Differential actions of naftopidil, doxazosin and nifedipine on platelet thromboxane generation and platelet-derived growth factor efflux in vitro.
We examined the effects of the alpha(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 micro 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 micro 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 40micro M naftopidil, respectively. Collagen-stimulated TxB(2) generation was inhibited 59.5 +/- 9.2% (P<0.01) by 40 micro M naftopidil and 53.7 +/- 11.3% (P<0.01) by 28 micro M nifedipine. Doxazosin (7.5 and 30 micro 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 micro M naftopidil, respectively. Doxazosin (30 micro M) inhibited adrenaline-induced PDGF release by 70.3 +/- 31.5% (P<0.05), whilst nifedipine (28 micro 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 alpha(1)-adrenoreceptor blocker or nifedipine, indicating that platelet alpha-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.
Centre for Clinical Pharmacology, Department of Medicine, The Rayne Institute, Royal Free and University College Medical School, London, UK.
N A
NA
Alarayyed
B N C
BN
Prichard
D J
DJ
Betteridge
C C T
CC
Smith
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000328:Adult; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D003094:Collagen / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D017292:Doxazosin / Q000494:pharmacology; D004336:Drug Antagonism; D004837:Epinephrine / Q000494:pharmacology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009281:Naphthalenes / Q000494:pharmacology; D009543:Nifedipine / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D010982:Platelet-Derived Growth Factor / Q000187:drug effects* / Q000378:metabolism; D013929:Thromboxane B2 / Q000096:biosynthesis / Q000378:metabolism*
D000317:Adrenergic alpha-Antagonists; D000959:Antihypertensive Agents; D009281:Naphthalenes; D010879:Piperazines; D010975:Platelet Aggregation Inhibitors; D010982:Platelet-Derived Growth Factor; D013929:Thromboxane B2; D003094:Collagen; D009543:Nifedipine; D017292:Doxazosin; C064357:naftopidil; D004837:Epinephrine