Effects of verapamil, diltiazem, nisoldipine and felodipine on sarcoplasmic reticulum

Verapamil, diltiazem, nisoldipine and felodipine, calcium antagonist drugs with different chemical structures, were studied for their effects on activities of sarcoplasmic reticulum (SR) isolated from dog cardiac and rabbit skeletal muscles. Nisoldipine and felodipine exerted biphasic actions on both cardiac and skeletal SR Ca²⁺-ATPase with maximum activation of 40–60% occurring at 20–40 μM for nisoldipine and 30–40% occurring at 15–30 μM for felodipine. At higher drug concentrations, Ca²⁺-ATPase was inhibited. In the presence of oxalate the maximum activation of the Ca²⁺ uptake rates at 5–20 μM nisoldipine were 30–50% for cardiac SR and 80–100 μM of the drug were 300–500% for skeletal SR. Felodipine inhibited the rate of Ca²⁺ uptake by dog cardiac SR, but activated Ca²⁺ uptake by rabbit skeletal SR with a maximum of 30–50% at 12–25 μM. At higher concentrations of the two drugs the rate of Ca²⁺ uptake was inhibited. In the absence of oxalate, i.e., limited tranport, nisoldipine shortened the duration of time that Ca²⁺ was bound to the cardiac and skeletal SR, while the rate of release of Ca²⁺ from skeletal SR was stimulated. Felodipine at low concentrations similarly caused a premature release of Ca²⁺ from skeletal SR at a rapid rate; at high concentrations both drugs did not alter Ca²⁺ binding but delayed Ca²⁺ release. Unlike nisoldipine and felodipine, verapamil and diltiazem inhibited the rates of Ca²⁺ transport both in cardiac and skeletal SR. The two drugs inhibited Ca²⁺-ATPase in cardiac SR but activated the enzyme in skeletal SR. Thus, these drugs caused complex and different effects on cardiac and skeletal SR, possibly resulting from perturbations of the lipid environment of the SR Ca²⁺-ATPase.