Transregulation of the alpha2-adrenergic signal transduction pathway by chronic beta-blockade: a novel mechanism for decreased platelet aggregation in patients.
Platelets play a pivotal role in the pathophysiology of acute coronary syndromes. Chronic beta-blockade has been shown to improve the long-term clinical outcome in coronary heart disease. Because platelets play a central role in thrombus formation, the aim of the present study was to investigate if chronic beta-blockade may transregulate the expression of alpha2-adrenergic receptors on human platelets and via this mechanism may modulate platelet activation. The densities of alpha2-adrenergic receptors of platelets were determined in healthy volunteers under chronic beta-blockade and as alpha2-adrenergic receptor-mediated function in catecholamine-induced platelet aggregation was determined. Chronic beta-blockade induced a time-dependent reduction of alpha2-adrenergic receptors. This reduction was accompanied by a decrease of the alpha-subunit of Gi proteins as demonstrated by Western blot analysis. This transregulation at both the receptor level and the G-protein level resulted in an almost complete loss of the alpha2-adrenergic receptor-mediated inhibition of adenylyl cyclase. The impairment of the alpha2-adrenergic receptor system correlated with a reduction of the catecholamine-induced activation and aggregation of human platelets. The functional transregulation of alpha2-adrenergic receptors by chronic beta-blockade in platelets and the consequent impairment of platelet activation may contribute to the therapeutic success of beta-blocker therapy.
Schwencke
Carsten
C
Medical Clinic II, Department of Cardiology, University of Technology Dresden, Dresden, Germany.
Schmeisser
Alexander
A
Weinbrenner
Christof
C
Braun-Dullaeus
Ruediger C
RC
Marquetant
Rainer
R
Strasser
Ruth H
RH
D000262:Adenylyl Cyclases / Q000378:metabolism; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000317:Adrenergic alpha-Antagonists / Q000378:metabolism; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000328:Adult; D001792:Blood Platelets / Q000187:drug effects; D002462:Cell Membrane / Q000187:drug effects; D003000:Clonidine / Q000494:pharmacology; D004591:Electrophoresis, Polyacrylamide Gel; D004837:Epinephrine / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000096:biosynthesis; D006801:Humans; D015151:Immunoblotting; D066298:In Vitro Techniques; D010974:Platelet Aggregation / Q000187:drug effects*; D018341:Receptors, Adrenergic, alpha-2 / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D015016:Yohimbine / Q000378:metabolism
D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D000319:Adrenergic beta-Antagonists; D018341:Receptors, Adrenergic, alpha-2; D015016:Yohimbine; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases; D003000:Clonidine; D004837:Epinephrine