Warner A L, Bellah K L, Raya T E, Roeske W R, Goldman S
Department of Internal Medicine, Tucson Veterans Administration Medical Center, AZ 85723.
Circulation. 1992 Nov;86(5):1584-95. doi: 10.1161/01.cir.86.5.1584.
beta-Adrenergic receptor blockade has been reported to improve hemodynamics and beta-adrenergic receptor-adenylate cyclase function in idiopathic dilated cardiomyopathy. The purpose of this study was to determine the effects of beta-adrenergic receptor blockade on the beta-adrenergic receptor system and myocardial function in a model of compensated ischemic heart failure.
We examined the effects of propranolol treatment on the beta-adrenergic receptor-adenylate cyclase system and isolated papillary muscle isometric function in noninfarcted left ventricular myocardium in rats after coronary artery ligation. In untreated rats with large myocardial infarction (MI), developed tension (DT) (3.0 +/- 0.7 versus 5.1 +/- 1.1 g/mm2), peak rate of tension rise (+dT/dt) (40.3 +/- 9.5 versus 71.2 +/- 12.0 g/mm2/sec), and peak rate of tension fall (-dT/dt) (24.4 +/- 5.0 versus 38.2 +/- 6.0 g/mm2/sec) were decreased (p < 0.05). In addition, DT, +dT/dt, and -dT/dt of untreated MI rats demonstrated an impaired response to isoproterenol stimulation compared with controls. beta-Adrenergic receptor density (Bmax) measured by [125I]iodocyanopindolol (ICYP) binding was decreased 23% after infarction (9.3 +/- 0.6 versus 12.0 +/- 1.8 fmol/mg protein [prot]) (p < 0.05); however, the dissociation constant (Kd) for ICYP was not changed (24.1 +/- 5.7 versus 33.2 +/- 12.1 pM). Adenylate cyclase activity in the presence of 10(-2) M MgCl2 was reduced (p < 0.05) in MI rats (30.3 +/- 10.8 versus 45.9 +/- 12.5 pmol cAMP/min/mg prot). Maximal isoproterenol (52.5 +/- 7.3 versus 79.9 +/- 10.0 pmol cAMP/min/mg prot), guanyl-5'-imidodiphosphate (GppNHp) (95 +/- 8 versus 141 +/- 25 pmol cAMP/min/mg prot) and forskolin (503 +/- 76 versus 753 +/- 157 pmol cAMP/min/mg prot) stimulation of adenylate cyclase was also decreased (p < 0.05). In addition, manganese-stimulated adenylate cyclase activity was depressed (p < 0.05) in MI rats compared with controls (23.5 +/- 2.8 versus 52.1 +/- 9.0 pmol cAMP/min/mg prot). Chronic propranolol treatment in MI rats improved DT (4.1 +/- 0.9 versus 3.0 +/- 0.7 g/mm2) and +dT/dt (54.4 +/- 11.3 versus 40.5 +/- 9.5 g/mm2/sec) (p < 0.05); however, isoproterenol-stimulated isometric function remained impaired. Propranolol treatment normalized Bmax (11.9 +/- 1.7 versus 9.3 +/- 0.6 fmol/mg prot) (p < 0.05), whereas adenylate cyclase activity remained depressed.
After large MI in rats, there is impaired papillary muscle function with decreased beta-adrenergic receptors and adenylate cyclase activity in the noninfarcted myocardium. Propranolol treatment improved basal isometric muscle function and beta-adrenergic receptor density in rats after myocardial infarction but did not improve adenylate cyclase activity or isoproterenol-stimulated muscle function. These data suggest that there is a primary defect in adenylate cyclase function that persists despite upregulation of receptors with propranolol treatment.
据报道，β-肾上腺素能受体阻滞剂可改善特发性扩张型心肌病的血流动力学及β-肾上腺素能受体-腺苷酸环化酶功能。本研究旨在确定β-肾上腺素能受体阻滞剂对代偿性缺血性心力衰竭模型中β-肾上腺素能受体系统及心肌功能的影响。
我们检测了普萘洛尔治疗对冠状动脉结扎后大鼠非梗死左心室心肌中β-肾上腺素能受体-腺苷酸环化酶系统及离体乳头肌等长功能的影响。在未经治疗的大面积心肌梗死（MI）大鼠中，舒张期张力（DT）（3.0±0.7对5.1±1.1 g/mm²）、张力上升峰值速率（+dT/dt）（40.3±9.5对71.2±12.0 g/mm²/秒）及张力下降峰值速率（-dT/dt）（24.4±5.0对38.2±6.0 g/mm²/秒）均降低（p<0.05）。此外，与对照组相比，未经治疗的MI大鼠的DT、+dT/dt及-dT/dt对异丙肾上腺素刺激的反应受损。通过[¹²⁵I]碘氰吲哚洛尔（ICYP）结合测定的β-肾上腺素能受体密度（Bmax）在梗死后降低了23%（9.3±0.6对12.0±1.8 fmol/mg蛋白[prot]）（p<0.05）；然而，ICYP 的解离常数（Kd）未改变（24.1±5.7对33.2±12.1 pM）。在存在10⁻²M 氯化镁的情况下，MI大鼠的腺苷酸环化酶活性降低（p<0.05）（30.3±10.8对45.9±12.5 pmol cAMP/分钟/毫克prot）。异丙肾上腺素（52.5±7.3对79.9±10.0 pmol cAMP/分钟/毫克prot）、鸟苷-5'-亚氨基二磷酸（GppNHp）（95±8对141±25 pmol cAMP/分钟/毫克prot）及福斯可林（503±76对753±157 pmol cAMP/分钟/毫克prot）对腺苷酸环化酶的最大刺激也降低（p<0.05）。此外，与对照组相比，MI大鼠中锰刺激的腺苷酸环化酶活性降低（p<0.05）（23.5±2.8对52.1±9.0 pmol cAMP/分钟/毫克prot）。MI大鼠长期接受普萘洛尔治疗可改善DT（4.1±0.9对3.0±0.
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