Up-regulation of beta 2-adrenergic receptors in previously transplanted, denervated nonfailing human hearts.
OBJECTIVE
The purpose of this study was to examine beta-adrenergic receptor signal transduction in denervated, previously transplanted human ventricular myocardium.


BACKGROUND
In model systems, surgical denervation typically results in both presynaptic and postsynaptic supersensitivity in beta-adrenergic receptor pathways and alteration in G protein-mediated signal transduction.


METHODS
We examined beta-adrenergic receptor signal transduction in the left and right ventricles removed from nine subjects with a previous transplant and surgical denervation 25 +/- 4 months after their first transplantation. Twenty-six hearts removed from organ donors served as control hearts.


RESULTS
Total beta-adrenergic receptor density and stimulation of muscle contraction in isolated right ventricular trabeculae by the nonselective agonist isoproterenol were similar in the transplant and donor groups. Beta 1-receptor density was not different in the left ventricles of the two groups but tended to be reduced (by 29%, p = 0.09) in transplant right ventricles. By contrast, beta 2-receptor density was higher in transplant left and right ventricles relative to the respective values in donor ventricles by 33% in left ventricles and 97% in right ventricles (both p < 0.05). Isoproterenol, which in particulate fractions of human heart stimulates adenylyl cyclase primarily via beta 2-receptors, produced a greater increase in cyclic adenosine monophosphate generation in membranes prepared from transplant left ventricles and right ventricles compared with donors. In contrast, guanosine 5'-[beta,gamma-imido]triphosphate, sodium fluoride and forskolin, which stimulate adenylyl cyclase through nonreceptor/G protein-sensitive mechanisms, yielded similar degrees of adenylyl cyclase stimulation in the two groups, and both pertussis toxin- and cholera toxin-catalyzed adenosine diphosphate ribosylation were not altered in transplanted left ventricles.


CONCLUSIONS
These data indicate that the transplanted human heart exhibits an up-regulation of functional beta 2-adrenergic receptors.
Farrukh
H M
HM
Department of Medicine, University of Colorado Health Sciences Center, Denver 80262.
White
M
M
Port
J D
JD
Handwerger
D
D
Larrabee
P
P
Klein
J
J
Roden
R A
RA
Skerl
L
L
Renlund
D G
DG
Feldman
A M
AM
D000262:Adenylyl Cyclases / Q000378:metabolism; D003714:Denervation; D005260:Female; D006321:Heart / Q000294:innervation*; D016027:Heart Transplantation / Q000502:physiology*; D006801:Humans; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D009206:Myocardium / Q000737:chemistry; D018342:Receptors, Adrenergic, beta-1 / Q000032:analysis / Q000502:physiology*; D012086:Reoperation; D015398:Signal Transduction / Q000502:physiology*; D015854:Up-Regulation / Q000502:physiology*
D018342:Receptors, Adrenergic, beta-1; D000262:Adenylyl Cyclases; D007545:Isoproterenol