From the Department of Medicine, University of Melbourne, Austin and
Repatriation Medical Centre, Heidelberg, Victoria, Australia. Drs Tikkanen are
currently at the Minerva Institute for Medical Research (T.T. and I.T.) and
the Department of Medicine, Helsinki University Central Hospital (I.T.),
Helsinki, Finland.
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 (P<0.001) or the NEP
inhibitor (P<0.001) 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%;
P<0.001) 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 (P<0.05).
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 (P<0.05). 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.
© 1998 American Heart Association, Inc.
Scientific Contributions
Dual Inhibition of Neutral Endopeptidase and Angiotensin-Converting Enzyme in Rats With Hypertension and Diabetes Mellitus
Key Words: natriuretic peptides • angiotensin • renal circulation • albuminuria • blood pressure
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