Ca2+-antagonists inhibit the N-methyltransferase-dependent synthesis of phosphatidylcholine in the heart

Evidence indicates that, in addition to the L-type Ca2+ channel blockade, C a(2+)antagonists target other functions including the Ca(2+)pumps. This stu dy was conducted to test the possibility that the reported inhibition of he art sarcolemmal (SL) and sarcoplasmic reticular (SR) Ca(2+)pumps by verapam il and diltiazem could be due to drug-induced depression of phosphatidyleth anolamine (PE) N-methylation which modulates these Ca(2+)transport systems. Three catalytic sites individually responsible for the synthesis of PE mon omethyl (site I), dimethyl (site II) and trimethyl (phosphatidylcholine (PC ), site III) derivates were examined in SL and SR membranes by employing di fferent concentrations of S-adenosyl-L-methionine (AdoMet). Total methyl gr oup incorporation into SL PE, in vitro, was significantly depressed by 10(6 )-10(3)M verapamil or diltiazem at site III. The catalytic activity of site I was inhibited by 10(3) M verapamil only, whereas the site II activity wa s not affected by these drugs. The inhibition induced by verapamil or dilti azem (10(5) M) was associated with a depression of the V-max value without any change in the apparent affinity for AdoMet. Both drugs decreased the SR as well as mitochondrial PE N-methylation at site III. A selective depress ion of site III activity was also observed in SL isolated from hearts of ra ts treated with verapamil in vivo. Furthermore, administration of [H-3-meth yl]-methionine following the treatment of animals with verapamil, reduced t he synthesis of PC by N-methyltransferase. Verapamil also depressed the N-m ethylation-dependent positive inotropic effect induced by methionine in the isolated Langendorff heart. Both agents depressed the SL Ca(2+-)pump and a lthough diltiazem also inhibited the SR Ca(2+-)pump, verapamil exerted a st imulatory effect. In addition, verapamil decreased SR Ca(2+-)release. These results suggest that verapamil and diltiazem alter the cardiac PE N-methyl transferase system. This action is apparently additional to the drugs' effe ct on L-type Ca2+ channels and may serve as a biochemical mechanism for the drugs' inhibition of the cardiac Ca(2+-)pumps and altered cardiac function .