Beta-adrenergic neuroeffector abnormalities in the failing human heart are produced by local rather than systemic mechanisms.
In order to investigate the general cause of beta-adrenergic receptor neuroeffector abnormalities in the failing human heart, we measured ventricular myocardial adrenergic receptors, adrenergic neurotransmitters, and beta-adrenergic receptor-effector responses in nonfailing and failing hearts taken from nonfailing organ donors, subjects with endstage biventricular failure due to idiopathic dilated cardiomyopathy (IDC), and subjects with primary pulmonary hypertension (PPH) who exhibited isolated right ventricular failure. Relative to nonfailing PPH left ventricles, failing PPH right ventricles exhibited (a) markedly decreased beta 1-adrenergic receptor density, (b) marked depletion of tissue norepinephrine and neuropeptide Y, (c) decreased adenylate cyclase stimulation in response to the beta agonists isoproterenol and zinterol, and (d) decreased adenylate cyclase stimulation in response to Gpp(NH)p and forskolin. These abnormalities were directionally similar to, but generally more pronounced than, corresponding findings in failing IDC right ventricles, whereas values for these parameters in nonfailing left ventricles of PPH subjects were similar to values in the nonfailing left ventricles of organ donors. Additionally, relative to paired nonfailing PPH left ventricles and nonfailing right ventricles from organ donors, failing right ventricles from PPH subjects exhibited decreased adenylate cyclase stimulation by MnCl2. These data indicate that: (a) Adrenergic neuroeffector abnormalities present in the failing human heart are due to local mechanisms; systemic processes do not produce beta-adrenergic neuroeffector abnormalities. (b) Pressure-overloaded failing right ventricles of PPH subjects exhibit decreased activity of the catalytic subunit of adenylate cyclase, an abnormality not previously described in the failing human heart.
Bristow
M R
MR
Heart Failure Treatment Program, University of Utah Medical Center, Salt Lake City 84132.
Minobe
W
W
Rasmussen
R
R
Larrabee
P
P
Skerl
L
L
Klein
J W
JW
Anderson
F L
FL
Murray
J
J
Mestroni
L
L
Karwande
S V
SV
D000262:Adenylyl Cyclases / Q000032:analysis; D000328:Adult; D002311:Cardiomyopathy, Dilated / Q000503:physiopathology; D002395:Catecholamines / Q000032:analysis; D005260:Female; D006321:Heart / Q000503:physiopathology*; D006333:Heart Failure / Q000503:physiopathology*; D006801:Humans; D006976:Hypertension, Pulmonary / Q000503:physiopathology*; D020120:Iodocyanopindolol; D007545:Isoproterenol / Q000378:metabolism; D008297:Male; D009200:Myocardial Contraction; D009478:Neuropeptide Y / Q000032:analysis; D010869:Pindolol / Q000031:analogs & derivatives / Q000378:metabolism; D011942:Receptors, Adrenergic, alpha / Q000032:analysis / Q000502:physiology; D011943:Receptors, Adrenergic, beta / Q000032:analysis / Q000502:physiology*
D002395:Catecholamines; D009478:Neuropeptide Y; D011942:Receptors, Adrenergic, alpha; D011943:Receptors, Adrenergic, beta; D020120:Iodocyanopindolol; D010869:Pindolol; D000262:Adenylyl Cyclases; D007545:Isoproterenol