Adrenomedullin (ADM) is a multifunctional peptide with important roles in the cardiovascular system, especially in the adjustment of cardiovascular and renal homeostasis. ADM is present in plasma, organs and tissues, and its activity increases during hypertension. It remains unknown whether the clearance of this peptide is altered during hypertension. Neutral endopeptidase (NEP) is the major enzyme in ADM’s degradation. We observed the activity and distribution of NEP and the expression of its mRNA in the plasma, cardiac ventricle, aorta, jejunum and kidney of spontaneously hypertensive rats (SHRs) in order to study the possible role of NEP in elevating tissue ADM concentrations during hypertension. ADM and NEP were diffuse in all tissues studied. The level of tissue ADM was generally higher in SHR tissues than in control tissues, except in the renal medulla, and its mRNA expression was higher in all tissues. Plasma NEP activity, general NEP activity and the expression of NEP mRNA in the left ventricle, aorta and jejunum in SHRs was lower than that of controls, and the level of ADM was inversely correlated with NEP activity. NEP activity and mRNA and protein expression in SHR kidneys were higher than in control kidneys; moreover, the ADM content was positively correlated with NEP activity in the renal cortex. NEP activity in the lung of SHRs did not differ from that of controls. Thus, in SHRs, the local concentration and action of ADM in the tissues may be differentially regulated by NEP. (Hypertens Res 2004; 27: 109-117)