Loss of high affinity cardiac beta adrenergic receptors in dogs with heart failure

D. E. Vatner, S. F. Vatner, A. M. Fujii, C. J. Homcy

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92 Scopus citations

Abstract

We studied the alterations in myocardial β-adrenergic receptor-adenylate cyclase activity and muscarinic receptor density in a canine model of left ventricular (LV) failure. LV failure was characterized by a doubling of LV weight/body weight ratio (3.3 ± 0.1 to 6.9 ± 0.4 g/kg) and an elevation of LV end-diastolic pressure, 32 ± 4.5 mmHg, compared with 7.7 ± 0.6 mmHg in normal dogs. Despite a 44% increase in receptor density as measured by antagonist binding studies with [3H]dihydroalprenolol, there was a twofold decrease in receptor affinity, i.e., an increase in the dissociation constant (K(d)) (5.6 ± 0.7 to 12 ± 1.6 nM) in heart failure. Agonist displacement of [3H]dihydroalprenolol binding with isoproterenol in the presence and absence of 5'-guanylylimidodiphosphate [Gpp(NH)p] demonstrated a striking loss of high affinity binding sites in heart failure (51 ± 16 to 11 ± 5%). β-Adrenergic receptor-mediated stimulation of adenylate cyclase and maximal stimulation with Gpp(NH)p or sodium fluoride was reduced in heart failure. There was a concomitant marked, P < 0.01, reduction in muscarinic receptor density (242 ± 19 vs. 111 ± 20 fmol/mg). Thus, while muscarinic receptor density fell, β-adrenergic receptor density actually increased in LV failure. However, a larger portion of the β-adrenergic receptors are not functionally coupled to the GTP-stimulatory protein (N(s)), as evidenced by a decrease in the fraction of receptors that bind agonist with high affinity.

Original languageEnglish (US)
Pages (from-to)2259-2264
Number of pages6
JournalJournal of Clinical Investigation
Volume76
Issue number6
DOIs
StatePublished - 1985
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Medicine(all)

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