Mechanism of antiatherogenic action of calcium antagonists

Dagenham Research Centre, Rhône-Poulenc Ltd., U.K. Analysis of literature reports on the actions of calcium antagonists on the progression of experimental arterial disease has revealed a significant association between efficacy and time of commencement of administration. In the majority of studies where commencement of administration of calcium antagonists preceded or coincided with initiation of atherogenesis, suppression of atherosclerotic changes has been observed. Where administration commenced after initiation of atherogenesis, suppression of atherosclerotic changes has rarely been seen. This distribution of results strongly suggests that calcium antagonists inhibit a process occurring early in atherogenesis. We have previously shown that calcium antagonists selectively inhibit the proliferation of smooth muscle cells that occurs in response to balloon catheter injury. We report here further investigations into this effect, using nifedipine. In the rat there is a 'time window' for the antiproliferative action of nifedipine, between 8 and 30 h after balloon injury. In the rabbit, delaying nifedipine administration so that it commenced 7 days after balloon catheterisation abolished its antiproliferative effect. These results show that nifedipine inhibits smooth muscle cell proliferation at an early stage, probably during the G0/G1 phase of the cell cycle, and that after this time smooth muscle cells are refractory to its antiproliferative action. We conclude that the antiatherogenic actions of calcium antagonists in experimental models of arterial disease are the result of early inhibition of smooth muscle cell proliferation.