Calcium channel blockers increase the amount of nitrite production in rabbits without decreasing the responsiveness of platelets to collagen

Abstract

By virtue of their ability to increase nitric oxide (NO) production, it is thought that calcium channel blockers (CCBs) may be involved in the inhibition of platelet aggregation. In an attempt to compare the abilities of different groups of calcium antagonists to affect NO generation and platelet aggregation, single doses of the calcium antagonists verapamil, nicardipine and diltiazem were administered to rabbits. It was found that each of these drugs increased the levels of nitrite significantly. It was also found that these drugs had different time courses of action. Of the CCBs used in this study, verapamil was found to induce the greatest increase in nitrite production (about a 4-fold increase over basal levels), peaking at 90 min (P<0.001). Diltiazem and nicardipine (3.5-fold and 2.5-fold increase over basal levels, respectively) were both found to induce increases in NO which peaked at 150 min (P<0.001 and P<0.01 respectively). Each of the drugs was then given at double the original dose; however, nicardipine was the only drug that was seen to further increase nitrite production (P<0.001). Blood samples taken from the animals were analysed using whole-blood aggregometry in order to assess the amount of collagen-induced platelet aggregation. At the time point when NO release was expected to be maximal (150 min), it was found that the collagen-induced platelet responses were not significantly altered in platelets from rabbits that had been treated with either verapamil or nicardipine. In contrast, at the 150-min time point, diltiazem treatment made the platelets hypersensitive to collagen stimulation. The results of this study demonstrate that treatment with calcium channel antagonists increases the levels of NO produced in rabbits, however, this increase in NO production is not accompanied by a decrease in the reactivity of platelets to collagen.