title: Relationship between steady-state depression of calcium-dependent action potentials and competition for binding sites by nifedipine, nitrendipine, and PY 108-068.
abstract: The objective of the present study was to determine the time-courses for depression and recovery of calcium-mediated action potentials in canine Purkinje fibers following exposure to dihydropyridine (DHP) calcium channel antagonists and to determine if the reported discrepancy (up to 1,000 X) between I50 values for inducing physiologic effects in isolated tissues and the dissociation constant (Kd) for [3H]nitrendipine binding to membrane sites could be reduced when physiologic measurements were made under experimentally determined steady-state conditions. Changes in dV/dtmax of slow calcium-mediated action potentials (20 mM KCl, 10(-6) M isoproterenol) were recorded at 10-min intervals during exposure (2-4 h) to nifedipine, nitrendipine, and PY 108-068 (10(-9) M-4 X 10(-8) M). Time to steady state was slow, with half-life t1/2 values of 40 min (nifedipine), 84 min (nitrendipine), and 81 min (PY 108-068). Steady state I50 values for depressing dV/dtmax were 12.08 (nifedipine), 5.74 (nitrendipine), and 4.88 nM (PY 108-068). In isolated cardiac sarcolemma preparations (37 degrees C), these compounds competed for [3H]nitrendipine binding sites with Ki values of 8.1, 1.3, and 4.9 nM, respectively. These results show that attainment of steady-state depression of calcium channel function can be slow, but that the discrepancy between the physiologic data and the binding data is reduced significantly (less than 5 X) when physiologic measurements are made at steady state and binding studies are performed at 37 degrees C.
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001667:Binding, Competitive; D002118:Calcium / Q000502:physiology*; D004285:Dogs; D006321:Heart / Q000187:drug effects / Q000502:physiology*; D066298:In Vitro Techniques; D009206:Myocardium / Q000378:metabolism; D009543:Nifedipine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D009568:Nitrendipine / Q000378:metabolism / Q000494:pharmacology*; D011690:Purkinje Fibers / Q000187:drug effects
chemical_list: D009568:Nitrendipine; D009543:Nifedipine; C034600:darodipine; D002118:Calcium