Cardiovascular safety of MnDPDP and MnCl2.
OBJECTIVE
To investigate the apparent discrepancy between expected basic physiological responses at the cellular level and the in vivo behaviour of both MnDPDP and MnCl2 administered i.v. prompted parallel investigations of these substances.


METHODS
Studies were performed in isolated perfused rat hearts, isolated bovine mesenteric arteries, conscious dogs, and dogs with acute ischaemic heart failure.


RESULTS
These studies confirmed that Mn+2 at high concentrations acted as a calcium antagonist inducing negative inotropy. Mn+2 at low concentrations was an effective superoxide scavenger, conserving nitric oxide and facilitating vasodilation. Mn+2 maintained or elevated heart rate (HR) and blood pressure (BP), and did not worsen existing cardiac failure. MnDPDP was about 10 times less potent than MnCl2 in eliciting these cardiovascular responses.


CONCLUSIONS
The ex vivo properties of Mn+2, inducing vasodilation and negative inotropy, are counter-balanced in vivo through the action of 2 mechanisms: extensive plasma protein binding reducing active M+2, and the release of catecholamines which maintain or even raise HR and BP. Taken together with pharmacokinetic factors, including maximal plasma concentrations in humans given the recommended 5 mumol/kg dose, it is concluded that MnDPDP in normal clinical use represents no safety risk to the cardiovascular system.
Jynge
P
P
Department of Physiology and Biomedical Engineering, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway. jynge@medisin.ntnu.no
Brurok
H
H
Asplund
A
A
Towart
R
R
Refsum
H
H
Karlsson
J O
JO
D000818:Animals; D002319:Cardiovascular System / Q000187:drug effects*; D002712:Chlorides / Q000494:pharmacology / Q000633:toxicity*; D003287:Contrast Media / Q000494:pharmacology / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004492:Edetic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000633:toxicity; D006801:Humans; D066298:In Vitro Techniques; D008345:Manganese / Q000494:pharmacology; D017895:Manganese Compounds / Q000494:pharmacology; D020149:Manganese Poisoning; D011732:Pyridoxal Phosphate / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000633:toxicity; D012449:Safety
D002712:Chlorides; D003287:Contrast Media; D017895:Manganese Compounds; D008345:Manganese; D011732:Pyridoxal Phosphate; D004492:Edetic Acid; C060076:N,N'-bis(pyridoxal-5-phosphate)ethylenediamine-N,N'-diacetic acid; C025340:manganese chloride