Nitrendipine accumulates highly in intact cardiac tissue, suggesting its pharmacological action is mediated by binding into a superficial hydrophobic compartment.
Supports compartmental binding for nitrendipine action in vitro; leaves open clinical translation from this animal model.
The binding of [3H]-nitrendipine to intact, electrically driven isolated left atria of guinea-pigs was investigated over the concentration range 10(-10) M to 3 X 10(-5) M. A high affinity binding site saturable in the nM range as found in ventricular homogenates could not be detected. Instead the accumulation of nitrendipine in intact atria was found to be proportional to the concentration from 10(-10) M to 10(-6) M; beyond 10(-6) M the binding started to become saturated. Nitrendipine was highly accumulated in atrial tissue. The cell:medium ratios amounted to about 120 in the range from 10(-10) M to 10(-6) M. The concentration-response curve for the negative inotropic action of nitrendipine yielded an ED50 of 3 X 10(-7) M, thus lying within the range of concentration-proportional accumulation. The reduction of the contractile force proceeded faster (t1/2 less than 10 min) than the uptake process t1/2 approximately 40 min) suggesting that it is the binding of nitrendipine into a superficial compartment, which interferes with the excitation-contraction coupling. The results suggest that the high concentration of nitrendipine present in hydrophobic cellular compartments such as the plasmalemma might be involved in its pharmacological action.
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Lüllmann et al. (1987) studied this question.
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