The effects of felodipine and bepridil on calcium-stimulated calmodulin binding and calcium pumping ATPase of cardiac sarcolemma before and after removal of endogenous calmodulin.
The Ca2+ channel blockers felodipine and bepridil are known to affect selectively functions of calmodulin. We studied their effects on calmodulin binding and ATPase activities of calmodulin-containing and calmodulin-depleted rabbit heart sarcolemma. Both drugs as well as the specific anti-calmodulin drug calmidazolium at a concentration of 50 microM, inhibited the Ca2+-stimulated calmodulin binding to calmodulin-depleted sarcolemma. Within the concentration range of 3 to 100 microM all three drugs also progressively inhibited Ca2+ pumping ATPase in calmodulin containing sarcolemma, although the enzyme was assayed at saturating Ca2+ (100 microM). The inhibitory potency of calmidazolium and bepridil, but not that of felodipine, increased when the membrane protein concentration in the ATPase assay was lowered. At low membrane protein concentration 30 microM calmidazolium completely blocked calmodulin-dependent Ca2+ pumping ATPase, whereas the inhibition caused by 30 microM felodipine or bepridil remained partially. A similar inhibition pattern of the drugs was found in the calmodulin binding experiments. Within a concentration range of 3 to 30 microM, all three drugs had negligible effects on the basal Ca2+ pumping ATPase which was measured in calmodulin-depleted sarcolemma. In conclusion, the characteristics of the anti-calmodulin action of felodipine on the rabbit heart sarcolemmal Ca2+ pumping ATPase are not different from those of bepridil. Both drugs may inhibit the enzyme by interference with the Ca2+-stimulated binding of calmodulin.
Lamers
J M
JM
Department of Biochemistry I, Erasmus University Rotterdam, The Netherlands.
Verdouw
P D
PD
Mas-Oliva
J
J
D000818:Animals; D015764:Bepridil; D002118:Calcium / Q000494:pharmacology; D000252:Calcium-Transporting ATPases / Q000378:metabolism*; D002147:Calmodulin / Q000378:metabolism / Q000502:physiology*; D015736:Felodipine; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism*; D009568:Nitrendipine / Q000031:analogs & derivatives* / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology*; D012508:Sarcolemma / Q000201:enzymology / Q000378:metabolism*
D002147:Calmodulin; D007093:Imidazoles; D011759:Pyrrolidines; C031938:calmidazolium; D015764:Bepridil; D009568:Nitrendipine; D000252:Calcium-Transporting ATPases; D015736:Felodipine; D002118:Calcium