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CARDIOVASCULAR

Regional Hemodynamic Effects of Neutral Endopeptidase Inhibition and Angiotensin (AT₁) Receptor Antagonism Alone or in Combination in Conscious Spontaneously Hypertensive Rats

Centre for Integrated Systems Biology and Medicine, School of Biomedical Sciences, University of Nottingham Medical School, Queen's Medical Centre, Nottingham, United Kingdom (S.M.G., J.E.M., P.A.K., T.B.); and Pfizer Global Research & Development, Sandwich Laboratories, Kent, United Kingdom (S.A.B.)

We tested the hypothesis that angiotensin (AT₁) 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 µg kg^-1 min^-1) or UK-489,329 (0.15 µg kg^-1 min^-1) had no significant cardiovascular effects, whereas candoxatrilat (6.4 µg kg^-1 min^-1) had a modest antihypertensive effect (-10.9 mm Hg on day 4) but no significant sustained effects on regional hemodynamics. Losartan caused a fall in blood pressure (maximum -29.2 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 (-14.6 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.

Address correspondence to: Dr. Sheila M. Gardiner, School of Biomedical Sciences, University of Nottingham Medical School, Queen's Medical Centre, Nottingham NG7 2UH, UK. E mail: sheila.gardiner{at}nottingham.ac.uk