In Vivo Pharmacology of Dual Neutral Endopeptidase/Angiotensin-Converting Enzyme Inhibitors

Aa, Seymour; Mm, Asaad; Be, Abboa-Offei; Pl, Smith; Rogers, W.L.; Cr, Dorso

doi:10.1097/00005344-199611000-00010

Cited by 17 publications

(21 citation statements)

References 12 publications

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“…This response was associated with a significant increase in FENa, thus indicating direct tubular effects. The natriuretic effect of omapatrilat may be mediated by local enhancement of ANP within the kidney (26,27), since ANP has been shown to be the primary determinant of sodium excretion stimulated by combinations of NEP and ACE inhibition (28). This notion is supported by the finding of an increased urinary excretion of ANP and cyclic guanosine monophosphate in monkeys given the same dose of omapatrilat intravenously as in our study (16).…”

Section: Discussionsupporting

confidence: 78%

Effects of Vasopeptidase Inhibition on Renal Function and Tubuloglomerular Feedback in Spontaneously Hypertensive Rats

Wang¹,

Takabatake²

2005

Hypertens Res

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Section: Discussionsupporting

confidence: 78%

Effects of Vasopeptidase Inhibition on Renal Function and Tubuloglomerular Feedback in Spontaneously Hypertensive Rats

Wang¹,

Takabatake²

2005

Hypertens Res

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“…Although fasidotrilat [12] and RB 105 [36] possess similar in vitro potencies against NEP and ACE, the two molecules may have different in vivo activities. By studying the effects of various mixed NEP/ACE inhibitors, Seymour et al [37] concluded that the in vivo efficacy of one molecule cannot be predicted from its in vitro potency.…”

Section: Discussionmentioning

confidence: 99%

Acute Natriuretic Effect of Fasidotrilat, a Mixed Inhibitor of Neutral Endopeptidase and Angiotensin I-Converting Enzyme, in Rats with Heart Failure

et al. 1998

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The acute diuretic and natriuretic effects of fasidotrilat, a mixed inhibitor of neutral endopeptidase (NEP) and angiotensin I-converting enzyme (ACE) were evaluated in control and myocardial-infarcted rats. Fasidotrilat injection (10 mg/kg i.v.) had no significant effect on arterial blood pressure and led to significant elevations in urine volume (+57% in control rats and +114% in infarcted rats) and of urinary sodium excretion (+81% in control rats and +225% in infarcted rats). Comparison between control and infarcted rats showed that fasidotrilat-induced changes in diuresis and natriuresis were higher in infarcted rats (2.4-fold for diuresis and 4.7-fold for natriuresis, p < 0.05), despite a lower perfusion pressure (–10 mm Hg) in infarcted rats. These data show the potential therapeutic interest of mixed NEP/ACE inhibitors in congestive heart failure.

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“…[15][16][17][18] The effects of NEP inhibition in hypertension associated with diabetes mellitus are largely unknown. In theory, enhanced vasodilating activity of natriuretic peptides after NEP inhibition may even promote glomerular hyperfiltration, leading to proteinuria and accelerated nephropathy in diabetic animals and humans.…”

mentioning

confidence: 99%

“…19 -21 Recently dual inhibitors of NEP and ACE have been introduced for the treatment of hypertension and heart failure. [15][16][17][18] Therefore, the antihypertensive, hormonal, and renal effects of NEP inhibition, ACE inhibition, and dual NEP/ACE inhibition in diabetic and nondiabetic spontaneously hypertensive rats (SHR) were evaluated.…”

mentioning

confidence: 99%

Dual Inhibition of Neutral Endopeptidase and Angiotensin-Converting Enzyme in Rats With Hypertension and Diabetes Mellitus

Tikkanen

Rockell

et al. 1998

Hypertension

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Abstract-It has been suggested that combined inhibition of angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP) may lower blood pressure more effectively than either treatment alone, independent of the degree of salt and volume status or the activity of the renin-angiotensin system. The effects of NEP inhibition in hypertension associated with diabetes mellitus are largely unknown. We therefore compared ACE inhibition, NEP inhibition, and dual NEP/ACE inhibition in diabetic hypertensive rats. Spontaneously hypertensive rats (SHR) aged 9 to 10 weeks were injected with either streptozotocin (45 mg/kg) or citrate buffer and randomized to receive either the ACE inhibitor captopril (25 mg/kg BID), the NEP inhibitor SCH 42495 (30 mg/kg BID), the dual NEP/ACE inhibitor S 21402 (25 or 50 mg/kg BID), or vehicle by gavage for 4 weeks. A group of diabetic SHR was also allocated to receive the combination of SCH 42495 (30 mg/kg BID) and captopril (25 mg/kg BID). The degree of renal NEP inhibition was determined by autoradiography, and plasma renin activity (PRA) was determined by radioimmunoassay. In diabetic SHR, the dual NEP/ACE inhibitor (50 mg/kg BID), as well as the combination of the NEP inhibitor and the ACE inhibitor, reduced systolic blood pressure more effectively than the ACE inhibitor (PϽ0.001) or the NEP inhibitor (PϽ0.001) alone. In nondiabetic SHR, the dual NEP/ACE inhibitor and the ACE inhibitor were equally effective, while the NEP inhibitor had only slight blood pressure-lowering effects. Relative heart weight decreased in parallel to the changes in blood pressure. Renal NEP was clearly inhibited (70% to 92%; PϽ0.001) by both the NEP inhibitor and the dual NEP/ACE inhibitor. Both the ACE inhibitor and the dual NEP/ACE inhibitor increased PRA, but the stimulating effect of dual NEP/ACE inhibition on PRA was less than that observed with ACE inhibition alone (PϽ0.05). Albuminuria in diabetic SHR was lower during treatment with both the dual NEP/ACE inhibitor (50 mg/kg BID) and the combination of NEP inhibition and ACE inhibition compared with vehicle treatment (PϽ0.05). In conclusion, the present study shows that hypertension in SHR with streptozotocin-induced diabetes is modulated by natriuretic peptides and thus is sensitive to NEP inhibition. The increased efficacy of dual NEP/ACE inhibition on blood pressure in diabetic SHR, compared with ACE or NEP inhibition alone, suggests that this therapeutic approach may prove beneficial in the treatment of hypertension associated with diabetes mellitus and other forms of volume-dependent hypertension.(Hypertension. 1998;32:778-785.)Key Words: natriuretic peptides Ⅲ angiotensin Ⅲ renal circulation Ⅲ albuminuria Ⅲ blood pressure I nhibitors of angiotensin-converting enzyme (ACE) have proved effective in the treatment of hypertension associated with diabetes mellitus. As shown in a meta-analysis of clinical trials, ACE inhibitors reduce proteinuria and attenuate progression of renal failure in patients with diabetic nephropathy more effectively than tre...

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In Vivo Pharmacology of Dual Neutral Endopeptidase/Angiotensin-Converting Enzyme Inhibitors

Cited by 17 publications

References 12 publications

Effects of Vasopeptidase Inhibition on Renal Function and Tubuloglomerular Feedback in Spontaneously Hypertensive Rats

Effects of Vasopeptidase Inhibition on Renal Function and Tubuloglomerular Feedback in Spontaneously Hypertensive Rats

Acute Natriuretic Effect of Fasidotrilat, a Mixed Inhibitor of Neutral Endopeptidase and Angiotensin I-Converting Enzyme, in Rats with Heart Failure

Dual Inhibition of Neutral Endopeptidase and Angiotensin-Converting Enzyme in Rats With Hypertension and Diabetes Mellitus

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