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

Abstract

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...

B-Type Natriuretic Peptide Prevents Acute Hypertrophic Responses in the Diabetic Rat Heart

“…Surprisingly, candoxatrilat exerted no net antihypertrophic or cyclic GMP stimulatory effect in hearts from streptozotocindiabetic rats. Neutral endopeptidase inhibition may also fail to reduce cardiac size in diabetic rats in vivo (7), unless secondary to a lowering of blood pressure (31). However, the question remains as to why acute neutral endopeptidase inhibition, which potentiates the actions of endogenous natriuretic peptides, did not act like BNP in diabetic heart.…”

“…Thus, infused ANP lowers systemic blood pressure in humans, while the neutral endopeptidase inhibitor candoxatril exerts a hypertensive effect (34) attributable to increased ET-1 activity (35). Moreover, combined inhibition of neutral endopeptidase/ ACE or neutral endopeptidase/endothelin-converting enzyme lowers blood pressure more effectively than either inhibitor alone in diabetes with concomitant hypertension (31), suggesting that dual inhibitors are a better therapeutic strategy particularly in diabetes. Alternatively, neutral endopeptidase (in addition to ACE) also metabolizes kinins in the heart (36).…”

Renoprotective effects of vasopeptidase inhibition in an experimental model of diabetic nephropathy

“…NEP inhibition: For NEP in vitro autoradiography, the p-nitrophenolic ester of RB104, a specific NEP inhibitor ligand (0.51 µg in 5.1 µl) was iodinated according to a minor modification of a previously published method using 1 mCi of 125 I (Amersham Radiochemicals, Amersham, UK) and chloramine T (25 µg in 50 µl) [29]. Autoradiography was done as previously described [15,19]. Quantification of binding density was determined by computerised densitometry and the optical density of the autoradiographs was converted to dpm·mm −2 with the use of radioactive standards.…”

“…Quantification of binding density was determined by computerised densitometry and the optical density of the autoradiographs was converted to dpm·mm −2 with the use of radioactive standards. ACE inhibition: ACE inhibition was assessed using a previously established method [19,30,31] including the radioligand, 125 I MK-351A, a derivative of the ACE inhibitor lisinopril. Specific binding densities were calculated as the difference between to-tal and nonspecific binding densities and quantitation carried out as the same for NEP binding.…”

“…In addition, an increasing number of studies have explored these agents in models of non-diabetic renal disease [13,17,18]. In a study comparing both selective ACE and NEP inhibitors and another less potent dual ACE/NEP inhibitor mixanpril, albuminuria was partially prevented in a 4 week study in diabetic SHR [19].…”