Lessons from the adrenomedullin knockout mouse

Because vasolidator peptide adrenomedullin (AM) exhibits complicated action, we developed AM knockout mice in order to elucidate the physiological and pathophysiological role of AM. The AM(-/-) mice were embryonic lethal, so we could not evaluate directly the role of AM in this mutant mice. Thus, we loaded angiotensin II (AngII) and salt in AM(+/-) mice, which were viable and fertile. As a result, AngII and salt loading caused coronary vascular damage and left ventricular hypertrophy in AM(+/-) mice more greatly than AM(+/+) mice. Moreover, cuff placement of femoral artery stimulated intimal thickening more severely. This treatment increased local AM levels in AM(+/+) mice but not in AM(+/-) mice. The accelerated organ damage in AM(+/-) mice was accompanied with enhanced production of oxidative stress. Thus, our data suggest that intrinsic AM play a vascular protective role.