Expert opinion on tilarginine in the treatment of shock.
Tilarginine is L-N-monomethyl arginine (L-NMMA) or N(G)-monomethyl-L-arginine HCL, a non-selective inhibitor of nitric oxide synthase (NOS), which has been studied in the treatment of septic shock and cardiogenic shock complicating myocardial infarction. Despite strong evidence that excessive nitric oxide (NO) production plays a pivotal role in the pathogenesis of septic shock and may contribute to the pathogenesis of cardiogenic shock complicating myocardial infarction, outcome studies in these two disorders have proved disappointing. L-NMMA therapy was associated with an excess mortality, particularly at doses > 5 mg/(kg h), in septic shock whereas the effects of a lower dose (1 mg/(kg h)) in cardiogenic shock complicating myocardial infarction were neutral. The excess mortality in patients with septic shock was almost certainly the result of unfavourable haemodynamic changes induced by L-NMMA (decreased cardiac output, increased pulmonary vascular resistance and reduced tissue oxygen delivery) whereas the lack of benefit in patients with cardiogenic shock complicating myocardial infarction may have been because the dose of L-NMMA was too low. Further studies of L-NMMA at doses < 5 mg/(kg h) in conjunction with inotrope support may produce more beneficial results. Conversely, the use of a selective inducible NOS inhibitor to reduce the pathological effects of excessive NO production although leaving the beneficial effects of vascular NO production by endothelial NOS unaltered may prove to be of value.
Howes
Laurence Guy
LG
Griffith University and Bond University Medical Schools, Gold Coast Hospital, Department of Pharmacology and Therapeutics, Nerang St, Southport, Queensland 4215, Australia. laurie_howes@health.qld.gov.au
Brillante
Divina Gracila
DG
D000818:Animals; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006321:Heart / Q000187:drug effects; D006801:Humans; D009569:Nitric Oxide / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D012770:Shock, Cardiogenic / Q000188:drug therapy*; D012772:Shock, Septic / Q000188:drug therapy*; D013564:Sympathetic Nervous System / Q000187:drug effects; D019323:omega-N-Methylarginine / Q000494:pharmacology / Q000627:therapeutic use*
D004791:Enzyme Inhibitors; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase