CARDIOVASCULAR SAFETY OF MNDPDP AND MNCL2

Purpose: To investigate the apparent discrepancy between expected basi c physiological responses at the cellular level and the in vivo behavi our of both MnDPDP and MnCl2 adminstered i.v. prompted parallel invest igations of these substances. Material and Methods: Studies were perfo rmed in isolated perfused rat hearts, isolated bovine mesenteric arter ies, conscious dogs, and dogs with acute ischaemic heart failure. Resu lts: These studies confirmed that Mn++ at high concentrations acted as a calcium antagonist inducing negative inotropy. Mn++ at low concentr ations was an effective superoxide scavenger, conserving nitric oxide and facilitating vasodilation. Mn++ maintained or elevated heart rate (HR) and blood pressure (BP), and did not worsen existing cardiac fail ure. MnDPDP was about 10 times less potent than MnCl2 in eliciting the se cardiovascular responses. Conclusion: The ex vivo properties of Mn+, inducing vasodilation and negative inotropy, are counter-balanced i n vivo through the action of 2 mechanisms: extensive plasma protein bi nding reducing active M++, and the release of catecholamines which mai ntain or even raise HR and BP. Taken together with pharmacokinetic fac tors, including maximal plasma concentrations in humans given the reco mmended 5 mu mol/kg dose, it is concluded that MnDPDP in normal clinic al use represents no safety risk to the cardiovascular system.