Smoke-derived nitric oxide and vascular prostacyclin are unable to counteract the platelet effect of increased thromboxane formation in healthy female smokers

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Abstract
The incidence of cigarette smoking tends to be higher in women, justifying directed studies on smoke-related mechanisms of cardiovascular disorder in females. Platelet activity plays an important etiological role in several settings of cardiovascular disease. Cigarette smoking facilitates platelet formation of proaggregatory thromboxane A2. However, cigarette smoke contains nitric oxide (NO), which has antiplatelet activity. Furthermore, the formation of anti-aggregatory prostacyclin (PGI2) may be higher in smokers than in non-smokers. Hence, the concerted action of NO and PGI2 on platelet activity in smoking females is important to elucidate. The metabolites of TxA2, NO, and PGI2, as well as cyclic guanosine 3':5'-monophosphate (cGMP; second messenger for NO in the platelets) and cyclic adenosine 3':5'-monophosphate (cAMP; second messenger for PGI2 in the platelets), were analysed in 23 healthy female smokers (daily consumption 11-20 cigarettes per day) and in 26 matched non-smokers. The urinary excretion of 2,3-dinor TxB2 (metabolite of TxA2) was considerably higher in smokers than in non-smokers (177 vs. 72 pg/mg creatinine, respectively; P<0.001). Plasma and urinary levels of nitrate (metabolite of inhaled NO) did not differ between the groups. Plasma and urinary cGMP were slightly increased (252 vs. 193 nmol/L; P<0.05 and 0.63 vs. 0.51 micromol/24 h; P<0.05, respectively) in smokers compared to non-smokers, while platelet cGMP was lower in smokers than in non-smokers (81 vs. 10.3 pmol/10(6) platelets, respectively; P<0.05). The urinary excretion of 2,3-dinor-6-keto-PGF1a (metabolite of PGI2) did not differ between the groups. Platelet or urinary cAMP did not differ between the groups either, while plasma cAMP was lower in smokers than in non-smokers (19.2 vs. 26.2 nmol/l, respectively; P<0.001). In healthy female smokers NO is not absorbed from the inhaled smoke, and endothelial PGI2 formation is not enhanced to counterbalance the increased platelet formation of proaggregatory TxA2.

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