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

Abstract

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...

Effect of bradykinin metabolism inhibitors on evoked hypotension in rats: rank efficacy of enzymes associated with bradykinin‐mediated angioedema

“…In the present study, the plasma concentration of candoxatrilat, the active metabolite of candoxatril, reached 7.82±0.64 μg ml −1 after a 10 mg kg −1 30‐min infusion. This concentration is above those previously demonstrated to produce a modest antihypertensive effect in conscious spontaneously hypertensive rats ( Gardiner et al , 2006 ), but it is a concentration at which selectivity for NEP would be expected, since even at vastly higher concentrations (up to 0.1 m M ) candoxatrilat was shown to exert no inhibitory activity at other well‐known peptidases, including ACE, carboxypeptidase A, leucine aminopeptidase, trypsin, chymotrypsin and renin ( Northridge et al , 1989 ; Barclay et al , 1991 ).…”

Losartan modulates muscular capillary density and reverses thiazide diuretic-exacerbated insulin resistance in fructose-fed rats

“…45 Thus, losartan may increase the CD through its vasodilator action or hypotensive effect. 46 In addition to the vasodilator or hypotensive effect, the proangiogenic effect of losartan may also be mediated by the following mechanism: ARB blocks AT1 receptors, whereas unbound angiotensin II stimulates AT2 receptors, which in turn increase angiogenic factors, such as vascular endothelial growth factor receptors, Tie-2 expression and the angiopoietin-1/angiopoietin-2 ratio. 47 In addition, You et al 48 reported that losartan administration resulted in an improvement in hindlimb ischemia-induced capillary rarefaction, and this improvement was associated with a restoration of progenitor cell-related function in spontaneously hypertensive rat.…”

Concomitant Angiotensin AT1 Receptor Antagonism and Neprilysin Inhibition Produces Omapatrilat-like Antihypertensive Effects Without Promoting Tracheal Plasma Extravasation in the Rat

“…In the last few years, there have been a few attempts to characterize the hemodynamic effects of simultaneous inhibition of the AT 1 receptor and NEP. 31,32 Recently, the preclinical and clinical antihypertensive profile of LCZ696, a fixed dose combination of valsartan (an ARB) and AHU-377 (an NEP inhibitor prodrug) has been reported. 33,34 Despite these advances, a systematic comparison of relative efficacy and the risk for angioedema for such a combination and its comparison to omapatrilat have not been established.…”