agn-192403 and efaroxan

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

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