Comparative Inhibitory Effects of Dihydropyridines on Platelet Aggregation, Calcium Uptake and Cyclic AMP Concentration

Abstract

We studied the in vitro effects of several calcium channel blockers from the dihydropyridine (DHP) family on platelet aggregation and endogenous serotonin secretion, calcium uptake and cyclic AMP (cAMP) concentration using washed rat platelets. We found that, after 1 min incubation, nifedipine (Nil), nitrendipine (Nit) and nisoldipine (Nis) inhibited the thrombin-induced platelet aggregation and serotonin secretion with IC50 of about 140, 5 and 2 μmol/l, respectively. Nis and Nit are thus much more active than Nif. We also found that the thrombin-induced Ca²⁺ uptake amounted to 2,600 ± 326 pmol Ca²⁺/10⁹ platelets in control conditions. In the presence of 10 μmol/l of the DHP, this uptake was decreased by 19, 49 or 77 %, with Nif, Nit or Nis, respectively. Compound BAY K 8644 (BK) with known agonistic properties on the calcium channel had inhibitory effects on the studied parameters. These compounds were in the order of Nif < BK < Nit < Nis. When added to previously aggregated platelets, Nit caused them to deaggregate. These results seem to be similar to those obtained with cAMP analogues or adenylate cyclase activators. The platelet resting cAMP concentration was therefore measured in the presence of the DHP. A nonsignificant increase was found with 20 μmol/l Nif whereas significant increases of 20 and 68 % as compared with controls were obtained with 20 μmol/l Nit and Nis, respectively. Partition studies between platelets and plasma lipoproteins indicated that the effects might be related to the lipophilicity of the compounds. These data suggest that these agents work on platelet activity by multiple effects located intracellularly or at the membrane level. We propose that these effects could work in combination to explain the in vivo potency of these agents in the treatment of cardiovascular disorders.

Risk of Hospitalized Gastrointestinal Bleeding in Persons Randomized to Diuretic, ACE‐Inhibitor, or Calcium‐Channel Blocker in ALLHAT

“…In the previous 2 decades, several investigators have raised concern about possible prohemorrhagic activity of CCBs, citing an association between use of CCBs and the occurrence of cerebral, surgical, or gastrointestinal (GI) hemorrhage . Laboratory studies have also suggested that both dihydropyridine and nondihydropyridine CCBs impair platelet activity, providing a possible mechanistic basis for the putative prohemorrhagic activity of CCBs …”

“…[12][13][14][15][16][17] Laboratory studies have also suggested that both dihydropyridine and nondihydropyridine CCBs impair platelet activity, providing a possible mechanistic basis for the putative prohemorrhagic activity of CCBs. [18][19][20][21] Nevertheless, the evidence regarding risk of bleeding associated with CCBs is inadequate for several reasons. First, there is a lack of randomized clinical trial evidence supporting the association between CCBs and GI hemorrhage, relative to other classes of antihypertensive agents.…”

Systematic review with meta‐analysis: the association between the use of calcium channel blockers and gastrointestinal bleeding

“…Apart from the usual reported adverse reactions of CCBs, there is a possibility of an increased risk of gastrointestinal bleeding (GIB) due to their potential anti‐platelet effect. This is further supported by animal, in vivo and ex vivo studies that demonstrated the inhibition of platelet aggregability of CCBs in putative pro‐haemorrhagic activity . The promotion of vasodilation by CCBs also opposes the usual vasoconstriction response to bleeding .…”

Platelet Aggregation and In Vivo Shear Forces

“…These parallel changes of wall shear stress and platelet aggregatory responses after nitrendipine treatment could have resulted from simultaneous effects of the Ca2+-antagonist on platelets, vascular smooth muscle and endothelial cells. Some authors have indeed reported a direct effect of high dihydropy ridine concentrations on platelet Ca2+ metabolism (43). However, the presence of dihydropyridine-sensitive voltage-dependent Ca2+ channels in human platelets remains controversial (44,45).…”