Effects of chronic treatment with verapamil on adrenoceptor-mediated contraction of rabbit aorta.

Rabbits received twice-a-day doses of verapamil for 8 days and, on day 9 they were sacrificed in order to test contractile responses of the aorta in vitro. Isolated rings of aorta received graded doses of KCl, norepinephrine and norepinephrine along with either phentolamine, phenoxybenzamine or additional (acute) verapamil. Treated rings (those from animals that received verapamil chronically) developed significantly less tension (E) in response to depolarizing doses of KCl, but the degree of developed tension was restored and, in fact, enhanced when the aortic tissue was tested after cold storage 24 hr later (day 10). Responses (E) to norepinephrine in verapamil-pretreated rings were less than in controls by amounts that correlated with the daily verapamil dose and these too were enhanced after cold storage for 24 hr. The equilibrium dissociation constant (KA) of norepinephrine for the alpha 1-adrenoceptor, determined by the method of partial receptor blockade, was increased (reduction in affinity) by amounts that also depended on the daily verapamil dose. In contrast to agonist affinity, phentolamine affinity, determined from Schild-plot analysis, was not different from controls, even for the highest daily dosage of verapamil. Stimulus-effect curves were also the same in control and verapamil-pretreated groups, thus suggesting that the chronic treatment did not affect the basic contractile process distal to the receptor. Further, aortae from pretreated rabbits showed more depression to acute verapamil than was seen in controls and this depression in Emax could not be overcome with even high doses of norepinephrine. In addition to the known alpha-blocking and calcium channel blocking actions of verapamil, these data show that chronic verapamil affects norepinephrine, but not phentolamine-receptor affinity, thus suggesting that the chronic action of this calcium entry blocker may preferentially alter a site on the receptor to which norepinephrine binds.