Myocardial beta-adrenergic receptor function during the development of pacing-induced heart failure

J Clin Invest. 1993 Mar;91(3):907-14. doi: 10.1172/JCI116312.

Abstract

The development of pacing-induced heart failure was studied in chronically instrumented, conscious dogs paced at a rate of 240 beats/min for 1 d (n = 6), 1 wk (n = 6), and 3-4 wk (n = 7). Left ventricular (LV) dP/dt was decreased (P < 0.0125) at 1 d, LV end-diastolic pressure and heart rate were increased (P < 0.0125) at 1 wk, but clinical signs of heart failure were only observed after 3-4 wk of pacing. Plasma norepinephrine rose (P < 0.0125) after 1 d of pacing, whereas LV norepinephrine was reduced (P < 0.0125) only after 3-4 wk of pacing. Both the fraction of beta-adrenergic receptors binding agonist with high affinity and adenylyl cyclase activity decreased (P < 0.0125) after 1 d of pacing. Total beta-adrenergic receptor density was not changed at any time point, but beta 1-adrenergic receptor density was decreased (P < 0.0125) after 1 wk. The functional activity of the guanine nucleotide binding protein, Gs, was not reduced, but the Gi alpha 2 isoform of the alpha subunit of the GTP-inhibitory protein rose after 3-4 wk of pacing. Thus, myocardial beta-adrenergic signal transduction undergoes change shortly (1d) after the initiation of pacing, before heart failure develops. The mechanism of beta-adrenergic receptor dysfunction in pacing-induced heart failure is characterized initially by elevated plasma levels of catecholamines, uncoupling of beta-adrenergic receptors, and a defect in the adenylyl cyclase catalytic unit. Selective down-regulation of beta 1-adrenergic receptors, increases in Gi alpha 2, and decreases in myocardial catecholamine levels occur as later events.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenylyl Cyclases / metabolism
  • Animals
  • Blood Pressure*
  • Cardiac Output, Low / blood
  • Cardiac Output, Low / physiopathology*
  • Diastole
  • Dogs
  • Female
  • GTP-Binding Proteins / metabolism
  • Heart / physiology
  • Heart / physiopathology*
  • Heart Rate*
  • Kinetics
  • Male
  • Myocardium / metabolism*
  • Norepinephrine / blood
  • Norepinephrine / metabolism
  • Receptors, Adrenergic, beta / metabolism*
  • Systole
  • Ventricular Function, Left

Substances

  • Receptors, Adrenergic, beta
  • GTP-Binding Proteins
  • Adenylyl Cyclases
  • Norepinephrine