“…When stimulated with agonists possibly acting directly, such as moxonidine or rilmenidine, the I 1 -receptor will mediate a fall in blood pressure and heart rate, thus reflecting centrally induced, peripheral sympathoinhibition [17][18][19]. The neuronal pathway involved is probably very similar to that activated by central ␣ 2 -adrenoceptor agonists such as ␣-methylnoradrenaline (derived from ␣-methyl-DOPA) or clonidine (Fig.…”
Section: Functional Rolementioning
confidence: 99%
“…As mentioned previously, the I 1 -receptors involved in the regulation of blood pressure and as targets of antihypertensive drugs are predominantly located in the RVLM in the brain, in various species [17][18][19]29]. I 1 -receptors have also been identified in various other brain structures (such as the striatum and the pallidum), which are not primarily involved in blood pressure regulation [35].…”
Section: Locationmentioning
confidence: 99%
“…More recently, imidazoline (subtype I 1 ) receptors in the CNS [17,18] have been recognized as a new, potentially interesting target of centrally acting antihypertensives such as moxonidine and rilmenidine. Their mode of action involves the stimulation of central imidazoline (I 1 )-receptors, thus leading to peripheral sympathoinhibition.…”
“…When stimulated with agonists possibly acting directly, such as moxonidine or rilmenidine, the I 1 -receptor will mediate a fall in blood pressure and heart rate, thus reflecting centrally induced, peripheral sympathoinhibition [17][18][19]. The neuronal pathway involved is probably very similar to that activated by central ␣ 2 -adrenoceptor agonists such as ␣-methylnoradrenaline (derived from ␣-methyl-DOPA) or clonidine (Fig.…”
Section: Functional Rolementioning
confidence: 99%
“…As mentioned previously, the I 1 -receptors involved in the regulation of blood pressure and as targets of antihypertensive drugs are predominantly located in the RVLM in the brain, in various species [17][18][19]29]. I 1 -receptors have also been identified in various other brain structures (such as the striatum and the pallidum), which are not primarily involved in blood pressure regulation [35].…”
Section: Locationmentioning
confidence: 99%
“…More recently, imidazoline (subtype I 1 ) receptors in the CNS [17,18] have been recognized as a new, potentially interesting target of centrally acting antihypertensives such as moxonidine and rilmenidine. Their mode of action involves the stimulation of central imidazoline (I 1 )-receptors, thus leading to peripheral sympathoinhibition.…”
“…Non-adrenoceptor well as on a different position of the cell surface in some [H]-idazoxan binding sites (NAIBS) appear to be phar-tissues (Diamant et al, 1992). macologically different from those labelled by [3H]-p-aminoEndogenous depression appears to be associated with inclonidine (Michel & Insel, 1989;Hieble & Ruffolo, 1992; creased brain M2-adrenoceptors ([3H]-clonidine and PH]-UK Ernsberger, 1992) and also differ from 2-adrenoceptors in 14304 binding) and down-regulation of these inhibitory receptors has been involved in the mechanism of action of various antidepressant drugs (Meana et (Barturen et al, 1992 and unpub-'. " Macmillan Press Ltd, 1993 lished results) and in platelet membranes from depressed patients (Piletz et al, 1990;1991).…”
1 The binding of [3H]-idazoxan in the presence of 1O6 M (-)-adrenaline was used to quantitate non-adrenoceptor idazoxan binding sites (NAIBS) in the rat brain after treatment with various psychotropic drugs. 2 Chronic treatment (14 days) with the monoamine oxidase (MAO) inhibitors clorgyline (0.3-10mg kg-', i.p.) and pargyline (10mg kg-', i.p.), but not with Ro 41-1049 (1 mg kg-', i.p.), markedly decreased (30-50%) the density of NAIBS in the cerebral cortex without any apparent change in the affinity of the radioligand.3 Acute (1 day) and/or chronic treatments (14 days) with other psychotropic drugs such as desipramine 7 Together the results indicate that the irreversible binding of clorgyline and pargyline to NAIBS found in vitro does not fully explain the marked decreases in the density of NAIBS found in vivo after the chronic treatments. It is suggested that the down-regulation of NAIBS induced in vivo by clorgyline and pargyline, through a direct or indirect mechanism, may have functional implications.
“…Clonidine and UK-14,304 have been identified as mixed agonists, stimulating CX2-adrenoceptors as well as imidazoline receptors (Bousquet et al, 1984;Ernsberger et al, 1988;Tibirica et al, 1991;Hieble & Ruffolo, 1992). Renal imidazoline receptor stimulation has been shown to increase urine flow rate by increasing osmolar but not free water clearance (Allan et al, 1993).…”
1 Clonidine, an a2-adrenoceptor agonist, will increase urine flow rate in the anaesthetized rat by increasing both free water and osmolar clearance. In the present study, we investigated whether these effects of clonidine were mediated at two sites which could be distinguished pharmacologically in uninephrectomized male Sprague-Dawley rats. 2 Clonidine (1.0 nmol kg-' min-1) infused into the renal artery increased osmolar and free water clearance. Following pretreatment with prazosin (0.15 mg kg-', i.v.), an antagonist with reported selectivity for the a2b-adrenoceptor subtype, the increase in free water but not osmolar clearance was decreased. Pretreatment with the opioid receptor antagonist, naltrexone (3.0 mg kg-', i.v.) attenuated the increase in osmolar but not free water clearance. This disparate antagonism of clonidine by prazosin and naltrexone was consistent with two distinct sites. 3 We submit the hypothesis that the au-and a2b-adrenoceptor subtypes mediated the clonidine-induced osmolar and free water clearance. The blockade in free water clearance by prazosin indicated a possible role of the a2b-adrenoceptor subtype whereas the au,-adrenoceptor subtype was considered as the site mediating the clonidine-induced increase in osmolar clearance. UK-14,304 (1.0 nmol kg-' min-'), a mixed a2-adrenoceptor/imidazoline receptor agonist with selectivity for the oeu-subtype, increased only osmolar clearance. This increase was blocked by naltrexone but not prazosin pretreatment. The imidazoline receptor was not involved, as naltrexone failed to alter the moxonidine (3.0 nmol kg-' -min-') induced increase in osmolar clearance. These data suggested to us that the aux-/a2b-subtype hypothesis should be investigated more closely in future studies. 4 These findings indicate that the increase in osmolar and free water clearance following clonidine can be distinguished pharmacologically indicating that two sites were involved. Furthermore, we propose the hypothesis that the acx-adrenoceptor subtype mediated osmolar clearance whereas the 12b-subtype mediated free water clearance. The prazosin-sensitive increase in free water clearance following clonidine suggested a possible role for the x2b-subtype. The naltrexone-sensitive increase in osmolar clearance following clonidine and UK-14,304 (but not moxonidine) suggested a possible role of the au-subtype.Clearly, this postulate requires further study.
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