Interactions of MEN 935 (adimolol), a long acting beta- and alpha-adrenolytic antihypertensive agent, with postsynaptic alpha-adrenoceptors in different isolated blood vessels — influence of angiotensin II

Summary

MEN 935 [1-(3-((3-(1-naphthoxy)-2-hydroxypropyl)amino)-3,3-dimethylpropyl)-2-benzimidazolinone-hydrochloride monohydrate, adimolol] is a long acting antihypertensive agent with beta- and alpha-adrenolytic properties. Preliminary experiments in pithed rats had led to the suggestion that the alpha-adrenolytic activity was of the alpha₂-subtype. The alpha-adrenolytic properties of MEN 935 were now tested in isolated vascular preparations of rat aorta, rabbit vena ischiadica and rabbit vena cava inferior against the selective alpha₁-adrenergic agonist phenylephrine (PE) and the selective alpha₂-adrenergic agonist BHT 920 [2-amino-6-allyl-5,6,7,8,-tetrahydro-4H-thiazolo-(4,5-d)azepine]. The experiments were performed in absence and in presence of 5×10⁻⁹ mol/l angiotensin II (A II).

MEN 935 antagonized contractions to phenylephrine as well as those to B-HT 920 in each vessel. A twofold shift to the right of the concentration-response curves to both agonists was obtained with concentrations between 1.9×10⁻⁸ and 1.4×10⁻⁵ mol/l, depending on the vessel under investigation. A II modulated the adrenolytic properties of MEN 935 in each vessel. However, irrespective of the presence or absence of A II, no pharmacologically relevant difference between antagonism against PE or B-HT 920 could be seen. In isolated vessels, MEN 935 exerts a nonselective alpha-adrenergic antagonism.

In receptor binding studies in rat cerebellar cortex, MEN 935 showed a K _i of 5.2×10⁻⁷ mol/l at alpha₁-adrenoceptors and a K _i of 1.3×10⁻⁵ mol/l at alpha₂-adrenoceptors. The K _i values were not influenced by 5×10⁻⁹ mol/l A II. These findings demonstrate an alpha₁-preference, but again no alpha-subtype selectivity.