Dysfunction of the beta- and alpha-adrenergic systems in a model of congestive heart failure. The pacing-overdrive dog.

Abstract

The functional integrity of the beta- and alpha-adrenergic stimulatory pathways in a rapid ventricular pacing model of congestive heart failure in dogs was investigated; normal dogs served as controls. Total beta-adrenergic receptor density was 35% lower (p less than 0.01) in the pacing-overdrive dogs, and the beta-adrenergic receptor-mediated stimulation of adenylate cyclase (Vmax) was found to be 68% and 72% lower (p less than 0.01) in the left and right ventricles of the paced dogs. In addition, the basal adenylate cyclase activity was found to be 56% and 68% lower (p less than 0.01) in the left and right ventricles of the failing heart. Similarly, the Vmax of 5'-guanylylimidodiphosphate (GppNHp) and forskolin stimulation of adenylate cyclase activity was significantly lower, 70% and 55%, respectively (p less than 0.01), in both ventricles of the paced dogs. However, although the concentration yielding half-maximal velocity for beta-agonist and GppNHp stimulation of adenylate cyclase was similar in both groups, that for forskolin stimulation of the enzyme was significantly increased (p less than 0.01). Pertussis toxin-mediated ADP-ribosylation of membranes from control and failing hearts revealed a significant decrease in the inhibitory guanine nucleotide binding protein content (48 +/- 9%, p less than 0.01) in the hearts of the paced dogs. Moreover, although the pertussis toxin treatment increased the basal and the forskolin-stimulated adenylate cyclase activity in both normal and failing heart membranes, the adenylate cyclase activity remained significantly depressed in the failing heart after pertussis toxin treatment (p less than 0.01). Consistent with the depressed adenylate cyclase activity, mechanical studies on isolated papillary muscles and trabeculae revealed a decrease in baseline total tension (from 7.0 +/- 0.7 to 3.8 +/- 0.4 g/mm2, p less than 0.01) and dT/dt (from 26 +/- 8 to 13 +/- 1 g/mm2/sec, p less than 0.01) in the pacing-overdrive model. Tension generation and dT/dt observed in the paced dogs in response to increasing concentrations of forskolin demonstrated a rightward shift in the dose-response curve and a decrease in maximal forskolin stimulation (p less than 0.01). Similarly, maximal tension and dT/dt in the presence of isoproterenol was significantly lower than in the normal dogs (p less than 0.01). The decrease in beta-adrenergic responsiveness was accompanied by a decrease and rightward shift in alpha 1-adrenergic responsiveness (increase in tension was 1.1 +/- 0.1 g/mm2 in paced dogs versus 2.1 +/- 0.1 g/mm2 in controls, p less than 0.01).(ABSTRACT TRUNCATED AT 400 WORDS)

Downregulation of cardiac guanosine 5'-triphosphate-binding proteins in right atrium and left ventricle in pacing-induced congestive heart failure.

“…Myocardial fAR and adenylyl cyclase activity. Although no previous study has addressed alterations in 3AR-mediated signal transduction in pacing-induced CHF in pigs, two prior studies using this model in dogs have been published (6,7 (34). Other data suggest that the ,3y dimer, rather than dissociated ai, may lead to inhibition of adenylyl cyclase, either through direct interaction with the catalytic subunit, or through associating with free Gsa, thereby preventing Gsa-mediated stimulation of adenylyl cyclase (35 However, right atrial Gsa mRNA levels were significantly increased (P < 0.04) after pacing-induced CHF.…”

“…This resurrection was due in part to the burgeoning interest in molecular and biochemical alterations associated with heart failure, but also reflected the simplicity and consistency of this model in comparison to others. Pacing-induced cardiac dysfunction is now a much-used animal model for the study of heart failure (6)(7)(8)(9)(10).…”

“…Since a major means for increasing cardiac output in severe heart failure is by increasing heart rate, factors affecting heart rate regulation are important. Second, what little attention that has been focused upon Gi-mediated events in the setting of pacing-induced heart failure have provided discordant data (6,7). Furthermore, the extent to which heart failure is dependent upon increased levels of cardiac Gi is unknown.…”

If channel inhibitor ivabradine lowers heart rate in mice with enhanced sympathoadrenergic activities

“…Persistent rapid pacing in larger laboratory species can cause cardiomyopathy and heart failure (Packer et al, 1986;Calderone et al, 1991). Although b-blockers yield a number of changes that may ultimately contribute to the overall efficacy in the setting of heart failure, reduction in HR by bblockers can reduce myocardial oxygen consumption and prolong diastolic period with increased coronary blood flow.…”

Cardiovascular Effects of a Phosphodiesterase III inhibitor in the Presence of Carvedilol in Dogs

“…First, whether the effects of carvedilol on dogs are comparable to the effects of this drug on humans is not known. Second, in dogs with heart failure, β-receptors are down-regulated [6,13,24] and intracellular cAMP concentrations are reduced [17,19]. Therefore, the responses of animals with heart failure to β-receptor agonists and PDE III inhibitors may differ from those of healthy animals.…”