Abnormality of adenylate cyclase regulation in human platelet membranes in renal insufficiency.
Adenylate cyclase in human platelets is under dual control of prostaglandins (PGI2 and PGE1) and catecholamines. The adenylate cyclase complex in membranes of platelets from ten patients with uraemia was investigated. The activation of the platelet cyclase by PGE1 is increased in the uraemic state, Vmax 4436 +/- 607 pmol cAMP mg-1 15 min-1. In the normal state Vmax is 2098 +/- 309 pmol cAMP mg-1 15 min-1. The alpha 2-adrenergic receptor was assayed with 3H-yohimbine binding. The density of receptors was equal in the uraemic (175 fmol mg-1 membrane protein) and the normal (170 fmol mg-1 membrane protein) states. Norepinephrine/3H-yohimbine competition binding revealed that catecholamines were bound with normal affinity in platelets in uraemia. Yet the inhibition of adenylate cyclase through the alpha 2-adrenergic receptor was diminished since Vmax values of adenylate cyclase with PGE1 and PGE2 + norepinephrine did not significantly differ. In the normal state, norepinephrine significantly (P less than 0.05) inhibited the PGE1 stimulated cyclase. It is concluded that platelet adenylate cyclase in the uraemia has an increased capacity for activation which is the result of both a sensitized stimulatory mechanism (prostaglandin mediated) and a deficient inhibitory mechanism (catecholamine mediated). It is suggested that a defect exists in the inhibitory nucleotide binding protein (NI) which is the coupling unit between the adenylate cyclase catalytic subunit (C).
Jacobsson
B
B
Ransnäs
L
L
Nyberg
G
G
Bergh
C H
CH
Magnusson
Y
Y
Hjalmarson
A
A
D000262:Adenylyl Cyclases / Q000097:blood*; D000328:Adult; D000527:Alprostadil; D001667:Binding, Competitive; D001792:Blood Platelets / Q000201:enzymology*; D002462:Cell Membrane / Q000201:enzymology; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D005921:Glomerulonephritis / Q000150:complications*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009638:Norepinephrine / Q000378:metabolism / Q000494:pharmacology; D011458:Prostaglandins E / Q000494:pharmacology; D011942:Receptors, Adrenergic, alpha / Q000378:metabolism; D014511:Uremia / Q000201:enzymology* / Q000209:etiology; D015016:Yohimbine / Q000378:metabolism
D011458:Prostaglandins E; D011942:Receptors, Adrenergic, alpha; D015016:Yohimbine; D000262:Adenylyl Cyclases; D000527:Alprostadil; D009638:Norepinephrine