Nifedipine, a Ca++ channel blocking drug used in cardiology, has been found to protect in clinical doses against a severe experimental thrombotic challenge. Although the Ca++ blockers are recognized as vasodilatory, antispasmodic and antiarrhythmic, evidence is accumulating that the antithrombotic effect may contribute to their clinical efficacy. It is therefore proposed to test, in a systematic quantitative manner, to what extent this class of drugs is antithrombotic and will protect against thrombotic sudden death. This will be done in a well-characterized mouse sudden death model which is both inexpensive and quantitative. The range of challenge agents will be substantially expanded to provide a wide variety of classes, ranging from intravenous thrombin, arachidonic acid, collagen, ADP and thromboxane A2 agonist to platelet-activating factor (PAF-acether). Sudden death induced by PAF-acether is anaphylactic rather than thrombotic, since mouse platelets are insensitive to PAF-acether in terms of aggregation. The Ca++ blocking drugs to be evaluated are nifedipine, verapamil, diltiazem, perhexilene and nitrendipine. These Ca++ blocking drugs will also be compared to the calmodulin antagonists trifluoperazine, pimozide and penfluridol. An especial effort will be made to evaluate post-challenge as well as pretreatment efficacy. Histopathological analyses will be used to relate thrombosis to degree of protection. EKG will be used to evaluate the extent to which the antiarrhythmic effect contributes to the protective action. The long term objective is to lay a sound experimental basis for an important and significant new application for Ca++ related drugs.
| Myers, A K; Nakanishi, T; Ramwell, P (1988) Antagonism of PAF-induced death in mice. Prostaglandins 35:447-58 |
| Myers, A; Duarte, A P; Ramwell, P (1987) Pharmacological manipulation of platelet-activating factor toxicity in rodents. Adv Prostaglandin Thromboxane Leukot Res 17B:833-7 |
| Myers, A K; Bader, T J (1987) Role of adrenal steroids in the recovery from platelet activating factor challenge. Circ Shock 23:143-50 |
| Myers, A K; Forman, G; Torres Duarte, A P et al. (1986) Comparison of verapamil and nifedipine in thrombosis models. Proc Soc Exp Biol Med 183:86-91 |
| Torres Duarte, A P; Ramwell, P; Myers, A (1986) Sex differences in mouse platelet aggregation. Thromb Res 43:33-9 |
| Myers, A K; Ramwell, P W (1985) Thromboxane in sudden death. Adv Prostaglandin Thromboxane Leukot Res 13:81-8 |
