Relative contribution of preload and afterload to the reduction in cardiac output caused by nitric oxide synthase inhibition with L-N(G)- methylarginine hydrochloride 546C88

Robert W. Harrison, Rajiv N. Thakkar, Hideaki Senzaki, Ulf E.G. Ekelund, Edward Cho, David A. Kass, Joshua M. Hare

Research output: Contribution to journalReview article

23 Scopus citations


Objective: The nitric oxide synthase inhibitor L-N(G)-methylarginine hydrochloride (L-NMMA HC1 546C88) causes reductions in cardiac output (CO), a potential limitation to clinical application. This drop in CO exceeds that from phenylephrine at matched systemic arterial pressure. We tested the hypothesis that the greater fall in CO attributable to L-NMMA primarily reflects a difference in venoconstriction between agents, such that phenylephrine produces larger increases in preload (an independent determinant of CO). Design: Random infusion of phenylephrine or L-NMMA. Setting: An animal research laboratory. Subjects: Eight healthy, conscious, male dogs. Interventions: L-N(G)-methylarginine hydrochloride (20 mg/kg for 1 hr) and phenylephrine (0.5 to 3 μg/kg/min) were administered into eight dogs chronically instrumented to measure left ventricular pressure and dimension. Data were measured at a constant heart rate (140 beats/min) to render CO proportional to stroke dimension. Measurements and Main Results: At a matched increase in afterload (effective arterial elastance), L-NMMA increased preload (end-diastolic dimension) to a lesser degree (3.8% ± 1.5%, p < .05) than phenylephrine (9.6% ± 1.6%, p < .05 vs. L-NMMA). Neither L-NMMA nor phenylephrine affected the slope of the end-systolic pressure dimension relationship, although L-NMMA shifted the relationship rightward (1.7 ± 0.7 mm, p < .05), consistent with a mild negative inotropic effect. L-NMMA decreased the stroke dimension to a greater extent than phenylephrine (-24.1% ± 6.8% and -10.6% ± 3.4%, respectively, p < .05). Conclusions: Differential CO responses to phenylephrine and L-NMMA were primarily attributable to changes in preload. Variable venular vs. arteriolar constrictor effects must be considered when evaluating the integrated cardiovascular response to a vasoactive agent.

Original languageEnglish (US)
Pages (from-to)1263-1268
Number of pages6
JournalCritical care medicine
Issue number5
StatePublished - Jan 1 2000



  • Cardiac output
  • L-N(G)-methylarginine hydrochloride
  • Myocardial contractility
  • Nitric oxide
  • Nitric-oxide synthase
  • Phenylephrine
  • Sepsis
  • Septic shock
  • Vascular endothelium
  • Vasoconstrictor agent

ASJC Scopus subject areas

  • Critical Care and Intensive Care Medicine

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