title: Hemodynamic effects of nitric oxide synthase inhibition at steady state and following tumor necrosis factor-alpha-induced myodepression.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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).
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Medicine, University of Texas Health Science Center at San Antonio 78284, USA.
authors.forename: D R
authors.initials: DR
authors.lastname: Murray
authors.forename: S D
authors.initials: SD
authors.lastname: Prabhu
authors.forename: G L
authors.initials: GL
authors.lastname: Freeman
mesh_terms: D000704:Analysis of Variance; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004285:Dogs; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006439:Hemodynamics / Q000187:drug effects*; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D013318:Stroke Volume / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D017725:Ventricular Pressure / Q000187:drug effects
chemical_list: D004791:Enzyme Inhibitors; D014409:Tumor Necrosis Factor-alpha; D000804:Angiotensin II; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester