2,6-Dichlorobenzylidene amino guanidine acetate (Wy-8678). A new hypotensive agent

Baum, Thomas; Eckfeld, Donald K.; Metz, N. K.; Dinish, J. L.; Rowles, Gary; Pelt, R. van; Shropshire, Allen T.; Fernández, Susana; Gluckman, Melvyn I.; Bruce, William F.

doi:10.1007/bf01901433

Cited by 32 publications

(21 citation statements)

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“…The view that guanfacine and guanabenz are potent a2-adrenoceptor agonists is in agreement with other published observations, where these drugs as well as clonidine have been demonstrated to decrease the magnitude of the responses to sympathetic nerve stimu lation in several organs (2,(18)(19)(20). Moreover, guanfacine and guanabenz have been reported to decrease 3H-norepinephrine overflow in response to postganglionic sympathetic nerve stimulation in isolated mouse atria (18), rat cortex slices (18) and isolated rabbit heart (19, 20).…”

Section: Resultssupporting

confidence: 91%

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Comparison of agonistic and antagonistic actions of guanabenz and guanfacin on .ALPHA.1 and .ALPHA.2-adrenoceptors in isolated smooth muscles.

1987

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Abstract-The effects of guanabenz, guanfacine and clonidine on a-adrenoceptors were investigated in isolated rat vas deferens and rabbit aortic strip. All 3 drugs at low concentrations (10-9-10-8 M) caused inhibition of twitch responses of the rat vas deferens induced by nerve stimulation. These effects were competitively antagonized by yohimbine. Guanfacine and clonidine at relatively high concen trations (10-°-10-4 M) produced contractions of the rat vas deferens which were antagonized by prazosin. These contractile responses were not much affected by denervation. Prazosin-sensitive contractions by guanfacine and clonidine were also observed in the rabbit aortic strip, which were not affected by reserpine pre treatment. In both tissues, the intrinsic activity of guanfacine was almost identical to that of norepinephrine, whereas that of clonidine was less than one half. Guanabenz and clonidine showed a competitive antagonistic effect against nor epinephrine and phenylephrine in both the rat vas deferens and rabbit aorta, the antagonisms being similar in potency. The results indicate that all 3 drugs are potent agonists on the presynaptic a2-adrenoceptor.In contrast, on the postsynaptic ai -adrenoceptor, guanfacine and guanabenz showed only agonistic and antagonistic actions, respectively, whereas clonidine exhibited partial agonistic characteristics.

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Section: Resultssupporting

confidence: 91%

“…Guanabenz and guanfacine are newly introduced antihypertensive drugs possessing a guanidine residue in their structural formula (1)(2)(3)(4)(5). In order to elucidate the mechanisms of action, many experiments have been carried out in a number of animals under various conditions.…”

mentioning

confidence: 99%

Comparison of agonistic and antagonistic actions of guanabenz and guanfacin on .ALPHA.1 and .ALPHA.2-adrenoceptors in isolated smooth muscles.

1987

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“…The magnitude of the rise elicited by these i3-blocking agents and the minimum doses of these agents required to cause the pressor action appeared to be related to their E3-blocking activities in the heart such as was also reported by several investigators (24)(25)(26)(27). Therefore, the magnitude of the rise and the minimum dose of these agents could be used to compare the relative ( blocking activity of these agents.…”

Section: Discussionsupporting

confidence: 55%

Effects of Several β-Blockers On Blood Pressure in the Rat

Yamamoto¹,

Sekiya²,

Maekawa³

1975

Japanese Journal of Pharmacology

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Abstract-Effects of practolol, alprenolol and pindolol on blood pressure in the rat were studied. Also effects of these three (3-blocking agents on blood pressure and heart rate in spinal rats during adrenaline infusion were studied and compared with those of propranolol.The 33-blocking agents produced a sustained pressor action in the rat, and in the spinal rat infused with adrenaline.The magnitude of the pressor action induced by the 3-blockers was in the following order: pindolol>propranolol~ alprenolol>practolol.Minimum doses of these j3-blockers required to cause a pres sor action in the spinal rat infused with adrenaline were in the following order; prac tolol>alprenolol>propranolol>pindolol.The magnitude of the pressor action produced by the same dose of these 5-blockers and minimum doses of these ;3-blockers required to cause a pressor action in the spinal rat infused with adrenaline seemed to be roughly proportional to their l3-receptor blocking activities. It was concluded that the minimum doses of these 5-blockers required to cause a pressor action and the magnitude of the pressor action induced by the 1s-blockers in the spinal rat in fused with adrenaline could be used to compare their ,5-blocking activities and that practolol, a cardioselective ,5-blocker, seems to block not only cardiac 15-receptor but to some extent also peripheral vascular receptors.Propranolol has been shown to produce little change or a fall in blood pressure in various species of experimental animals (1-3). Clinically, hypotensive effects of this agent after prolonged oral administration were reported in patients with several types of hyper tension (4-7).On the other hand, it was shown in our previous papers (8-10) that propranolol pro duces a sustained rise in blood pressure in the rat, and in the spinal rat during the infusion of i3-adrenergic stimulating agents. This pressor action in the rat may be due to the block ade of the i3-adrenoceptive vasodilator tone in the peripheral vascular beds which was probably mediated by direct sympathetic discharges from the central nervous system and the catecholamines released from the adrenal glands. Also the pressor response to pro pranolol in the spinal rat is considered to be due to the blockade of the (3-adrenoceptive vasodilator tone which was induced artificially by the infusion of 13-adrenergic stimulating agents.If this view were correct, other j3-blocking agents would produce a sustained pressor action in the rat, and in the spinal rat in which the 3-receptor vascular tone was induced by infusions of '3-adrenergic stimulating agents as well as propranolol . The present study was undertaken to examine this assumption, and further to investigate the mechanism of

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“…As shown in the lower right part in Fig. 1 (1,2,(8)(9)(10) and are also in part, approx. 1/3, attributed to inhibitory actions on peripheral adrenergic transmission such as a presynaptic a-receptor stimulating action for both agents and an additional guan ethidine-like neuron blocking action for guanabenz (3, 6).…”

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confidence: 73%

Central and peripheral cardiovascular responses of rats to guanabenz and clonidine.

Misu

Kubo

1982

Jpn.J.Pharmacol

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Guanabenz (2, 6 dichlorobenzylidene aminoguanidine acetate) is an anti-hyper tensive agent (1) possessing a combined structure of the active moieties of both clonidine and guanethidine. The primary mechanism of the antihypertensive action is thought to be mainly mediated via a clonidine like agonistic action on central a-adre noceptors (2). Guanabenz also inhibits peri pheral adrenergic transmission via presynaptic a-receptor stimulation, and there was no evidence showing a guanethidine-like adre nergic neuron blocking activity (2). However, in a previous paper (3), we first differentiated the dual inhibitory actions of guanabenz on peripheral adrenergic transmission, pre synaptic a-receptor stimulation and adrenergic neuron blockade. In the present experiments, we attempted to clarify whether or not these peripheral actions of a moderate concentration of guanabenz play a role in the cardiovascular responses of rats, in com parison with clonidine and guanethidine. We compared the cardiovascular responses of anesthetized rats with those of pithed rats, the spinal cord of which was continuously stimulated at a low frequency of 2 Hz. This frequency was selected so that the basal heart rate and blood pressure was matched to that in anesthetized rats as much as possible.Male normotensive Wister rats, weighing 250 to 300 g, were anesthetized with ether, and the left femoral artery and vein were cannulated. The trachea was cannulated, and the animal was pithed through one orbit to the sacral region with a steel rod 1.0 mm in diameter as described by Gillespie and Muir (4) and immediately artificially respired. Atropine at 1 mg/kg and d-tubocurarine at 1 mg/kg was intravenously injected through the cannula. The spinal cord was continuously stimulated electrically by 1 msec supra maximal (50 V) pulses at a frequency of 2 Hz by use of an electronic stimulator (Model DIPS-10, Dia Medical System). The pithing rod served as the stimulating electrode and a steel needle with an outer diameter of 0.5 mm placed subcutaneously in the dorsum as an indifferent electrode. Some rats were anesthetized with sodium pentobarbitone, 50 mg/kg injected i.p., and the left femoral artery and vein were cannulated.Arterial blood pressure recordings were made via the femoral cannula using a Toyo pressure transducer connected to a Sanei recorder (Biophysio graph 180 System). Mean blood pressure was calculated as diastolic pressure +1 /3 (systolic pressure diastolic pressure). Heart rate was continuously computed from the blood pressure pulse wave by a cardiotachometer (Sanei-2140).Drugs used were guanabenz(Nipponshoji), clonidine hydrochloride (Boehringer), guane thidine hemisulfate (CI BA-Geigy), atropine sulfate, and d-tubocurarine (Sigma). Drugs were dissolved in 0.9% NaCI solution, and all solutions were administered intravenously in volumes of 1 ml/kg.Data are reported as the means±S.E.

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2,6-Dichlorobenzylidene amino guanidine acetate (Wy-8678). A new hypotensive agent

Cited by 32 publications

References 0 publications

Comparison of agonistic and antagonistic actions of guanabenz and guanfacin on .ALPHA.1 and .ALPHA.2-adrenoceptors in isolated smooth muscles.

Comparison of agonistic and antagonistic actions of guanabenz and guanfacin on .ALPHA.1 and .ALPHA.2-adrenoceptors in isolated smooth muscles.

Effects of Several β-Blockers On Blood Pressure in the Rat

Central and peripheral cardiovascular responses of rats to guanabenz and clonidine.

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