Differential requirements for platelet aggregation and inhibition of adenylate cyclase by epinephrine. Studies of a familial platelet alpha 2-adrenergic receptor defect.
We describe a family whose members have impaired platelet aggregation and secretion responses to epinephrine with normal responses to adenosine diphosphate and collagen. Platelet alpha 2-adrenergic receptors (measured using 3H methyl-yohimbine) were diminished in the propositus (78 sites per platelet), his two sisters (70 and 27 sites per platelet), and parents (37 and 63 sites per platelet), but not in two maternal aunts (12 normal subjects, 214 +/- 18 sites per platelet; mean +/- SE). However, the inhibition of cyclic adenosine monophosphate (cAMP) levels by epinephrine in platelets exposed to 400 nmol/L PGI2 was similar in the patients and five normal subjects (epinephrine concentration for 50% inhibition, 0.04 +/- 0.01 mumol/L v 0.03 +/- 0.01 mumol/L; P greater than .05). In normal platelets, the concentration of yohimbine (0.18 mumol/L) required for half maximal inhibition of aggregation induced by 2 mumol/L epinephrine was lower than that for inhibition of its effect on adenylate cyclase (1.6 mumol/L). In quin2 loaded platelets, thrombin (0.1 U/mL) stimulated rise in cytoplasmic Ca2+ concentration, [Ca2+]i, was normal in the two patients studied. The PGI2 analog ZK 36,374 completely inhibited thrombin-induced rise in [Ca2+]i; the reversal of this inhibition by epinephrine was normal in the two patients. Thus, despite the impaired aggregation response to epinephrine, platelets from these patients have normal ability to inhibit PGI2-stimulated cAMP levels. These patients with an inherited receptor defect provide evidence that fewer platelet alpha 2-adrenergic receptors are required for epinephrine-induced inhibition of adenylate cyclase than for aggregation.
Rao
A K
AK
Thrombosis Research Center, Temple University School of Medicine, Philadelphia, PA.
Willis
J
J
Kowalska
M A
MA
Wachtfogel
Y T
YT
Colman
R W
RW
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000262:Adenylyl Cyclases / Q000097:blood*; D001792:Blood Platelets / Q000502:physiology*; D002118:Calcium / Q000097:blood; D003094:Collagen / Q000494:pharmacology; D004837:Epinephrine / Q000494:pharmacology*; D011464:Epoprostenol / Q000494:pharmacology; D006801:Humans; D009154:Mutation; D010974:Platelet Aggregation / Q000187:drug effects; D011942:Receptors, Adrenergic, alpha / Q000502:physiology*; D012701:Serotonin / Q000378:metabolism; D013917:Thrombin / Q000502:physiology; D015016:Yohimbine / Q000494:pharmacology
D011942:Receptors, Adrenergic, alpha; D015016:Yohimbine; D012701:Serotonin; D000244:Adenosine Diphosphate; D003094:Collagen; D011464:Epoprostenol; D013917:Thrombin; D000262:Adenylyl Cyclases; D002118:Calcium; D004837:Epinephrine