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PubMed1991

Muscarinic receptors and parasympathetic neurotransmission in guinea-pig trachea.

Muscarinic receptors involved in cholinergic neurotransmission were studied in isolated innervated guinea-pig tracheas using preganglionic (nerve) and postganglionic (field) stimulation, after blocking sympathetic effects with bethanidine (5 microM). Neostigmine (10 nM) significantly increased responses to nerve and field stimulation. The M1 antagonist pirenzepine (0.1-100 nM) selectively reduced tracheal responses to nerve stimulation in control and in neostigmine-treated tissues. The M2 antagonist gallamine (0.1-100 microM) significantly increased tracheal responses to nerve and field stimulation in control and in neostigmine-treated preparations. At concentrations that increased baseline tone, oxotremorine, arecoline and pilocarpine decreased responses to nerve and field stimulation. Gallamine (30 microM) selectively reduced the inhibitory effects of these agonists on responses to nerve and field stimulation. The findings indicate that cholinergic neurotransmission in guinea-pig trachea is modulated by facilitatory M1 receptors at parasympathetic ganglia and inhibitory M2 receptors at the postganglionic nerve endings.

Animals↗
PubMed1994

Tolerance to peripheral, but not central, effects of ropinirole, a selective dopamine D2-like receptor agonist.

Studies were conducted to determine possible development, and underlying mechanisms, of tolerance to the hypotensive effects of ropinirole (4-[2-(dipropylamino)ethyl]-1-3-dihydro-2H-indol-2-one HCl), a selective dopamine receptor agonist, following twice daily oral administration to cynomolgus monkeys and spontaneously hypertensive rats (SHR). Tolerance to the hypotensive effects of the compound developed in both species within one week of repeated dosing. Tolerance which developed in rats was dose-related and could not be attributed to altered plasma/drug concentrations or be overcome by increasing the i.v. challenge dose of ropinirole. Cross-tolerance was shown to the dopamine receptor agonist bromocriptine. Similar hypotensive responses to bethanidine were seen in rats treated with ropinirole or vehicle. Tolerance to hypolocomotor effects of the compound were not apparent in the same time frame. The dopamine D2 receptor antagonist, domperidone, caused hypertension in ropinirole-but not vehicle-treated rats. Results reported in this paper are not consistent with a down-regulation of peripheral dopamine D2-like receptors but suggest a compensatory increase in basal sympathetic tone.

Administration, Oral↗
PubMed1981

Influence of sympatholytic drugs on the cardiovascular response to isometric exercise.

1. The effects of single oral doses of various sympatholytic drugs on the heart rate and blood pressure increases during isometric handgrip contraction were studied in six healthy subjects. 2. Bethanidine reduced both the systolic and diastolic increases in pressure. Clonidine reduced the systolic but not the diastolic increase. Oxprenolol alone or in combination with phentolamine or phenyoxybenzamine failed to influence the pressor response. 3. The increase in systemic blood pressure associated with sustained contraction of voluntary muscle appears to be relatively resistant to acute sympathetic adrenoreceptor blockade in man.

Adult↗
PubMed1977

Effect of lipid solvents on cutaneous moisture loss.

Application of various lipid solvents and dimethyl sulphoxide to the skin of cattle, sheep, eland and African buffalo exposed to an air temperature of 20 degrees C caused an increase in cutaneous moisture loss. The effect did not occur after exposure to an air temperature of 40 degrees C or after adrenaline administration. Blockage of sweating by either bethanidine or phenoxybenzamine did not affect the response. Camel, donkey, dog and man showed no increase in cutaneous moisture loss after lipid solvent application to the skin. It is concluded that lipid solvents directly stimulate the secretory cells of the sweat glands of members of the family Bovidae and that this is not due to the release of transmitter substance nor to stimulation of adrenergic receptors, but is due to direct stimulation of the sweat glands themselves.

Animals↗
PubMed1978

The response of the circular muscle layer of the guinea-pig isolated vas deferens to transmural electrical stimulation.

1 Four preparations are described for the isolation of the response of the circular muscle of the guinea-pig vas deferens. These are the ;Furchgott' strip, the ;Vane' strip, the chain preparation and the perfused preparation.2 The four preparations were stimulated transmurally with pulses of supramaximal voltage. The threshold pulse width to which the strips and the perfused preparation responded was 0.025 ms and the maximum responses occurred at 0.1 ms. The threshold frequency was 2 Hz for strip and perfused preparations, the maxima being 20 or 50 Hz for strip preparations and 100 Hz for perfused preparations. The effect of varying the number of pulses per train was also investigated on the perfused vas. Responses occurred to train lengths of 8, 16, 32, 128 pulses, the maximum response being given at 128 pulses at 100 Hz; 256 pulses per train did not produce a further increase in response. The perfused preparation exhibited an after-response at certain frequencies and train lengths.3 Tetrodotoxin and the local anaesthetics, procaine and lignocaine, reversibly abolished the responses of strip and perfused preparations to transmural stimulation.4 The response to intramural nerve fibre stimulation was abolished by guanethidine or bethanidine; this abolition was reversed by dexamphetamine. Noradrenaline contracted strip preparations of circular muscle and raised the pressure in perfused preparations; noradrenaline was competitively antagonized by thymoxamine. The major part of the motor innervation of the circular layer seems to be noradrenergic.

Anesthetics, Local↗
PubMed1982

Evaluation of drug-induced changes in myocardial repolarisation using the paced evoked response.

The use of the pace evoked response system in the assessment of drug-induced changes in myocardial repolarisation is reported. Using a conventional pacing electrode lead for both pacing and sensing, this system records the dominantly local repolarisation which follows a controlled (paced) depolarisation from the same site. Measurements of the latency of the ventricular evoked response at matched heart rates before and after drug administration permit the accurate direct comparison of the effects of drugs with class 3 mode of action on cardiac muscle repolarisation. Using this method we have evaluated the effect on the timing of the evoked T wave of two drugs which are known to prolong phase 2 of the action potential. Intravenous amiodarone (5 mg/kg) prolonged the stimulus-peak evoked T wave interval by an average of 39-4 ms (15% of control values); three hours after oral bethanidine (2 mg/kg) this interval increased by an average of 25.8 ms (10% of control values). The effect of therapeutic interventions on the latency of the local paced evoked response provides a simple, accurate assessment of their effect on the cellular action potential duration and constitutes a new tool in electrophysiological investigations.

Amiodarone↗
PubMed1976

Exertional hypotension due to postganglionic sympathetic blocking drugs.

Debrisoquine, guanethidine and bethanidine may produce troublesome hypotensive symtoms related to exertion. Thirteen patients with such symptoms were exercised on a treadmill and the response of blood pressure and heart rate was compared to that of thirty patients without these symptoms, who were exercised to the same extent. There was a slight drop of systolic and diastolic pressures on standing in both groups, but after exertion there was a significantly greater drop of systolic pressure in the group with symptoms than in the asymptomatic group. The diastolic pressure after exertion was significantly lower in the group with symptoms. It was impossible to predict from the standing blood pressure levels at rest which patients would develop hypotensive symptoms after exertion. All three drugs had a similar negative chronotropic effect at rest and on exercise. It is suggested that patients are exercised during control of hypertension in order to identify those prone to exertional hypotension. Patients with such hypotension should be exercised on each attendance before the blood pressure is measured. Treatment other than postganglionic sympathetic blocking drugs should be employed whenever possible in patients with milder hypertension.

Bethanidine↗
PubMed1976

Angina in hypertensive patients. With particular reference to the negative chronotropic effects of sympatholytic therapy.

There was no significant difference in the blood pressure and heart rate response of hypertensive patients with and without angina to standardised exercise on a treadmill before and after anti-hypertensive treatment. There was no improvement in exercise tolerance in the hypertensive patients with angina treated with bethanidine, debrisoquine or guanethidine despite a reduction of resting and exercise heart rates after treatment. The negative chronotropic effect of these sympatholytic drugs was less than that of oxprenolol or propranolol, but the hypotensive response was greater. Both of these beta-receptor blocking drug produced an an improvement in exercise tolerance in patients with angina either alone or in combination with other hypotensive therapy. The best control of blood pressure and angina was often achieved by a combination of a sympatholytic drug and beta-receptor blocking drug. In hypertensive patients treated for several years, angina at presentation was occassionally reduced by reduction of blood pressure. Later onset of angina appeared to be unrelated to control of hypertension but to be due to coincidental coronary occlusion. There was no evidence that myocardial infarction was precipitated by postural or exercise hypotension although these effects occasionally precipitated angina.

Adrenergic beta-Antagonists↗
PubMed1976

Dihydroergotamine: an effective treatment for postural hypotension due to antihypertensive drugs (ganglion-blocking agents excepted).

In this study the effect of DHE on postural hypotension induced by major antihypertensive drugs was evaluated in 40 patients. 30 patients were treated with methyldopa, five with guanoxan sulphate and five with bethanidine sulphate. To obtain a more accurate picture of the effectiveness of DHE and to test the reproducibility of its effect, each patient was observed during five separate, successive periods: in the first period the antihypertensive agent was given alone; in the second period it was given along with placebo; in the third period it was given with DHE; in the fourth period the antihypertensive agent was given alone again; and in the fifth period it was again given with DHE. In the third and in the fifth period, DHE was administered at the same time as the antihypertensive agent in a dose of 9-15 mg/24 h (3-5 mg three times daily). The first dose was given 1 h before rising, and the daily dosage was progressively increased. The beneficial effect of DHE on postural hypotension was evaluated by assessing the clinical symptoms in a semiquantitative manner and by measuring the arterial blood pressure and heart rate in a recumbent and standing position. The results were classified as follows: excellent, good, moderate and no response. In most cases, DHE was found to be an effective drug for the treatment of postural hypotension, an improvement in clinical symptoms being noted in 57.5% of patients tested (excellent and good results). In these patients the standing arterial blood pressure showed a significant response (p less than 0.01). DHE did not interfere with the therapeutic effect of the antihypertensive agents. Furthermore, DHE did not affect the heart rate, nor did it give rise to any adverse reactions.

Adolescent↗
PubMed1978

Effect of mianserin hydrochloride on peripheral uptake mechanisms for noradrenaline and 5-hydroxytryptamine in man.

1. Mianserin seems to have little effect on peripheral noradrenaline (NA) re-uptake mechanisms as shown by its lack of effects on the tyramine dose and NA dose/pressor response. 2. Mianserin has no effect on the hypotensive action of bethanidine. 3. Mianserin in vivo has a significant action on platlet transport (Vmax) of 5-hydroxytryptamine (5-HT), which changes toward normal values in depressive patients on the drug. This action is not observed in vitro. 4. It is possible that a metabolite of mianserin is responsible for this effect, and that this may be of therapeutic importance.

Antidepressive Agents↗
PubMed1978

Cardiovascular responses to mianserin hydrochloride: a comparison with tricyclic antidepressant drugs.

1. The cardiovascular responses of mianserin hydrochloride and tricyclic antidepressant drugs were investigated using non-invasive methods of cardiac investigation. A study of the interaction of mianserin and antihypertensive drug therapy is reported. 2. In six normal volunteers, mianserin hydrochloride 20 mg was shown to prolong the corrected Q-T interval at 150 min (P less than 0.001). It did not affect heart rate, systolic time intervals or the peak normalized derivative of the apexcardiogram. Amitriptyline 50 mg increased the corrected pre-ejection period interval (PEPI) and the PEP/left ventricular ejection time (LVET) ratio of the systolic time intervals at 150 min (P less than 0.001). Q-T interval was shortened at 90 minutes. 3. In a double-blind patient study, clomipramine increased heart rate, P-R interval, QRS and corrected Q-T interval in one patient at 2 weeks. Mianserin prolonged corrected Q-T interval at 1 week but this returned to the pretreatment time by 2 weeks in two patients. 4. In an open study, mianserin 20 mg three times daily did not antagonize the hypotensive action of propranolol or propranolol and hydrallazine in three patients. 5. In a double-blind study in three patients with desmethylimipramine 25 mg three times daily, mianserin 20 mg three times daily did not antagonize the hypotensive action of either guanethidine or bethanidine.

Adult↗
PubMed1977

A non-adrenergic inhibitory innervation in the rat stomach.

The inhibitory response to nerve stimulation was studied in three isolated preparations of the rat stomach. Bethanidine and guanethidine in doses sufficient to block adrenergic neurotransmission reduced but never abolished the inhibitory response to field stimulation of the rat stomach strip. In similar concentration of these drugs, the response to vagus nerve stimulation was diminished; higher doses of blocking agent abolished this response. Relaxation to both field and vagus nerve stimulation could be evoked in stoamchs removed from rats which had received sufficient reserpine to deplte tissue stores of noradrenaline. The response to vagus nerve stimulation was abolished by each of three known ganglion blocking agents. These results show that the rat stomach contains a non-adrenergic inhibitory innervation which is probably the final stage in a vagal pathway.

Adrenergic Agents↗
PubMed1981

Studies on the mechanism of action of the abortive effect of 6-hydroxydopamine in rats.

Administration of repeated large doses of 6-hydroxydopamine (6-OHDA)(100 mg/kg) to pregnant rats causes a 75% decrease in the litter size, which is accounted for a corresponding increase in the number of foetuses resorbed or stillborn. Guanethidine, which like 6-OHDA, causes a prolonged sympathectomy did not interfere with the course of the pregnancy nor did bethanidine which interferes with sympathetic transmission without causing ultrastructural damage. When 6-OHDA was given only prior to mating the abortive effect was no longer present, even though the concentration of noradrenaline in the peripheral sympathetic nerves was reduced for the entire duration of the pregnancy. The reported alpha-adrenoreceptor blocking effects of 6-OHDA are not exclusively responsible for the abortive effect, since injection of sympathectomised rats with phentolamine (10 mg/kg) had no abortive effect. There were normal concentrations of noradrenaline in the brains of pups born to mothers treated during pregnancy with 6-OHDA. Whether the same is true of those foetuses resorbed, remains unresolved. It seems likely that the abortive effect is not related to the depletion of noradrenaline but is due to other effects of 6-OHDA.

Abortifacient Agents↗
PubMed1976

The involvement of noradrenergic nerves in the cardiovascular reflex responses to lower body negative pressure in the anaesthetised rabbit.

1. Resting cardiovascular status and the reflex responses to lower body negative pressure (LBNP) were examined in control rabbits and in rabbits sympathectomised with 6-hydroxydopamine (6-OHDA). 2. Resting systemic arterial pressure and total peripheral resistance were significantly higher in control than in 6-OHDA treated animals. 3. Control animals responded to LBNP at -25 mm Hg with a peripheral vasoconstriction and tachycardia. These responses were absent in 6-OHDA-treated animals. 4. Control animals responded to LBNP at -70 mm Hg with a peripheral vasoconstriction and a bradycardia followed by a tachycardia. There was no significant change in heart rate in response to this stimulus in 6-OHDA-treated animals, although a slight vasoconstriction was seen. 5. Bethanidine blocked the tachycardia and vasoconstriction seen in response to LBNP in control and 6-OHDA-treated rabbits. Under these conditions there was no significant difference between the total peripheral resistance of the control and treated animals. 6. The results indicated that neither the maintenance of the resting systemic arterial pressure nor the reflexes elicited by LBNP in control or in chronically sympathectomised rabbits involved hormonal mechanisms, but LBNP was maintained for 1 min only. These findings are discussed in the context of previous observations.

Animals↗
PubMed1984

Antidysrhythmic actions of meobentine sulfate.

The antiarrhythmic efficacy of meobentine sulfate, a bethanidine derivative lacking inhibitory effects on adrenergic neuronal function, was assessed in three canine models. Intravenous meobentine sulfate, administered in dosages of 5.0, 10,0, and 20.0 mg/kg, produced a dose-related increase in the ventricular fibrillation threshold (VFT) under nonischemic conditions (7.6 +/- 1.8 mA vs 37.8 +/- 8.6 mA) (20 mg/kg; p less than 0.05) and during regional myocardial ischemia (5.6 +/- 1.5 mA vs 41.8 +/- 9.1 mA) (20 mg/kg; p less than 0.05). The VFT was also increased in the presence of chronic ischemic injury (6.4 +/- 1 mA to 31 +/- 10 mA) (20 mg/kg; p 0.05). In the conscious dog, 4 days after an anterior myocardial infarction, programmed electrical stimulation (PES) produced nonsustained ventricular tachycardia (VT) in five dogs. After meobentine sulfate administration, eight of nine animals had sustained VT and one animal developed ventricular fibrillation (VF). At a dose of 20 mg/kg, there was prolongation of the cycle length of the VT (169 +/- 11 msec to 237 +/- 20 msec), prolongation of the QRS duration (58 +/- 2.6 msec to 71 +/- 3.7 msec), and prolongation of the delay in epicardial activation. There was an enhanced potential after meobentine administration for programmed stimulation to produce ventricular arrhythmias with the introduction of fewer premature impulses. In the third canine model, conscious dogs with a previous anterior myocardial infarction developed VF in response to electrically induced left circumflex coronary artery injury. Meobentine (20 mg/kg) failed to prevent VF in eight of eight dogs. These results suggest that while meobentine sulfate significantly increases the electrical VFT, it does not protect the conscious canine from the induction of ventricular tachyarrhythmias in response to PES, and it does not prevent VF in a conscious canine model of sudden coronary death.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

Meobentine sulfate: antiarrhythmic and electrophysiologic effects assessed by programmed electrical stimulation and ambulatory monitoring in patients with complex ventricular tachyarrhythmia. Report of a multicenter evaluation.

Five cardiology centers conducted open-label prospective trials of meobentine sulfate, an intravenously and orally available analog of bethanidine, to assess its potential for treatment of recurrent, drug refractory ventricular tachycardia (VT) or fibrillation (VF), and complex ventricular arrhythmias. The study population comprised 26 patients (mean age, 61 years); 18 were men. Coronary artery disease was present in 15, cardiomyopathy in six, and valvular heart disease in three. Patients presented with both VT and VF (seven), sustained VT alone (12), or frequent ventricular ectopy (PVCs) and nonsustained VT (seven). Of the 26 patients, 5 were enrolled in antiarrhythmic studies (chronic PVC suppression) and 21 were enrolled in programmed electrical stimulation (PES) studies. Two of five in the chronic PVC study showed greater than 75% arrhythmia suppression. Among 21 patients in PES studies, there were eight intravenous (16 mg/kg) and 19 oral trials (400 to 1000 mg every 6 hours, 3 days/dose interval). Five of 22 patients showed efficacy at repeat PES study (neither VT nor VF), one showed partial efficacy, and four were not restudied because of clinical arrhythmia (three) and/or adverse effects (two). Overall, three patients (12%) were continued on the drug for an extended period of time. Adverse experience included hypotension in 50% and gastrointestinal effects (nausea, vomiting, or diarrhea) in 56% (oral trials only). Adverse reactions led to drug discontinuation in six and dosage reduction in eight patients. Thus, meobentine may prevent induction of VT or VF or reduce frequency of complex PVCs in selected patients refractory to other antiarrhythmic agents, but the response rate is relatively low. Symptomatic hypotension or gastrointestinal adverse effects are common and may limit utility of meobentine as a chronic oral antiarrhythmic agent.

Administration, Oral↗
PubMed1986

Lorcainide therapy in a cardiac arrest population.

Thirty-eight patients with prior history of cardiac arrest underwent programmed electrical stimulation (PES) studies and serial drug testing. Lorcainide was tested acutely in all 38 patients and prevented ventricular tachycardia (VT) or ventricular fibrillation (VF) induction in 14 patients and failed in 24 (efficacy rate 37%). Procainamide had failed clinically (cardiac arrest or breakthrough VT) in 16 patients, seven patients had previously severe adverse side effects, and thus only 15 were tested on procainamide at PES testing with seven protected. Following initial studies, 14 patients were started on lorcainide oral therapy and 24 on other therapy determined effective at PES testing (N-acetylprocainamide-two, flecainide-nine, bethanidine-three, slow-release procainamide hydrochloride-three, quinidine-two, cibenzoline-one, amiodarone-four). After 29 +/- 7 months follow-up, three are alive on lorcainide therapy, five discontinued therapy due to side effects; six died--three sudden deaths (33%) and two cardiac deaths (both myocardial infarctions). Twenty out of 24 patients are alive who were started on PES predicted effective therapy other than lorcainide; four died--three sudden deaths (13%) and one cardiac nonsudden death. Antiarrhythmic therapy guided by PES studies gives overall encouraging results in a cardiac arrest group of patients. Lorcainide, however, is not tolerated well and affords less protection against a sudden death recurrence than is noted in a population on other antiarrhythmic therapy predicted effective at PES testing.

Arrhythmias, Cardiac↗
PubMed1975

Current therapy of hypertension. A pharmacologic approach.

Adequate treatment of hypertension requires that the physician understand the pharmacologic actions of antihypertensive agents. Although no drug is without adverse reactions, it should be possible to choose an agent or combination of agents which can effectively lower blood pressure and be tolerated by the patient. The indications, proposed mechanisms of actions and adverse effects of the following antihypertensive drugs are discussed: thiazide diuretics, spironolactone, triamterene, trimethaphan, Rauwolfia alkaloids. guanethidine, bethanidine, methyldopa, clonidine, pargyline, propranolol, hydrazaline, minoxidil, guancydine, diazoxide and sodium nitroprusside.

Adrenergic alpha-Antagonists↗