Diltiazem: lack of myocardial beta-adrenergic receptor-binding capacity

It has been suggested that the mechanism of action of the calcium blocker diltiazem (DZ) is via beta-receptor blockade. In order to test this hypothesis, the effects of DZ on the competitive binding of 3H-dihydroalprenolol (3H-DHA) to myocardial beta-receptors were evaluated and compared to those of a known beta-receptor agonist. Preliminary validation studies indicate that binding sites for 3H-DHA exhibit stereospecificity for isoproterenol (IP) (l-IP>d-IP) and show greater affinity for l-epinephrine compared to l-norepinephrine. In order to test the binding capacity of DZ to beta-adrenergic receptors, binding-concentration relationships were constructed for 3H-DHA (3--60 nM) in the presence of no drugs, l-IP (10(-4) M), or DZ (2.2 x 10(-6) M). 3H-DHA binding was significantly inhibited over the entire concentration range by 1-IP but was unaffected by the other conditions. This study was repeated using two different concentrations of DZ (2.2 x 10(-5) and 2.2 x 10(-7) M) with a similar lack of inhibition of 3H-DHA binding. These data indicate that DZ does not bind to myocardial beta-receptors and, therefore, does not appear to act via a beta-receptor-blocking activity.