Effects of indoramin in rat vas deferens and aorta: concomitant alpha1-adrenoceptor and neuronal uptake blockade. (1/14)

1. The actions of the alpha1-adrenoceptor antagonist indoramin have been examined against the contractions induced by noradrenaline in the rat vas deferens and aorta taking into account a putative neuronal uptake blocking activity of this antagonist which could result in self-cancelling actions. 2. Indoramin behaved as a simple competitive antagonist of the contractions induced by noradrenaline in the vas deferens and aorta yielding pA2 values of 7.38+/-0.05 (slope=0.98+/-0.03) and 6.78+/-0.14 (slope=1.08+/-0.06), respectively. 3. When the experiments were repeated in the presence of cocaine (6 microM) the potency (pA2) of indoramin in antagonizing the contractions of the vas deferens to noradrenaline was increased to 8.72+/-0.07 (slope=1.10+/-0.05) while its potency remained unchanged in the aorta (pA2=6.69+/-0.12; slope=1.04+/-0.05). 4. In denervated vas deferens, indoramin antagonized the contractions to noradrenaline with a potency similar to that found in the presence of cocaine (8.79+/-0.07; slope=1.09+/-0.06). 5. It is suggested that indoramin blocks alpha1-adrenoceptors and neuronal uptake in rat vas deferens resulting in Schild plots with slopes not different from unity even in the absence of selective inhibition of neuronal uptake. As a major consequence of this double mechanism of action, the pA2 values for this antagonist are underestimated when calculated in situations where the neuronal uptake is active, yielding spurious pKB values.  (+info)

Prokinetic effect of indoramin, an alpha-adrenergic antagonist, on human gall-bladder. (2/14)

BACKGROUND: The effects of alpha- and beta-adrenergic agents on gall-bladder motility remain undefined. AIM: To determine the effects of alpha- and beta-antagonists on gall-bladder motility in healthy humans. METHODS: In this single, blind, three-way crossover study, a slow-release formulation of propranolol 80 mg (beta-antagonist), indoramin 25 mg (post-synaptic alpha1-antagonist) and placebo were administered to 10 healthy volunteers on three separate days 8 h before the assessment of gall-bladder volumes by ultrasonography. Gall-bladder volumes were assessed in the fasting state and at 5-min intervals for 50 min after a standard proprietary enteral feed (Ensure 186 mL, Abbott). RESULTS: The fasting gall-bladder volumes of subjects who received placebo or indoramin were significantly different (mean +/- S.E.M.: 16.50 +/- 2.78 mL and 13.47 +/- 2.24 mL, respectively; P < 0.001, two-way analysis of variance). The fasting gall-bladder volume after the administration of propranolol was 17.49 +/- 2.37 mL and was not significantly different from placebo (16.50 +/- 2.78 mL). When the mean post-prandial gall-bladder volumes were compared, indoramin significantly enhanced post-prandial gall-bladder emptying compared to placebo (P < 0.001). There was no significant post-prandial volume difference between placebo and propranolol. CONCLUSIONS: Indoramin, an alpha-adrenergic antagonist, acts as a prokinetic agent, enhancing post-prandial gall-bladder emptying in healthy individuals.  (+info)

Anti-arrhythmic properties of the alpha-adrenoceptor blocking drug indoramin. (3/14)

1. The anti-arrhythmic properties of the alpha-adrenoceptor blocking drug indoramin were compared with the effect of disopyramide and placebo in a randomised, single-blind, cross-over study. Two doses of indoramin were tested, 25 mg and 50 mg and the dose of disopyramide was 150 mg. All treatments were administered three times daily. 2. Forty patients with benign ventricular arrhythmia were studied. 3. Assessment was by 24 h ambulatory electrocardiography at entry and at the end of each 2 week treatment period. 4. Indoramin was found to have a significant anti-arrhythmic effect compared with placebo, but only at the higher dose tested. 5. The anti-arrhythmic effect was less than that achieved with disopyramide. 6. The mechanism for this anti-arrhythmic effect is unknown but these results suggest that alpha-adrenoceptor blockade may merit further attention as an anti-arrhythmic treatment.  (+info)

The pharmacokinetics of oral indoramin during pregnancy. (4/14)

1. The pharmacokinetics of indoramin (Baratol; Wyeth) and its active metabolite 6-hydroxyindoramin administered to 13 women as a single 37.5 mg dose of indoramin were compared under pregnant and post-partum conditions. 2. No significant differences were observed between values determined under pregnant and post-partum conditions, for any pharmacokinetic parameter. Cmax and AUC values in individual subjects differed, in most cases, by no more than two-fold, i.e. the same order of magnitude as intra-subject variation seen in volunteers dosed repeatedly with indoramin. 3. Median values of Cmax, AUC(0.24) and t 1/2,z were of a similar order to values seen previously in normal volunteers after a single 37.5 mg dose. 4. It is concluded that in treating hypertension associated with pregnancy, this study does not provide evidence to depart from the usual clinical practice of titrating indoramin dosage with control of blood pressure as the end-point, keeping in mind the restriction of the dose-limiting side-effect of sedation.  (+info)

Improvement in angina pectoris with alpha adrenoceptor blockade. (5/14)

The effects of indoramin, a selective alpha 1 adrenoceptor antagonist, on exercise tolerance were studied in 15 patients using a random double blind crossover protocol. All patients had chronic stable angina, for which 13 had been receiving beta adrenoceptor blocking drugs and nitrates, and these were continued unchanged throughout the study. An initial open challenge with indoramin in eight patients with chronic stable angina showed no serious adverse effects. In a dose of 25 mg three times daily indoramin prolonged exercise duration and increased oxygen consumption during exercise, while the maximal double product was unchanged. The increased exercise capacity was associated with a reduction in ST segment depression during exercise. Side effects included failure of ejaculation in one patient and tiredness in five. These results indicate than alpha 1 adrenoceptor blockade may provide useful additional benefit to patients with stable angina pectoris who are already receiving beta blockers and nitrates.  (+info)

Intravenous tyramine response in migraine before and during treatment with indoramin. (6/14)

We studied the response of 31 migraine sufferers (20 women, 11 men) to intravenous tyramine (the tyraminedose)pressor response test). Patients were treated either with pacebo tablets or indoramin, and alpha-adrenergic blocking agent, in a double-blind crrossover trial. We found that patients with migraine required significantly less tyramine to increase their cystolic blod pressure by 30 mm Hg when compared with matched controls. Indoramin significantly increased the amount of tyramine needed to raise the systolic blood pressure among migraine suffers and reduced the incidence of posttyramine migraine for m 46% while patients were on placebo tablets to 8% when they were receiveing indoramin. There was no association between tyramine sensitivity and a history of premenstrual or dietary migraine, nor was there a significant difference in the indierenence in the incidence of post-tyramine migrain between men women. We conclude that the intravenous tyramine test may be valuable in assessing migraine suffers who will respond to an alpha-advenergic blocking agent such as indoramin.  (+info)

Indoramin-prolongation of repolarization time, a mechanism of bradycardia in man? (7/14)

The effect of indoramin, a selective alpha 1-adrenoceptor antagonist, on ECG time intervals in normal man was studied. Significant prolongation of QTc was observed after indoramin 100 mg, with no change in QRS duration. In addition, the slope of the RR/QT relationship was changed by indoramin 100 mg. These results suggest that indoramin may have Class III antiarrhythmic activity. If such activity were to affect the SA node, it may explain at least in part the observed lack of reflex tachycardia after indoramin administration.  (+info)

Investigation into the cardioregulatory properties of the alpha 1-adrenoceptor blocker indoramin. (8/14)

The cardioregulatory properties of the alpha 1-adrenoceptor blocker indoramin have been compared with those of prazosin in the anaesthetized rat. The effects of autonomic blockade on heart rate responses evoked by these two agents and their effects on blood pressure and heart rate after peripheral or central administration have been compared. Cumulative administration of indoramin (0.8-25.6 mg kg-1 i.v.) evoked significant decreases in arterial blood pressure and a concomitant bradycardia. Pithing or autonomic blockade, by pretreatment with a combination of practolol and bilateral vagotomy, prevented the bradycardia evoked by indoramin (0.8-3.2 mg kg-1 i.v.). Atropine sulphate pretreatment abolished the bradycardia until a cumulative dose of 25.6 mg kg-1(i.v.) of indoramin had been reached. Bilateral vagotomy, intravenous administration of atropine methylnitrate or practolol pretreatment attenuated the bradycardia. Prazosin (0.02-0.64 mg kg-1 i.v.) evoked a fall in arterial blood pressure of similar magnitude to that observed following indoramin. A bradycardia was evoked only at a relatively high dose (0.64 mg kg-1 i.v.). Intracisternal injection of indoramin or prazosin evoked bradycardia and hypotension at a dose which had no effect after intravenous injection (25 micrograms). Intracerebroventricular injection of indoramin (25 micrograms) had no significant effect on heart rate or blood pressure compared to control values, whereas prazosin (25 micrograms) evoked a significant tachycardia and hypotension. It is concluded that the bradycardia evoked by indoramin in the rat is not due to a direct action on the heart except possibly at high doses. Central alpha 1-adrenoceptor blockade, possibly in the brainstem region, results in a bradycardia and this may explain the lack of reflex tachycardia following the administration of indoramin.  (+info)

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