Distribution and function of human ventricular beta adrenergic receptors in congestive heart failure.
This study examined the characteristics and distribution of sarcolemmal and light vesicular beta-adrenergic receptors (BAR) in left ventricular myocardium from 15 adults (aged 17 to 58 years) without left ventricular dysfunction or coronary artery disease and 29 patients (aged 14 to 53 years) with end-stage congestive heart failure (CHF). Sarcolemmal and intracellular fractions were prepared by 40,000 x g and 108,000 x g centrifugation, respectively. Agonist and antagonist binding properties were assessed by nonlinear computer modelling of isoproterenol-125I-pindolol (IPIN) displacement curves. Adenylate cyclase activity was also examined. Distribution of intracellular and sarcolemmal BAR was similar in normal and failing left ventricular myocardium, with intracellular BAR comprising 4.5 +/- 2.2% of total BAR in normal human heart and 5.7 +/- 5.1% of total BAR in CHF patients. For sarcolemmal BAR, antagonist affinity was similar for normal and CHF patients (KD IPIN in normals, 21.7 +/- 2.6 pM; KD IPIN in CHF, 20 +/- 2.3 pM). Agonist affinity was somewhat higher in CHF patients (KD isoproterenol in normals, 33 +/- 4.9 nM; KD isoproterenol in CHF, 6.2 +/- 1.5 nM). Sarcolemmal BAR number was reduced in CHF from 21.4 +/- 2.9 to 16.4 +/- 1.3 fmol/mg protein (P less than 0.04). Cyclic AMP production (pmol/mg protein/min above basal) was less in CHF after Gpp(NH)p stimulation (normals, 82 +/- 20; CHF, 27 +/- 9; P less than 0.01) and after stimulation with Gpp(NH)p + isoproterenol (normals, 129 +/- 25; CHF, 56 +/- 13; P less than 0.02). Stimulation with manganese + forskolin resulted in similar levels of cyclic AMP production in normals and in CHF patients. We conclude that: (a) sarcolemmal BAR number is reduced in CHF, but BAR are not redistributed intracellularly and (b) beta-adrenergic transmembrane signalling in CHF is also impaired at the level of the guanine nucleotide regulatory proteins.
Denniss
A R
AR
Department of Medicine, Brigham and Women's Hospital, Boston 02115.
Colucci
W S
WS
Allen
P D
PD
Marsh
J D
JD
D000262:Adenylyl Cyclases / Q000378:metabolism*; D000293:Adolescent; D000328:Adult; D001667:Binding, Competitive; D019204:GTP-Binding Proteins / Q000378:metabolism*; D006333:Heart Failure / Q000378:metabolism*; D006352:Heart Ventricles / Q000378:metabolism*; D006801:Humans; D007545:Isoproterenol / Q000378:metabolism; D008875:Middle Aged; D010869:Pindolol / Q000378:metabolism; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*
D011943:Receptors, Adrenergic, beta; D010869:Pindolol; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases; D007545:Isoproterenol