Mechanism of action of guanethidine

The early hypotensive action of intravenous guanethidine in rabbits, rats and cats anaesthetized with urethane is reversed after pretreatment with iproniazid. The fall in blood pressure following injection of guanethidine in rabbits is reduced after previous administration of reserpine. Reserpine, like adrenalectomy and splenectomy, suppresses the early pressor effect of guanethidine in cats anaesthetized with chloralose. Guanethidine inhibits the action of tyramine and nicotine, but potentiates the effect of noradrenaline on isolated rabbit atria. Guanethidine is also a weak inhibitor of monoamine oxidase activity. The results are discussed and compared with those shown by reserpine. It is concluded that the early effects of guanethidine are mainly due to the release of endogenous catechol amines.     

Observations during hyperventilation effects of guanethidine,reserpine, and hypothermia

Summary The effects of hyperventilation were studied in twenty hypertensive patients during oral treatment with guanethidine and in ten hypertensive patients during surgical procedures under general anaesthesia, following intravenous administration of reserpine. Hyperventilation prior to any treatment did not produce arterial pressure changes of any significance. During therapy, a depressor effect took place, which in some of the patients was markedly pronounced. Similarly, hyperventilation was studied in ten normotensive patients undergoing surgery under general anaesthesia with moderate hypothermia. We noted that during the early stages of hypothermia, hyperventilation produced a pressor effect, which in some patients was very pronounced. Contrary to this, in the late stages of hypothermia, hyperventilation did not produce any arterial pressure changes. The pressor effect observed at the beginning of hypothermia is probably related to an increased catecholamine release taking place during the early stage of induction of cooling.     

Effect of guanethidine and of reserpine on angiotensin responsiveness in man.

The respective effects of guanethidine and reserpine on angiotensin responsiveness in man have been investigated. Oral administration of 0.5 mg guanethidine per kg for a week has been found to reduce angiotensin responsiveness considerably, while plasma renin activity remained unaffected. Daily 1 mg reserpine for a week did not influence either angiotensin responsiveness or renin activity. Comparison of the results obtained with the enhancing effect of alphamethyldopa on angiotensin responsiveness has led to the conclusion that there is no relationship between the hypotensive activity of the two drugs in question and their respective effects on angiotensin responsiveness.     

The chronotropic actions of guanethidine and reserpine on the isolated dog heart

Summary Administration of reserpine to a heart-lung preparation about 140 min after the addition of guanethidine, when the chronotropic action of the latter had levelled off, produces a rise in heart rate with a peak equal to that observed when reserpine is given alone. Addition of reserpine to a heart-lung prepared from reserpinized dogs after partial repletion of the stores with noradrenaline does not increase the heart rate in contrast to the action of guanethidine which under the same conditions results in a marked increase in rate. These experiments indicate that guanethidine and reserpine act on different sites and lend further support to the concept that at least two noradrenaline stores exist.With 2 Figures in the Text     

Evidence for a competitive antagonism of guanethidine by dexamphetamine

After guanethidine had blocked the response of the cat nictitating membrane to sympathetic nerve stimulation, dexamphetamine restored the responses to all frequencies of stimulation. Dexamphetamine antagonized the sympathetic nerve block by guanethidine in the isolated sympathetically innervated rabbit ileum; the evidence suggests that the antagonism was competitive. Dexamphetamine antagonized the sympathetic nerve block by guanethidine in the isolated hypogastric nerve-vas deferens preparation of the guinea-pig. Doses of dexamphetamine, larger than those required to antagonize the blocking action of guanethidine, abolished the responses of the nictitating membrane, ileum and vas deferens to nerve stimulation. Dexamphetamine did not influence the depletion of noradrenaline by guanethidine in the heart and spleen of rabbits. The hypothesis is advanced that both dexamphetamine and guanethidine act on the store of noradrenaline at sympathetic nerve endings.     

Modification of some actions of guanethidine by the acute administration of reserpine

Summary The pressor action of guanethidine (4 mg/kg) is enhanced by previous administration of reserpine (2 mg/kg), when the time elapsing between the injections of the two drugs is varied between 2 min and 8 hr. This enhancement was observed in the dog (anaesthetized, or spinal or nialamide-pretreated animals) and in the cat. The pressor effects of adrenaline and noradrenaline were not modified by reserpine. Guanethidine caused the nictitating membrane of the dog and the cat, as well as isolated cat spleen strips, to contract and the contractions were enhanced by reserpine; however, the contractions of the nictitating membrane induced by electrical stimulation of the postganglionic sympathetic nerve were not changed by reserpine. Similarly, the pressor effect caused by electrical stimulation of the central end of the vagus nerve was not enhanced. Several mechanisms are discussed in order to explain the observed potentiation; the results are in good agreement with the hypothesis of the existence of different noradrenaline pools.Calouste Gulbenkian Foundation Scholar.     

Effects of reserpine, guanethidine and methyldopa on cardiac output and its distribution.

In anaesthetized rats with a renal model of hypertension, effects of reserpine, guanethidine and methyldopa on cardiac output (the dye-dilution method) and its distribution among the heart, the lung, the kidney, the large and small intestine, the stomach, the liver, the spleen, skeletal muscle and skin (the rubidium method) were studied. Several hours administration of all three drugs under study, a definite decrease in cardiac output was observed. Cardiac output then escaped from the influence of the drugs despite a reduction in heart rate. Fall of arterial pressure 24 hr after administration of the drugs was only due to the decrease in total peripheral resistance. Effects of the drugs on distribution of cardiac output were studied at the time when cardiac output was not changed to any significant extent. Under this condition the features common to all the drugs were an increase of the cardiac output fractions to the gastro-intestinal tract and a decrease to the heart and the spleen. This fact indicates that decrease in resistance of gastro-intestinal vascular region plays a basic role in the hypotensive effect of reserpine, guanethidine and methyldopa.     

Cannabinoids and serotonin uptake by blood platelets: Evidence for multiple sites of action

The effect of cannabinoids on parameters of 5-hydroxytryptamine (5-HT) uptake by human platelets was examined. Natural and synthetic cannabinoids differing in the pyrene ring of the hydro-phobic side chain or in steric configuration, inhibited differentially the saturation level of 5-HT uptake, the active uptake and the passive transport of the neurotransmitter, indicating multiple sites of action of the drugs. The pattern of inhibition did not correlate with the psychomimetic specificity of the cannabinoids.     

Influence of reserpine and guanethidine on the responses of the isolated rat ileum to catecholamines

The sensitivity of the isolated ileum of the rat to catecholamines has been investigated using normal, reserpinized and guanethidine treated animals. Both reserpine and guanethidine treatment produces supersensitivity to adrenaline, noradrenaline and to a greater extent to isoprenaline.     

Factors affecting the action of guanethidine on adrenergic neurones

1. The uptake of guanethidine by adrenergic neurones has been studied indirectly by testing the ability of various procedures to prevent or reverse adrenergic neurone blockade in the periarterially stimulated isolated ileum preparation.2. Adrenergic neurone blockade was prevented but not reversed by equilibration with guanethidine (3.3 x 10(-6)M) at low temperatures (10 degrees C), in the absence of sodium or in the presence of tetrodotoxin (0.3 x 10(-6)M) or noradrenaline (1.2 x 10(-3)M).3. Calcium (5 x 10(-2)M) both prevented and, to some extent, reversed the adrenergic neurone blocking action of guanethidine.4. Equilibration with guanethidine in the presence of mersalyl (0.6 x 10(-7)M) or in the absence of potassium or calcium could neither prevent nor reverse adrenergic neurone blockade.     

Liquid membrane phenomenon in reserpine action

Reserpine was shown to generate a liquid membrane. Transport of adrenaline, noradrenaline, dopamine, 5-hydroxytryptamine, glutamic acid, and gamma-aminobutyric acid in the presence of the reserpine liquid membrane was studied. The data indicate that the phenomenon of liquid membrane formation is likely to play a role in the mechanism of reserpine action.     

The action of reserpine on teleost melanophores

Reserpine caused darkening of both pencil fish and angelfish, this effect lasted for at least 10 and 25 days respectively.The aggregation of pigment granules within the melanophores evoked by stimulation of the nerves supplying the melanophores was inhibited by reserpine in both species. Reserpine caused a lowering of the catecholamine content of pencil fish skin. The time course both these effects paralleled the time course of darkening. The response of the melanophores of the angelfish to adrenaline, noradrenaline, dopamine, and melatonin was not affected by treatment with reserpine for 3 days. However, reserpine treatment for 14 days induced a marked sensitivity to noradrenaline. Reserpine partially abolished the response to tyramine in both pencil fish and angelfish. Small doses of noradrenaline and adrenaline given to reserpine-treated angelfish partially restored the response of the melanophores to nerve stimulation. No action of ACTH, MSH, nor direct effect of reserpine could be demonstrated on melanophores of either species. It was concluded that reserpine acts on the melanophores of pencil fish and angelfish in an indirect way by depletion of catecholamines from the sympathetic nerves supplying the melanophores.