Relative presynaptic and postsynaptic effects of urapidil on adrenoceptors in the rabbit pulmonary artery

Urapidil is a new antihypertensive drug which is thought to possess unique antiadrenergic properties. It is definitely a post-synaptic alpha adrenergic antagonist, but it also claimed to be a presynaptic alpha adrenergic agonist resulting in inhibition of norepinephrine release. To test the relative presynaptic and postsynaptic activity and selectivity in an isolated rabbit pulmonary arterial preparation, two series of studies were performed. The first evaluated the effects of urapidil on electrically evoked 3H overflow in the superfused vascular strip preincubated with [3H]norepinephrine. No significant inhibition of 3H overflow was observed. Rather, urapidil appeared to possess relatively weak presynaptic alpha-2 adrenergic antagonistic properties which were reversed by clonidine. The concentration producing a 30% increase in 3H overflow (EC30pre) was 7070 nM. The second series of studies evaluated the effects of urapidil on the concentration-contractile response curve to norepinephrine. Schild plot analysis yielded a pA2 value of 6.24 and a KBpost of 575 nM. One measure of the relative pre- and postsynaptic antagonistic potency is the EC30pre/KBpost ratio. For urapidil, this was 12.3, suggesting that the drug is a partially selective postsynaptic alpha adrenergic antagonist, with approximately 4.5 times the postsynaptic selectivity of phentolamine, but with 1/18 the potency of phentolamine to block postsynaptic alpha receptors.