Ionic mechanisms contributing to the vasorelaxant properties of iodinated contrast media: a comparison of iohexol and iodixanol in the rabbit isolated aorta

1 We have used rings of rabbit thoracic aorta to investigate the vasorelaxant properties of two different classes of non‐ionic iodinated radiographic contrast media (IRCM) and the mechanisms, underlying their mode of action. Iohexol (a triiodinated monomer) was compared with iodixanol (a hexaiodinated dimer). 2 Iohexol and iodixanol both relaxed phenylephrine (0.3 μm) constricted rabbit aorta in a concentration‐dependent manner that did not depend on the presence of an intact endothelium. When expressed as a function of iodine concentration, iodixanol caused significantly less relaxation than iohexol. However, the extent of relaxation was similar for both IRCM when expressed on a molar basis. Furthermore, increasing the molarity of the buffer to comparable levels with mannitol evoked only a small (∼ 15%) relaxation of phenylephrine‐induced tone. 3 Ouabain (10 μm) significantly inhibited both iohexol‐ and iodixanol‐induced relaxations by ∼30%. 5‐(N‐Ethyl‐N‐isopropyl)‐amiloride (EIPA, 100 nM) significantly inhibited iohexol‐induced relaxation to the same extent as ouabain, but did not alter the vasorelaxant effect of iodixanol. Co‐incubation with ouabain and EIPA had an additive effect in the case of iohexol, increasing inhibition of relaxation to ∼60%, whereas inhibition of iodixanol‐induced relaxation by the combination of ouabain plus EIPA did not differ from that of ouabain alone. 4 Replacing NaCl with N‐methyl‐D‐glucamine (NMDG) to lower extracellular [Na+] and thereby inhibit Na+‐Ca2+ exchange, attenuated the relaxation evoked by iohexol or by iodixanol (by ∼25%) in each case. 5 We conclude that iohexol‐ and iodixanol‐induced vasorelaxation in rabbit aorta is mediated through a direct action on vascular smooth muscle that is not simply a consequence of altered osmolality. It involves modulation of the Na+‐K+ ATPase and, in the case of iohexol, Na+‐H+ exchange. Both agents also appear to modulate Na+‐Ca2+ exchange, through direct and/or indirect mechanisms. This is the first study to show specific pharmacological differences between monomeric and dimeric contrast media in vascular smooth muscle.