Dysfunction of the beta- and alpha-adrenergic systems in a model of congestive heart failure. The pacing-overdrive dog.
Dysfunction of the beta- and alpha-adrenergic systems in a model of congestive heart failure. The pacing-overdrive dog.
复制标题
充血性心力衰竭模型中β-和α-肾上腺素能系统的功能障碍。
作者：
A. Calderone;Michel Bouvier;K. Li;C. Juneau;J. Champlain;Jean
研究了犬充血性心力衰竭快速心室起搏模型中β -和α -肾上腺素能刺激通路的功能完整性；正常的狗作为对照。节律过度犬的β -肾上腺素能受体总密度降低35% (p < 0.01)， β -肾上腺素能受体介导的腺苷酸环化酶（Vmax）刺激在左心室和右心室分别降低68%和72% （p < 0.01）。左、右心室腺苷酸环化酶活性分别降低56%和68% （p < 0.01）。同样，5′-冠酰脲二磷酸（GppNHp）和福斯克林刺激腺苷酸环化酶活性的Vmax在两心室均显著降低，分别为70%和55% （p < 0.01）。然而，尽管β -激动剂和GppNHp刺激腺苷酸环化酶的半最大速度浓度在两组中相似，但福斯克林刺激腺苷酸环化酶的半最大速度浓度显著增加（p < 0.01）。百日咳毒素介导的对照组和衰竭心脏膜adp核糖基化显示，节律狗心脏中抑制性鸟嘌呤核苷酸结合蛋白含量显著降低（48 +/- 9%,p < 0.01）。此外，尽管百日咳毒素处理增加了正常和衰竭心膜中腺苷酸环化酶的基础活性和福斯克林刺激的腺苷酸环化酶活性，但百日咳毒素处理后衰竭心膜中腺苷酸环化酶活性仍显著降低（p < 0.01）。与腺苷酸环化酶活性降低一致，对孤立乳头肌和小梁的力学研究显示，在起搏器过度驱动模型中，基线总张力（从7.0 +/- 0.7降至3.8 +/- 0.4 g/mm2， p小于0.01）和dT/ dT（从26 +/- 8降至13 +/- 1 g/mm2/sec， p小于0.01）降低。随着福斯克林浓度的增加，有节奏的狗的张力产生和dT/ dT呈剂量-反应曲线右移，最大福斯克林刺激减少（p < 0.01）。异丙肾上腺素组的最大张力和dT/ dT值显著低于正常组（p < 0.01）。β -肾上腺素能反应性的降低伴随着α -肾上腺素能反应性的降低和右移（有节奏狗的张力增加为1.1 +/- 0.1 g/mm2，对照组为2.1 +/- 0.1 g/mm2, p < 0.01）。（摘要删节为400字）
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)