Disease relevance of Wy 8678

• Guanabenz, in some patients, is an effective monotherapy for the treatment of hypertension [1].
• The data are consistent with selectively reduced renal sympathetic activity affecting sodium transport and provide a basis for the absence of edema and sodium retention associated with guanabenz therapy [2].
• Four of the 5 non-arterial pressure-related neurons in the gigantocellular reticular nucleus, on the other hand, manifested no basic modification in their spike frequencies in relation to the hypotension induced by guanabenz [3].
• Participation of nucleus reticularis gigantocellularis in guanabenz-promoted hypotension, decrease in cardiac contractility and bradycardia in rats [4].
• They were produced by a lower dose per unit body weight in the rat whereas this was less marked for the alpha 2-adrenoceptor agonist guanabenz [5].

Psychiatry related information on Wy 8678

• Clonidine (0.02-0.2 mg kg(-1) i.p.) and guanabenz (0.1-0.3 mg kg(-1) i.p.) induced amnesia in a dose-dependent manner [6].
• The disposition of guanabenz, a centrally acting antihypertensive agent, was compared in 10 normotensive patients (eight males and two females) with chronic hepatic disease secondary to alcohol abuse and 10 healthy male volunteers after a 16 mg oral dose [7].
• Conversion to guanabenz, a clonidine-like alpha 2 agonist, promptly relieved the opiate withdrawal symptoms without side effect recurrence [8].

High impact information on Wy 8678

• Clonidine preserves RBF and GFR both acutely and chronically, guanabenz decreases RBF acutely but not chronically, and alpha-methyl dopa preserved RBF but decreases GFR [9].
• Conscious rats with CHF showed elevated plasma catecholamines and enhanced responses of mean arterial pressure (MAP), heart rate (HR), and renal sympathetic nerve activity (RSNA) to air stress and to intracerebroventricular (ICV) injection of the alpha 2-adrenergic receptor agonist guanabenz compared with sham-operated rats [10].
• Intracerebroventricular preinjection of 0.3 microgram ouabain significantly enhanced blood pressure and RSNA responses to air stress and intracerebroventricular guanabenz in Dahl S rats given regular sodium to the levels observed in Dahl S rats given high sodium [11].
• Similarly, ICI 118,551 administered into the lateral hypothalamus or lateral cerebral ventricle, or guanabenz (alpha 2-adrenoceptor agonist) given into the posterior hypothalamus, had no effects on the renal or mean arterial pressure responses to air stress [12].
• Guanabenz therapy had no significant natriuretic or antinatriuretic effects in patients with an effective BP decrease, although it had the ability to produce and sustain a water diuresis [1].

Chemical compound and disease context of Wy 8678

• 1. The effect of the administration of pertussis toxin (PTX) as well as modulators of different subtypes of K+ channels on the antinociception induced by clonidine and guanabenz was evaluated in the mouse hot plate test [13].
• Losartan injected into the MnPO reversed the salt-sensitive component of the hypertension and normalized the depressor response to guanabenz but did not change responses to air-jet stress [14].
• Patients with mild to moderate essential hypertension were treated with guanabenz plus placebo (26 patients) or guanabenz plus hydrochlorothiazide (26 patients) for one year [15].
• Although drowsiness and dry mouth occurred more frequently with guanabenz, evidence of fluid retention, such as weight gain, edema, and congestive heart failure, was significantly more frequent with methyldopa than with guanabenz [16].
• This detrimental effect was prevented by pretreatment with the alpha2-antagonist yohimbine (1-3 mg kg(-1) i.p.) and by the alpha2A-antagonist BRL-44408 (0.3-1 mg kg(-1) i.p.). By contrast, the alpha(2B,C) antagonists ARC-239 (10 mg kg(-1) i.p.) and prazosin (1 mg kg(-1) i.p.) did not revert the amnesia induced by both clonidine and guanabenz [6].

Biological context of Wy 8678

• Guanabenz therapy caused a modest but reversible reduction in glomerular filtration rate (12% to 18%), effective renal plasma flow (9% to 17%), and renal blood flow (12% to 20%) [1].
• In Dahl S but not R rats, high salt significantly increased BP and HR; enhanced BP, HR, and renal sympathetic nerve activity responses to air stress and guanabenz; and attenuated cardiopulmonary and arterial baroreflex control of renal sympathetic nerve activity and HR [17].
• At 9 weeks of age, blood pressure (BP), heart rate (HR), central venous pressure, and renal sympathetic nerve activity were recorded in conscious rats at rest and in response to air stress and to intracerebroventricular alpha2-agonist guanabenz (50 microg) and ouabain (0.5 microg) [17].
• This study evaluated two aspects of this complex quantitative trait, enhanced renal sympathoexcitation with air-jet stress and enhanced renal sympathoinhibition with guanabenz, as a candidate intermediate phenotype [18].
• The air jet stress-induced increase in mesenteric vascular resistance was reduced by 25 micrograms guanabenz [19].

Anatomical context of Wy 8678

• Effects of guanabenz therapy on renal function and body fluid composition [1].
• Clonidine, guanfacine, guanabenz and alpha-methyl-dioxyphenylalanine (DOPA), the prototypes of centrally acting antihypertensives, are assumed to induce peripheral sympathoinhibition and a reduction in blood pressure via the stimulation of alpha2-adrenoceptors in the brain stem [20].
• The alpha-2 adrenergic receptor agonists, clonidine, lofexidine and guanabenz, blocked stress- but not cocaine-induced reinstatement of cocaine seeking at doses that suppressed footshock-induced release of noradrenaline in prefrontal cortex and amygdala [21].
• Renal effects of infusion of rilmenidine and guanabenz in conscious dogs: contribution of peripheral and central nervous system alpha 2-adrenoceptors [22].
• In the submaxillary gland the potency of guanabenz to decrease the secretory response to methacholine was increased by a factor of 30 [23].

Associations of Wy 8678 with other chemical compounds

• As a result, compounds such as guanethidine, guanabenz, guanfacine, and pinacidil have been introduced in antihypertensive drug therapy [24].
• Naphthazarin-induced cytotoxicity was evidenced by the ordered development of lysosomal acridine orange relocation, decrease in mitochondrial potential, cytochrome c release, and caspase-9 activation, and was inhibited by guanabenz, rilmenidine, and AGN 192403 [25].
• Compared with intracerebroventricular (i.c.v.) administration of isotonic saline vehicle which did not affect baseline systemic and regional haemodynamic measurements, guanabenz produced significant decreases in baseline MAP and heart rate but did not affect regional vascular resistances [19].
• 5. The administration of the Ca2+-gated K+ channel blocker apamin (0.5-2.0 ng per mouse, i.c.v.) never modified clonidine and guanabenz analgesia [13].
• On day 14 in conscious rats, CSF was sampled and BP, HR, and RSNA were recorded at rest and in response to air stress, intracerebroventricular alpha2-adrenoceptor agonist guanabenz, intracerebroventricular ouabain, and intravenous phenylephrine and nitroprusside to estimate baroreflex function [26].

Gene context of Wy 8678

• The high affinity of guanabenz to CYP1A2 and the distinct selectivity of this P450 isozyme toward guanabenz confirms the in vitro guanabenz N-hydroxylation to be a suitable metabolic marker for CYP1A2 in biotransformation studies [27].
• Guanfacine and guanabenz, agonists acting preferentially at rat alpha-2A (R alpha-2A)/human alpha-2A (H alpha-2A) AR, mimicked the antinociceptive and motor actions of xylazine and UK 14,304 and likewise inhibited NA synthesis [28].
• The antiinflammatory action of guanabenz is mediated through 5-lipoxygenase and cyclooxygenase inhibition [29].
• Furthermore, the N-hydroxylation of guanabenz was found to be catalyzed by enriched cytochrome P450 (P450) fractions in reconstituted systems [27].
• Similarly, guanabenz reduced LTB4 (IC50 = 37.4 microM) and PGE2 (IC50 = 13.8 microM) synthesis by A23187-stimulated rat glycogen elicited neutrophils [29].

Analytical, diagnostic and therapeutic context of Wy 8678

• A single dose of guanabenz was examined for effects upon blood pressure, heart rate, plasma catecholamines, and plasma renin activity in a randomized, double-blind, crossover design [30].
• Surgical renal denervation or pretreatment with an alpha 2-adrenergic receptor antagonist (rauwolscine, 30 micrograms i.c.v.) attenuated the ability of guanabenz to inhibit renal sympathetic nerve activity or increase urinary sodium excretion in SHR and WKY on either normal or high sodium intake [31].
• Furthermore, [123I]MIBG scintigraphy after oral administration of an alpha 2 agonist (guanabenz acetate; 4 mg) demonstrated that myocardial uptake and clearance of MIBG returned to normal, as did the %LF [32].
• Administration of the selective alpha-2 adrenergic receptor agonists B-HT 933 (2-20 nmol) and guanabenz (1.7-17 nmol) into the kidney produced only small increases in PG output and perfusion pressure, whereas another selective alpha-2 adrenergic receptor agonist xylazine (1-20 nmol) failed to increase perfusion pressure or PG output [33].
• Microinjection of guanabenz directly into the ventro-medial portion of the nucleus reticularis gigantocellularis, at an ineffective systemic concentration (500 ng), produced significant and prolonged reduction in arterial pressure, cardiac contractility and heart rhythm [4].

References