Mangafodipir (MnDPDP)-and MnCl2-induced endothelium-dependent relaxation in bovine mesenteric arteries

Abstract

Mn++ complexed to DPDP (N,N'-dipyridoxylethylenediamine-N,N'-diacetate-5,5'-bis(phosphate) generic name: mangafodipir), abbreviated MnDPDP, acts as an effective contrast enhancing agent for liver MRI. In clinical trials, a commonly reported side effect after i.v. administration of MnDPDP was facial flushing, most probably due to peripheral vasodilation. The present study was conducted to address possible mechanisms to explain the flushing effect. Nitric oxide is known to be stabilized in the presence of both uncomplexed and complexed Mn++ and this stabilization is probably due to the superoxide-scavenging properties of Mn++. The present study has demonstrated that both MnDPDP and MnCl2 relax phenylephrine precontracted bovine mesenteric artery strips in concentration-dependent manner. It was also found that a concentration of 10 microM MnDPDP, MnEDTA or MnCl2 gave approximately the same relaxation response as 0.1 microM acetylcholine. DPDP and EDTA had no appreciable intrinsic relaxation potential Mn(++)-induced relaxation was abolished when the endothelial layer was removed from the arteries. In addition, the Mn(++)-induced relaxation was attenuated by the nitric oxide synthase inhibitor N-nitro-arginine and the putative superoxide anion generator 6-anilino-5,8-quinolinedione, but not by the cyclooxygenase inhibitor indomethacin. Both N-nitro-arginine and 6-anilino-5,8-quinolinedione were found to induce an endothelium-dependent constriction of the bovine mesenteric artery strips. An approximately 2-fold increase in the intracellular concentration of cyclic GMP was detected after the addition of 10 microM MnDPDP or 0.1 microM acetylcholine. The increase in cyclic GMP coincided with the onset of relaxation and was effectively abolished by pretreatment with N-nitro-arginine.(ABSTRACT TRUNCATED AT 250 WORDS)