Platelets in nonresponders to epinephrine stimulation showed reduced response to ADP.
It has been reported that platelets from some healthy donors did not respond to epinephrine (Epi). To identify the cause for the lack of response, we examined the alpha(2) adrenoceptor in the platelets and their signal transduction pathways. No differences in the genomic (-2076 to 1526 bp) and coding region of alpha(2A) adrenoceptor complementary DNA (cDNA) were found between the responders (R) and nonresponders (NR). No expression of alpha(2B) or alpha(2C) adrenoceptor was detected in platelets. When UK14,304 was used to induce platelet aggregation, similar effect to Epi was observed between R and NR, and any involvement of the alpha(1) and beta adrenoceptor was ruled out. Radioligand binding assay showed similar number of alpha(2) binding sites between the two groups (139+/-25/platelet vs. 145+/-37/platelets). However, platelets from NR showed a weaker response to adenosine diphosphate (ADP, 52.3+/-17.8% vs. 80.5+/-8.7% from R, P<.01). In the presence of P2Y(1) antagonist adenosine 3',5'-diphosphosulfate (A3P5PS), ADP failed to induce platelet aggregation in NR (7.8+/-4.7% vs. 64.7+/-11.2% in R, P<.01). Addition of SQ22,536 to inhibit adenylyl cyclase did not convert NR to R. These observations demonstrate that there is an impaired platelet responsiveness to ADP as well as to Epi in NR, due to a difference in downstream of the signal transduction pathway but independent of adenylyl cyclase inhibition.
Nakahashi
T K
TK
Vascular Biology and Thrombosis, Maryland Research Laboratories, Otsuka Maryland Research Institutes, LLC, Rockville, MD 20850, USA.
Kambayashi
J
J
Nakamura
T
T
Le
S N
SN
Yoshitake
M
M
Tandon
N N
NN
Sun
B
B
D000244:Adenosine Diphosphate / Q000494:pharmacology*; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D001483:Base Sequence; D001665:Binding Sites; D001792:Blood Platelets / Q000187:drug effects*; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D004837:Epinephrine / Q000494:pharmacology*; D006801:Humans; D008565:Membrane Proteins; D010974:Platelet Aggregation / Q000187:drug effects; D058919:Purinergic P2 Receptor Antagonists; D018341:Receptors, Adrenergic, alpha-2 / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D018048:Receptors, Purinergic P2 / Q000378:metabolism; D058925:Receptors, Purinergic P2Y12; D015398:Signal Transduction
D000316:Adrenergic alpha-Agonists; D008565:Membrane Proteins; C548576:P2RY12 protein, human; D058919:Purinergic P2 Receptor Antagonists; D018341:Receptors, Adrenergic, alpha-2; D018048:Receptors, Purinergic P2; D058925:Receptors, Purinergic P2Y12; D000244:Adenosine Diphosphate; D000242:Cyclic AMP; D004837:Epinephrine