NG-methyl-L-arginine, an inhibitor of nitric oxide formation, acts synergistically with dobutamine to improve cardiovascular performance in endotoxemic dogs.
OBJECTIVE
To evaluate the hemodynamic effects of the nitric oxide inhibitor, NG-methyl-L-arginine, and dobutamine during experimental endotoxemia.


METHODS
Prospective, randomized, controlled animal study.


METHODS
University research laboratory.


METHODS
Adult, male mongrel dogs.


METHODS
After catheterization with a flow-directed, thermal-dilution pulmonary artery flotation catheter and arterial catheter, awake dogs received either NG-methyl-L-arginine or dobutamine alone or in combination (controls; n = 5). Other animals were administered endotoxin (50 micrograms/kg), then received either NG-methyl-L-arginine alone or in combination with dobutamine after the onset of hypotension (endotoxin-treated; n = 5).


RESULTS
Both dobutamine and NG-methyl-L-arginine alone had a small, but significant vasopressor effect on control animals. In contrast, administration of the combination of NG-methyl-L-arginine and dobutamine resulted in a 48.6% increase in mean arterial pressure, an effect which was dose-dependent with respect to NG-methyl-L-arginine. In dogs treated with 50 micrograms/kg of endotoxin, hypotension could be only partially reversed by NG-methyl-L-arginine, mainly due to a decline in cardiac output. Co-infusion of dobutamine reversed this depression of cardiac output and resulted in a complete restoration of blood pressure.


CONCLUSIONS
Later stages of septic shock are characterized by hypotension and decreased myocardial performance. A major mediator of hypotension is nitric oxide, a vasodilatory agent derived from L-arginine. Administration of the arginine derivative, NG-methyl-L-arginine, improved systemic vascular resistance but not myocardial performance. The addition of an inotropic agent to NG-methyl-L-arginine, a nitric oxide synthase inhibitor, resulted in an enhancement of the antihypotensive action of NG-methyl-L-arginine through the restoration of cardiac output. The synergistic action between dobutamine and NG-methyl-L-arginine may be of therapeutic value in the treatment of septic shock.
Kilbourn
R G
RG
Department of Genitourinary Oncology, University of Texas, M. D. Anderson Cancer Center, Houston 77030.
Cromeens
D M
DM
Chelly
F D
FD
Griffith
O W
OW
D000818:Animals; D001120:Arginine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D002319:Cardiovascular System / Q000187:drug effects* / Q000503:physiopathology; D004280:Dobutamine / Q000008:administration & dosage*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D008297:Male; D009569:Nitric Oxide / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D011446:Prospective Studies; D011897:Random Allocation; D012772:Shock, Septic / Q000188:drug therapy* / Q000503:physiopathology; D013997:Time Factors; D019323:omega-N-Methylarginine
D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D004280:Dobutamine; D001120:Arginine