Circulation, Vol 74, 1290-1302, Copyright © 1986 by American Heart Association
MB Fowler, JA Laser, GL Hopkins, W Minobe and MR Bristow
We developed methods for identifying beta-adrenergic receptors in human
right ventricular endomyocardial biopsy tissue with the radioligand (-
)[125I]iodocyanopindolol (ICYP). Specific ICYP binding in a crude, high-
yield membrane preparation derived from endomyocardial biopsy tissue was
high (specificity greater than 90%), of high affinity (KD around 20 pM),
saturable and stereospecific for the (-) vs the (+) isomer of
isoproterenol. Subjects with mild-moderate and severe biventricular
dysfunction had respective decreases in beta-adrenergic receptor density of
38.2% and 57.7% when normalization methods were averaged, with no
significant differences in ICYP dissociation constant. A subgroup of
subjects was subdivided by left ventricular ejection fraction (LVEF) into
those with mild cardiac dysfunction (LVEF less than 0.50 greater than 0.40)
and severe heart failure (LVEF less than 0.20) and given graded sequential
infusions of dobutamine and calcium gluconate. Those with severe cardiac
dysfunction had marked impairment of the dobutamine dP/dt and stroke work
index response, whereas these responses to calcium did not differ in the
two groups. These data indicate that in the intact human heart
endomyocardial biopsy may be used for direct analysis of beta-adrenergic
receptors, heart failure- associated myocardial beta-adrenergic
down-regulation begins with mild- moderate ventricular dysfunction,
reduction in myocardial beta-receptor density is related to degree of heart
failure, and beta-receptor down- regulation is associated with
pharmacologically specific impairment of the beta-agonist-mediated
contractile response.
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Assessment of the beta-adrenergic receptor pathway in the intact failing human heart: progressive receptor down-regulation and subsensitivity to agonist response
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