The Effect of Vincristine on Platelet Aggregation in the Rat Studied with an Aortic Loop Technique

Abstract

We have developed the technique used by Honstra (1970, British Journal of Haematology, 19, 321) for studying platelet function using a filter and have studied the effects of vincristine (VCR) on platelet aggregation induced by adenosine diphosphate (ADP) in the rat.The filter (Veco Ltd) has 20 pm pores and is supported in a chamber with connecting polyethylene tubing with a total volume of approximately 1 ml. This is inserted into the abdominal aorta of heparinized male Wistar rats anaesthetized with urethane. Proximal and distal blood pressure were recorded with a mean pressure drop of approximately 5 mmHg across the filter. ADP was infused at rates of 0.16-4.2 ,ug/min for 30 s proximal to the filter. Platelet aggregation was apparent by a rise in proximal and fall in distal pressure from which an aggregation index was calculated.In 10 control rats two dose-response curves were constructed. The second, after a saline bolus intravenously, showed less aggregation than the first. In 10 test rats vincristine (0.03 mg/kg) was injected intravenously after the first curve and highly significant depression was seen in the second. There was no significant difference between the first doseresponse curves in test and control animals but the differences in the second curves were significant at all infusion rates ( P < 0.001-< 0.02).VCR depolymerizes platelet microtubules in vitro. We have shown that in the dose used platelet aggregation was depressed in vivo in the rat within minutes. 86.Prostacyclin (PGI,) is synthesized by vascular enuothelial cells and is one of the most potent inhibitors of platelet aggregation so far described. PGI, may therefore play an important role in haemostasis. Like other prostaglandins (PG) which inhibit platelet aggregation (e.g. PGE, and PGDJ, an essential property of PGI, is its ability to stimulate adenylate cyclase activity in platelet membranes, and thereby to raise platelet cyclic AMP levels. The greater potency of PGI, compared with other PG types on platelets raised the question as to whether it is also the most potent agonist in other PG-responsive tissues.We have been interested in the role of PG types as boneresorbing agents in the pathogenesis of malignant hypercalcaemia. Previous studies suggested that PGE, had the greatest bone-resorbing activity but it had been impossible to test the effects of the more unstable prostanoids (PG endoperoxides, thromboxanes and PGI,) in conventional bone culture systems. We have made use of a hormone-responsive induced transplantable osteogenic sarcoma in the rat as a model of bone cell metabolism. In freshly isolated tumour cells, the ability of various stable PG types to stimulate cyclic AMP production is closely related to their bone-resorbing activity. We have studied the actions of some unstable prostanoids on these cells compared with their effects on human blood platelets.Cyclic AMP production by intact platelets and adenylate cyclase activity in isolated platelet membranes were elevated by PGI, and by PGE,, PGD,, PGE, and PGF2, in decrea...

The Effects of Vincristine on Platelet Aggregation Studied by a Filter Loop Technique in the Rat

“…We have simplified and modified Hornstra's technique to study the effects of vincristine on adenosine diphosphate (ADP)-induced aggregation in blood passing through a filter inserted into the aorta of the rat. Our preliminary results have been published (Martin, Suggett & Thwaites, 1978).…”