Differential actions of naftopidil, doxazosin and nifedipine on platelet thromboxane generation and platelet-derived growth factor efflux in vitro

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We examined the effects of the f 1 -adrenoreceptor blockers naftopidil and doxazosin and the Ca 2+ antagonist nifedipine on platelet function with reference to stimulus-induced thromboxane (TxB 2 ) generation and platelet-derived growth factor (PDGF) efflux. Collagen (5 w g/ml) caused a 12.5-fold increase in TxB 2 generation, from a basal level of 7.69 - 1.28 ng/10 8 platelets to 96.34 - 13.37 ng/10 8 platelets ( P <0.001). Adrenaline (16 w M) increased TxB 2 production 3-fold from 2.44 - 0.61 to 8.02 - 1.08 ng/10 8 platelets ( P <0.01). Adrenaline-induced TxB 2 generation was inhibited 42.5 - 10.3% ( P <0.05) and 81.8 - 7.5% ( P <0.05) by 10 and 40 w M naftopidil, respectively. Collagen-stimulated TxB 2 generation was inhibited 59.5 - 9.2% ( P <0.01) by 40 w M naftopidil and 53.7 - 11.3% ( P <0.01) by 28 w M nifedipine. Doxazosin (7.5 and 30 w M) did not influence adrenaline- or collagen-induced TxB 2 synthesis. Collagen increased PDGF efflux from 1.17 - 0.39 to 4.25 - 0.51 ng/10 8 platelets ( P <0.01), whilst adrenaline raised concentrations from 1.08 - 0.19 to 5.37 + 1.02 ng/10 8 platelets ( P <0.01). Naftopidil had no effect on collagen-induced PDGF release. Adrenaline-stimulated PDGF efflux was, however, inhibited 82.9 - 13.7% ( P <0.001) and 125.7 - 16.3% ( P <0.001) by 10 and 40 w M naftopidil, respectively. Doxazosin (30 w M) inhibited adrenaline-induced PDGF release by 70.3 - 31.5% ( P <0.05), whilst nifedipine (28 w M) had no effect on collagen-stimulated release. We conclude that naftopidil, like nifedipine, may block stimulated TxB 2 generation via inhibition of phospholipase A 2 , the Ca 2+ -dependent, rate-limiting enzyme in thromboxane synthesis. Although adrenaline-induced PDGF release was inhibited by naftopidil and doxazosin, collagen-induced release was unaffected by either f 1 -adrenoreceptor blocker or nifedipine, indicating that platelet f -granular release is not dependent on Ca 2+ mobilisation or thromboxane generation. Thus, the effects of these drugs on PDGF release may be mediated through alternative cellular signalling mechanisms.