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PubMed1985

Does capsaicin cause reflex bronchospasm in guinea-pigs?

Capsaicin given intravenously (i.v.) into the vena cava or intra-arterially (i.a.) into the aortic arch of anesthetized guinea-pigs induced dose-dependent increases in pulmonary-flow resistance (R) and dynamic thoracic elastance (E). Threshold doses were 0.5-1.0 micrograms/kg body weight; greater than 8.0 micrograms/kg induced tachyphylaxis. These responses to capsaicin, i.v. or i.a., were similar after decentralization, bilateral vagotomy, or glossopharyngealotomy, and after autonomic blockers (mecamylamine, atropine, mepyramine, and bethanidine). Morphine significantly reduced responses to capsaicin but had no effect on responses to substance P (SP). Naloxone did not reverse the inhibitory effect of morphine, and neither reduced nor enhanced capsaicin-induced increases. Of the two antagonists to SP examined (given i.v.), [D-Pro2,D-Trp7,9]SP had no effect on SP-induced increases but abolished capsaicin-induced increases in R, though without affecting increases in E, and [D-Arg1,D-Pro2,D-Trp7,9,Leu11]SP reduced increases in R induced by both SP and capsaicin but had no effect on increases in E. Capsaicin (2.0-32.0 micrograms/kg i.v. or i.a.) had no bronchospastic effect in guinea-pigs given this drug (50.0 mg/kg s.c.) 7 days earlier. We conclude that in guinea-pigs--unlike other species--capsaicin causes bronchospasm without stimulating any afferent receptors in a centrally mediated bronchospastic reflex arc.

Animals↗

PubMed1985

Increased body fat due to elevated energetic efficiency following chronic administration of inhibitors of sympathetic nervous system activity.

The effects on energy balance of drugs known to inhibit the sympathetic nervous system at different sites and with various modes of action were studied in lean mice of the CFLP strain. Metabolizable energy intake was monitored continuously over seven-week experimental periods and energy expenditure was determined by the comparative carcass method as well as by measurements of 24-hour oxygen consumption. Administration of either propranolol, phenoxybenzamine, clonidine, or mecamylamine had no influence on energy balance nor on body composition. On the other hand, administration of alpha-methyl para tyrosine, reserpine, and bethanidine, ie, drugs capable of reducing the levels of noradrenaline at sympathetic terminals, resulted in significant increases in body fat by 38%, 24%, and 46% respectively: this effect was brought about by a reduction in the metabolic rate of these drug-treated groups and the efficiency of energy utilization (both gross and net) was increased by three to nine times. These studies indicate that chronic administration of drugs that act at the receptor level to inhibit sympathetic activity fail to influence metabolic rate, thereby suggesting that thermogenesis under noradrenaline control may involve mechanisms other than the alpha and beta classification of adrenergic receptors. Nonetheless, the ability of some drugs which both reduce noradrenaline levels and decrease metabolic rate would support the concept of an important role of the sympathetic nervous system in the overall control of thermogenesis and in energy balance regulation.

Adipose Tissue↗

PubMed1990

Functional relationships between platelet alpha 2-adrenoceptors and sympathetic nerve activity in clinical hypertensive states.

Tritiated yohimbine binding was used to estimate platelet membrane alpha 2-adrenoceptor characteristics in normal subjects (n = 12) and patients with essential hypertension (n = 30), primary hyperaldosteronism (n = 10) and phaeochromocytoma (n = 10). There was a 20-fold increase in mean levels of resting norepinephrine and epinephrine in the phaeochromocytoma group. Total binding sites (Bmax) and dissociation constant (Kd) for 3H-yohimbine did not differ significantly among the four groups. Following curative surgery for phaeochromocytoma, plasma catecholamine levels were normalized but the Bmax remained unchanged. Following surgery for primary hyperaldosteronism, levels of plasma norepinephrine rose but Bmax was not changed. In all but the phaeochromocytoma patients, Bmax values correlated positively (r = 0.437, n = 48, P less than 0.01) with resting plasma norepinephrine. A significant negative correlation was observed between the change in plasma norepinephrine in response to postural change and resting Bmax. Treatment for 2-4 weeks with guanabenz or bethanidine induced a parallel fall in both Bmax and plasma norepinephrine. Treatment with reserpine was followed by a comparable fall in plasma norepinephrine, but Bmax values were unchanged. The findings support the view that platelet alpha 2-adrenoceptor density is functionally regulated in parallel with sympathetic nerve activity rather than circulating catecholamine levels, although it is not known which neuronal substance(s) may participate in this regulation.

Adrenal Gland Neoplasms↗

PubMedDate not supplied

Cardiovascular effects of carbachol and other cholinomimetics administered into the cerebral ventricles of conscious cats.

1. The cholinomimetic substances acetylcholine, nicotine, tetramethylammonium chloride and carbachol were infused intracerebroventricularly (i.c.v.) into conscious, normotensive cats and their effects on behaviour, blood pressure and heart rate recorded. 2. Intracerebroventricular acetylcholine, nicotine and tetramethylammonium chloride each produced small, mainly stimulant, effects on the cardiovascular system which were not accompanied by any marked behavioural effects. 3. Intracerebroventricular carbachol at a dose of 30 microgram produced marked and persistent cardiovascular stimulant effects accompanied by a striking rage/fear reaction. When the dose of carbachol was reduced to 7.5 microgram the behavioural effects were no longer seen but marked cardiovascular stimulant effects remained. 4. The cardiovascular stimulant effects of i.c.v. carbachol were apparently mediated via the peripheral sympathetic system since they were abolished by peripheral adrenergic neurone blockade. 5. The blood pressure and heart rate increases produced by i.c.v. carbachol were blocked by prior i.c.v. treatment with atropine, hexamethonium, guanethidine, bethanidine or propranolol. 6. The data are consistent with an interaction between central cholinergic and catecholaminergic neural pathways involved in central regulation of blood pressure and further suggest the involvement of beta-adrenoreceptors in the responses to centrally-administered cholinomimetics.

Acetylcholine↗

PubMed1969

The accumulation of guanethidine by human blood platelets.

1. When human blood platelets were incubated aerobically in plasma containing 2 x 10(-7) to 10(-3)M radioactive guanethidine for 10 min to 6 hr, the drug was accumulated against a concentration gradient until concentration ratios (platelet/plasma) of up to 80:1 were obtained.2. The decline in rate of uptake after 3 hr appeared to result from a decrease in platelet viability, because accumulation was reduced by prolonged incubation before addition of guanethidine.3. Uptake was energy-dependent because it was inhibited by cold and ouabain.4. Sodium ions were essential for guanethidine uptake and retention of 5-hydroxytryptamine (5-HT).5. Accumulation was inhibited by 5-HT, desipramine, cocaine, dexamphetamine, bretylium, tyramine and noradrenaline; bethanidine, p-chlorophenylalanine and (-)-alpha-methyldopa were inactive.6. Guanethidine was tightly bound to platelets, only 10% being lost from labelled cells during 60 min incubation in drug-free plasma; but efflux was increased by addition of amphetamine.7. The binding sites for guanethidine seemed to be different from those for 5-HT since guanethidine accumulation was independent of 5-HT levels, and neither guanethidine uptake or release were affected by reserpine.8. Guanethidine was not metabolized by platelets or plasma in vitro.9. We consider that, if our results regarding uptake, binding and release of guanethidine are confirmed in vivo, and also found to apply to other pharmacologically active agents, then the eventual loss of a platelet-bound substance may increase pharmacological action by raising plasma levels.

Autonomic Agents↗

PubMed1969

The role of the sympathetic nervous system in the cardiovascular responses to angiotensin in the pithed rat.

1. Angiotensin (200-500 ng, intravenously) produced a biphasic pressor response accompanied by reflex bradycardia in rats anaesthetized with sodium pentobarbitone. In pithed rats and in anaesthetized animals treated with a ganglion blocking agent there was a similar pressor response but an increase in the heart rate which was coincident with the second phase of the pressor response. In pithed preparations an increase in cardiac contractile force accompanied the heart rate changes.2. Acute or chronic adrenalectomy did not alter the pressor responses and chronotropic effect of angiotensin in the pithed rat. Propranolol abolished the chronotropic and inotropic action of angiotensin, but left the biphasic pressor response unaltered. Bethanidine, or pretreatment with reserpine, altered the pressor response to a simple rise, and also abolished the chronotropic action of angiotensin. Phentolamine also abolished the second pressor component. Desmethylimipramine produced a marked potentiation of the cardiovascular effects of angiotensin at all dose levels tested (10-500 ng).3. It is concluded that in the rat only large doses of angiotensin are capable of indirectly stimulating the sympathetic nerves either at the site of their ganglionic cells or their post-ganglionic nerve ending.

Adrenalectomy↗

PubMed1976

Cardiovascular effects of diethylcarbamazine citrate.

1 The cardiovascular effects of the anthelmintic drug diethylcarbamazine citrate (DECC) were examined in cats anaesthetized with pentobarbitone. There were two quite distinct haemodynamic responses, an initial transient hypotension (occurring within 10 s of an intravenous injection) and a pronounced secondary hypertension which reached a peak 30-60 s after the injection. 2 Within 10 s of an intravenous injection of DECC (2.5 to 10 mg/kg) there was hypotension, bradycardia and there were reductions in left ventricular and carotid artery dP/dt max. These effects were most pronounced following injections into the pulmonary artery; they were not observed after bilateral vagotomy or after injections into the lumen of the left ventricle. It is suggested that DECC, like nicotine, stimulates vagal receptors in the pulmonary vascular bed. 3 The secondary phase was characterized by marked systemic and pulmonary hypertension, by contractions of the nictitating membrane and by increases in left ventricular dP/dt (at fixed isovolumic pressures), in cardiac output and in myocardial blood flow. All these effects were prevented, or markedly reduced, following the administration of hexamethonium or bethanidine and the pressor response was prevented by phentolamine. It is concluded that, in doses similar to those used in therapeutics, DECC stimulates sympathetic ganglia and releases noradrenaline. The relevance of this finding to the reported side effects of the drug are discussed. 4 DECC (5 or 10 mg/kg) significantly inhibited prostaglandin F2alpha-induced increases in peak inspiratory intra-tracheal pressure without modifying its pulmonary hypertensive effect. The possible relevance of this finding to the use of DECC in asthma is discussed.

Animals↗

PubMed1991

Implantable pharmacological defibrillator (AIPhD): preliminary investigations in animals.

The treatment of ventricular fibrillation (VF) by means of automatic implantable cardioverter defibrillators (AICD) poses many severe problems and limitations at the present time. In order to overcome these problems, we propose a totally new way to terminate VF or ventricular sustained tachycardia (VST). Our proposal consists of replacing the electric shock, which is dangerous, delayed, and sometimes ineffective, with a "chemical" shock: i.e., a chemical bolus retroperfused in the coronary sinus (CS) immediately after VF arises. The possible device is hypothesized and preliminary investigations in animals, performed to verify the theoretical assumption, are presented. In rabbits, and in larger animals (sheep and swine). Drugs were perfused in the coronary bed: lidocaine was used in 86% and bretylium tosylate in 14% of the animals. The results were: lidocaine immediately terminated VF in 100% and sinus rhythm was restored in rabbits; lidocaine terminated VF in VST in sheep; and in swine, bretylium immediately produced sinus rhythm in one case; in another one, only delayed sinus rhythm was achieved but lasted a short time; in the last case ventricular tachycardia at 128 beats/min appeared. Because new drugs, which are really "defibrillating" drugs, are available (bretylium tosylate, bethanidine, clofilium, tricyclic antidepressants, phenotiazine derivatives), we plan to investigate these defibrillating drugs in isolated hearts, found in suitable animals like dogs (sheep and swine are difficult to defibrillate) and in humans during routine electropharmacological studies.

Animals↗

PubMed1980

Central cardiovascular and biochemical effects of baclofen in the conscious rat.

Baclofen (beta-D-chlorophenyl-GABA, 1.25-10 mg kg-1 i.p.) elicited dose-dependent increases in blood pressure and heart rate in conscious rats. similar responses were observed after intracisternal or intracerebroventricular injections of baclofen 0.125-1 microgram kg-1. Baclofen i.p. was largely ineffective after spinal transection at C7. Pretreatment with phenoxybenzamine, bethanidine or hexamethonium antagonized the cardiovascular effects of i.p. baclofen. These actions were significantly attenuated after catecholamine depletion and synthesis inhibition by means of alpha-methyl-m-tyrosine and alpha-methyl-p-tyrosine. The responses to baclofen were not affected by bilateral adrenal demedullation but abolished by pentobarbitone anaesthesia. Hence, the cardiovascular effects of baclofen are probably evoked from central nervous structures and mediated via the sympathetic nervous system. In doses corresponding to those used in the circulatory studies i.p. baclofen increaed endogenous concentrations of brain DA and decreased DA utilization but only slightly affected brain NA concentrations and utilization.

Anesthesia↗

PubMed1969

The kidneys and arterial pressure in immature and adult rabbits.

1. The effect of stepwise haemorrhage on arterial pressure in adult and immature (9-15 days old) rabbits lightly anaesthetized with sodium pentobarbitone is described.2. Bethanidine (1 or 3 mg/kg) lowered initial arterial pressure but did not impair the maintenance of arterial pressure in immature or adult rabbits during stepwise haemorrhage.3. Arterial pressure was only slightly lower in nephrectomized than in intact adult rabbits; in some immature rabbits nephrectomy caused a substantial fall of resting arterial pressure. This fall was largest in animals of low body weight and low haematocrit. Nephrectomy reduced the ability of both immature and adult rabbits to maintain arterial pressure during haemorrhage.4. Arterial pressure fell more precipitately on stepwise haemorrhage in adult rabbits in which the carotid sinus and depressor nerves had been cut than in intact rabbits. No such difference was seen in immature rabbits despite the fact that initial arterial pressure was higher in denervated animals at all ages.5. The responses to stepwise haemorrhage were compared in dummy operated and nephrectomized immature and adult rabbits with carotid sinus and depressor nerves cut to minimize changes of sympathetic tone. Under these conditions the presence or absence of kidneys made no significant difference in the response to stepwise bleeding in adult rabbits. In immature rabbits maintenance of arterial pressure was greatly impaired in the absence of the kidneys.6. The results suggest that a pressor mechanism of renal origin may be relatively more important in the maintenance of arterial pressure in the face of haemorrhage in immature than in adult rabbits.7. Resting arterial pressure in small and anaemic immature rabbits may partly depend on the presence of the kidneys. At birth arterial pressure is higher in rabbits of higher haematocrit but this relationship reverses in the second week of life when the haematocrit level is falling.

Age Factors↗

PubMed1969

Sweat gland function of the donkey (Equus asinus).

1. Donkeys sweat on exposure to heat and in response to intravenous adrenaline infusion.2. Thermal sweating was abolished by the adrenergic-neurone blocking agent bethanidine but not by atropine.3. Sympathetic decentralization (by preganglionic sympathectomy) abolished thermal sweating but adreno-medullary denervation had no effect.4. Exercise resulted in sweating from both sympathetically innervated and decentralized skin and from the innervated skin of animals which had previously undergone adreno-medullary denervation.5. Insulin-induced hypoglycaemia resulted in sweating from sympathetically decentralized skin and from innervated skin in two out of four animals. Adreno-medullary denervation abolished the sweat gland response to insulin administration.6. Cold exposure inhibited the response of innervated sweat glands but not that of decentralized glands to adrenaline infusion.7. It was concluded that heat-induced and exercise-induced sweating of the donkey is controlled by adrenergic nerves; adreno-medullary secretion may contribute to sweating during exercise, and that cutaneous blood flow is important in the response of the glands to humoral stimulation.

Adrenal Medulla↗

PubMed1972

Outpatient treatment trial of mild and severe hypertension.

Not much is known about the feasibility or the advantages of treatment of subjects with only mild hypertension. There are also many unresolved problems in the outpatient management of hypertension of any severity. In this study an analysis is made of the results of a controlled treatment trial of 56 subjects with mild hypertension, 26 of whom were treated with active drug and 30 initially with placebo, and a treatment programme involving 81 patients with moderate or severe hypertension, all of whom received treatment with active drug. The drugs used in this study were bethanidine, debrisoquine, and guanethidine.Follow-up for 12 months or more was achieved in 87% of individuals admitted to the study with mild hypertension and in 80% with severe hypertension. Many subjects with only mildly raised blood pressure were found to have cardiac enlargement on chest x-ray (up to 45%) and left ventricular hypertrophy on electrocardiogram (up to 51%). Rapid rates of rise of blood pressure were observed in many placebo-treated subjects; but good blood pressure control was achieved in 63 out of 104 patients (61%) receiving active drug in both the mild and the severe hypertension groups. The drugs used showed approximately equal effectiveness in controlling blood pressure.

Adult↗

PubMed1982

Community care compared with hospital outpatient care for hypertensive patients.

Three hundred and seventy-six patients with treated diastolic blood pressures of less than 105 mm Hg and no history of accelerated hypertension or renal failure were selected from among those attending the Hammersmith Hospital hypertension clinic. Their average lying treated blood pressure was 146 mm Hg systolic and 90 mm Hg diastolic and average age 56 years; 18% were black, 6% Asian, and 76% white. The patients were mostly having multiple treatment, 90% receiving a diuretic, 35% methyldopa, 33% propranolol, 18% atenolol, 9% hydrallazine, and 7% bethanidine. They were randomly allocated to either two years of further hospital outpatient care or referred back to their general practitioners. During the two years 19 (10%) of the 187 patients followed up in hospital defaulted and three had their treatment discontinued. Twelve (6%) of the 189 followed up by their general practitioners defaulted from follow-up and nine had their treatment discontinued. At the end of the trial the average lying blood pressure was 148 mm Hg systolic and 88 mm Hg diastolic in the hospital group and 149 mm Hg systolic and 90 mm Hg diastolic in the general practice group. The change in blood pressure was calculated for each individual and showed an average fall of 1.6 mm Hg in standing diastolic pressure in the hospital group and a rise of 1.4 mm Hg in the general practice group (p less than 0.05). The 90% confidence limits for a difference in standing diastolic pressure between the groups were 1 and 5 mm Hg with the pressure lower in the hospital group. General practice care was not quite as effective in controlling blood pressure as continued specialist supervision over two years in this selected group of treated outpatients with mild or moderate hypertension, but these results show that the discharge back to general practitioners of patients who are well controlled after hospital treatment is a sensible policy.

Adult↗

PubMed1973

Side effects of hypotensive agents evaluated by a self-administered questionnaire.

A self-administered symptom questionnaire was completed by 477 patients in a hypertension clinic. The complaints of the patients were analysed according to the type of therapy being given and the dose of drug taken. Methyldopa therapy was associated with sleepiness, weakness of the limbs, sleeping longer at night, and rising more frequently at night to pass urine. Diarrhoea, impotence, failure of ejaculation, blurred vision, depression, and the symptoms of postural hypotension were not related to methyldopa therapy. Bethanidine administration was related to postural hypotension, impotence, and failure of ejaculation but not to weakness of the limbs, blurred vision, depression, or diarrhoea. Patients receiving guanethidine complained of postural hypotension, failure of ejaculation, and had their bowels open more frequently. Similarly, patients receiving propranolol had an increased frequency of defaecation but also tended to complain of weakness of the limbs.Considering each drug individually, 5% of patients failed to take the prescribed dose of diuretic whereas

Antihypertensive Agents↗

PubMed1972

Drug interactions in patients on long-term oral anticoagulant and antihypertensive adrenergic neuron-blocking drugs.

The occurrence of drug interactions was studied in outpatients on anticoagulant or adrenergic neuron-blocking drugs. In the anticoagulant group (254 patients) a theoretical potential drug interaction with warfarin was noted in 33% of patients with drugs supplied by prescription and in 30% of patients with drugs taken as self-medication, though a probable adverse drug interaction was documented in only 9% of patients. The deficiency in the transfer of information about current drug therapy and the lack of awareness of patients about the hazards of anticoagulant therapy was clear.In the 64 patients on the adrenergic neuron-blocking drugs guanethidine, bethanidine, or debrisoquine a theoretical potential drug interaction was noted in 34%, but a probable adverse drug interaction was documented in only three patients. Further studies are required of other well-recognized groups of patients on drugs which are known to interact to assess the relevance and clinical importance of the formidable lists of interactions which are now available to doctors who prescribe drugs.

Adult↗

PubMed1989

Amiodarone: biochemical evidence for binding to a receptor for class I drugs associated with the rat cardiac sodium channel.

Amiodarone has multiple pharmacological effects in heart. Electrophysiological data suggest that among its other effects, amiodarone is a sodium channel blocker. Using a radioligand assay, we determined whether amiodarone interacted with a previously described receptor for type I agents associated with the cardiac sodium channel. The radioligand was [3H]batrachotoxinin A 20 alpha-benzoate ([ 3H]BTXB), a toxin that binds to the activated state of the sodium channel. We have previously shown that class I antiarrhythmic drugs inhibit [3H]BTXB binding. The purpose of this study was to assess whether amiodarone and other class III agents interact with this receptor. Amiodarone inhibited [3H]BTXB binding in a dose-dependent fashion, with an estimated IC50 value of 3.6 microM. This IC50 value is similar to reported clinically effective serum concentrations of amiodarone. In contrast to amiodarone, the IC50 values for other class III drugs (bretylium, sotalol, bethanidine, N-acetylprocainamide) were much higher than their therapeutic concentrations and bore no relation to them. Scatchard analysis of [3H]BTXB binding showed that amiodarone reduced the maximal binding for [3H]BTXB; this finding indicates irreversible inhibition or (more likely) allosteric inhibition by amiodarone. The latter agrees with electrophysiological data suggesting that amiodarone binds to inactivated sodium channels. Sodium channel blockade by amiodarone may contribute to its overall electrophysiological effect.

Allosteric Site↗

PubMed1970

Guanethidine and related agents. 3. Antagonism by drugs which inhibit the norepinephrine pump in man.

Antagonism of the antihypertensive action of guanethidine by the tricyclic antidepressants, desipramine and protriptyline, has been demonstrated in controlled studies. These antidepressants also prevent the effect of the related ring-substituted guanidinium adrenergic neuron blockers, bethanidine and debrisoquin. That the rise in blood pressure when desipramine is added to guanethidine therapy is not due simply to a pressor action of the two drugs in combination was demonstrated by the lack of an increase in blood pressure when guanethidine was added to desipramine therapy. Investigations were conducted to determine whether antagonism of guanethidine's clinical effect could result from blockade by the tricyclic antidepressants of the norepinephrine pump in the adrenergic neuron membrane, thereby preventing the uptake of guanethidine into the neuron by this pump. Like guanethidine, the indirectly acting pressor amine, tyramine, enters the neuron via the norepinephrine pump. Desipramine, protriptyline, and amitriptyline in clinical doses all were found to block the pressor action of tyramine while potentiating the pressor effect of norepinephrine. The amino acid, methyldopa, does not enter the neuron via the norepinephrine pump, and its antihypertensive action is not altered by concomitant administration of tricyclic antidepressants. It is concluded from the evidence in this investigation together with the results of previous studies in experimental animals that clinical doses of desipramine-like drugs inhibit the norepinephrine pump in the peripheral adrenergic neuron in man and thereby prevent uptake of guanethidine to its site of action.

Antidepressive Agents↗

PubMed1988

Clinical suppression of refractory ventricular tachycardia with oral bretylium not predicted by electrophysiologic drug testing.

We report the findings in a patient in whom intravenous bretylium was the only effective agent to suppress refractory ventricular tachycardia and ventricular fibrillation. After attempts to switch the patient to amiodarone and bethanidine (an oral analogue of bretylium) caused proarrhythmic effects, he was successfully converted to oral therapy with bretylium. Electrophysiologic testing was not predictive of the clinical response from oral bretylium. To our knowledge, this is the first report of a proarrhythmic effect from bethanadine and it suggests a divergence in the actions of various class 3 antiarrhythmic agents.

Administration, Oral↗