beta-Adrenergic and endothelin receptor interaction in dilated human cardiomyopathic myocardium.
BACKGROUND
Although end-stage dilated cardiomyopathy (DCM) is characterized by defects in beta-adrenergic receptor (beta-AR) activity and increased endothelin-1 (ET-1), possible interactions between these 2 systems remain to be defined. Accordingly, the goal of this study was to determine the effects of ET receptor activation on beta-AR signaling through measurement of cyclic adenosine monophosphate (cAMP) in normal and DCM myocardium.


RESULTS
Myocardial sarcolemmal preparations were prepared from normal human (n = 6), dilated cardiomyopathic (n = 10), and ischemic cardiomyopathic (ICM, n = 10) tissue. Basal cAMP production was measured in the presence of ET-1 alone (10(-6) to 0(-9) mol/L) as well as after (-)isoproterenol (10(-6) to 10(-2) mol/L) or forskolin (0.05 to 30.0 micromol/L) stimulation. beta-AR and ET receptor profiles were determined by radiolabeled ligand assays. ET-1 inhibited basal cAMP production in all preparations in a concentration-dependent manner. However, beta-AR-stimulated cAMP production by either isoproterenol or forskolin was not significantly affected by ET-1. beta-AR receptor density was reduced, and a selective reduction of the ET(B) receptor occurred in both forms of DCM.


CONCLUSIONS
Under basal conditions, ET receptor stimulation reduced cAMP levels, which may influence contractility, particularly with DCM.
Walker
C A
CA
Division of Cardiothoracic Surgery Research, Medical University of South Carolina, Charleston, SC 29425, USA.
Ergul
A
A
Grubbs
A
A
Zile
M R
MR
Zellner
J L
JL
Crumbley
A J
AJ
Spinale
F G
FG
D000293:Adolescent; D000328:Adult; D000818:Animals; D009202:Cardiomyopathies / Q000378:metabolism*; D000242:Cyclic AMP / Q000096:biosynthesis*; D019332:Endothelin-1 / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008875:Middle Aged; D009206:Myocardium / Q000378:metabolism*; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D017466:Receptors, Endothelin / Q000378:metabolism*; D015398:Signal Transduction; D013552:Swine
D019332:Endothelin-1; D011943:Receptors, Adrenergic, beta; D017466:Receptors, Endothelin; D000242:Cyclic AMP