DUAL INHIBITION OF NEUTRAL ENDOPEPTIDASE AND ANGIOTENSIN-CONVERTING ENZYME IN RATS WITH HYPERTENSION AND DIABETES-MELLITUS

It has been suggested that combined inhibition of angiotensin-converti ng enzyme (ACE) and neutral endopeptidase (NEP) may lower blood pressu re more effectively than either treatment alone, independent: of the d egree of salt and volume status or the activity of the renin-angiotens in system. The effects of NEP inhibition in hypertension associated wi th diabetes mellitus are largely unknown. We therefore compared ACE in hibition, NEP inhibition, and dual NEP/ACE inhibition in diabetic hype rtensive rats. Spontaneously hypertensive rats (SHR) aged 9 to 10 week s were injected with either streptozotocin (45 mg/kg) or citrate buffe r 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 wee ks. A group of diabetic SHR was also allocated to receive the combinat ion of SCH 42495 (30 mg/kg BID) and captopril (25 mg/kg BID). The degr ee of renal NEP inhibition was determined by autoradiography, and plas ma renin activity (PRA) was determined by radioimmunoassay. In diabeti c SHR, the dual NEP/ACE inhibitor (50 mg/kg BID), as well as the combi nation of the NEP inhibitor and the ACE inhibitor, reduced systolic bl ood 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 in hibitor and the ACE inhibitor were equally effective, while the NEP in hibitor had only slight blood pressure-lowering effects.. Relative hea rt weight decreased in parallel to the changes in blood pressure. Rena l NEP was clearly inhibited (70% to 92%; P<0.001) by both the NEP inhi bitor and the dual NEP/ACE inhibitor. Both the ACE inhibitor and the d ual NEP/ACE inhibitor increased PRA, but the stimulating effect of dua l NEP/ACE inhibition on PRA was less than that observed with ACE inhib ition alone (P<0.05). Albuminuria in diabetic SHR was lower during tre atment with both the dual NEP/ACE inhibitor (50 mg/kg BID) and the com bination of NEP inhibition and ACE inhibition compared with vehicle tr eatment (P<0.05). In conclusion, the present study shows that hyperten sion in SHR with streptozotocin-induced diabetes is modulated by natri uretic peptides and thus is sensitive to NEP inhibition. The increased efficacy of dual NEP/ACE inhibition on blood pressure in diabetic SHI I, compared with ACE or NEP inhibition alone, suggests that this thera peutic approach may prove beneficial in the treatment of hypertension associated with diabetes mellitus and other forms of volume-dependent hypertension.