INFLUENCE OF URAPIDIL ON α‐ AND β‐ADRENORECEPTORS IN PITHED RATS

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Abstract
The interaction of urapidil with pre- and postsynaptic .alpha.-adrenoreceptors and with postsynaptic .beta.-adrenoreceptors was studied in pithed normotensive rats and compared to the effects of clonidine, prazosin, and atenolol. I.v. injection of urapidil did not substantially change blood pressure, while clonidine raised blood pressure. Urapidil dose-dependently antagonized the pressor effects of the .alpha.1-agonist L-phenylephrine (pDR2 6.8) and of the .alpha.2-agonist azepexole (pDR2 5.2). Compared to urapidil, prazosin was a more potent antagonist of phenylephrine at postsynaptic vascular .alpha.1-adrenoreceptors (pDR2 8.7) and of azepexole at .alpha.2-adrenoreceptors (pDR2 5.6). Urapidil inhibited the tachycardia produced by discontinuous or continuous electrical stimulation of the thoracic spinal outflows (ID50 4.8 and 27.2 .mu.mol/kg, respectively). In contrast to the inhibitory action of clonidine (ID50 0.039 and 0.023 .mu.mol/kg, respectively), the inhibition by urapidil was not reversed by the selective .alpha.2-antagonist rauwolscine (10 .mu.mol/kg). Prazosin did not change stimulation-evoked tachycardia but atenolol caused pronounced inhibition (ID50 0.158 .mu.mol/kg, discontinuous stimulation). Urapidil dose-dependently antagonized the tachycardic effect of isoprenaline at .beta.1-adrenoreceptors (pDR2 5.1) but also exhibited intrinsic activity by increasing basal heart rate (maximum effect of urapidil was 30% of that of isoprenaline). Urapidil did not change the vasodilatory .beta.2-adrenoreceptor-mediated effect of isoprenaline. The results suggest that urapidil is an antagonist at postsynaptic vascular .alpha.1- and .alpha.2-adrenoreceptors, with a greater potency against .alpha.1-adrenoreceptors. An agonistic interaction of urapidil with presynaptic .alpha.2-adrenoreceptors could not be demonstrated in pithed rats. Instead, the inhibition by urapidil of stimulation-evoked tachycardia could be accounted for by its .beta.1-adrenoreceptor antagonistic effect.