DYSFUNCTION OF THE BETA-ADRENERGIC AND ALPHA-ADRENERGIC SYSTEMS IN A MODEL OF CONGESTIVE-HEART-FAILURE - THE PACING-OVERDRIVE DOG

被引:122
作者
CALDERONE, A
BOUVIER, M
LI, K
JUNEAU, C
DECHAMPLAIN, J
ROULEAU, JL
机构
[1] CHU SHERBROOKE,RES CTR,SHERBROOKE J1H 5N4,QUEBEC,CANADA
[2] HOP SACRE COEUR,CTR RECH,MONTREAL H4J 1C5,QUEBEC,CANADA
[3] UNIV MONTREAL,DEPT PHYSIOL,MONTREAL H3C 3J7,QUEBEC,CANADA
[4] UNIV MONTREAL,DEPT BIOCHIM,MONTREAL H3C 3J7,QUEBEC,CANADA
关键词
RAPID VENTRICULAR PACING; CONGESTIVE HEART FAILURE; ADENYLATE CYCLASE; BETA-ADRENERGIC RECEPTORS; ALPHA-ADRENERGIC RECEPTORS; CONTRACTILITY;
D O I
10.1161/01.RES.69.2.332
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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 < 0.01) in the pacing-overdrive dogs, and the beta-adrenergic receptor-mediated stimulation of adenylate cyclase (V(max)) was found to be 68% and 72% lower (p < 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 < 0.01) in the left and right ventricles of the failing heart. Similarly, the V(max) of 5'-guanylylimidodiphosphate (GppNHp) and forskolin stimulation of adenylate cyclase activity was significantly lower, 70% and 55%, respectively (p < 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 < 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 < 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 < 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 < 0.01) and dT/dt (from 26 +/- 8 to 13 +/- 1 g/mm2/sec, p < 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 < 0.01). Similarly, maximal tension and dT/dt in the presence of isoproterenol was significantly lower than in the normal dogs (p < 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 < 0.01). This decrease in alpha-1-adrenergic responsiveness occurred despite no change in receptor density, suggesting that the abnormality resides beyond the receptor. We suggest that a decrease in adenylate cyclase reactivity contributes to the blunted beta-adrenergic response to catecholamine stimulation in the pacing-overdrive model of heart failure. These abnormalities to the beta-adrenergic signal transduction pathway were accompanied by a decrease in activity of the membrane-bound enzyme Na+,K+-ATPase (p < 0.01). These defects may be a reflection of more widespread dysfunction of sarcolemmal-bound enzymes and may play a role in the decrease in contractility and the development of heart failure in this model.
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收藏
页码:332 / 343
页数:12
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