We tested the hypothesis that angiotensin (AT 1 ) receptor antagonism (with losartan) would enhance the cardiovascular actions of neutral endopeptidase (NEP) inhibition [with candoxatrilat or (2S)-2-{[1-({[(1S)-1-carboxy-2-(5-phenyl-1,3-oxazol-2-yl)ethyl]amino}carbonyl)cyclopentyl]methyl}-4-methoxybutanoic acid (UK-489,329)] in conscious spontaneously hypertensive rats (SHR). Four-day continuous intravenous infusion of candoxatrilat (1.9 g kg Ϫ1 min Ϫ1 ) or UK-489,329 (0.15 g kg Ϫ1 min Ϫ1 ) had no significant cardiovascular effects, whereas candoxatrilat (6.4 g kg Ϫ1 min Ϫ1 ) had a modest antihypertensive effect (Ϫ10.9 mm Hg on day 4) but no significant sustained effects on regional hemodynamics. Losartan caused a fall in blood pressure (maximum Ϫ29.2 mm Hg on day 4) that was associated with renal, mesenteric, and, to a lesser extent, hindquarters vasodilatation. The combination of losartan with either dose of candoxatrilat had no greater antihypertensive or vasodilator effects than losartan alone, with the exception of the increase in renal vascular conductance, which was greater with the combination of the drugs than with either drug alone (significant only in the lower dose study). Losartan combined with UK-489,329 showed a greater antihypertensive effect than losartan alone (Ϫ14.6 mm Hg greater on day 4), although the effects of the combination were not significantly greater than the sum of the effects of both agents administered separately. However, losartan combined with UK-489,329 caused increases in renal and hindquarters vascular conductance that were significantly greater with the combination than with either agent given alone. Thus, in conscious SHR, the renin-angiotensin system may act to oppose a vasodilator action of NEP inhibition, particularly in the renal vascular bed.Neutral endopeptidase 24.11 (NEP) is a zinc metalloprotease responsible for the breakdown of a number of short linear or cyclic peptides, such as the natriuretic peptides, bradykinin, angiotensin II, and endothelin. Other members of the zinc metalloprotease family that may be involved in the metabolism of biologically active peptides include endothelin-converting enzyme and soluble secreted endopeptidase (SEP) (Ikeda et al., 1999). Although NEP inhibitors were developed as antihypertensive agents, their effectiveness has turned out to be limited, probably because of their short half-life in the circulation, together with the fact that the breakdown of not only vasodilator/natriuretic peptides, but also vasoconstrictor peptides, such as angiotensin II and endothelin, is reduced (Richards et al., 1993;McDowell et al., 1997). In fact, some studies have found predominant vasoconstrictor effects of NEP inhibition in humans (Ferro et al., 1998). In animal studies, NEP inhibition with, for example, candoxatrilat, has only consistently been shown to exert antihypertensive effects in salt-sensitive models of hypertension (Shepperson et al., 1991;Hirata et al., 1994), and in human essential hypertension, candoxatril is reported to ha...