Effect Of Diltiazem On Platelet Activation And Cytosolic Calcium During Percutaneous Transluminal Coronary Angioplasty

[Background] Percutaneous transluminal coronary angioplasty is an alternative interventional procedure of revasularization in the presence of coronary artery disease. PTCA dilates narrow coronary artery by splitting of the atheromatous plaque, dissection of endothelium and fibrous tissue rupture. The procedure also produces exposure of subendothelial components, inducing activation of the hemostasis system. The generation of thrombin and intracoronary deposition of activated platelets may be responsible for acute and subacute thromboses. Platelet adhesion, aggregation and secretion may further lead to vasoconstriction and release of PDGF, limiting the immediate and short-term success of PTCA.Cytosolic calcium plays a pivotal role in the regulation of platelet function. In vitro and clinical studies have shown that many calcium channel blockers inhibit platelet activation. Diltiazem may be more potent than verapamil and the dihydropyridines in inhibiting ADP- and collagen-induced aggregation in vitro. Single oral dose of diltiazem tends to inhibit aggregation induced by various agonists in healthy subjects and have additive effects in the combination with low dose aspirin.However, it is unclear whether or not diltiazem attenuate platelet activation caused by impairment procedures such as PTCA in vivo.Mechanisms of effects of diltiazem treatment on platelet function are not yet defined. Diltiazem and verapamil completely inhibit thapsigargin-induced aggregation, suggesting their inhibitory effect on calcium store release. However, diltiazem and verapamil do not exert any inhibitory effect on thrombin-mediated calcium elevation. Effect of diltiazem on cytosolic calcium mobilization in the process of platelet activation in vivo is still to study. Although in vitro studies demonstrate diltiazem significantly inhibits production of thromboxane 62, it is unclear of its effect on sunoTinal 玼 JLiiIuoiiic acid iiictauUiisiii icsuttcd from ujiiip'K-dlcil fALluis in vivo. Trie common pathway of aggregation is the conformation transformation of GP II b/nia and its binding with fibrinogen. P-selectin is an activation marker which only appears in the surfaces of platelets after secretion of a -granules. It is also unknown whether diltiazem affects expression of GP II b/IIIa and P-selectin on platelets.[Objective]1 > To investigate expression of glycoproteins in platelet surfaces and release ofthromboxane during PTCA to prove the hypothesis that intervention proceduressuch as coronary artery dilation cause platelet activation and also observe changeof cytoslic calcium during the procedure.2^ To evaluate effect of pretreatment with oral and intravenous diltiazem onPTCA-induced platelet activation and potential mechanisms of its antiplateletfunction.[Method] We enrolled in the study 35 patients with documented myocardial ischemia who were undergoing PTCA. Patients were randomly divided into diltiazem treatment group given oral and intravenous treatment of diltiazem and control group only pretreated with oral aspirin and ticlopidine. Blood samples were collected beforeand after dilation procedure from coronary sinus or peripheral vein. Expression of GP Ilb/nia and P-selectin, production of thromboxane B2 and cytosolic calcium concentration were measured, respectively, by whole blood flow cytometry, radioimmunoassay and fluorospectrophotometry. [Results]1 -> Percentage of PAC-1 positive platelets increased after dilation in control group, with a peak at 5 min after the procedure. There were no differences of percentage of PAC-1 positive platelets, mean fluorescence intensity and binding index before and after dilation in diltiazem treatment group. Percentage of PAC-1 positive platelete and binding mdex in diltiazem treatment group were significantly lower than in control group at 5 min and 10 min after dilation.2^ Percentage of PAC-1 positive platelets increased 10 min after PICA in control group, followed by decrease from the high level at 24 hours and 48 hours after...