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

Abstract

We studied the alterations in myocardial beta-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 (Kd) (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%). Beta-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 less than 0.01, reduction in muscarinic receptor density (242 +/- 19 vs. 111 +/- 20 fmol/mg). Thus, while muscarinic receptor density fell, beta-adrenergic receptor density actually increased in LV failure. However, a larger portion of the beta-adrenergic receptors are not functionally coupled to the GTP-stimulatory protein (Ns), as evidenced by a decrease in the fraction of receptors that bind agonist with high affinity.

• Authors: D E Vatner, S F Vatner, A M Fujii, C J Homcy
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 76 Issue 6 Pg. 2259-64 (Dec 1985) ISSN: 0021-9738 [Print] United States
• PMID: 3001147 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Receptors, Adrenergic, beta
• Receptors, Muscarinic
• Guanylyl Imidodiphosphate
• Adenylyl Cyclases
• Sodium-Potassium-Exchanging ATPase
• Isoproterenol
• Norepinephrine

Topics

• Adenylyl Cyclases (metabolism)
• Animals
• Disease Models, Animal
• Dogs
• Female
• Guanylyl Imidodiphosphate (metabolism)
• Heart Failure (metabolism)
• Isoproterenol (metabolism)
• Male
• Myocardium (metabolism)
• Norepinephrine (metabolism)
• Receptors, Adrenergic, beta (metabolism)
• Receptors, Muscarinic (metabolism)
• Sodium-Potassium-Exchanging ATPase (metabolism)