Cardiovascular safety of MnDPDP and MnCl 2

Abstract

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

Material and 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⁺⁺ at high concentrations acted as a calcium antagonist inducing negative inotropy. Mn⁺⁺ at low concentrations was an effective su-peroxide scavenger, conserving nitric oxide and facilitating vasodilation. Mn⁺⁺ 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.

Conclusion: The ex vivo properties of Mn⁺⁺, inducing vasodilation and negative inotropy, are counter-balanced in vivo through the action of 2 mechanisms: extensive plasma protein binding reducing active M⁺⁺, 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 μmol/kg dose, it is concluded that MnDPDP in normal clinical use represents no safety risk to the cardiovascular system.