Verapamil competitively inhibits alpha 1-adrenergic and muscarinic but not beta-adrenergic receptors in rat myocardium.

Recent studies indicate that antagonism of calcium channels may not be the only mechanism whereby drugs such as verapamil alter myocardial function. We have examined the effect of verapamil on the binding of [3H]prazosin (alpha 1-adrenergic), [3H]quinuclidinyl benzilate (QNB, muscarinic) and [3H]dihydroalprenolol (DHA, beta-adrenergic) to membranes prepared from rat heart. Verapamil competed for the binding of these radioligands in the following rank order: [3H]prazosin greater than [3H]QNB greater than [3H]DHA (Ki for verapamil = 0.6 microM, 7 microM, and 72 microM, respectively). Verapamil (10 microM) competitively inhibited [3H]prazosin binding to rat ventricular membranes; the apparent dissociation constant (KD) of [3H]prazosin increased from 0.13 +/- 0.02 to 1.5 +/- 0.6 nM (SD) without change in maximal binding capacity (Bmax). The effect of verapamil on the affinity of [3H]prazosin was completely reversed by washing the membranes. The verapamil derivative D-600 also inhibited [3H]prazosin binding (Ki = 1.1 microM). Verapamil (30 microM) competitively inhibited [3H]QNB binding in both atria and ventricles and increased the apparent KD of [3H]QNB fivefold (from 0.07 nM to 0.32 nM) without decreasing Bmax. Verapamil was a less potent inhibitor of [3H]DHA binding and its effect was noncompetitive: the KD for DHA was unaltered by 100 microM verapamil while the Bmax decreased severalfold. We conclude that verapamil, at concentrations clinically achieved in the myocardium (approximately 1 microM), competitively inhibits binding to alpha 1-adrenergic and muscarinic receptors and that this inhibition may play a role in the effects of verapamil on the heart.