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Mouse antithrombotic assay: the effects of Ca++ channel blockers are platelet-independent
Insights
Calcium channel blockers offer significant protection in a mouse antithrombotic assay, reducing mortality by influencing factors beyond platelet aggregation and thromboxane production.
Area of Science:
- Pharmacology
- Cardiovascular Research
- Hemostasis and Thrombosis
Background:
- Thrombosis is a major cause of mortality.
- Aspirin is a common antithrombotic agent.
- The role of calcium channel blockers in antithrombotic effects requires further investigation.
Purpose of the Study:
- To evaluate the efficacy of calcium channel blockers (nitrendipine, nicardipine, nifedipine, verapamil) in the Mouse Antithrombotic Assay.
- To compare their effects with aspirin.
- To elucidate the mechanisms underlying their antithrombotic activity.
Main Methods:
- Administration of aspirin and calcium channel blockers to mice.
- Assessment of mortality following collagen-epinephrine infusion and hardened red blood cell injection.
- Measurement of thromboxane B2 and platelet factor-4 levels.
- Evaluation of platelet aggregation and circulating platelet counts.
Main Results:
- Aspirin and calcium channel blockers reduced mortality in the collagen-epinephrine model.
- Nitrendipine and nicardipine showed high protection rates (80-85%).
- Calcium channel blockers did not inhibit thromboxane B2 production or platelet aggregation but reduced mortality in the red blood cell model, suggesting alternative mechanisms.
Conclusions:
- Calcium channel blockers demonstrate significant antithrombotic efficacy in mice.
- Their protective effects appear to involve mechanisms independent of direct platelet aggregation inhibition or thromboxane synthesis.
- These findings suggest potential therapeutic applications for calcium channel blockers in thrombotic conditions, particularly those involving red blood cell-induced mortality.
Abstract:
In the Mouse Antithrombotic Assay aspirin (30-300 mg/kg) protected mice from death by 15 and 42%, respectively. Four Ca++ channel blockers (nitrendipine, nicardipine, nifedipine and verapamil) were effective in reducing the mortality. At the dose of 100 mg/kg nitrendipine and nicardipine gave 80 and 85% protection respectively. Whereas aspirin almost suppressed completely thromboxane (Tx)B2 and platelet factor-4 release after collagen-epinephrine infusion, neither nitrendipine nor nicardipine modified TxB2 release and only reduced slightly platelet factor-4 release. The treatment with aspirin, nitrendipine or nicardipine did not counteract the fall in circulating platelets counted 1 min after the aggregation challenge, but at 3 min platelet count was significantly higher in aspirin-treated mice than in animals given either Ca++ channel blocker. Mouse platelet aggregation induced in vitro by the combination of collagen and epinephrine was inhibited in samples obtained from mice pretreated with aspirin but was unaffected by the treatment with nitrendipine or nicardipine. The i.v. injection of a 12.5% suspension of hardened red blood cells resulted in death of about 80% of mice within 1 to 2 min. Neither circulating platelet count nor plasma TxB2 level were modified significantly by red cell injection. Aspirin was ineffective whereas both Ca++ channel blockers lowered mortality to 50%. These data suggest that Ca++ channel blockers reduce the mortality in the Mouse Antithrombotic Assay by influencing factors other than platelet aggregation and/or Tx production. These factors might be important in mediating mortality occurring after infusion of hardened red cells.