Antithrombotic Activities Of Alkaloids From Veratrum Patulum Loos And Veratrum Nigrum Var. Ussuriense Nakai

Thrombotic disease which greatly damaged people's health is one of the most common causes of mortality and morbidity in the world. There are many drugs used for thrombotic disease, but they often caused serious adverse effects such as excessive bleeding. Looking for efficient antithrombotic drugs which cause little adverse effects are still the key issues for medical scientists.The Chinese traditional medicine "Lilu" has been used for aphasia arising from apoplexy, scabies, etc. Veratrum patulum Loos and Veratrum nigrum var. ussuriense Nakai both are widely distributed in Northeastern China. Total alkaloids from Veratrum nigrum var. ussuriense Nakai (VnA) have been reported to possess antithrombotic activities, but the effects of total alkaloids from Veratrum patulum Loos (VpA) on thrombus have not been reported. The antithrombotic effects of VpA, VnA, single alkaloids (P1-P2, N1-N6) were studied to provide scientific basis for antithrombotic researches of "Lilu" in this paper.The effects of VpA on carotid artery thrombus, on platelet aggregation, on coagulation parameters, on blood viscosity, on bleeding time, and the effects of VpA, P1?P2 on vena cava thrombus in rat were studied. The results showed:(1) VpA significantly inhibit thrombus formation and collagen-induced platelet aggregation (P< 0.01), the similar trends and the same peak times were observed on the time-response curves of inhibition effects on artery thrombus and on collagen-induced platelet aggregation which suggested that the antithrombotic effects of VpA were largely due to its inhibition effects on collagen-induced platelet aggregation. (2) VpA and P1 both significantly inhibit the formation of venous thrombus (P< 0.01) which suggested that P1 was one of the antithrombotic components in VpA; the effects of P2 on venous thrombus showed gender differences. (3) VpA showed no significant effects on coagulation parameters or blood viscosity (P> 0.05). (4) VpA significantly shortened rat tail bleeding time 9 min after administration (P< 0.05), then gradually extended the bleeding time, and the extension reached to the strongest level 60 min after administration, but the longest bleeding time caused by VpA was not longer than those caused by positive control medicines (lysine-aspirin and heparin) which suggested that VpA may hardly cause excessive bleeding when used for treatment of thrombotic disease.The effects of VnA, N1-N6 on rat vein thrombus, on rat coagulation parameters, and on rabbit platelet aggregation were studied. The results showed:(1) VnA and N1?N5 all significantly inhibit venous thrombus formation (P< 0.01) while N2 showed stronger inhibition effects on venous thrombus formation than VnA at all dose levels, which indicated that N2 was one of main antithrombotic components of VnA; N6 showed no significant effects on venous thrombus (P> 0.05). (2) VnA, N1?N5 all inhibit adenosine diphosphate(ADP)-induced and thrombin-induced platelet aggregations (P< 0.01), increased thrombin time(TT) (P< 0.01), which suggested that the inhibition of platelet aggregation and extension of TT contribute to their antithrombotic activities; N6 showed no significant effects on platelet aggregation or on coagulation parameters (P> 0.05).Although VpA and VnA both possess antithrombotic activities, there were differences among their antithrombotic features and antithrombotic mechanisms.The relationship between antithrombotic activities of alkaloids and their chemical structures suggested that cevanine type and jervine type skeleton were effective antithrombotic skeletal structures, and the easter substitute at C-3 enhance inhibition effects of cevanine type alkaloids on venous thrombus formation and on ADP-induced platelet aggregation.