1 h-1) and rauwolscine (0.5 mg kg-1 + 0.1 mg kg-1 h-1) increased the basal plasma noradrenaline level without any increase of renal sympathetic nerve activity. They also enhanced the nitroprusside-induced increase in plasma noradrenaline without any enhancement of the nitroprusside-induced increase in sympathetic firing. The hypotensive response to nitroprusside was attenuated, whereas the heart rate response was augmented. These results, as well as the mean arterial pressure-sympathetic nerve activity and the sympathetic nerve activity-plasma noradrenaline function curves indicate that the main effect of yohimbine and rauwolscine was to increase the average release of noradrenaline per action potential. The simultaneous measurement of postganglionic sympathetic nerve activity and the arterial plasma noradrenaline concentration proved suitable to differentiate central (or ganglionic; this distinction was not possible) effects of alpha 2-adrenoceptor ligands from peripheral presynaptic effects. The results show that endogenous presynaptic, alpha 2-adrenergic autoinhibition of noradrenaline release from postganglionic sympathetic neurones operates physiologically in anaesthetized rabbits with ongoing, uninterrupted sympathetic nerve activity. The results also indicate that blockade of alpha 2-autoreceptors enhances the sympathetic reflex compensatory response to a hypotensive stimulus.
Research Interests: Brain, Blood Pressure, Female, Animals, Male, and 15 moreHeart rate, Animal Model, Norepinephrine, SYNAPSES, Peripheral nerves, Sympathetic Nervous System, Rabbits, Phenylephrine, Sodium Nitroprusside, Sympathetic nerve activity, Clonidine, nitroprusside, Mean Arterial Pressure, Yohimbine, and Pharmacology and pharmaceutical sciences
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ABSTRACT
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The aim of this study was to determine whether alpha2-adrenoceptors or imidazoline I1-receptors are responsible for the central sympathoinhibition produced by rilmenidine and moxonidine, two clonidine-like antihypertensive drugs.... more
The aim of this study was to determine whether alpha2-adrenoceptors or imidazoline I1-receptors are responsible for the central sympathoinhibition produced by rilmenidine and moxonidine, two clonidine-like antihypertensive drugs. Rilmenidine and moxonidine were compared with the indirectly acting alpha2-adrenoceptor agonist alpha-methyldopa. Three antagonists were used. Yohimbine and SK&F86466 were used as selective alpha2-adrenoceptor antagonists. They were compared with efaroxan which is also an alpha2-adrenoceptor antagonist, but, in addition, possesses affinity for imidazoline I1-receptors. According to some but not all studies, the affinity of efaroxan for I1-receptors is much higher than its affinity for alpha2-adrenoceptors. Drugs were administered into the cisterna cerebellomedullaris of conscious rabbits by a catheter implanted previously under halothane anaesthesia. Rilmenidine (10 microg kg(-1)), moxonidine (0.3 microg kg(-1)) and alpha-methyldopa (0.4 mg kg(-1)) lowered blood pressure and the plasma noradrenaline concentration; the degree of sympathoinhibition produced by the three agonists was very similar. When injected after the agonists, efaroxan (0.1-14 microg kg(-1); cumulative doses), yohimbine (0.4-14 microg kg(-1)) and SK&F86466 (0.4-44 microg kg(-1)) counteracted the effects of the agonists on blood pressure and the plasma noradrenaline concentration. Efaroxan was about tenfold more potent than yohimbine and SK&F86466 at antagonizing the hypotensive effects of alpha-methyldopa. Similarly, efaroxan was two- to tenfold more potent than yohimbine and SK&F86466 against rilmenidine and moxonidine. Finally, efaroxan was about as potent against alpha-methyldopa as against rilmenidine and moxonidine. The results confirm previous observations that selective alpha2-adrenoceptor antagonists are capable of completely antagonizing effects of rilmenidine and moxonidine. The effects of the alpha2-adrenoceptor antagonist with an additional high affinity for imidazoline I1-receptors, efaroxan, can also be explained by blockade of alpha2-adrenoceptors. Efaroxan was more potent against rilmenidine and moxonidine than the selective alpha2-adrenoceptor antagonists. This was probably due to the fact that the affinity of efaroxan for alpha2-adrenoceptors is higher than the affinity of yohimbine and SK&F86466, since efaroxan was also the most potent of the three antagonists against the indirectly acting alpha2adrenoceptor agonist alpha-methyldopa. The observation that efaroxan was equally potent against rilmenidine and moxonidine and against alpha-methyldopa suggests that the same receptors were involved in the effects of the three agonists, alpha2-adrenoceptors; this observation is not compatible with the high I1/alpha2 selectivity of efaroxan and the hypothesis that rilmenidine and moxonidine activate I1-receptors, whereas alpha-methyldopa activates alpha2-adrenoceptors. Thus, the data do not indicate involvement of I1 imidazoline receptors in the central sympathoinhibition elicited by rilmenidine and moxonidine in rabbits. It is likely that rilmenidine and moxonidine produce sympathoinhibition by activating the same receptors which are activated by the indirectly acting catecholamine alpha-methyldopa, namely alpha2-adrenoceptors.
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Alpha(2)-adrenoceptors mediate diverse functions of the sympathetic system and are targets for the treatment of cardiovascular disease, depression, pain, glaucoma, and sympathetic activation during opioid withdrawal. To determine whether... more
Alpha(2)-adrenoceptors mediate diverse functions of the sympathetic system and are targets for the treatment of cardiovascular disease, depression, pain, glaucoma, and sympathetic activation during opioid withdrawal. To determine whether alpha(2)-adrenoceptors on adrenergic neurons or alpha(2)-adrenoceptors on nonadrenergic neurons mediate the physiological and pharmacological responses of alpha(2)-agonists, we used the dopamine beta-hydroxylase (Dbh) promoter to drive expression of alpha(2A)-adrenoceptors exclusively in noradrenergic and adrenergic cells of transgenic mice. Dbh-alpha(2A) transgenic mice were crossed with double knockout mice lacking both alpha(2A)- and alpha(2C)-receptors to generate lines with selective expression of alpha(2A)-autoreceptors in adrenergic cells. These mice were subjected to a comprehensive phenotype analysis and compared with wild-type mice, which express alpha(2A)- and alpha(2C)-receptors in both adrenergic and nonadrenergic cells, and alpha(2A)/alpha(2C) double-knockout mice, which do not express these receptors in any cell type. We were surprised to find that only a few functions previously ascribed to alpha(2)-adrenoceptors were mediated by receptors on adrenergic neurons, including feedback inhibition of norepinephrine release from sympathetic nerves and spontaneous locomotor activity. Other agonist effects, including analgesia, hypothermia, sedation, and anesthetic-sparing, were mediated by alpha(2)-receptors in nonadrenergic cells. In dopamine beta-hydroxylase knockout mice lacking norepinephrine, the alpha(2)-agonist medetomidine still induced a loss of the righting reflex, confirming that the sedative effect of alpha(2)-adrenoceptor stimulation is not mediated via autoreceptor-mediated inhibition of norepinephrine release. The present study paves the way for a revision of the current view of the alpha(2)-adrenergic receptors, and it provides important new considerations for future drug development.
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The hypothesis of the present work was that activation of CB1 cannabinoid receptors inhibits GABAergic neurotransmission between basket and Purkinje cells in the cerebellar cortex. The aim was to test this hypothesis under... more
The hypothesis of the present work was that activation of CB1 cannabinoid receptors inhibits GABAergic neurotransmission between basket and Purkinje cells in the cerebellar cortex. The aim was to test this hypothesis under near-physiological conditions. Action potentials of basket cells and spontaneous inhibitory postsynaptic currents (sIPSCs) in synaptically coupled Purkinje cells were recorded simultaneously in rat brain slices. The cannabinoid agonists (R)-(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl) methyl] pyrrolo[1,2,3-de]-1,4-benzoxazinyl]-(1-naphthalenyl)methanone mesylate (WIN 55212-2) and (-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)-phenyl]-trans-4-(3-hydroxy-propyl)-cyclohexanol (CP55940) decreased the amplitude of sIPSCs occurring simultaneously with basket cell action potentials and lowered the success rate of synaptic transmission. These effects were prevented by the CB1 receptor antagonist N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichloro-phenyl)-4-methyl-3-pyrazole-carboxamide (SR141716). Depolarization of Purkinje cells also led to suppression of neurotransmission; prevention of this suppression by CP55940 and SR141716 indicates that endocannabinoids released from Purkinje cells were involved. WIN 55212-2 lowered the amplitude of autoreceptor currents recorded in basket cells (autoreceptor currents are due to the action of GABA released from axon terminals on GABAA autoreceptors of the same axon terminals); this is novel proof of the presynaptic action of cannabinoids. Autoreceptor current experiments also indicated that endogenous cannabinoids are not released by basket cell axon terminals. A presynaptic action is additionally supported by the observation that WIN 55212-2 lowered the frequency of miniature IPSCs recorded in the presence of tetrodotoxin and the calcium ionophore ionomycin. In conclusion, activation of CB1 receptors by exogenous cannabinoids and by endogenous cannabinoids released by Purkinje cells presynaptically inhibits GABAergic neurotransmission between basket and Purkinje cells. This was demonstrated under near-physiological conditions: transmitter release was elicited by action potentials generated by spontaneously firing intact presynaptic neurons.