Murray D R, Prabhu S D, Freeman G L
Department of Medicine, University of Texas Health Science Center at San Antonio 78284, USA.
Cardiovasc Res. 1999 Dec;44(3):527-35. doi: 10.1016/s0008-6363(99)00226-6.
Nitric oxide (NO) has been proposed as a common mediator of tumor necrosis factor-alpha (TNF alpha)-induced vasodilation and myocardial dysfunction. Accordingly, we performed an extensive assessment of the influence of NO synthase inhibition on left ventricle (LV) and circulatory performance in conscious dogs at steady state and after establishment of TNF alpha mediated myodepression.
Autonomically blocked, chronically instrumented dogs were studied at steady state and 6 h after initiation of a 1-h rhTNF alpha infusion (40 micrograms/kg). Ventricular performance was evaluated using the pressure-volume framework. Dogs were then treated with either NG-nitro-L-arginine methylester (L-NAME, 40 mg/kg bolus) or angiotensin II (250-500 ng/kg).
L-NAME, under control conditions or following recombinant human (rh) TNF alpha-induced ventricular dysfunction, produced marked increases in afterload with attendant increases in LV pressure, volume, and prolonged isovolumic relaxation without adversely influencing coronary blood flow. regardless of whether the dogs received rhTNF alpha, L-NAME did not affect the slopes of the end-systolic pressure-volume and stroke-work (SW)-end-diastolic volume (EDV) relations (force-based measure of contractility), whereas the slope of the dP/dtmax-EDV relation, a velocity dependent parameter of LV systolic function, declined. Overall ventricular performance, as seen by the circulation, was reduced by L-NAME in control as well as rhTNF alpha-treated dogs, evidenced by rightward shifts of the SW-EDV and dP/dtmax-EDV relations. Similar findings were observed in the separate cohorts of dogs, at steady state and 6 h after rhTNF alpha, following angiotensin II at matched systolic pressure.
Systemic NO synthase inhibition with L-NAME does not acutely reverse rhTNF alpha-induced myocardial dysfunction. The detrimental influence of L-NAME on LV size, relaxation, and velocity-based measures of contractility is likely attributable to its effects on increasing afterload.
一氧化氮（NO）被认为是肿瘤坏死因子-α（TNFα）诱导血管舒张和心肌功能障碍的共同介质。因此，我们对一氧化氮合酶抑制在稳态和TNFα介导的心肌抑制建立后对清醒犬左心室（LV）和循环功能的影响进行了广泛评估。
对自主神经阻断、长期植入仪器的犬在稳态下以及在开始1小时重组人（rh）TNFα输注（40微克/千克）后6小时进行研究。使用压力-容积框架评估心室功能。然后用NG-硝基-L-精氨酸甲酯（L-NAME，40毫克/千克推注）或血管紧张素II（250-500纳克/千克）治疗犬。
在对照条件下或rhTNFα诱导的心室功能障碍后，L-NAME使后负荷显著增加，伴随左心室压力、容积增加，等容舒张期延长，而对冠状动脉血流无不利影响。无论犬是否接受rhTNFα，L-NAME均不影响收缩末期压力-容积关系和每搏功（SW）-舒张末期容积（EDV）关系（基于力的收缩性测量）的斜率，而dP/dtmax-EDV关系的斜率（左心室收缩功能的速度依赖性参数）下降。从循环角度看，L-NAME使对照犬以及rhTNFα治疗犬的整体心室功能降低，表现为SW-EDV和dP/dtmax-EDV关系右移。在单独的犬组中，在稳态下以及rhTNFα后6小时，在匹配收缩压下给予血管紧张素II后也观察到类似结果。
用L-NAME进行全身一氧化氮合酶抑制不能急性逆转rhTNFα诱导的心肌功能障碍。L-NAME对左心室大小、舒张和基于速度的收缩性测量的有害影响可能归因于其增加后负荷的作用。
