Inhibition of Platelet Aggregation Following Chronic In Vivo Treatment of Rats with Nicotine: Prevention by Simultaneous Application of Propranolol

Platelet aggregability is known to be enhanced and platelet-survival time shortened in smokers when compared with nonsmokers. Up to now it is unknown which of the substances in tobacco smoke are responsible for these effects. To evaluate a possible role of nicotine, rats were chronically treated with the alkaloid (10 mg/kg/ day), continuously released from subcutaneously implanted osmotic minipumps. Surprisingly, after 8 weeks, platelet sensitivity toward the aggregating stimulus adenosine 5ʼ-diphosphate (ADP) was markedly reduced. The mean ADP concentration required to induce half the maximum rate of aggregation (EC50) was 0.88 μmol/L in nicotine-treated animals, as compared with 0.67 μmol/L in controls (p < 0.002). Platelet aggregability remained normal when the rats were treated simultaneously with nicotine and the G3 blocker propranolol (3.5 mg/kg/day); for these animals, the mean EC50 for ADP was 0.73 μmol/L. These results are suggestive of a catecholamine-mediated action of nicotine. However, neither the basal levels of cAMP in platelet-rich plasma, nor the cAMP levels attained after stimulation of platelet adenylate cyclase with prostaglandin E1, (PGE1), were affected by 8 weeks of treatment with nicotine or nicotine plus propranolol. No effect on platelet aggregation was observed when the rats were treated with nicotine for only 2 weeks, or when nicotine or nicotine plus cotinine were added to platelet-rich plasma in vitro in concentrations equal to those attained in vivo after 8 weeks. Thus, pro-longed application of nicotine in vivo caused an inhibition of ADP-induced rat platelet aggregation presumably mediated by β-catecholaminergic stimulation of platelets.