Effect of alpha-methyl-dopa (Dopegyt) and other antihypertensive drugs (guanethidine, bethanidine) on the isotope renogram.
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Adult↗
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[Comparative pharmacodynamic actions of guanethidine, bethanidine and bretylium in rats].
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Animals↗
[The use of bethanidine sulfate (Esbatal) in hypertension].
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Adult↗
[Pharmacological effects of [(octahydro-2-azocinyl)methyl] guanidine(guanazodine): its action mechanism and hypotensive effect].
Cardiovascular effects of guanazodine, a new antihypertensive drug, in anesthetized dogs, rabbits and rats and also isolated atria and arteries were compared with those of guanethidine and bethanidine. Guanazodine caused a sustained decrease in the systemic blood pressure of spontaneously hypertensive rats, renal hypertensive dogs and normal cats. No tachyphylaxis developed when the drug was administered orally to the rats once a day for 10 days. The heart rate decreased. Guanazodine relaxed the cat nictitating membrane, attenuated the positive chronotropic response to sympathetic nerve stimulation in anesthetized dogs and in isolated rabbit aorta to transmural electrical stimulation. Guazazodine potentiated the pressor response to noradrenaline but attenuated the response to tyramine in anesthetized cats. The noradrenaline content of rat hearts was significantly reduced 4 hr or later after the injection of guanazodine, while the content in brains and adrenal glands was unaffected. The LD50 of guanazodine injected intravenously to male rats was 136 +/- 11 mg/kg which was approximately 4 times the value of guanethidine and 7 times the value of bethanidine. It may be concluded that the hypotensive effect of guanazodine is related to adrenergic neuron blocking action, the noradrenaline-depleting action in peripheral tissues is similar to the effect of guanethidine and bethanidine, and that the extent and the duration of the hypotension induced by guanazodine are approximately the same as those with guanethidine but appreciably greater than those with bethanidine. Toxicity and side effects appear to be less with guanazodine than with guanethidine and bethanidine.
Adrenal Glands↗
Factors predisposing to postural hypotensive symptoms in the treatment of high blood pressure.
Symptoms due to orthostatic and exertional hypotension occurred in 23-4 per cent of 448 hypertensive patients treated with guanethidine, debrisoquine, or bethanidine. Symptoms were significantly more frequent in patients treated with guanethidine than in those treated with bethanidine or debrisoquine. Women rather than men and patients with radiological evidence of cardiomegaly, electrocardiographic evidence of left ventricular hypertrophy, or ST/T wave changes, developed these symptoms significantly more often than other patients. A raised blood urea was found more frequently in patients with postural hypotensive symptoms. Characteristically guanethidine produced early morning postural hypotensive symptoms, wheras hypotensive symptoms caused by bethanidine and debrisoquine occurred at other times of the day and particularly one to two hours after tablet ingestion. Debrisoquine and guanethidine had a significantly greater negative chronotropic effect than bethanidine. It is suggested that negative chronotropic effects of these drugs may potentiate hypotensive symptoms in patients with cardiovascular, renal, or cerebrovascular disease. It should be possible to minimize symptoms of postural hypotension by attention to predisposing factors and selection of treatment accordingly.
Bethanidine↗
Concerning the role of the amine pump of the adrenergic innervation of rabbit aorta in sustaining the neuron blockade produced by bethanindine and bretylium.
Adrenergic neuron blockade produced in rabbit aortic strips by bretylium and bethanidine has been studied. Differences were noted in the characteristics of approximately equal, strong neuron blockade produced by bretylium was readily reversed by washout of the drug from the tissue bath whereas blockade produced by bethanidine was slowly reversed. Desmethylimipramine prevented the onset of blockade from bretylium whereas it only delayed the onset of blockade due to bretylium but only slightly antagonized an established blockade due to bethanidine. It is suggested that the differences observed between these two neuron blocking agents are the result of their differential retention inside the neuron: bretylium is not firmly bound, leaks out of the neuron and goes through a process of recycling across the cell membrane, while bethanidine is more firmly bound inside the neuron than bretylium, only slowly leaks out of the neuron and is not recycled back across the cell membranes.
Action Potentials↗
The antagonism of adrenergic neurone blockade by amphetamine and dexamphetamine in the rat and guinea-pig.
1. In isolated rat mesentery preparations, intra-arterial injection of the following drugs rapidly suppressed vasoconstrictor responses to sympathetic nerve stimulation: bretylium (75-100 mug), guanethidine (10-20 mug) and bethanidine (20-30 mug); with phenoxypropylguanidine (15-30 mug) the onset of blockade was slower. The blockade caused by these or higher concentrations was rapidly abolished by intra-arterial injection of amphetamine (100 mug) as also was the blockade caused by infusing bretylium or guanethidine for 10-20 min. Partial blockade was produced by 20 mug of reserpine and this was only slightly and briefly antagonized by amphetamine.2. In mesentery preparations taken from rats 24 h after subcutaneous injection of bretylium 50 mg/kg, guanethidine 10 mg/kg, phenoxypropylguanidine 10 mg/kg or reserpine 0.1 mg/kg, responses to sympathetic nerve stimulation were greatly impaired. Only in the preparations from the bretylium-treated rats did amphetamine antagonize the blockade. The adrenergic neurone blocking effect of bethanidine 10 mg/kg was evident at 12 h but not at 24 h after injection.3. In rat mesentery amphetamine did not cause vasoconstriction but briefly potentiated the vasoconstrictor effect of sympathetic nerve stimulation. Responses to noradrenaline were not importantly affected.4. The contractile responses of the rat inferior eyelid caused by stimulation of the cervical sympathetic nerve was greatly reduced 17-27 h after subcutaneous injection of bretylium 300 mg/kg, bethanidine 30 mg/kg, guanethidine 10 mg/kg or reserpine 0.3 mg/kg. Intravenous dexamphetamine (0.5 mg/kg) powerfully antagonized the effect of bretylium, weakly antagonized the blockade by bethanidine and guanethidine and caused no change in the response of reserpine-treated animals.5. The vas deferens taken from guinea-pigs 24 h after subcutaneous injection of either bretylium or guanethidine showed greatly impaired responses to hypogastric nerve stimulation. Amphetamine largely restored the contractile response in bretylium-treated rats but caused only weak antagonism in the guanethidine-treated animals.
Amphetamine↗
Possible role of brain norepinephrine in the hypothalamic hypophyseal adrenal system.
Intracisternal injection of bethanidine in rats decreased brain norepinephrine turnover without affecting its endogenous level, and increased both cardiac norepinephrine turnover and serum corticosterone level. A negative correlation was observed between brain norepinephrine turnover rate and serum corticosterone level. On the other hand, when cardiac norepinephrine turnover was suppressed by intraperitoneal injection of bethanidine, serum corticosterone did not change significantly. Next, ether inhalation was added after intracisternal injection of bethanidine. Then, serum corticosterone increased more even brain norepinephrine turnover was suppressed only slightly. These data may indicate that serum corticosterone increases by selective decrease in brain norepinephrine turnover via the humoral route; from the hypothalamus down to the adrenal cortex. Inversely, intracisternal injection of corticosterone increased brain norepinephrine turnover. These results suggest that brain norepinephrine may play an inhibitory role in the tonic regulation of CRF-ACTH secretion in the higher center than the hypothalamus and there may be a closed-loop feedback system between brain norepinephrine and serum corticosterone.
Animals↗
New drugs in hypertension.
Clonidine, propranolol, bethanidine and debrisoquine effectively decrease blood pressure by suppressing renin secretion or interfering with function of the sympathetic nervous system. In man these compounds exert an antihypertensive effect within several hours or days and their duration of action is sufficient to permit administration twice or thrice daily. Clonidine and propranolol are especially useful if sexual dysfunction or postural hypotension is undesirable. Although bethanidine and debrisoquine may produce these adverse effects, they are beneficial in severe hypertension and produce fewer side effects than guanethidine. Clonidine frequently causes sedation, and rebound hypertension may occur with sudden cessation of therapy. Injudicious use of propranolol may provoke heart failure or asthma in susceptible individuals. The combination of a thiazide diuretic with propranolol and one of hydralazine, bethanidine and debrisoquine may be used to treat severe or complicated hypertension.
Antihypertensive Agents↗
Comparative effects of antiarrhythmic drugs on the ventricular fibrillation threshold.
The purpose of this study was to compare the effects of several different antiarrhythmic drugs on the ventricular fibrillation threshold (VFT). Experiments were performed on open-chest dogs anesthetized with pentobarbital. The VFT was measured on the right ventricle by scanning the vulnerable period with a single 10-ms electrical stimulus. The following antiarrhythmic drugs were each given intravenously to eight different dogs: procainamide (25 mg/kg), lidocaine (2 mg/kg + 70 micrograms/kg/min), flecainide (3 mg/kg), timolol (0.1 mg/kg), clofilium (1 mg/kg), dl-sotalol (5 mg/kg), and bethanidine (4 mg/kg). The drugs resulted in the following increases in the VFT: procainamide, 33 +/- 13%; lidocaine, 21 +/- 5%; flecainide, 38 +/- 10%; timolol, 19 +/- 6%; clofilium, 14 +/- 6%; sotalol, 33 +/- 10%; and bethanidine, 69 +/- 15%. The changes in VFT were all significant (p less than 0.01) except for clofilium. Only procainamide and sotalol caused stimulus-induced runs of nonsustained polymorphic ventricular tachycardia that spontaneously reverted to sinus rhythm after 4 s or more. In individual experiments, the occurrence of nonsustained polymorphic tachycardia that resembled ventricular fibrillation could not be correlated with a change in the VFT. In addition, there appeared to be no relationship between a drug-induced increase of the VFT and alterations in the QRS duration, the QT interval, or the ventricular effective refractory period. Bethanidine had the greatest effect on the VFT, in spite of the fact that this drug shortened the ventricular effective refractory period.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Central autonomic effects of prostaglandin F2 alpha on the cardiovascular system of the dog.
1. Prostaglandin F(2alpha) infused into the vertebral artery of the anaesthetized greyhound in doses which had no effect when given intravenously ((8-64 ng/kg)/min) caused an increase in blood pressure and heart rate.2. This response was not significantly altered by beta-adrenoceptor blockade with propranolol (10 mg i.v.) or by cervical cord section at C(4-6).3. The tachycardia was abolished and the pressor response greatly reduced by vagotomy or atropine (250 mug/kg i.v.).4. The pressor response which remained after vagotomy was abolished by subsequent sympathetic blockade with bethanidine (2-3 mg/kg i.v.) or bretylium (10 mg/kg i.v.).5. In contrast to the effects of propranolol or cervical cord section bethanidine (4-5 mg/kg i.v.) or bretylium (10 mg/kg i.v.) significantly reduced blood pressure and heart rate responses to intravertebral prostaglandin F(2alpha). This result suggests that bethanidine and bretylium have some central actions.6. It is concluded that the cardiovascular effects of intravertebral infusions of prostaglandin F(2alpha) are mediated by the autonomic nervous system and that the preferential pathway is withdrawal of vagal tone to the heart.
Animals↗
Drinking behaviour in the cat induced by renin, angiotensin I, II and isoprenaline.
1. Angiotensin I, II and hog renin, infused into the lateral cerebral ventricles (I.C.V.) of water replete cats, each induced water drinking behaviour. 2. Intravenous infusion of high doses of angiotensin I or II also elicited a drinking response. The dipsogenic effect of I.V. renin was not marked. 3. Drinking in response to I.C.V. angiotensin II was abolished after autonomic ganglion blockade with I.V. hexamethonium or pempidine and was significantly reduced after I.V. atropine methonitrate. 4. The dipsogenic response to I.C.V. angiotensin II was unaffected by either peripheral adrenergic neurone blockade with I.V. bethanidine, alpha-adrenoceptor blockade with phentolamine or beta-adrenoceptor blockade with sotalol. 5. Atropine, atropine methonitrate, hexamethonium and pempidine given I.C.V did not inhibit the diposgenic response to I.C.V. angiotensin II. 6. Bethanidine I.C.V. produced a dose related reduction in the dipsogenic response to I.C.V. angiotensin II. 7. The alpha-adrenoceptor blocking agents tolazoline and phenoxybenzamine given I.C.V did not affect angiotensin induced drinking but the response was regularly inhibited by phentolamine I.C.V. 8. The beta-adrenoceptor blocking agents propranolol and practolol given I.C.V. each inhibited angiotensin induced drinking. The L-isomer of propranolol was a more effective blocker than the D-isomer. 9. Isoprenaline given I.C.V induced drinking in ten of sixteen cats. Subcutaneous administration of isoprenaline also elicited drinking but the onset of the response was delayed and the amount consumed slightly less than after I.C.V infusion.
Angiotensin II↗
Sympathetic component of the pressor response to angiotensin II in the pithed rat after pretreatment with disulfiram.
Pressor responses to angiotensin II in the pithed rat were unaffected or slightly increased by procedures such as reserpine pretreatment, alpha and beta adrenoceptor blocking agents or bethanidine which inhibit the sympathetic system. Disulfiram-induced inhibition of angiotensin II pressor responses was unaffected by pretreatment with either alpha-adrenoceptor blockers or bethanidine. Pretreatment with disulfiram prevented infusions of angiotensin II from increasing the responses to spinal sympathetic outflow stimulation. After inhibition of pressor responses to angiotensin II by disulfiram the responses were restored by infusions of noradrenaline, or alpha-methyldopa. The restored responses, unlike control responses, were inhibited by phentolamine. The results suggest that angiotensin II facilitates neuronal release of noradrenaline and that this effect is revealed most clearly when post-synaptic angiotensin II receptors are blocked.
Adrenergic alpha-Antagonists↗
The central action of clonidine and its antagonism.
1. We have examined the central actions of clonidine (2-(2-6-dichlorphenylamine)-2-imidazoline hydrochloride). It has been confirmed that when infused into the vertebral artery at 2 mug/min, it caused a decrease in blood pressure and a slight increase in heart rate. The same dose given intravenously or into the carotid artery had no effect.2. Intravertebral clonidine also greatly reduced the reflex response to carotid occlusion and the effects of an intravertebral infusion of angiotensin (1 ng/kg)/min.3. This central action of clonidine was antagonized by the adrenergic neurone blocking drug bethanidine (4-5 mg/kg intravenously) even after the cervical cord had been transected at C(4)-C(6) suggesting that bethanidine also has central actions.4. Other drugs which also antagonized the central effects of clonidine were guanethidine (4-5 mg/kg intravenously), bretylium (10 mg/kg intravenously) and phentolamine (0.2 mg/kg intravenously).5. It is suggested that there are central adrenergic neurones which inhibit cardiovascular autonomic reflexes and that the central autonomic effects of clonidine are due to stimulation of inhibitory adrenoceptors. The antagonism by adrenergic neurone blocking drugs of the effect of clonidine could therefore be due to blockade of these inhibitory pathways.6. The central action of clonidine could only be demonstrated when a high concentration was infused into the vertebral artery and could not be shown with oral doses of (20 mug/kg)/day for seven days. It is concluded that the hypotensive action of therapeutic doses is unlikely to be due to the central action of clonidine.
Angiotensin II↗
Thyroxine deiodination during cold exposure in the rat.
1. The urinary radio-iodide excretion following injection of [(131)I]thyroxine and tri-iodothyronine is increased in acutely cold-exposed, thyroidectomized rats.2. This cold response is demonstrable in animals which are fed or fasted or deprived of both food and water. Cold exposure does not increase the rate of urinary excretion of a tracer dose of radio-iodide. It is concluded that cold exposure accelerates the rate of deiodination of both thyroxine and tri-iodothyronine.3. It is confirmed that both adrenaline and noradrenaline administered in vivo can enhance the rate of thyroxide deiodination.4. The sympathetic blocking agents guanethidine and bethanidine reduce the extra deiodination of thyroxine induced by cold exposure. Bethanidine was also found to reduce the deiodination of tri-iodothyronine during cold.5. There is a positive correlation between the deiodination of thyroxine and the urinary catecholamine excretion in the cold-exposed but not the warm-exposed rat.6. It is suggested that the enhanced deiodination during cold exposure is mediated by the release of noradrenaline from the sympathetic nervous system.
Animals↗
The pattern and control of sweating in the sheep and the goat.
1. The pattern and control of sweating in one breed of goat and six breeds of sheep have been studied.2. Heat exposure of both sheep and goats resulted in periodic discharges of moisture on to the surface of the skin of the shorn mid-side. The frequency of discharge showed considerable variation between individual animals, varying from less than 1/hr to 14/hr. Approximate counts of the number of active sweat glands suggested that the same glands were involved at each discharge.3. The amount of moisture produced at each discharge declined upon continued heat exposure. The rate of decline was independent of the frequency of discharge.4. Adreno-medullary denervation had no effect on the pattern of sweating in either the sheep or the goat.5. Intravenous adrenaline administration (5 mug/kg body wt.) caused the sweat glands to discharge, but noradrenaline had no effect at the same dose.6. Thermal sweating was inhibited by bethanidine and phenoxybenzamine but not by propranolol. Sweating induced by intravenous adrenaline administration was blocked by phenoxybenzamine but not by bethanidine or propranolol.7. It is concluded that sweating on the mid-side of the sheep and goat is controlled by an adrenergic mechanism, that secretion from the adrenal medulla under conditions of mild heat stress does not stimulate the glands and that sweating is mediated by adrenergic alpha-receptors.
Adrenal Medulla↗
Treatment of hypertension with propranolol.
When used in the treatment of hypertension propranolol is at least of similar potency to bethanidine, guanethidine, and methyldopa. Propranolol does not produce postural or exercise hypotension and it seems that it is often more acceptable to patients than conventional drugs. It usually produces the best control of the supine blood pressure.A series of 109 hypertensive patients was treated with propranolol; in nine the drug was withdrawn. In 92 of the patients a supine or standing blood pressure of 100 mm. Hg or less was achieved. Eighty of the patients had previously been treated with other potent drugs, and close comparisons and prolonged follow-up in 17 patients showed that diastolic pressures of 100 mm. Hg or less were achieved in more patients after propranolol than with guanethidine, bethanidine, or methyldopa.Sensitivity to propranolol varies widely, and dosage should be increased gradually. The hypotensive effect often takes six to eight weeks to reach its maximum. Propranolol reduces cardiac output but may also act by reducing the cardiac component of pressor stimuli; as a result the baroreceptors gradually regulate the blood pressure at a lower level. It is contraindicated in patients with obstructive airways disease or in uncompensated heart failure.
Blood Pressure↗