Impaired responsiveness of platelets from patients with stable angina pectoris to antiaggregating and cyclicAMP-elevating effects of prostaglandin E1.
The antiplatelet effects of prostacyclin (PGI2) and prostaglandin E1 (PGE1) are mediated by the same receptor and are secondary to intraplatelet cyclicAMP formation. Therefore, any dysfunction in PGI2/PGE1-stimulated cyclicAMP generation might lead to pathologically increased platelet aggregation. This possible consequence has not yet been studied. We examined antiaggregating effects of PGE1 in comparison with its cyclicAMP-elevating potency in platelets obtained from normal subjects and patients with stable angina pectoris; platelet hyperaggregability in such patients has been documented by us previously. ADP-induced aggregation was measured in platelet-rich plasma (PRP); PGE1 was added to platelets 0.5 min after ADP for assessment of reversal of incipient aggregation. Concentrations of PGE1 associated with 50% reversal of aggregation (C50) were 2.4 +/- 0.3 x 10(-8) M in normal subjects and 6.3 +/- 1.6 x 10(-7) M in patients (p < 0.01). PGE1 produced a concentration-dependent increase in intraplatelet cyclicAMP, and there was a strong correlation between cyclicAMP-stimulating and antiaggregating effects of PGE1. Maximal increases in cyclicAMP with PGE1 10(-4) M were 330 +/- 10% for normal subjects and 220 +/- 20% for patients (p < 0.01). Thus, the observed decrease in PGE1-induced reversal of platelet aggregation in patients can be attributed to a suppressed cyclicAMP response to PGE1. These results are likely also to imply reduced platelet sensitivity in vivo to endogenous PGE1 and PGI2, which in turn might contribute to platelet hyperaggregability observed in cardiovascular diseases.
Chirkov
Y Y
YY
Department of Cardiology, Queen Elizabeth Hospital, University of Adelaide, Australia.
Chirkova
L P
LP
Sage
R E
RE
Horowitz
J D
JD
D000244:Adenosine Diphosphate / Q000009:adverse effects; D000328:Adult; D000367:Age Factors; D000368:Aged; D000527:Alprostadil / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D000787:Angina Pectoris / Q000188:drug therapy* / Q000503:physiopathology; D001792:Blood Platelets / Q000187:drug effects; D015331:Cohort Studies; D000242:Cyclic AMP / Q000097:blood*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*
D010975:Platelet Aggregation Inhibitors; D000244:Adenosine Diphosphate; D000242:Cyclic AMP; D000527:Alprostadil