Calderone A, Bouvier M, Li K, Juneau C, de Champlain J, Rouleau J L
Département de Physiologie, Université de Montréal, Sherbrooke, Canada.
Circ Res. 1991 Aug;69(2):332-43. doi: 10.1161/01.res.69.2.332.
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)
研究了犬充血性心力衰竭快速心室起搏模型中β-和α-肾上腺素能刺激途径的功能完整性；正常犬作为对照。起搏超速驱动犬的总β-肾上腺素能受体密度降低35%（p<0.01），并且在起搏犬的左心室和右心室中，β-肾上腺素能受体介导的腺苷酸环化酶刺激（Vmax）分别降低68%和72%（p<0.01）。此外，在衰竭心脏的左心室和右心室中，基础腺苷酸环化酶活性分别降低56%和68%（p<0.01）。同样，起搏犬两个心室中5'-鸟苷酰亚胺二磷酸（GppNHp）和福斯高林刺激的腺苷酸环化酶活性的Vmax显著降低，分别为70%和55%（p<0.01）。然而，尽管两组中β-激动剂和GppNHp刺激腺苷酸环化酶产生半数最大速度的浓度相似，但福斯高林刺激该酶的浓度显著增加（p<0.01）。百日咳毒素介导的对照心脏和衰竭心脏膜的ADP-核糖基化显示，起搏犬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脏膜中的基础和福斯高林刺激的腺苷酸环化酶活性，但百日咳毒素处理后衰竭心脏中的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，对离体乳头肌和小梁的力学研究显示，起搏超速驱动模型中的基线总张力（从7.0±0.7降至3.8±0.4g/mm2，p<0.01）和dT/dt（从26±8降至13±1g/mm2/sec，p<0.01）降低。起搏犬中观察到的张力产生和dT/dt对福斯高林浓度增加的反应表明剂量反应曲线向右移动，最大福斯高林刺激降低（p<0.01）。同样，异丙肾上腺素存在下的最大张力和dT/dt显著低于正常犬（p<0.01）。β-肾上腺素能反应性降低伴随着α1-肾上腺素能反应性降低和向右移动（起搏犬中张力增加为1.1±0.1g/mm2，而对照组为2.1±0.1g/mm2，p<0.01）。（摘要截断于400字）
