benzofurans and moxonidine

Locomotor sensitization to repeated ethanol (EtOH) administration is proposed to play a role in early and recurring steps of addiction. The present study was designed to examine the effect of agmatine on EtOH-induced locomotor sensitization in mice.. Mice received daily single intraperitoneal injection of EtOH (2.5 g/kg, 20 v/v) for 7 consecutive days. Following a 3-day EtOH-free phase, the mice were challenged with EtOH on day 11 with a single injection of EtOH. Agmatine (10 to 40 μg/mouse), endogenous agmatine enhancers (l-arginine [80 μg/mouse], arcaine [50 μg/mouse], aminoguanidine [25 μg/mouse]), and imidazoline receptor agonist/antagonists were injected (intracerebroventricular [i.c.v.]) either daily before the injection of EtOH during the 7-day development phase or on days 8, 9, and 10 (EtOH-free phase). The horizontal locomotor activity was determined on days 1, 3, 5, 7, and 11.. Agmatine (20 to 40 μg/mouse) administration for 7 days (development phase) significantly attenuated the locomotor sensitization response of EtOH challenge on day 11. Further, the agmatine administered only during EtOH-free period (days 8, 9, and 10) also inhibited the enhanced locomotor activity on the 11th day to EtOH challenge as compared to control mice indicating blockade of expression of sensitization. Daily treatment (i.c.v.) with endogenous agmatine enhancers like l-arginine (80 μg/mouse) or arcaine (50 μg/mouse) and aminoguanidine (25 μg/mouse) restrained the development as well as expression of sensitization to EtOH. Imidazoline I. Inhibition of EtOH sensitization by agmatine is mediated through imidazoline receptors and project agmatine and imidazoline agents in the pharmacotherapy of alcohol addiction.

Topics: Agmatine; Animals; Arginine; Benzofurans; Biguanides; Central Nervous System Sensitization; Dose-Response Relationship, Drug; Drug Interactions; Ethanol; Guanidines; Idazoxan; Imidazoles; Imidazoline Receptors; Infusions, Intraventricular; Male; Mice; Microinjections; Motor Activity

The dorsal diencephalic conduction system connects limbic forebrain structures to monaminergic mesencephalic nuclei via a distinct relay station, the habenular complexes. Both habenular nuclei, the lateral as well as the medial nucleus, are considered to play a prominent role in mental disorders like major depression. Herein, we investigate the effect of the polyamine agmatine on the electrical activity of neurons within the medial habenula in rat. We present evidence that agmatine strongly decreases spontaneous action potential firing of medial habenular neurons by activating I1-type imidazoline receptors. Additionally, we compare the expression patterns of agmatinase, an enzyme capable of inactivating agmatine, in rat and human habenula. In the medial habenula of both species, agmatinase is similarly distributed and observed in neurons and, in particular, in distinct neuropil areas. The putative relevance of these findings in the context of depression is discussed. It is concluded that increased activity of the agmatinergic system in the medial habenula may strengthen midbrain dopaminergic activity. Consequently, the habenular-interpeduncular axis may be dysregulated in patients with major depression.

Topics: Action Potentials; Agmatine; Animals; Benzofurans; Depression; Female; Habenula; Humans; Idazoxan; Imidazoles; Imidazoline Receptors; Male; Middle Aged; Neurons; Rats, Wistar; Ureohydrolases

The purpose of this work was a comparative analysis of the brain adrenergic and imidazoline receptors activation effects in laboratory rats with normal and elevated activity of the sympathetic nervous system. The experiments were carried out on male rats of Wistar and Wistar-Kyoto lines and spontaneously hypertensive (SHR) line. In freely moving rats the mean arterial pressure, heart beat-to-beat interval and cardiochronotropic component of baroreceptor reflex were recorded and analyzed at rest and emotional stress, caused by a conditioned signal. Agonist of imidazoline and adrenergic receptor clonidine, a primary agonist of imidazoline receptor moxonidine, selective alpha 2-adrenoreceptor blocker yohimbine and blocker of imidazoline and alpha - adrenergic receptor efaroksan were used for neurochemical analysis of adrenergic and imidazoline systems role in mechanisms of regulation of blood circulation. Our data have shown, that if adrenergic systems of the brain provide its participation in the long-term regulation of blood pressure, stimulation of imidazoline receptors activate the central link of baroreceptor reflex arc at the level of the medulla oblongata and also strengthening the processes of its suprabulbar modulation, caused by emotional stress.

Topics: Adrenergic alpha-Agonists; Adrenergic alpha-Antagonists; Animals; Baroreflex; Benzofurans; Blood Pressure; Brain; Clonidine; Heart Rate; Imidazoles; Imidazoline Receptors; Male; Rats; Rats, Inbred SHR; Rats, Wistar; Sympathetic Nervous System; Yohimbine

Centrally acting antihypertensive action of moxonidine is a result of activation of Imidazoline-1 receptor (I1R) in the rostral ventrolateral medulla (RVLM). Hypertension shows an increase in reactive oxygen species (ROS) in the RVLM. The present objective was to determine the phosphoinositide-3 kinase (PI3K) signaling pathway involved in the effect of moxonidine on ROS generation in the RVLM of spontaneously hypertensive rat (SHR).. Wistar-Kyoto rats and SHR received intracisternal infusion (2 weeks) of tested agents which were subjected to subsequent experiments. In-situ ROS in the RVLM was evaluated by the oxidative fluorescence dye. Western blot and PCR analysis were performed to detect the expression levels of PI3K signaling pathway. Lentivirus was injected bilaterally into the RVLM for silencing PI3K signaling.. ROS production in the RVLM was dose-dependently reduced in SHRs treated with infusion of moxonidine (20 nmol/day), which was prevented by the I1R antagonist efaroxan but not by the α2-adrenoceptor antagonist yohimbine. Moxonidine pretreatment significantly blunted cardiovascular sensitivity to injection of tempol (5 nmol) or angiotensin II (10 pmol) into the RVLM in SHR. Expression levels of PI3K/Akt, nuclear factor kappa-B (NFκB), NADPHase (NOX4), and angiotensin type I receptor (AT1R) in the RVLM were markedly decreased in SHR treated with moxonidine. Infection of lentivirus containing PI3K shRNA in the RVLM effectively prevented effects of moxonidine on cardiovascular activity and expression levels of Akt, NFκB, NOX4, and AT1R.. The centrally antihypertensive drug moxonidine decreases ROS production in the RVLM through inactivation of the PI3K/Akt signaling pathway in hypertension.

Topics: Animals; Antihypertensive Agents; Benzofurans; Disease Models, Animal; Hypertension; Imidazoles; Male; Medulla Oblongata; Phosphatidylinositol 3-Kinases; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Reactive Oxygen Species; Signal Transduction

This in vivo study assessed the potential of the imidazoline receptor (IR) ligands moxonidine (selective I1-IR), BU224 (selective I2-IR) and LSL61122 (mixed I1/I2-IR) to dampen excitotoxic signalling induced by kainic acid (KA; 45 mg/kg) in the mouse brain (hippocampus and cerebral cortex). KA triggered a strong behavioural syndrome (seizures; maximal at 60-90 minutes) and sustained stimulation (at 72 hours with otherwise normal mouse behaviour) of pro-apoptotic c-Jun-N-terminal kinases (JNK) and calpain with increased cleavage of p35 into neurotoxic p25 (cyclin-dependent kinase 5 [Cdk5] activators) in mouse hippocampus. Pretreatment (five days) with LSL61122 (10 mg/kg), but not moxonidine (1 mg/kg) or BU224 (20 mg/kg), attenuated the KA-induced behavioural syndrome, and all three IR ligands inhibited JNK and calpain activation, as well as p35/p25 cleavage after KA in the hippocampus (effects also observed after acute IR drug treatments). Efaroxan (I1-IR, 10 mg/kg) and idazoxan (I2-IR, 10 mg/kg), postulated IR antagonists, did not antagonise the effects of moxonidine and LSL61122 on KA targets (these IR ligands showed agonistic properties inhibiting pro-apoptotic JNK). Brain subcellular preparations revealed reduced synaptosomal postsynaptic density-95 protein contents (a mediator of JNK activation) and indicated increased p35/Cdk5 complexes (with pro-survival functions) after treatment with moxonidine, BU224 and LSL61122. These results showed that I1- and I2-IR ligands (moxonidine and BU224), and especially the mixed I1/I2-IR ligand LSL61122, are partly neuroprotective against KA-induced excitotoxic signalling. These findings suggest a therapeutic potential of IR drugs in disorders associated with glutamate-mediated neurodegeneration.

Topics: Animals; Benzofurans; Cerebral Cortex; Cyclin-Dependent Kinase 5; Glutamic Acid; Hippocampus; Idazoxan; Imidazoles; Imidazoline Receptors; Kainic Acid; Ligands; Male; Mice; Neurodegenerative Diseases; Neuroprotective Agents; Styrenes; Time Factors

Various imidazoline receptor (IR) proteins have been proposed to mediate the effects of selective I1- and I2-IR drugs. However, the association of these IR-binding proteins with classic I1- and I2-radioligand binding sites remains somewhat controversial. In this study, three IR antibodies (anti-NISCH and anti-nischarin for I1-IRs; and anti-IRBP for I1/I2-IRs) were used to immunodetect, characterize and compare IR protein patterns in brain (mouse and human; total homogenate, subcellular fractionation, grey and white matter) and some cell systems (neurones, astrocytes, human platelets). Various immunoreactive IRs (specific molecular weight bands coincidently detected with the different antibodies) were related to I1-IR (167 kDa, 105/115 kDa and 85 kDa proteins) or I2-IR (66 kDa, 45 kDa and 30 kDa proteins) types. The biochemical characterization of cortical 167 kDa protein, localized in the membrane/cytosol but not in the nucleus, indicated that this I1-IR also forms part of higher order nischarin-related complexes. The contents of I1-IR (167 kDa, 105/115 kDa, and 85 kDa) proteins in mouse brain cortex were upregulated by treatment with I1-drugs (moxonidine, efaroxan) but not with I2-drugs (BU-224, LSL 61122). Conversely, the contents of I2-IR (66 kDa, 45 kDa and 30 kDa) proteins in mouse brain cortex were modulated by treatment with I2-drugs (decreases after BU-224 and LSL 61122, and increases after idazoxan) but not with I1-drugs (with the exception of moxonidine). These findings further indicate that brain immunoreactive IR proteins exist in multiple forms that can be grouped in the already known I1- and I2-IR types, which are expressed both in neurones and astrocytes.

Topics: Adult; Animals; Antibodies; Benzofurans; Binding Sites; Brain; Cell Membrane; Cytosol; Female; Humans; Idazoxan; Imidazoles; Imidazoline Receptors; Imidazolines; Male; Mice; Styrenes; Up-Regulation

Although bupropion has been widely used in the treatment of depression, the precise mechanism of its therapeutic actions is not fully understood. The present study investigated the role of agmatine in an antidepressant like effect of bupropion in mouse forced swim test. The antidepressant like effect of bupropion was potentiated by pretreatment with agmatine (10-20mg/kg, ip) and by the drugs known to increase endogenous agmatine levels in brain viz., l-arginine (40 μg/mouse, icv), an agmatine biosynthetic precursor, ornithine decarboxylase inhibitor, dl-α-difluoromethyl ornithine hydrochloride, DFMO (12.5 μg/mouse, icv), diamine oxidase inhibitor, aminoguanidine (6.5 μg/mouse, icv) and agmatinase inhibitor, arcaine (50 μg/mouse, icv) as well as imidazoline I1 receptor agonists, moxonidine (0.25mg/kg, ip) and clonidine (0.015 mg/kg, ip) and imidazoline I2 receptor agonist, 2-(2-benzofuranyl)-2-imidazoline hydrochloride, 2-BFI (5mg/kg, ip). Conversely, prior administration of I1 receptor antagonist, efaroxan (1mg/kg, ip) and I2 receptor antagonist, idazoxan (0.25mg/kg, ip) blocked the antidepressant like effect of bupropion and its synergistic combination with agmatine. These results demonstrate involvement of agmatine in the antidepressant like effect of bupropion and suggest agmatine and imidazoline receptors as a potential therapeutic target for the treatment of depressive disorders.

Topics: Agmatine; Animals; Antidepressive Agents; Arginine; Benzofurans; Biguanides; Bupropion; Clonidine; Dose-Response Relationship, Drug; Drug Interactions; Eflornithine; Guanidines; Idazoxan; Imidazoles; Immobility Response, Tonic; Injections, Intraventricular; Male; Mice; Motor Activity

Enhancement of renal sympathetic nerve activity during renal ischemia and norepinephrine overflow from the kidney after reperfusion play important roles in the development of ischemic acute kidney injury. Recently, we have found that moxonidine, an α2/imidazoline Ι1-receptor agonist, has preventive effects on ischemic acute kidney injury by suppressing the excitation of renal sympathetic nervous system after reperfusion. In the present study, to clarify the renoprotective mechanisms of moxonidine (360 nmol/kg, i.v.) against ischemic acute kidney injury, we investigated the effect of intravenous (i.v.) and intracerebroventricular (i.c.v.) injection of efaroxan, an α2/Ι1 receptor antagonist, on the moxonidine-exhibited actions. Ischemic acute kidney injury was induced by clamping the left renal artery and vein for 45 min followed by reperfusion, 2 weeks after contralateral nephrectomy. The suppressive effect of moxonidine on enhanced renal sympathetic nerve activity during renal ischemia was not observed in the rat treated with either i.v. (360 nmol/kg) or i.c.v. (36 nmol/kg) of efaroxan. Furthermore, i.v. injection of efaroxan eliminated the preventive effect of moxonidine on ischemia/reperfusion-induced kidney injury and norepinephrine overflow, and i.c.v. injection of efaroxan did not completely inhibit the moxonidine's effects. These results indicate that moxonidine prevents the ischemic kidney injury by sympathoinhibitory effect probably via α2/Ι1 receptors in central nervous system and by suppressing the norepinephrine overflow through α2/Ι1 receptors on sympathetic nerve endings.

Topics: Acute Kidney Injury; Animals; Benzofurans; Cytoprotection; Imidazoles; Imidazoline Receptors; Kidney; Male; Norepinephrine; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Sympathetic Nervous System; Veins

The group of imidazoline-1 receptors (I(1)-IR) agonists encompasses drugs are currently used in treatment of high blood pressure and hyperglycemia. The I(1)-IR protein structures have not been determined yet, but Nischarin protein that binds numerous imidazoline ligands inducing initiation of various cell-signaling cascades, including apoptosis, is identified as strong I(1)-IR candidate. In this study we examined apoptotic activity of rilmenidine (potent I(1)-IR agonist), moxonidine (moderate I(1)-IR agonist), and efaroxan (I(1)-IR partial agonist) on cancer cell line (K562) expressing Nischarin. The Nischarine domains mapping was performed by use of the Informational Spectrum Method (ISM). The 3D-Quantitative Structure-Activity Relationship (3D-QSAR) and virtual docking studies of 29 I(1)-IR ligands (agonists, partial agonists, and antagonists) were carried out on I(1)-IR receptors binding affinities. The 3D-QSAR study defined 3D-pharmacophore models for I(1)-IR agonistic and I(1)-IR antagonistic activity and created regression model for prediction of I(1)-IR activity of novel compounds. The 3D-QSAR models were applied for design and evaluation of novel I(1)-IR agonists and I(1)-IR antagonists. The most promising I(1)-IR ligands with enhanced activities than parent compounds were proposed for synthesis. The results of 3D-QSAR, ISM, and virtual docking studies were in perfect agreement and allowed precise definition of binding mode of I(1)-IR agonists (Arg 758, Arg 866, Val 981, and Glu 1057) and significantly different binding modes of I(1)-IR antagonists or partial I(1)-IR agonists. The performed theoretical study provides reliable system for evaluation of I(1)-IR agonistic and I(1)-IR antagonistic activity of novel I(1)-IR ligands, as drug candidates with anticancer activities.

Topics: Antineoplastic Agents; Apoptosis; Benzofurans; Cell Proliferation; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Imidazoles; Imidazoline Receptors; K562 Cells; Ligands; Models, Molecular; Molecular Docking Simulation; Oxazoles; Quantitative Structure-Activity Relationship; Rilmenidine; Tumor Cells, Cultured

The purpose of this study is to assess the change of uveoscleral outflow induced by moxonidine and to investigate whether the increase of uveoscleral outflow induced by moxonidine is mediated by alpha1, alpha2, or I1 receptors.. 0.05% moxonidine was topically and unilaterally administered in rabbit eyes with or without pretreatment of prazosin, yohimbine, efaroxan, or AGN 192403, as indicated. We injected fluorescein isothiocyanate-bovine serum albumin (FITC-BSA) into the anterior chamber and observed the fluorescence intensity of the uveoscleral outflow. Finally, the volume of uveoscleral outflow was calculated based on the fluorescence intensities captured.. A bilateral increase of fluorescence intensity was observed along the uveoscleral outflow pathway following moxonidine administration, especially in the ciliary body and supraciliochoroidal space. Pretreatment with prazosin further enhanced the bilateral increase of fluorescence intensity at between 2 and 4 hours after moxonidine administration. The response of moxonidine was antagonized by either yohimbine, an alpha2 receptor antagonist, or efaroxan, an I1/alpha2 receptor antagonist. The antagonizing effect of yohimbine was more potent than that of efaroxan. The moxonidne-induced response was not antagonized by AGN 192403, an I1 receptor antagonist. The bilateral volumes of aqueous humor within the uveoscleral pathway increased significantly induced by moxonidine (p < 0.01 versus control). The increased bilateral volumes of uveoscleral outflow were 0.381 +/- 0.073 and 0.376 +/- 0.095 mu l/min, respectively.. These results suggest that topical, unilateral administration of moxonidine causes a bilateral increase of aqueous humor via the uveoscleral outflow pathway. The moxonidine-induced increase of uveoscleral outflow is mediated by alpha2 adrenergic receptors, not by I1 imidazoline receptors.

Topics: Administration, Topical; Adrenergic alpha-Antagonists; Animals; Aqueous Humor; Benzofurans; Bridged Bicyclo Compounds; Drug Synergism; Fluorescein-5-isothiocyanate; Heptanes; Imidazoles; Imidazoline Receptors; Prazosin; Rabbits; Receptors, Adrenergic, alpha-2; Sclera; Serum Albumin, Bovine; Uvea; Yohimbine

To determine the effects of the centrally antihypertensive drug moxonidine injected into the rostral ventrolateral medulla (RVLM) on baroreflex function in spontaneously hypertensive rats (SHR).. Baroreflex sensitivity control of renal sympathetic nerve activity (RSNA) and barosensitivity of the RVLM presympathetic neurons were determined following application of different doses of moxonidine within the RVLM.. Three doses (0.05, 0.5, and 5 nmol in 50 nL) of moxonidine injected bilaterally into the RVLM dose-dependently reduced the baseline blood pressure (BP) and RSNA in SHR. At the highest dose (5 nmol) of moxonidine injection, the maximum gain (1.24%+/-0.04%/mmHg) of baroreflex control of RSNA was significantly decreased. However, the lower doses (0.05 and 0.5 nmol) of moxonidine injection into the RVLM significantly enhanced the baroreflex gain (2.34%+/-0.08% and 2.01%+/-0.07%/mmHg). The moxonidine-induced enhancement in baroreflex function was completely prevented by the imidazoline receptor antagonist efaroxan but not by the alpha(2)-adrenoceptor antagonist yohimbine. A total of 48 presympathetic neurons were recorded extracellularly in the RVLM of SHR. Iontophoresis of applied moxonidine (30-60 nA) dose-dependently decreased the discharge of RVLM presympathetic neurons but also significantly increased the barosensitivity of RVLM presympathetic neurons.. These data demonstrate that a low dose of moxonidine within the RVLM has a beneficial effect on improving the baroreflex function in SHR via an imidazoline receptor-dependent mechanism.

Topics: Adrenergic alpha-Antagonists; Animals; Antihypertensive Agents; Baroreflex; Benzofurans; Blood Pressure; Dose-Response Relationship, Drug; Imidazoles; Imidazoline Receptors; Iontophoresis; Kidney; Medulla Oblongata; Microinjections; Neurons; Rats; Rats, Inbred SHR; Sympathetic Nervous System; Synaptic Potentials; Yohimbine

To explore the therapeutic potential of imidazoline I(1) receptor ligands in motor dysfunction related to the basal ganglia, rigidity was induced in mice by intraperitoneal administration of reserpine. The imidazoline I(1) receptor agonists moxonidine and tizanidine reduced rigidity in a dose-dependent manner. Although rigidity was reduced by efaroxan (an imidazoline I(1) receptor and alpha(2)-adrenoceptor antagonist) and idazoxan (an imidazoline I(1) and I(2) receptor and alpha(2)-adrenoceptor antagonist), SKF86466 and yohimbine, both of which are alpha(2)-adrenoceptor antagonists with no affinity for imidazoline receptors, also suppressed rigidity, suggesting that activation rather than blockade of imidazoline I(1) receptors contributes to reduction of reserpine-induced muscle rigidity.

Topics: Adrenergic alpha-Agonists; Adrenergic alpha-Antagonists; Animals; Antiparkinson Agents; Benzazepines; Benzofurans; Clonidine; Disease Models, Animal; Dose-Response Relationship, Drug; Electromyography; Idazoxan; Imidazoles; Imidazoline Receptors; Injections, Intraperitoneal; Ligands; Male; Mice; Muscle Rigidity; Muscle, Skeletal; Parkinsonian Disorders; Reserpine; Time Factors; Yohimbine

A partial recovery of locomotor functions has been shown in spinal cord-transected (Tx) cats after regular treadmill training and repeated administration of clonidine, an alpha(2)-adrenoreceptor agonist. However, clonidine has generally failed to show prolocomotor effects in other models (e.g., rat or mudpuppy in vitro-isolated spinal cord preparations). The reasons for this discrepancy remain unclear, but they may suggest condition- or species-specific effects induced by clonidine. This study is aimed at examining both the acute (at 6 or 41 days post-Tx) and chronic effects of repeated (once a week for one month) clonidine administration (0.25-5.0 mg/kg i.p.) on hindlimb movement generation in Tx mice (thoracic segment9/10). Locomotor-like (LM) and nonlocomotor movements (NLM) were assessed both in open-field and treadmill conditions. The results show that clonidine consistently failed, in both conditions, to induce LM and NLM at all time points even though control experiments revealed hindlimb movements steadily induced by 8-hydroxy-2-(di-N-propylamino)-tetralin (8-OH-DPAT), a serotonin receptor agonist. In turn, clonidine acutely suppressed (I(1)-imidazoline receptor-mediated) the frequency of spontaneously occurring LM and NLM but apparently increased spinal excitability over time, because the frequency of spontaneous LM and NLM was significantly greater in clonidine-treated (before an injection) than vehicle-treated animals after repeated administration for a few weeks. The results clearly show that clonidine can not acutely induce hindlimb movements in untrained and otherwise nonstimulated (e.g., no tail or perineal pinching) Tx mice, although repeated administration may progressively facilitate the expression of spontaneous hindlimb movements.

Topics: Adrenergic alpha-2 Receptor Agonists; Adrenergic alpha-2 Receptor Antagonists; Adrenergic alpha-Agonists; Adrenergic alpha-Antagonists; Animals; Benzofurans; Clonidine; Hindlimb; Imidazoles; Imidazoline Receptors; Male; Mice; Mice, Inbred Strains; Movement; Receptors, Adrenergic, alpha-2; Spinal Cord; Spinal Cord Injuries; Yohimbine

This study investigated the involvement of the imidazoline receptors in the antidepressant-like effect of agmatine in the forced swimming test. The antidepressant-like effects of agmatine (10 mg/kg, i.p.) in the forced swimming test was blocked by pretreatment of mice with efaroxan (1 mg/kg, i.p., an imidazoline I1/alpha2-adrenoceptor antagonist), idazoxan (0.06 mg/kg, i.p., an imidazoline I2/alpha2-adrenoceptor antagonist) and antazoline (5 mg/kg, i.p., a ligand with high affinity for the I2 receptor). A subeffective dose of agmatine (0.001 mg/kg, i.p.) produced a synergistic antidepressant-like effect with clonidine (0.06 mg/kg, i.p, an imidazoline I1/alpha2-adrenoceptor agonist), moxonidine (0.5 mg/kg, i.p., an imidazoline I1/alpha2-adrenoceptor agonist), antazoline (1 mg/kg, i.p.) and MK-801 (0.001 mg/kg, i.p., a non-competitive NMDA receptor antagonist), but not with efaroxan (1 mg/kg, i.p.) and idazoxan (0.06 mg/kg, i.p.). Pretreatment of mice with yohimbine (1 mg/kg, i.p., an alpha2-adrenoceptor antagonist) blocked the synergistic antidepressant-like effect of agmatine (0.001 mg/kg, i.p.) with clonidine (0.06 mg/kg, i.p). A subeffective dose of MK-801 (0.001 mg/kg, i.p.) produced a synergistic antidepressant-like effect with antazoline (5 mg/kg, i.p.), but not with efaroxan (1 mg/kg, i.p.) or idazoxan (0.06 mg/kg, i.p.). In conclusion, this study suggests that the anti-immobility effect of agmatine in the forced swimming test is dependent on its interaction with imidazoline I1 and I2 receptors.

Topics: Agmatine; Animals; Antazoline; Antidepressive Agents; Benzofurans; Clonidine; Female; Imidazoles; Imidazoline Receptors; Male; Mice; Receptors, Adrenergic, alpha-2; Receptors, Drug; Receptors, N-Methyl-D-Aspartate; Swimming

Moxonidine is a second-generation centrally acting antihypertensive drug that has a high affinity for I(1)-imidazoline receptors (I(1)R). The caudal ventrolateral medulla (CVLM), an important region involved in cardiovascular activity, contains binding sites for centrally acting drugs. Our study aimed to determine the effects of moxonidine injected into the CVLM on cardiovascular activity in anesthetized rats. Unilateral microinjection of moxonidine (0.4 and 4 nmol) into the CVLM dose-dependently increased blood pressure (BP) by 8+/-2 and 18+/-2 mmHg and renal sympathetic nerve activity (RSNA) by 19+/-3 and 48+/-5% without modifying heart rate. Microinjection of the I(1)R/alpha(2)-adrenoceptor antagonist efaroxan (4 nmol) into the CVLM produced significant decreases in baseline BP and RSNA, but also completely abolished the increases in BP (2+/-1 versus 18+/-2 mmHg, P<0.01) and RSNA (3+/-2 versus 45+/-10%, P<0.01) evoked by subsequent injection of moxonidine (4 nmol). However, prior injection of yohimbine (500 pmol), a selective antagonist of alpha(2)-adrenoceptors, into the CVLM had no significant (P>0.05) effect on the moxonidine-induced increase in BP (18+/-2 versus 17+/-3 mmHg) and RSNA (45+/-10 versus 42+/-7%). The current data suggest that moxonidine injection into the CVLM has an excitatory effect on cardiovascular activity, which is mediated by an I(1)R dependent mechanism.

Topics: Adrenergic alpha-Antagonists; Anesthesia; Animals; Benzofurans; Blood Pressure; Dose-Response Relationship, Drug; Drug Interactions; Heart Rate; Imidazoles; Imidazoline Receptors; Male; Medulla Oblongata; Rats; Rats, Sprague-Dawley; Sympathetic Nervous System; Sympatholytics; Yohimbine

We have previously shown that acute intravenous injections of moxonidine and clonidine increase plasma atrial natriuretic peptide (ANP), a vasodilator, diuretic and natriuretic hormone. We hypothesized that moxonidine stimulates the release of ANP, which would act on its renal receptors to cause diuresis and natriuresis, and these effects may be altered in hypertension. Moxonidine (0, 10, 50, 100 or 150 microg in 300 microl saline) and clonidine (0, 1, 5 or 10 microg in 300 microl saline) injected intravenously in conscious normally hydrated normotensive Sprague-Dawley rats (SD, approximately 200 g) and 12-14-week-old Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR) dose-dependently stimulated diuresis, natriuresis, kaliuresis and cGMP excretion, with these effects being more pronounced during the first hour post-injection. The actions of 5 microg clonidine and 50 microg moxonidine were inhibited by yohimbine, an alpha2-adrenoceptor antagonist, and efaroxan, an imidazoline I1-receptor antagonist. Moxonidine (100 microg) stimulated (P<0.01) diuresis in SHR (0.21+/-0.04 vs 1.16+/-0.06 ml h(-1) 100 g(-1)), SD (0.42+/-0.06 vs 1.56+/-0.19 ml h(-1) 100 g(-1)) and WKY (0.12+/-0.04 vs 1.44+/-0.21 ml h(-1) 100 g(-1)). Moxonidine-stimulated urine output was lower in SHR than in SD and WKY. Moxonidine-stimulated sodium and potassium excretions were lower in SHR than in SD, but not WKY, demonstrating an influence of strain but not of pressure. Pretreatment with the natriuretic peptide antagonist anantin (5 or 10 microg) resulted in dose-dependent inhibition of moxonidine-stimulated urinary actions. Anantin (10 microg) inhibited (P<0.01) urine output to 0.38+/-0.06, 0.12+/-0.01, and 0.16+/-0.04 ml h(-1) 100 g(-1) in SD, WKY, and SHR, respectively. Moxonidine increased (P<0.01) plasma ANP in SD (417+/-58 vs 1021+/-112 pg ml(-1)) and WKY (309+/-59 vs 1433+/-187 pg ml(-1)), and in SHR (853+/-96 vs 1879+/-229 pg ml(-1)). These results demonstrate that natriuretic peptides mediate the urinary actions of moxonidine through natriuretic peptide receptors.

Topics: Animals; Antihypertensive Agents; Benzofurans; Clonidine; Cyclic GMP; Diuresis; Dose-Response Relationship, Drug; Female; Imidazoles; Imidazoline Receptors; Natriuresis; Natriuretic Peptides; Peptides, Cyclic; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Rats, Sprague-Dawley; Receptors, Adrenergic, alpha-2; Receptors, Drug; Yohimbine

We previously reported that imidazoline receptors in the central nervous system are involved in modulation of halothane-epinephrine arrhythmias. These receptors have been subclassified as I1 and I2 subtypes, but it is not known which receptor subtype is involved in halothane-epinephrine-induced arrhythmias. We designed the present study to clarify the involvement of central imidazoline receptor subtype in the modulation of halothane-epinephrine-induced arrhythmias. Rats were anesthetized with halothane and monitored continuously for systemic arterial blood pressure and premature ventricular contractions. The arrhythmogenic dose of epinephrine was defined as the smallest dose that produces three or more premature ventricular contractions within a 15-s period. Intracisternal moxonidine dose-dependently inhibited the epinephrine-induced arrhythmias during halothane anesthesia. Intracisternal efaroxan, a selective I1 antagonist with little affinity for I2 subtype, but not rauwolscine, an alpha2 antagonist without affinity for imidazoline receptors, blocked the antiarrhythmic effect of moxonidine. Intracisternal BU 224 and 2-BFI, selective I2 ligands, also inhibited the epinephrine-induced arrhythmias dose-dependently; however, these effects were abolished by efaroxan. We conclude that central I1, but not I2, receptors play an important role in inhibition of halothane-epinephrine arrhythmia.

Topics: Animals; Arrhythmias, Cardiac; Benzofurans; Blood Pressure; Dose-Response Relationship, Drug; Epinephrine; Halothane; Heart Rate; Imidazoles; Imidazoline Receptors; Male; Rats; Rats, Sprague-Dawley; Receptors, Drug

Imidazoline receptors are divided into I(1) and I(2) subtypes. I(1)-imidazoline receptors are distributed in the heart and are upregulated during hypertension or heart failure. The aim of this study was to define the possible role of I(1)-imidazoline receptors in the regulation of atrial natriuretic peptide (ANP) release in hypertrophied atria. Experiments were performed on isolated, perfused, hypertrophied atria from remnant-kidney hypertensive rats. The relatively selective I(1)-imidazoline receptor agonist moxonidine caused a decrease in pulse pressure. Moxonidine (3, 10, and 30 micromol/l) also caused dose-dependent increases in ANP secretion, but clonidine (an alpha(2)-adrenoceptor agonist) did not. Pretreatment with efaroxan (a selective I(1)-imidazoline receptor antagonist) or rauwolscine (a selective alpha(2)-adrenoceptor antagonist) inhibited the moxonidine-induced increases in ANP secretion and interstitial ANP concentration and decrease in pulse pressure. However, the antagonistic effect of efaroxan on moxonidine-induced ANP secretion was greater than that of rauwolscine. Neither efaroxan nor rauwolscine alone has any significant effects on ANP secretion and pulse pressure. In hypertrophied atria, the moxonidine-induced increase in ANP secretion and decrease in pulse pressure were markedly augmented compared with nonhypertrophied atria, and the relative change in ANP secretion by moxonidine was positively correlated to atrial hypertrophy. The accentuation by moxonidine of ANP secretion was attenuated by efaroxan but not by rauwolscine. These results show that moxonidine increases ANP release through (preferentially) the activation of atrial I(1)-imidazoline receptors and also via different mechanisms from clonidine, and this effect is augmented in hypertrophied atria. Therefore, we suggest that cardiac I(1)-imidazoline receptors play an important role in the regulation of blood pressure.

Topics: Adrenergic alpha-Agonists; Adrenergic alpha-Antagonists; Animals; Antihypertensive Agents; Atrial Function; Atrial Natriuretic Factor; Benzofurans; Blood Pressure; Cardiomegaly; Clonidine; Heart Atria; Hemodynamics; Imidazoles; Imidazoline Receptors; Male; Rats; Rats, Sprague-Dawley; Receptors, Drug; Yohimbine

We studied the ability of moxonidine to interact with alpha2-adrenoceptors and Ii-imidazoline receptors in isolated mouse large intestine. Moxonidine caused contractions of longitudinal muscles in the large intestine, which depended on the dose of this preparation. Pretreatment with yohimbine (alpha2-adrenoceptor antagonist with low affinity for Ii-imidazoline receptors) and efaroxan (Ii-imidazoline receptor antagonist with low affinity for alpha2-adrenoceptors) abolished the effect of moxonidine. Antagonistic activity and relative selectivity of yohimbine and efaroxan suggest that the effects of moxonidine on mouse large intestine are realized via alpha2-adrenoceptors.

Topics: Animals; Benzofurans; Imidazoles; Imidazoline Receptors; In Vitro Techniques; Intestine, Large; Mice; Muscle Contraction; Receptors, Adrenergic, alpha-2; Receptors, Drug; Yohimbine

To determine the involvement of central imidazoline receptors in the cardiovascular actions of the chronically administered antihypertensive agents moxonidine, rilmenidine and clonidine.. In 21 rabbits with implanted fourth-ventricular catheters, we investigated the central effects of three cumulative doses of an I(1)-imidazoline/alpha(2)-adrenoceptor antagonist, efaroxan, and of an alpha(2)-adrenoceptor antagonist, 2-methoxyidazoxan (2-MI), on the changes in blood pressure and heart rate (HR) elicited by chronic subcutaneous administration of moxonidine, rilmenidine and clonidine, after 1 and 3 weeks of treatment. A low, medium and high dose of 2-MI was matched to three doses of efaroxan, such that each produced equal reversal of the hypotension induced by fourth-ventricular alpha-methyldopa and hence produced a similar degree of alpha(2)-adrenoceptor blockade.. Clonidine and moxonidine, at doses of 1 mg/kg per day, and rilmenidine at 5 mg/kg per day, produced sustained reductions in mean arterial pressure of 13 +/- 3, 15 +/- 2 and 13 +/- 2 mmHg, respectively over the 3-week treatment period, but did not alter HR. Central administration of efaroxan on day 9 and day 23 of treatment produced a greater increase in blood pressure than did 2-MI with all three antihypertensive agents. Blood pressure reached levels that were significantly above the original control values. By contrast, the alpha(2)-adrenoceptor antagonist 2-MI only induced a rebound blood pressure effect in clonidine- and to a lesser extent in rilmenidine-treated rabbits. Both efaroxan and 2-MI produced a similar degree of tachycardia in moxonidine-, rilmenidine- and clonidine-treated animals.(2). The greater effect of efaroxan compared to the alpha(2)-adrenoceptor antagonist 2-MI suggests that the hypotension induced by chronic subcutaneous administration of moxonidine, rilmenidine and clonidine is mediated predominantly via an action on central imidazoline receptors. Furthermore, all agents showed a propensity to produce rebound hypertension with imidazoline receptor blockade. However, only clonidine showed a rebound phenomenon when challenged by acute central alpha(2)-adrenoceptor blockade

Topics: Adrenergic alpha-2 Receptor Antagonists; Animals; Antihypertensive Agents; Benzofurans; Blood Pressure; Cardiovascular System; Clonidine; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Fourth Ventricle; Heart Rate; Idazoxan; Imidazoles; Imidazoline Receptors; Injections, Intraventricular; Male; Oxazoles; Rabbits; Receptors, Drug; Rilmenidine

It is known that moxonidine acts as an agonist at presynaptic alpha(2)-adrenoceptors of the postganglionic sympathetic nerve terminals and leads to a reduction in noradrenaline release. In addition, it is conceivable that I(1)-binding sites located in other regions of the pre- and postganglionic sympathetic neurons are involved in this effect. Our aim was to investigate whether and to what extent activation of the I(1)-binding sites contributes to the moxonidine-induced inhibition of noradrenaline release. Noradrenaline release was induced in pithed spontaneously hypertensive rats (pretreated with phenoxybenzamine/desipramine at 10/0.5 mg/kg) by stimulation of sympathetic overflow from the spinal cord. Noradrenaline overflow was reduced using moxonidine (0.18, 0.6, and 1.8 mg/kg) by 39.4, 70.4, or 78.7%, respectively, even when all alpha(1)-/alpha(2)-adrenoceptors were blocked effectively by phenoxybenzamine. In contrast, the I(1)-antagonist efaroxan (0.1, 1, and 3 mg/kg) increased noradrenaline overflow from 453 (control) to 1710, 1999, or 2754 pg/ml, suggesting an autoreceptor-like function of I(1)-binding sites. In consequence, moxonidine (0.18, 0.6, and 1.8 mg/kg) reduced the increase in noradrenaline overflow in efaroxan-treated animals (1 mg/kg) by 22.7, 41.7, and 50.5%, respectively. Agmatine (6 and 60 mg/kg), an endogenous agonist at I(1)-binding sites, reduced noradrenaline overflow (-36 or 53%), even under alpha(2)-adrenoceptor blockade. When 2-endo-amino-3-exo-isopropylbicyclo[2.2.1]heptane (AGN192403) (10 mg/kg) was injected, a selective blocker of I(1)-binding sites, noradrenaline overflow was not influenced by agmatine. It is concluded that moxonidine reduces noradrenaline overflow by acting at I(1)-binding sites in addition to its agonistic property at alpha(2)-adrenoceptors. The exact location of the I(1)-binding sites on the pre- or postsynaptic sympathetic neurons is unknown, but the location in the pre- or postsynaptic membrane of the sympathetic ganglion is the most plausible explanation.

Topics: Adrenergic alpha-Antagonists; Agmatine; Animals; Antihypertensive Agents; Benzofurans; Binding Sites; Blood Pressure; Disease Models, Animal; Heart Rate; Idazoxan; Imidazoles; Male; Norepinephrine; Phenoxybenzamine; Rats; Rats, Inbred SHR; Receptors, Adrenergic, alpha-2

Hypertension is commonly accompanied by obesity, hyperlipidemia, and insulin resistance in humans, a cluster of abnormalities known as metabolic syndrome X. With the notable exception of inhibitors of the renin-angiotensin system, which have mildly beneficial effects on insulin resistance, most antihypertensive agents worsen one or more components of metabolic syndrome X. Second-generation centrally acting antihypertensive agents such as rilmenidine and moxonidine have mixed effects on components of metabolic syndrome X, which might reflect in part actions on two different receptors: I(1)-imidazoline and alpha(2)-adrenergic. Using a rat model of metabolic syndrome X, we sought to separate the influence of these two receptors on glucose and lipid metabolism by using selective antagonists. Rilmenidine and moxonidine acutely raised glucose and lowered insulin, thereby further worsening glucose tolerance. These effects were entirely mediated by alpha(2)-adrenergic receptors. Rilmenidine and moxonidine also lowered glucagon, an effect that was mediated solely by I(1)-imidazoline receptors since it was potentiated by alpha(2)-blockade, but eliminated in the presence of I(1)-antagonists. Lowering of triglyceride and cholesterol levels followed the same pattern as glucagon, implicating I(1)-imidazoline receptors in lipid-lowering actions. Chronic treatment with moxonidine reproduced the beneficial effects on glucagon and lipids while the acute hyperglycemic response did not persist. Thus, alpha(2)-adrenergic receptors mediate an acute deterioration of glucose tolerance, whereas in contrast I(1)-imidazoline receptors appear to mediate the persistent long-term improvements in glucose tolerance. The therapeutic action of I(1)-imidazoline agonists may be primarily mediated through reduced glucagon secretion.

Topics: Adrenergic alpha-Antagonists; Animals; Antihypertensive Agents; Benzofurans; Blood Pressure; Disease Models, Animal; Female; Glucagon; Glucose; Glucose Tolerance Test; Humans; Imidazoles; Imidazoline Receptors; Lipid Metabolism; Male; Metabolic Syndrome; Obesity; Oxazoles; Rats; Rats, Inbred SHR; Receptors, Adrenergic, alpha-2; Receptors, Drug; Rilmenidine; Yohimbine

The function of presynaptic imidazoline-1 receptors (I1-R) in the heart remains unclear. In rat hearts, UK14.304 and moxonidine reduced norepinephrine (NE) release. AGN192403 had no influence on NE, whereas rilmenidine, agmatine, rauwolscine, and efaroxan increased NE. These effects of moxonidine and rilmenidine were not affected by AGN192403 adminstration. Conversely, after pretreatment with UK14.304, only moxonidine displayed a pronounced inhibitory action on NE release (sensitive to AGN192403), indicating a synergistic inhibitory action at I1-R under conditions of a stimulated alpha2-adrenergic autoinhibition.

Topics: Adrenergic alpha-Agonists; Adrenergic alpha-Antagonists; Agmatine; Animals; Benzofurans; Bridged Bicyclo Compounds; Brimonidine Tartrate; Drug Synergism; Heart; Heptanes; Imidazoles; Imidazoline Receptors; Norepinephrine; Oxazoles; Quinoxalines; Rats; Rats, Wistar; Receptors, Adrenergic, alpha-2; Receptors, Drug; Rilmenidine; Sympathetic Nervous System; Sympatholytics; Yohimbine

In pithed spontaneous hypertensive rats, noradrenaline overflow was diminished by moxonidine even when alpha(2)-adrenoceptors were blocked quantitatively using phenoxybenzamine, suggesting an I(1)-receptor-mediated mechanism of noradrenaline release. This hypothesis was confirmed, since the noradrenaline overflow was (1) increased under alpha(2)-adrenoceptors blockade by the mixed I(1)/alpha(2)-antagonists efaroxan or idazoxan, (2) still reduced by moxonidine when both alpha(2)- and I(1)-receptors were blocked, and (3) diminished by agmatine after pretreatment with phenoxybenzamine, but not with AGN192403. An indirect ganglionic I(1)-receptor-mediated mechanism of noradrenaline release is supposed.

Topics: Adrenergic alpha-Antagonists; Agmatine; Animals; Benzofurans; Blood Pressure; Bridged Bicyclo Compounds; Electric Stimulation; Heptanes; Hypertension; Idazoxan; Imidazoles; Imidazoline Receptors; Male; Norepinephrine; Phenoxybenzamine; Rats; Rats, Inbred SHR; Receptors, Adrenergic, alpha-2; Receptors, Drug; Spinal Cord

Imidazoline and guanidiniun-substituted isoindoline compounds have been reported to demonstrate affinity for the putative imidazoline receptors (I(1)) and alpha-2 (alpha(2)) adrenoceptors. The purpose of this study was to determine the relative contribution of I(1) receptors to ocular actions of moxonidine (MOX) and brimonidine (BRIM) by utilizing relatively selective alpha(2) and I(1) antagonists. MOX, an alpha(2)/I(1) receptor agonist, BRIM, a selective alpha( 2) agonist, efaroxan (EFA), an I(1)/alpha(2) antagonist and rauwolscine (RAU), a relatively selective alpha(2) antagonist, were utilized to study alterations in sympathetically evoked contractions of the cat nictitating membrane (CNM). MOX (1-10 microg) suppressed, dose dependently, contractions of the CNM elicited by electrically stimulating the cervical preganglionic sympathetic trunk. The suppressive effect of MOX was antagonized more effectively by EFA (333 microg) than by rauwolscine (333 microg). In contrast, RAU, but not EFA, completely reversed the suppressive effects of BRIM on electrically induced contractions of the CNM. In conclusion, these in vivo data suggest that I(1) receptors are involved in the pre-junctional (neuronal) modulation of contractions in the CNM (Supported by NIH grant EY06338).

Topics: Adrenergic alpha-Agonists; Adrenergic alpha-Antagonists; Animals; Benzofurans; Brimonidine Tartrate; Cats; Dose-Response Relationship, Drug; Electric Stimulation; Imidazoles; Imidazoline Receptors; Nictitating Membrane; Ocular Physiological Phenomena; Platelet Aggregation Inhibitors; Quinoxalines; Receptors, Adrenergic, alpha-2; Receptors, Drug; Yohimbine

The blockade of exocytosis induced by the putative endogenous ligand for imidazoline receptors, agmatine, was studied by using on-line measurement of catecholamine release in bovine adrenal medullary chromaffin cells. Agmatine inhibited the acetylcholine-evoked release of catecholamines in a concentration-dependent manner (IC(50)=366 microM); the K(+)-evoked release of catecholamines was unaffected. Clonidine (100 microM) and moxonidine (100 microM) also inhibited by 75% and 50%, respectively, the acetylcholine-evoked response. In cells voltage-clamped at -80 mV, the intermittent application of acetylcholine pulses elicited whole-cell inward currents (I(ACh)) that were blocked 63% by 1 mM agmatine. The onset of blockade was very fast (tau(on) = 31 ms); the recovery of the current after washout of agmatine also occurred very rapidly (tau(off = 39 ms). Efaroxan (10 microM) did not affect the inhibition of I(ACh) elicited by 1 mM agmatine. I(ACh) was blocked 90% by 100 microM clonidine and 50% by 100 microM moxonidine. The concentration-response curve for acetylcholine to elicit inward currents was shifted to the right in a non-parallel manner by 300 microM agmatine. The blockade of I(ACh) caused by agmatine (100 microM) was similar at various holding potentials, around 50%. When intracellularly applied, agmatine did not block I(ACh). At 1 mM, agmatine blocked I(Na) by 23%, I(Ba) by 14%, I(K(Ca)) by 16%, and I(K(VD)) by 18%. In conclusion, agmatine blocks exocytosis in chromaffin cells by blocking nicotinic acetylcholine receptor currents. In contrast to previous views, these effects seem to be unrelated to imidazoline receptors.

Topics: Acetylcholine; Agmatine; Animals; Benzofurans; Binding Sites; Binding, Competitive; Calcium Channels; Catecholamines; Cattle; Cells, Cultured; Chromaffin Cells; Clonidine; Dose-Response Relationship, Drug; Electric Stimulation; Imidazoles; Imidazoline Receptors; Membrane Potentials; Potassium; Potassium Channels; Receptors, Drug; Receptors, Nicotinic; Sodium Channels

Local injection of 4 nmol moxonidine (unilaterally) into the rostroventrolateral medulla of spontaneously hypertensive rats (SHR-SP) decreased mean blood pressure and heart rate by 24+/-3 and 3+/-4%, respectively. Pretreatment with the I1/alpha2-receptor antagonist efaroxan abolished the moxonidine-induced decrease in mean blood pressure, but had no effect on heart rate. Yohimbine blocked hypotension, delayed bradycardia (8 nmol), or completely inhibited the effects of moxonidine (16 nmol). Our results indicate that both I1-imidazoline receptors and alpha2-adrenoceptors of the rostroventrolateral medulla are involved in the realization of moxonidine-induced changes.

Topics: Adrenergic alpha-2 Receptor Antagonists; Adrenergic alpha-Antagonists; Animals; Antihypertensive Agents; Benzofurans; Blood Pressure; Heart Rate; Hemodynamics; Imidazoles; Imidazoline Receptors; Male; Medulla Oblongata; Rats; Rats, Inbred SHR; Receptors, Adrenergic, alpha-2; Receptors, Drug; Yohimbine

The purpose of this work is to determine the relative contributions of central imidazoline (I(1)) receptors to the ocular hydrodynamic action of moxonidine. Moxonidine (MOX), an alpha(2) and I(1) receptor agonist, and efaroxan (EFA), a relatively selective I(1) antagonist, were utilized to study alterations in intraocular pressure (IOP) and aqueous flow in New Zealand white rabbits subjected to intracerebroventricular (i.c.v.) cannulation and sympathectomy. Intracerebroventricular administration of MOX (0.033, 0.33 and 3.33 microg) to normal rabbits produced dose-dependent, bilateral IOP decreases of 3, 6, and 8 mmHg, respectively. The ocular hypotensive response to MOX was immediate (10 min. post drug), lasted for one hour, and was inhibited by prior administration of efaroxan (3.33 microg i.c.v.). In unilaterally sympathectomized (SX) rabbits, the ocular hypotensive response induced by i.c.v MOX in the denervated eye was attenuated approximately 50%, but the duration of ocular hypotension in the surgically altered eye was longer than that of the normal eye. MOX (0.33 microg i.c.v.), caused a statistically significant decrease (2.24 to 1.59 ml/min.) in aqueous flow in normal eyes. In SX eyes, there was no change in aqueous flow by MOX, suggesting that IOP effect in i.c.v. MOX observed in the SX eye might be mediated by changes in outflow resistance. Sedation was observed in all the rabbits treated with MOX (i.c.v.) and was dose-dependent. These in vivo data support the suggestion that centrally located I(1) receptors modulate the early contralateral response to topically administered MOX and are involved in lowering of IOP and aqueous flow in rabbit. In addition, expression of the full ocular hypotensive effect of centrally applied MOX depends on intact sympathetic innervation. Ocular hypotension induced by MOX in the SX eye may involve an effect on uveoscleral outflow.

Topics: Adrenergic alpha-Antagonists; Animals; Antihypertensive Agents; Aqueous Humor; Benzofurans; Brain; Dose-Response Relationship, Drug; Female; Imidazoles; Imidazoline Receptors; Injections, Intraventricular; Intraocular Pressure; Male; Rabbits; Receptors, Drug; Sympathectomy; Sympathetic Nervous System

Moxonidine is a mixed I(1) imidazoline/alpha(2)moxonidine=morphine. The I(1) imidazoline preferring antagonist efaroxan produced a dose-dependent antagonism of both moxonidine (5.0 mg/kg) and clonidine (0.5 mg/kg). In addition, the alpha(2)-adrenergic receptor antagonist yohimbine produced a dose-related antagonism of moxonidine, but only partially antagonized clonidine. Prazosin failed to block the effects of either moxonidine or clonidine, indicating a lack of involvement of alpha(1) as well as alpha(2B) and alpha(2C) receptors. The present results suggest that alpha(2)-adrenergic receptors play an important role in mediating the effects of moxonidine in producing antinociception in the formalin test. Further, the present results demonstrate that the mechanism of action of moxonidine and clonidine differ in that clonidine, but not moxonidine, produces an antinociceptive effect through a yohimbine-insensitive mechanism in the formalin test.

Topics: Adrenergic alpha-2 Receptor Agonists; Adrenergic alpha-2 Receptor Antagonists; Adrenergic alpha-Agonists; Adrenergic alpha-Antagonists; Analgesics, Non-Narcotic; Animals; Benzofurans; Clonidine; Dose-Response Relationship, Drug; Formaldehyde; Imidazoles; Imidazoline Receptors; Injections, Subcutaneous; Male; Pain; Pain Measurement; Prazosin; Rats; Rats, Sprague-Dawley; Receptors, Drug; Time Factors; Yohimbine

In the mouse medulla oblongata, we characterized binding properties and functional responses of two recognition sites for imidazoline compounds: I(1)-imidazoline and alpha(2)-adrenergic receptors. The mouse medulla expresses a higher density of I(1)-receptors than in the rat, whereas alpha(2)-receptor densities were similar between the two species. In anesthetized, ventilated and paralyzed mice, we tested the hypotensive actions of the I(1)/alpha(2) agonist moxonidine, determined its central site of its actions, and the relative roles of I(1) and alpha(2)-receptors. Experiments were performed in C(57)Bl(6) wild type and alpha(2A)-adrenergic receptor deficient mice. In both types of mice, neuronal activation within the rostral ventrolateral medulla (RVLM) region by glutamate microinjection elicited increases in arterial pressure. Moxonidine (0.5 nmol/site/10 nl) microinjected bilaterally into this vasopressor region decreased arterial pressure by 30% and heart rate by 11% in wild type mice. Efaroxan, the I(1)/alpha(2) antagonist (0.4 nmol) when microinjected into the RVLM elevated blood pressure itself and abolished the action of moxonidine, whereas alpha(2)-blockade with SK&F 86466 had no significant effect on blood pressure and did not attenuate moxonidine's effect. To more definitively test the role of alpha(2)-adrenergic receptors in the action of moxonidine, moxonidine was microinjected into the RVLM of alpha(2A)-adrenergic deficient mice. The decreases in arterial pressure were nearly identical to those of wild type mice, whereas bradycardia was attenuated. Thus, in the mouse moxonidine acts within the RVLM region to lower arterial pressure mainly through the I(1)-imidazoline receptor independent of alpha(2)-adrenergic receptors.

Topics: Adrenergic alpha-2 Receptor Antagonists; Adrenergic alpha-Antagonists; Amygdala; Animals; Antihypertensive Agents; Benzofurans; Binding, Competitive; Blood Pressure; Brain Chemistry; Glutamic Acid; Heart Rate; Hypertension; Imidazoles; Imidazoline Receptors; Injections, Intravenous; Medulla Oblongata; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Microinjections; Pons; Receptors, Adrenergic, alpha-2; Receptors, Drug

Moxonidine, an antihypertensive imidazoline compound, reduces blood pressure by selective activation of central imidazoline I(1)-receptors and inhibition of sympathetic nerve activity and by direct actions on the kidney, with both mechanisms resulting in diuresis and natriuresis. We hypothesized that the hypotensive and renal actions of moxonidine may be mediated by atrial natriuretic peptide (ANP), a cardiac peptide involved in pressure and volume homeostasis through its vasodilatory, diuretic, and natriuretic actions. Renal parameters were measured on an hourly basis over a period of 4 hours in conscious rats that received bolus intravenous injections of moxonidine (1 to 150 microg/300 microL saline). During the first hour, moxonidine dose-dependently stimulated diuresis, natriuresis, kaliuresis, and urinary cGMP, the index of ANP activity. Moxonidine (50 microg) significantly (P<0.001) stimulated urinary volume (0.35+/-0.04 versus 1.05+/-0.09 mL/h per 100 g), sodium (14. 3+/-2.5 versus 51.8+/-6.5 micromol/h per 100 g), potassium (10.5+/-2. 3 versus 32.3+/-3.2 micromol/h per 100 g), and cGMP (325+/-52 versus 744+/-120 pmol/h per 100 g). Pretreatment with a selective imidazoline receptor antagonist, efaroxan, dose-dependently inhibited moxonidine-stimulated renal parameters. Efaroxan (25 microg per rat) significantly inhibited moxonidine-stimulated diuretic and natriuretic effects and urinary cGMP excretion (744+/-120 versus 381+/-137 pmol/h per 100 g, P<0.02). The alpha(2)-adrenoceptor antagonist yohimbine (50 microg per rat) partially yet significantly inhibited moxonidine-stimulated diuresis and natriuresis but not cGMP excretion. Plasma ANP was dose-dependently increased by moxonidine and was inhibited by pretreatment with efaroxan (220.8+/-36.9 versus 100.3+/-31.7 pg/mL, P<0.03) but not by yohimbine. In conclusion, selective in vivo activation of imidazoline receptors by moxonidine is associated with dose-dependent diuresis, natriuresis, and kaliuresis as well as stimulated plasma ANP and urinary cGMP excretion, thus implicating ANP in the renal actions of moxonidine.

Topics: Adrenergic alpha-Antagonists; Animals; Antihypertensive Agents; Atrial Natriuretic Factor; Benzofurans; Cyclic GMP; Diuresis; Dose-Response Relationship, Drug; Female; Imidazoles; Imidazoline Receptors; Injections, Intravenous; Kidney; Natriuresis; Potassium; Rats; Rats, Sprague-Dawley; Receptors, Drug; Yohimbine

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 obser

Topics: Adrenergic alpha-Agonists; Adrenergic alpha-Antagonists; Animals; Antihypertensive Agents; Benzazepines; Benzofurans; Blood Pressure; Dose-Response Relationship, Drug; Drug Interactions; Female; Heart Rate; Imidazoles; Imidazoline Receptors; Male; Methyldopa; Norepinephrine; Oxazoles; Rabbits; Receptors, Adrenergic, alpha-2; Receptors, Drug; Rilmenidine; Sympathetic Nervous System; Yohimbine

alpha2-Adrenergic receptor (AR)-selective compounds produce antihypertensive and antinociceptive effects. Moxonidine alleviates hypertension in multiple species, including humans. This study demonstrates that intrathecally administered moxonidine produces antinociception in mice. Antinociception was detected via the (52.5 degrees C) tail-flick and Substance P (SP) nociceptive tests. Moxonidine was intrathecally administered to ICR, mixed C57BL/6 x 129/Sv [wild type (WT)], or C57BL/6 x 129/Sv mice with dysfunctional alpha2aARs (D79N-alpha2a). The alpha2AR-selective antagonist SK&F 86466 and the mixed I1/alpha2AR-selective antagonist efaroxan were tested for inhibition of moxonidine-induced antinociception. Moxonidine prolonged tail-flick latencies in ICR (ED50 = 0.5 nmol; 0. 3-0.7), WT (0.17 nmol; 0.09-0.32), and D79N-alpha2a (0.32 nmol; 0. 074-1.6) mice. Moxonidine inhibited SP-elicited behavior in ICR (0. 04 nmol; 0.03-0.07), WT (0.4 nmol; 0.3-0.5), and D79N-alpha2a (1.1 nmol; 0.7-1.7) mice. Clonidine produced antinociception in WT but not D79N-alpha2a mice. SK&F 86466 and efaroxan both antagonized moxonidine-induced inhibition of SP-elicited behavior in all mouse lines. SK&F 86466 antagonism of moxonidine-induced antinociception implicates the participation of alpha2ARs. The comparable moxonidine potency between D79N-alpha2a and WT mice suggests that receptors other than alpha2a mediate moxonidine-induced antinociception. Conversely, absence of clonidine efficacy in D79N-alpha2a mice implies that alpha2aAR activation enables clonidine-induced antinociception. When clinically administered, moxonidine induces fewer side effects relative to clonidine; moxonidine-induced antinociception appears to involve a different alpha2AR subtype than clonidine-induced antinociception. Therefore, moxonidine may prove to be an effective treatment for pain with an improved side effect profile.

Topics: Adrenergic alpha-2 Receptor Agonists; Adrenergic alpha-Agonists; Adrenergic alpha-Antagonists; Analgesics, Non-Narcotic; Animals; Autoreceptors; Benzazepines; Benzofurans; Dose-Response Relationship, Drug; Female; Imidazoles; Imidazoline Receptors; Injections, Spinal; Male; Mice; Mice, Inbred C57BL; Mice, Inbred ICR; Nerve Endings; Norepinephrine; Pain Measurement; Receptors, Adrenergic, alpha-2; Receptors, Drug; Spinal Cord

Topics: Adrenergic alpha-Antagonists; Animals; Antihypertensive Agents; Benzofurans; Brain; Clonidine; Dihydroxyphenylalanine; Imidazoles; Male; Quinolines; Rats; Rats, Sprague-Dawley; Serotonin; Serotonin Antagonists; Tryptophan Hydroxylase; Tyrosine 3-Monooxygenase

We examined the role of I1-imidazoline (I1-IR) receptors in control of airway function, by testing the effects of systemic administration of the I1-IR agonist moxonidine on reflex responses of tracheal smooth muscle (TSM) tone to either lung deflation or mechanical stimulation of intrapulmonary rapidly adapting receptors. Experiments were performed in either alpha-chloralose anesthetized or decorticate, paralyzed, and mechanically ventilated beagle dogs. Moxonidine (10-100 micrograms/kg) administered via three different routes (femoral vein, muscular branch of superior thyroid artery, and vertebral artery) attenuated TSM responses to stimulation of airway sensory nerve fibers by two different ways and caused a decrease in arterial pressure and heart rate. These effects were dose dependent and were significantly reversed by efaroxan (an I1-IR and alpha 2-adrenergic blocker) administered via the vertebral artery. Intravertebral efaroxan abolished the hemodynamic effects of moxonidine. Intravenous moxonidine (10-100 micrograms/kg) did not alter airway smooth muscle responses to electrical stimulation of the peripheral vagus nerve. In addition, in vitro moxonidine (1-100 micrograms/ml) had no effect on contractile responses to increasing doses of acetylcholine. These findings indicate that moxonidine may act at a central site to suppress reflex airway constriction, even when given into the systemic circulation. Given the presence of I1-IR sites and alpha 2-adrenergic receptors in brain regions participating in airway reflexes, these receptor classes may be involved in brainstem control of the cholinergic outflow to the airways.

Topics: Acetylcholine; Adrenergic alpha-Antagonists; Animals; Antihypertensive Agents; Benzofurans; Blood Pressure; Decerebrate State; Dogs; Efferent Pathways; Electric Stimulation; Heart Rate; Imidazoles; Imidazoline Receptors; In Vitro Techniques; Lung; Muscle, Smooth; Nerve Fibers; Neurons, Afferent; Receptors, Drug; Reflex; Trachea; Vagus Nerve

To study the effect of moxonidine (Mox) on carotid sinus baroreflex.. By perfusing the carotid sinus in anesthetized rats, the functional parameters of baroreflex were measured. The femoral artery was perfused with constant flow and the change of perfusing pressure was recorded to determine the effect of Mox on vascular tone.. Mox 32 and 100 mumol.L-1 shifted the functional curve of carotid sinus baroreflex to the right and upward, with the reduction in peak slope and in reflex decrease of mean arterial pressure, suggesting that Mox produced an inhibitory effect on baroreflex. The effect of Mox 100 mumol.L-1 on baroreflex was completely blocked by efaroxan 100 mumol.L-1. Mox increased vascular resistance.. Mox inhibits carotid baroreflex via its constrictive action on sinus wall.

Topics: Adrenergic alpha-Antagonists; Animals; Antihypertensive Agents; Baroreflex; Benzofurans; Blood Pressure; Carotid Sinus; Imidazoles; Male; Rats; Vascular Resistance

We examined the role of I1-imidazoline receptors in the control of airway function, by testing the effects of systemic administration of the I1-imidazoline agonist moxonidine on reflex responses of tracheal smooth muscle (TSM) tone to either lung deflation or mechanical stimulation of intrapulmonary rapidly adapting receptors. Experiments were performed in either alpha-chloralose anaesthetized or decorticate, paralyzed and mechanically ventilated beagle dogs. Moxonidine (10-100 microg/kg) administered via three different routes (the femoral vein, muscular branch of superior thyroid artery, and vertebral artery) attenuated TSM responses to stimulation of airway sensory nerve fibers by two different ways, and caused a decrease in arterial pressure and heart rate. These effects were dose-dependent, and were significantly reversed by efaroxan (an I1-imidazoline and alpha2-adrenergic blocker) administered via the vertebral artery. Intravertebral efaroxan abolished the hemodynamic effects of moxonidine. Intravenous moxonidine (10-100 microg/kg) did not alter airway smooth muscle responses to electrical stimulation of the peripheral vagus nerve. In addition, in vitro moxonidine (1-100 microg/ml) had no effect on contractile responses to increasing doses of acetylcholine. These findings indicate that moxonidine may act at a central site to suppress reflex airway constriction, even when given into the systemic circulation. Given the presence of I1-imidazoline sites and alpha2-adrenergic receptors in brain regions participating in airway reflexes, these receptor classes may be involved in brainstem control of the cholinergic outflow to the airways.

Topics: Acetylcholine; Adrenergic alpha-Antagonists; Animals; Antihypertensive Agents; Benzofurans; Blood Pressure; Cholinergic Fibers; Dogs; Electric Stimulation; Heart Rate; Imidazoles; Imidazoline Receptors; Mechanoreceptors; Muscle Contraction; Muscle, Smooth; Nerve Endings; Neurons, Afferent; Receptors, Drug; Trachea; Vagus Nerve; Vasodilator Agents

Rat PC 12 pheochromocytoma cells lack alpha2-adrenergic receptors but express plasma membrane I1-imidazoline receptors. In response to the I1-agonist moxonidine, diglycerides are generated via phosphatidylcholine-selective phospholipase C, and prostaglandin E2 is released. This report characterizes I-receptor-mediated release of arachidonic acid, the precursor to the prostaglandins. PC12 cells were incubated with [3H]arachidonic acid for 24 h and superfused with 0.01% bovine serum albumin in Krebs' physiological buffer at 1 ml/min. Calcium ionophore increased arachidonic acid release only marginally, implying that in PC12 cells arachidonic acid release is not driven by calcium. The I1-agonist moxonidine at concentrations between 10 nM and 1.0 microM rapidly elicited up to two-fold increases in [3H]arachidonic acid release. Guanabenz, a potent alpha2-agonist and I2-ligand, had no effect. The selective I1-antagonist efaroxan blocked the action of moxonidine. The phospholipase A2 inhibitor aristolochic acid had no effect, suggesting that arachidonic acid release may be through an indirect pathway, possibly involving diglycerides. Thus, I1-imidazoline receptors in PC12 cells are coupled to arachidonic acid release through an as yet unknown pathway.

Topics: Adrenergic alpha-Agonists; Adrenergic alpha-Antagonists; Animals; Arachidonic Acid; Aristolochic Acids; Benzofurans; Enzyme Inhibitors; Guanabenz; Imidazoles; Imidazoline Receptors; PC12 Cells; Phenanthrenes; Phospholipases A; Phospholipases A2; Rats; Receptors, Drug

In rabbit's aqueous humor, norepinephrine, epinephrine, dopamine and serotonin were detected simultaneously by a high performance liquid chromatography with electrochemical detection. Furthermore, the changes in catecholamine levels in aqueous humor were evaluated after topical application of moxonidine, an imidazoline1/alpha 2 receptor agonist, in the presence and absence of efaroxan. The level of norepinephrine in aqueous humor was reduced by moxonidine treatment. However, under the same set of conditions, there were no significant changes in the levels of dopamine, epinephrine or serotonin. Pretreatment with efaroxan antagonized moxonidine-induced suppression of norepinephrine levels. In other in vivo experiments, moxonidine caused a decrease in intraocular pressure which was antagonized by pretreatment with efaroxan. In the superior cervical ganglion preparation, norepinephrine release was increased 5-fold by the presence of a high K+ medium. The K(+)-evoked norepinephrine secretion was reduced by 55% by moxonidine. Pretreatment with efaroxan blocked the moxonidine-induced inhibition of norepinephrine release. It is concluded that inhibition of norepinephrine release from the superior cervical ganglion and suppression of aqueous norepinephrine levels contribute to the moxonidine-induced lowering of intraocular pressure. Moreover, the antagonism of moxonidine's in vivo and in vitro effects by efaroxan suggests the involvement of imidazoline1 receptors, but does not preclude activity on alpha 2 adrenoceptors.

Topics: Administration, Topical; Animals; Antihypertensive Agents; Aqueous Humor; Benzofurans; Dopamine; Female; Imidazoles; Intraocular Pressure; Male; Norepinephrine; Ocular Hypotension; Rabbits; Superior Cervical Ganglion

The I1-subtype of imidazoline binding sites has been characterized concerning binding specificity and tissue localization, and several physiological functions have been ascribed to it. However, the signaling pathways coupled to this putative receptor are not known. Pheochromocytoma PC12 cells express I1-imidazoline binding sites in plasma membrane and lack alpha2-adrenergic receptors, which recognize many I1-imidazoline ligands. In this cellular model, diacylglycerol (DAG), a second messenger, is generated in response to the putative I1-imidazoline agonist moxonidine. Using radioflux with [3H]myristate and direct measurements of DAG mass, we showed a rapid and transient peak of DAG in undifferentiated PC12 cells within the first 1 min of agonist exposure. In PC12 cells treated with nerve growth factor to initiate differentiation, DAG accumulation at 15 sec was facilitated, and the increase in DAG mass persisted throughout 10 min of agonist treatment. Efaroxan, a putative I1-antagonist, attenuated the effect of moxonidine on DAG accumulation in nerve growth factor-treated cells, as did D609, an inhibitor of phosphatidylcholine-selective phospholipase C. Phospholipase D did not seem to be involved in generation of DAG in response to I1-receptor activation, nor was there accumulation of phosphatidic acid. These findings suggest coupling of I1-imidazoline receptors to a phospholipase C to generate DAG as a second messenger, a process regulated by neuronal differentiation and possibly participating in the physiological responses to I1-imidazoline receptor activation.

Topics: Animals; Benzofurans; Diglycerides; Dose-Response Relationship, Drug; Imidazoles; Imidazoline Receptors; Nerve Growth Factors; PC12 Cells; Phospholipase D; Rats; Receptors, Drug; Type C Phospholipases

To determine the involvement of central imidazoline receptors in the cardiovascular actions of the antihypertensive agents moxonidine, rilmenidine and clonidine administered systemically.. We determined the relative potency of these drugs with respect to their effects on mean arterial pressure and heart rate by performing cumulative intravenous dose-response relationship studies in six conscious rabbits. In another eight rabbits with implanted fourth-ventricular catheters, we investigated the central effects of three cumulative doses of an l1-imidazoline/ alpha 2-adrenoceptor antagonist, efaroxan, and of an alpha 2-adrenoceptor antagonist, 2-methoxyidazoxan (2-Ml), on the hypotension and bradycardia elicited by a single intravenous dose of the above agents. The doses of antagonists were matched for an equal reversal of the hypotension induced by fourth-ventricular alpha-methyldopa (an alpha 2-adrenoceptor agonist) and hence for similar alpha 2-adrenoceptor blockade.. Moxonidine and rilmenidine were sevenfold and eightfold less potent, respectively, than was clonidine in eliciting hypotension. By comparison, moxonidine and clonidine were more potent than was rilmenidine in producing bradycardia. Efaroxan and 2-Ml reversed the hypotension and bradycardia induced by a single dose of all three agents dose-dependently. However, efaroxan was more effective than was 2-Ml at reversing the effects of rilmenidine and moxonidine. Complete reversal of their hypotensive effect was observed with the highest dose of efaroxan but the highest dose of 2-Ml reversed approximately 50% of that effect. In contrast, the two antagonists were equally effective at reversing the responses to clonidine.. These results suggest that the hypotension and bradycardia induced by intravenous administration of moxonidine and rilmenidine were mediated mainly by actions on central imidazoline receptors whereas clonidine appears to act predominantly on central alpha 2-adrenoceptors.

Topics: Adrenergic alpha-2 Receptor Antagonists; Animals; Antihypertensive Agents; Benzofurans; Blood Pressure; Cardiac Catheterization; Clonidine; Dose-Response Relationship, Drug; Female; Heart Rate; Idazoxan; Imidazoles; Imidazoline Receptors; Injections, Intravenous; Male; Oxazoles; Rabbits; Receptors, Drug; Rilmenidine; Time Factors

I1-imidazoline receptor activation by moxonidine has potent antigastric secretory and gastroprotective effects in rats. We therefore tested whether an imidazoline receptor antagonist, efaroxan, would influence gastric secretion and block the antisecretory and antiulcer effects of moxonidine. When given intracerebroventricularly (i.c.v.), moxonidine inhibited basal acid output in conscious rats to a maximum of 38%. Moxonidine given i.p. also significantly increased gastric adherent mucus levels in rats subjected to cold-restraint stress. Efaroxan alone given i.c.v., did not influence gastric secretion nor did it affect moxonidine's ability to decrease gastric secretion. Similarly, peripherally administered efaroxan did not block the antisecretory effect of moxonidine given i.c.v. However, when both compounds were given i.p., efaroxan pretreatment at all but the lowest doses significantly blocked the antigastric secretory effect of moxonidine. Efaroxan alone (i.p.) did not influence stress-induced gastric mucosal injury or adherent mucus levels. However, pretreatment of rats with efaroxan i.p. significantly blocked the mucus-preserving effect of i.p. moxonidine. These results demonstrate that central (i.c.v.) or peripheral (i.p.) administration of the I1-imidazoline receptor agonist moxonidine is associated with gastroprotection. The ability of i.p. efaroxan to block the effects of i.p. moxonidine but not i.c.v. moxonidine indicates that imidazoline receptors located centrally and peripherally may represent two unique sites associated with gastroprotection.

Topics: Animals; Benzofurans; Dose-Response Relationship, Drug; Gastric Acid; Gastric Mucosa; Imidazoles; Imidazoline Receptors; Male; Rats; Rats, Sprague-Dawley; Receptors, Drug

In order to study the pharmacology of the putative imidazoline receptor involved in stimulation of insulin secretion, the potent and selective imidazoline I1 receptor agonist, moxonidine, was employed. Surprisingly, this agent caused a rapid and complete inhibition of glucose-induced insulin secretion in isolated rat islets of Langerhans. This response was reversible upon removal of the compound but was only partially attenuated under conditions of complete alpha 2 blockade, suggesting that it did not derive entirely from the weak alpha 2-adrenoceptor agonist activity of moxonidine. Furthermore, the response could not be attributed to activation of imidazoline I1 receptors since it was not reproduced by a second potent imidazoline I1 receptor agonist, cimetidine, and could not be alleviated by the imidazoline I1 receptor antagonist efaroxan. The results confirm that the imidazoline receptor involved in control of insulin secretion differs from the I1 subclass and suggest that moxonidine inhibits insulin secretion by a mechanism unrelated to imidazoline I1 receptor agonism.

Topics: Adrenergic alpha-2 Receptor Antagonists; Adrenergic alpha-Antagonists; Animals; Benzofurans; Cimetidine; Depression, Chemical; Female; Glucose; Histamine H2 Antagonists; Imidazoles; Imidazoline Receptors; In Vitro Techniques; Insulin; Insulin Secretion; Islets of Langerhans; Male; Rats; Rats, Wistar; Receptors, Drug

The rostral ventrolateral medulla (RVLM) is the primary region maintaining vasomotor tone, and a site of action for central antihypertensive agents. In vitro [125I]p-iodoclonidine binding studies showed that moxonidine was selective for I1-imidazoline over alpha 2-adrenergic receptors in the RVLM. We identified efaroxan and SK&F 86466 as selective I1- and alpha 2-antagonists, respectively. We tested moxonidine's action within the RVLM of spontaneously hypertensive rats (SHRs) on I1-imidazoline or alpha 2-adrenergic receptors, and determined whether the RVLM mediates the action of systemic moxonidine. SHRs were anesthetized, paralyzed, and ventilated and the RVLM was localized by testing for a pressor response to 2 nmol glutamate. To test whether I1 or alpha 2 mediates hypotensive effects of moxonidine, the I1/alpha 2 antagonist efaroxan (4 nmol) or the alpha 2-blocker SK&F 86466 (10 nmol) was administered 15 min before 4 nmol moxonidine. Efaroxan elevated blood pressure and abolished the action of moxonidine, whereas alpha 2-blockade with SK&F 86466 slightly lowered blood pressure and only partially attenuated moxonidine's effect. The depressor effect of intravenous moxonidine (40 micrograms/kg) was reversed within 10 min by microinjection of 10 nmol efaroxan into the RVLM. Prior bilateral microinjections of efaroxan (10 nmol in 80 nl/site) into the RVLM prevented the hypotensive action of moxonidine given i.v. (40 micrograms/kg). Pharmacokinetic studies showed that at the peak vasodepressor response (8 min post-injection), [3H]moxonidine spread less than 1 mm from the injection site. Moxonidine is a centrally acting antihypertensive with a selective action on I1-imidazoline receptors in RVLM.

Topics: Adrenergic alpha-Antagonists; Affinity Labels; Animals; Antihypertensive Agents; Benzazepines; Benzofurans; Binding, Competitive; Blood Gas Analysis; Blood Pressure; Blood Pressure Determination; Cattle; Clonidine; Disease Models, Animal; Heart Rate; Hypertension; Imidazoles; Imidazoline Receptors; In Vitro Techniques; Medulla Oblongata; Microinjections; Radioligand Assay; Rats; Rats, Inbred SHR; Receptors, Drug

1) Moxonidine (MOX), injected icvt into the anterior lateral ventricle of NZW rabbits, induced bilateral, ocular hypotension (> 7.0 mmHg) that persisted for two hrs. 2) Oxymetazoline (OXY), injected icvt into the anterior lateral ventricle of NZW rabbits, induced bilateral ocular hypotension (> 7.0 mmHg) that peaked at two hrs. 3) Unilateral topical application of OXY induced maximal, bilateral ocular hypotension (> 12 mmHg), at 3 hrs, in both the contralateral and ipsilateral eyes, that persisted more than 12 hrs. 4) The putative imidazoline (I1) antagonist, efaroxan, injected icvt into the anterior lateral ventricle, inhibited significantly the ocular hypotension produced by icvt MOX, icvt OXY, and unilateral topical OXY. 5) Imidazoline (I1) receptors, located in the CNS, play a role in MOX- and OXY-induced ocular hypotension, as suggested by the ability of the putative imidazoline (I1) receptor antagonist efaroxan, to inhibit icvt MOX-, icvt OXY- and topical OXY-induced ocular hypotension.

Topics: Administration, Topical; Animals; Aqueous Humor; Benzofurans; Brain; Catheters, Indwelling; Imidazoles; Imidazoline Receptors; Injections, Intraventricular; Intraocular Pressure; Male; Ocular Hypotension; Oxymetazoline; Pupil; Rabbits; Receptors, Drug