agn-192403 and moxonidine

This study shows that in spontaneously hypertensive rats (SHR) of 14-weeks-old, the sympathetically-induced, but not noradrenaline-induced tachycardic response are higher than age-matched Wistar normotensive rats. Furthermore, in SHR the sympathetically-induced tachycardic response was: (1) unaffected by moxonidine (3μg/kgmin); (2) partially inhibited by B-HT 933 (30μg/kgmin), both at the lowest doses; and (3) completely inhibited by the highest doses of B-HT 933 (100μg/kgmin), moxonidine (10μg/kgmin) or agmatine (1000 and 3000μg/kgmin) while the noradrenaline-induced tachycardic responses remained unaffected by the above compounds, except by 3000μg/kgmin agmatine. In SHR, 300μg/kg rauwolscine failed to block the sympatho-inhibition to 100μg/kgmin B-HT 933 or 10μg/kgmin moxonidine, but 1000μg/kg rauwolscine abolished, partially antagonized, and did not modify the sympatho-inhibition to the highest doses of B-HT 933, moxonidine, and agmatine, respectively, 3000μg/kg AGN 192403 or 300μg/kg BU224 given alone had no effect in the moxonidine- or agmatine-induced sympatho-inhibition, and the combination rauwolscine plus AGN 192403 but not plus BU224, abolished the sympatho-inhibition to the highest doses of moxonidine and agmatine. In conclusion, the sympathetically-induced tachycardic responses in SHR are inhibited by moxonidine and agmatine. The inhibition of moxonidine is mainly mediated by prejunctional α

Topics: Agmatine; Animals; Bridged Bicyclo Compounds; Heart; Heart Rate; Hemodynamics; Heptanes; Imidazoles; Male; Norepinephrine; Rats; Rats, Inbred SHR; Rats, Wistar; Sympathetic Nervous System; Yohimbine

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

This study analysed the inhibition produced by the agonists moxonidine (imidazoline I(1) receptors>alpha(2)-adrenoceptors) and agmatine (endogenous ligand of imidazoline I(1)/I(2) receptors), using B-HT 933 (6-ethyl-5,6,7,8-tetrahydro-4H-oxazolo[4,5-d]azepin-2-amine dihydrochloride; alpha(2)-adrenoceptors) for comparison, on the rat cardioaccelerator sympathetic outflow. Male Wistar rats were pithed and prepared to stimulate the cardiac sympathetic outflow or to receive i.v. bolus of exogenous noradrenaline. Sympathetic stimulation or noradrenaline produced, respectively, frequency-dependent and dose-dependent tachycardic responses. I.v. continuous infusions of moxonidine (3 and 10 microg/kg min), agmatine (1000 and 3000 microg/kg min) and B-HT 933 (30 and 100 microg/kg min) inhibited the tachycardic responses to sympathetic stimulation, but not those to noradrenaline. The cardiac sympatho-inhibition by either moxonidine (3 microg/kg min) or B-HT 933 (30 microg/kg min) was not modified by i.v. injections of saline or the antagonists AGN192403 [(+/-)-2-endo-Amino-3-exo-isopropylbicyclo[2.2.1]heptane hydrochloride; 3000microg/kg; imidazoline I(1) receptors] or BU224 (2-(4,5-dihydroimidazol-2-yl)quinoline hydrochloride; 300 microg/kg; imidazoline I(2) receptors) and abolished by rauwolscine (300 microg/kg; alpha(2)-adrenoceptors). At the same doses of these compounds, the sympatho-inhibition to moxonidine (10 microg/kg min) and agmatine (1000 microg/kg min) was: (1) not modified by saline, AGN192403 or BU224; (2) partially blocked by rauwolscine or the combination of rauwolscine plus BU224; and (3) abolished by the combination of rauwolscine plus AGN192403. These results demonstrate that the cardiac sympatho-inhibition to: (1) 3 microg/kg min moxonidine or 30 microg/kg min B-HT 933 involves alpha(2)-adrenoceptors; and (2) 10 microg/kg min moxonidine or 1000 microg/kg min agmatine involves alpha(2)-adrenoceptors and imidazoline I(1) receptors.

Topics: Adrenergic alpha-2 Receptor Agonists; Agmatine; Animals; Azepines; Brain; Bridged Bicyclo Compounds; Electric Stimulation; Heart Rate; Heptanes; Imidazoles; Infusions, Intravenous; Male; Norepinephrine; Rats; Rats, Wistar; Sodium Chloride; Substrate Specificity; Sympathetic Nervous System; Tachycardia; Time Factors; Yohimbine

Imidazoline I1-receptors are present in the heart and may be involved in atrial natriuretic peptide (ANP) release. The following studies investigated whether moxonidine (an antihypertensive imidazoline I1-receptor and alpha2-adrenoceptor agonist) acts directly on the heart to stimulate ANP release, and to characterize the receptor type involved in this action. Perfusion of rat (200-225 g) isolated hearts with moxonidine (10(-6) and 10(-5) M), for 30 min, resulted in ANP release (83+/-29 and 277+/-70 ng/30 min, above basal, respectively), significantly (P<0.01) different from perfusion with buffer (-6+/-31 ng/30 min). ANP release stimulated by moxonidine (10(-6) M) was inhibited by co-perfusion with the antagonists, AGN192403 (imidazoline I1-receptor), phenoxybenzamine (alpha2>alpha1-adrenoceptors), and prazosin (alpha1>alpha2-adrenoceptors), but increased by rauwolscine (alpha2-adrenoceptors). Perfusion with 10(-5) M brimonidine (full alpha2-adrenoceptor agonist) inhibited moxonidine-stimulated ANP release. Similarly, moxonidine (10(-6) M) tended to reduce coronary flow, but significantly increased coronary flow in the presence of brimonidine, which was vasoconstrictive when perfused alone. Coronary flow was reduced by 10(-5) M each, brimonidine>clonidine>moxonidine; while similar bradycardia was observed with clonidine and moxonidine, but not with brimonidine. In conclusion, these results argue in favor of moxonidine acting primarily on imidazoline I1-receptors to release ANP, with both alpha2-adrenoceptor and imidazoline I1-receptors exerting inhibitory inter-relation. In contrast, the coronary vasodilatory effect of moxonidine requires full activation of alpha2-adrenoceptor. The sympatholytic and ANP-releasing effects of moxonidine appear to be mediated by cardiac imidazoline receptors that may be differentially localized. Most importantly, moxonidine can stimulate ANP release from the heart without contribution of the central nervous system.

Topics: Adrenergic alpha-2 Receptor Agonists; Adrenergic alpha-2 Receptor Antagonists; Adrenergic alpha-Agonists; Adrenergic alpha-Antagonists; Animals; Antihypertensive Agents; Atrial Natriuretic Factor; Bridged Bicyclo Compounds; Brimonidine Tartrate; Clonidine; Coronary Circulation; Drug Synergism; Female; Heart; Heart Rate; Heptanes; Imidazoles; Imidazoline Receptors; In Vitro Techniques; Myocardium; Perfusion; Phenoxybenzamine; Prazosin; Quinoxalines; Rats; Rats, Sprague-Dawley; Receptors, Adrenergic, alpha-2; Receptors, Drug; 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

Moxonidine is an antihypertensive drug that lowers sympathetic vasomotor tone by stimulating either alpha2-adrenergic (alpha2-AR) or imidazoline I1 receptors within the rostral ventrolateral medulla (RVL). In this study, we investigated the effects of moxonidine (10 microM) on RVL neurons in brain stem slices of neonatal rats. We recorded mainly from retrogradely labeled RVL bulbospinal neurons (putative presympathetic neurons) except for some extracellular recordings. Prazosin was used to block alpha1-adrenoceptors. Moxonidine inhibited the extracellularly recorded discharges of all spontaneously active RVL neurons tested (bulbospinal and unidentified). This effect was reversed or blocked by the selective alpha2-AR antagonist SKF 86466 (10 microM). In contrast, the I1 imidazoline ligand AGN 192403 (10 microM) had no effect on the spontaneous activity. In whole cell recordings (holding potential -70 mV), moxonidine produced a small and variable outward current (mean 7 pA). This current was observed in both tyrosine hydroxylase-immunoreactive and other bulbospinal neurons and was blocked by SKF 86466. Excitatory postsynaptic currents (EPSCs) evoked by focal electrical stimulation were isolated by incubation with gabazine and strychnine, and inhibitory postsynaptic currents (IPSCs) were isolated with 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). Moxonidine reduced the amplitude of the evoked EPSCs (EC(50) = 1 microM; 53% inhibition at 10 microM) but not their decay time constant (5.6 ms). The effect of moxonidine on EPSCs persisted in barium (300 microM) and was reduced approximately 80% by SKF 86466. Moxonidine also reduced the amplitude of evoked IPSCs by 63%. In conclusion, moxonidine inhibits putative RVL presympathetic neurons both presynaptically and postsynaptically. All observed effects in the present study are consistent with an alpha2-AR agonist activity of moxonidine.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Adrenergic alpha-2 Receptor Agonists; Adrenergic alpha-Agonists; Adrenergic alpha-Antagonists; Animals; Antihypertensive Agents; Baclofen; Barium; Benzazepines; Bridged Bicyclo Compounds; Excitatory Amino Acid Antagonists; Excitatory Postsynaptic Potentials; GABA Agonists; GABA Antagonists; Glycine Agents; Heptanes; Imidazoles; Imidazoline Receptors; In Vitro Techniques; Kinetics; Ligands; Medulla Oblongata; Neurons; Pyridazines; Rats; Rats, Sprague-Dawley; Receptors, Drug; Strychnine