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.
Alarayyed
N A
NA
Centre for Clinical Pharmacology, Department of Medicine, The Rayne Institute, Royal Free and University College Medical School, London, UK.
Prichard
B N C
BN
Betteridge
D J
DJ
Smith
C C T
CC
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