Verapamil Inhibits Platelet Aggregation by a Calcium-Independent Mechanism

Abstract

SummaryWe studied the inhibitory effects of the calcium channel blocker verapamil both on platelet aggregation and intracellular calcium [Ca2+]i in platelets loaded with a fluorescent indicator (quin 2).The inhibitory effects of verapamil on the platelet aggregation response to both thrombin and ionomycin were seen to be clearly dissociated from the verapamil-induced inhibition of the [Ca2+]i increase produced by these agonists. Verapamil-induced inhibition of platelet aggregation was also obtained when using the “calcium-independent” agonist phorbol-myristate acetate (PMA). It may be deduced that a calcium-independent mechanism plays a role in verapamil-induced inhibition of platelet aggregation. We postulate that this mechanism may operate via a protein-kinase C pathway.

Effects of early and late verapamil administration on the development of cardiomyopathy in experimental chronic Trypanosoma cruzi (Brazil strain) infection

“…In this regard, it should be noted that verapamil treatment reduced the expression of cytokines and iNOS in the myocardium of T. cruzi-infected mice (Huang et al 1999b). In addition, verapamil has been demonstrated to alter vascular flow by inhibiting platelet aggregation (Bonadonna et al 1986) and by inhibiting the release of endothelin-1 by endothelial cells ( Haug et al 1998). Therefore, the actions of verapamil in ameliorating chagasic heart disease may be multi-factorial.…”

“…The precise role of verapamil in the amelioration of chronic chagasic cardiomyopathy is not clear. However, verapamil has many actions, including the modulation of vascular flow, endothelin synthesis/release (Haug et al 1998), platelet aggregation (Bonadonna et al 1986) and inflammation (Berrebi et al 1994), which could explain the observations.…”

Chagas heart disease clinical-pathological correlation

“…Marked basement membrane thickening in myocardial capillaries (up to 20 times the normal thickness) has been detected in chronic chagasic human hearts (84,85), similar to the thickening, either with or without multilayering, reported to occur in basement membranes of capillaries of patients with diabetes mellitus (86) and myxedema (87), in KK mice with genetically-transmitted cardiomyopathy associated with diabetes mellitus (88), and in renovascular hypertensive streptozotocin diabetic cardiomyopathic rats (89). Long-term administration of verapamil, a calcium channel blocker drug, markedly decreased myocardial inflammation and fibrosis in T. cruzi chronically-infected mice, producing a ten times decrease in mortality rate during a 70-day period of infection (90), probably through the maintenance of vascular perfusion due to its vasodilatatory action on smooth muscle cells and to its inhibitory effect on platelet aggregation (82,91). In vitro studies of infection demonstrated increased platelet adherence and aggregation related to infection-associated endothelial cell dysfunction (92).…”

Efeitos de terapêutica antiplaquetária e vasodilatadora microcirculatória sobre os distúrbios microvasculares e sintomas anginosos que ocorrem na cardiopatia crônica da doença de Chagas. Estudo prospectivo com coronariografia e cintilografia miocárdica de perfusão

“…Assim, o verapamil foi utilizado neste estudo por sua propriedade de vasodilatação da microcirculação (Tanowitz et al, 1989), bem como pelo seu efeito de diminuição da agregação plaquetária, este efeito independentemente da inibição da entrada de cálcio na célula (Bonadonna et al, 1986). Em estudo seminal de modelos experimentais com murinos infectados por T. cruzi, o uso de verapamil reduziu o dano miocárdico e a morbidade dos animais analisados (Morris et al, 1989).…”