Nitric oxide scavenging by hydroxocobalamin may account for its hemodynamic profile.
BACKGROUND
Antidotal doses of hydroxocobalamin are associated with transient increases in blood pressure in some animals and humans. These studies in anesthetized rabbits were undertaken to explore the possible mechanisms underlying the hemodynamic effects of hydroxocobalamin by investigating 1) possible hemodynamic effects of cyanocobalamin, which is formed on a molar-to-molar basis when hydroxocobalamin binds cyanide, and 2) the interference of hydroxocobalamin with the endothelial nitric oxide system.


METHODS
Study 1 investigated the hemodynamic effects of cyanocobalamin. This study included two treatment arms: 1) cyanocobalamin (75 mg/kg, IV) followed by saline (n = 7) and 2) saline followed by cyanocobalamin (n = 7). Study 2 assessed the hemodynamic effects of hydroxocobalamin (75 mg/kg, IV) in the presence and absence of the nitric oxide synthase inhibitor L-Nomega-nitro-L-arginine methyl ester (L-NAME; 30 mg/kg, IV). Nitric oxide synthase inhibition itself increases blood pressure. Thus, as part of Study 2, the hemodynamic effects of hydroxocobalamin were also investigated in the presence of an equipressor dose of angiotensin II (ANGII; 0.05 microg/kg/min, IV) in order to determine whether elevated blood pressure per se could interfere with hydroxocobalamin's hemodynamic effects. This study included six treatment arms (designated as first treatment + second treatment): saline + saline (n = 5), L-NAME + saline (n = 7), saline + hydroxocobalamin (n = 7), L-NAME + hydroxocobalamin (n = 7), ANGII + hydroxocobalamin (n = 7), and ANGII + saline (n = 7).


RESULTS
In Study 1, the effects of cyanocobalamin on hemodynamic parameters were indistinguishable from those of saline. In Study 2, hydroxocobalamin infusion was associated with moderate hemodynamic effects, including an increase in systemic vascular resistance, an increase in blood pressure, and a decrease in cardiac output. Administration of L-NAME abolished the effects of hydroxocobalamin on all hemodynamic parameters. ANGII at a dose producing a pressor response comparable to that of L-NAME did not influence the hydroxocobalamin-associated hemodynamic changes.


CONCLUSIONS
These studies in anesthetized rabbits demonstrate that the moderate pressor effect of hydroxocobalamin is not related to the formation of cyanocobalamin but is very likely related to the scavenging of nitric oxide by hydroxocobalamin.
Gerth
Klaus
K
Merck KGaA, Darmstadt, Germany. Klaus-Georg.Gerth@merck.de
Ehring
Thomas
T
Braendle
Marian
M
Schelling
Pierre
P
D000818:Animals; D000931:Antidotes / Q000494:pharmacology*; D001794:Blood Pressure; D002302:Cardiac Output; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000494:pharmacology*; D006439:Hemodynamics / Q000187:drug effects*; D006879:Hydroxocobalamin / Q000494:pharmacology*; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D011817:Rabbits; D014655:Vascular Resistance
D000931:Antidotes; D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D006879:Hydroxocobalamin; D019331:NG-Nitroarginine Methyl Ester