The effect of urapidil on responses to phenylephrine, angiotensin and isoprenaline in man.

Intravenous urapidil, 40 mg bolus followed by an infusion of 18 mg.h-1 for 2 h was administered to 6 female non-patient volunteers. Randomised cumulative dose response curves to angiotensin, phenylephrine and isoprenaline were performed before and commencing 30 min after the start of the infusion of urapidil. Urapidil significantly reduced supine systolic blood pressure, 118.5 mm Hg to 105.3. The diastolic blood pressure was not significantly reduced, heart rate was not affected. Urapidil did not affect the responses to angiotensin or isoprenaline. Urapidil inhibited the pressor response to phenylephrine. The dose required to increase systolic blood pressure by 20 mm Hg increased from 156.9 micrograms.min-1 before to 685 micrograms.min-1 during urapidil; Dose ratio from individual values of 4.58. Urapidil concentrations were not significantly different before and after each agonist infusion. It is concluded that urapidil has alpha 1-adrenoceptor blocking activity in man without any non specific vasodilator action and that it is devoid of beta adrenoceptor blocking action.

Selective beta-adrenoceptor partial agonist effects of pindolol and xamoterol on skeletal muscle assessed by plasma creatine kinase changes in healthy subjects.

1. The effects of selective beta-adrenoceptor partial agonist activity on plasma creatine kinase (CK) and skeletal muscle symptoms were studied in normal volunteers. 2. A drug with beta 1-selective partial agonist activity (xamoterol) and one with partial agonist activity acting mainly through beta 2-adrenoceptors (pindolol) were each given for 3 weeks in a randomised double-blind crossover study in 10 subjects. Five additional subjects received only one drug. Plasma CK levels were monitored during a baseline placebo run-in phase, the active treatment period and a placebo washout phase which continued until CK levels returned to baseline. 3. The degree of beta-adrenoceptor antagonism was determined by the inhibition of exercise-induced tachycardia and was similar for the two drug doses used. 4. During pindolol administration plasma CK levels rose compared with pretreatment baseline levels and with levels during xamoterol administration which did not rise. After pindolol was withdrawn CK levels reached higher peaks in some subjects after 1-5 days. 5. Muscle cramps were reported by five subjects during pindolol administration and by one of these subjects but to a lesser extent during xamoterol administration. 6. Pindolol may produce this effect, which was not seen with xamoterol, because of its specific beta 2-adrenoceptor partial agonist activity. Elevations in plasma CK produced by this type of drug or its withdrawal may cause confusion in the diagnosis of muscle disease or myocardial infarction unless the myocardial isoenzyme is measured.

Urapidil, a multiple-action alpha-blocking drug.

Investigations in animals indicate that urapidil has a number of actions that may be relevant to its antihypertensive effect. It has an alpha 1-blocking action, a weak beta 1-blocking effect, an interaction with a serotonin receptor and a central depression of sympathetic tone. Urapidil is well absorbed orally with a bioavailability of about 70% and a time to peak concentration of about 4 hours after a sustained release capsule. It is metabolized in the liver at a half-life of 4.7 hours. Peripheral alpha 1-blocking activity has been demonstrated in humans. A shift to the right in the dose-response curve to phenylephrine has been found after urapidil, whereas responses to angiotensin are not affected. Evidence for beta 1-blocking activity is marginal. Urapidil does not inhibit the exercise increase in heart rate. Some investigators have suggested a possible inhibition of isoprenaline tachycardia; others have found no evidence. There is some evidence suggestive of a central action of urapidil in humans as lower single doses result in a decrease in blood pressure and an increase in heart rate. With higher doses the hypotensive effect continues but the tachycardia no longer occurs. However, urapidil has been reported to increase noradrenaline levels, although there has been a report with a high dose reducing vanillylmandelic acid excretion. Evidence for changes in renin is inconsistent. Hemodynamic studies have revealed findings that are compatible with peripheral alpha 1 blockade. After intravenous administration, peripheral resistance is reduced along with arterial pressure, and cardiac output is increased.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical pharmacology of urapidil.

Animal investigations suggest that the mechanism of the antihypertensive effect of urapidil may be complex. Suggestions have included an alpha 1-blocking action, a weak beta 1-blocking effect, an interaction with a serotonin receptor and a central depression of sympathetic tone. Peripheral alpha 1-blocking activity has been demonstrated in man, and a shift to the right in the dose-response curve to phenylephrine has been found after administration of urapidil, while responses to angiotensin are not affected. Evidence for beta 1-blocking activity is marginal, but urapidil does not inhibit the exercise-induced increase in the heart rate, and there is only some suggestion of a possible inhibition of isoprenaline-induced tachycardia. Possible central activity may be deduced from the observation that while lower single doses reduce blood pressure and increase the heart rate, with higher doses the hypotensive effect continues but the tachycardia no longer occurs. However, lower doses of urapidil lead to an increase in noradrenaline levels, while changes in renin are less constant, but there has been a report that a high dose reduced vanillylmandelic acid excretion. Urapidil reduces peripheral resistance along with arterial pressure, and cardiac output is increased. In spite of a reduced arterial pressure, renal blood flow is maintained, presumably due to dilation of renal vessels. Urapidil is well absorbed orally with a bioavailability of about 70% and a tmax at about 4 h after a sustained release capsule. It is metabolized in the liver with a t1/2 of 4.7 h. In conclusion there is evidence that urapidil is an alpha 1-blocking drug in man.(ABSTRACT TRUNCATED AT 250 WORDS)