title: 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.
abstract: 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).
  
  
  METHODS
  Random infusion of phenylephrine or L-NMMA.
  
  
  METHODS
  An animal research laboratory.
  
  
  METHODS
  Eight healthy, conscious, male dogs.
  
  
  METHODS
  L-N(G)-methylarginine hydrochloride (20 mg/kg for 1 hr) and phenylephrine (0.5 to 3 microg/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.
  
  
  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.
authors.affiliation: Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD, USA.
authors.forename: R W
authors.initials: RW
authors.lastname: Harrison
authors.forename: R N
authors.initials: RN
authors.lastname: Thakkar
authors.forename: H
authors.initials: H
authors.lastname: Senzaki
authors.forename: U E
authors.initials: UE
authors.lastname: Ekelund
authors.forename: E
authors.initials: E
authors.lastname: Cho
authors.forename: D A
authors.initials: DA
authors.lastname: Kass
authors.forename: J M
authors.initials: JM
authors.lastname: Hare
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D002302:Cardiac Output / Q000187:drug effects* / Q000502:physiology; D004285:Dogs; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D008297:Male; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D010656:Phenylephrine / Q000494:pharmacology; D012772:Shock, Septic / Q000503:physiopathology; D014655:Vascular Resistance / Q000187:drug effects / Q000502:physiology; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D016277:Ventricular Function, Left / Q000187:drug effects*; D019323:omega-N-Methylarginine / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D014662:Vasoconstrictor Agents; D010656:Phenylephrine; D019323:omega-N-Methylarginine; D019001:Nitric Oxide Synthase