HEMODYNAMIC AND HUMORAL EFFECTS OF CHRONIC TREATMENT WITH THE NEUTRALENDOPEPTIDASE INHIBITOR SCH-42495 IN SPONTANEOUSLY HYPERTENSIVE RATS

Blockade of atrial natriuretic factor (ANF) degradation by specific ne utral endopeptidase (NEP) inhibitors may be useful in treatment of hyp ertension because of the potential diuretic, natriuretic, and arterial pressure (AP)-lowering effects. To test this possibility, we examined the effects of chronic oral treatment with the NEP inhibitor SCH 4249 5 on BP, diuresis, natriuresis, plasma ANF, cyclic GMP, and the renin- angiotensin system (RAS) in conscious unrestrained spontaneously hyper tensive rats (SHR) and compared them with the effects induced by the a ngiotensin-converting enzyme (ACE) inhibitor spirapril (SPIR). Four gr oups of adult SHR were treated orally for 4 weeks with placebo, SCH 42 495 3 mg/kg twice daily (b.i.d.), SCH 42495 30 mg/kg b.i.d., and spira pril 1 mg/kg b.i.d. Systolic BP (SBP) was measured weekly, and 24-h ur ine was collected every week for measurement of urinary volume, sodium , potassium, and cyclic GMP excretion. Plasma ANF, cyclic GMP, renin a ctivity (PRA), and aldosterone (ALDO) were determined from blood colle cted when the rats were killed. After 4-week treatment with SCH 42495, circulating levels of ANF were similar in both SCH 42495- and placebo -treated SHR; plasma cyclic GMP was higher, however, in the treated ra ts than in controls and urinary cyclic GMP increased only with the hig her dose of SCH 42495. PRA and plasma ALDO tended to be lower in both SCH 42495-treated groups than in controls, yet BP, diuresis, and natri uresis throughout the study were not different from controls. In contr ast, spirapril decreased BP; this effect was associated with significa nt increments in renin and decrements in ALDO and ANF, without changes in plasma and urinary cyclic GMP. The results suggest that chronic or al treatment with the NEP inhibitor SCH 42495 increases endogenous ANF activity, as indicated by the increase in its second messenger cyclic GMP, and slightly reduces circulating renin and ALDO but does not aff ect AP and natriuresis. In contrast, SPIR has a clear depressor and hu moral effect. These results cast doubts on the possibility to affect B P and sodium and water excretion with a NEP inhibitor, at least in a v olume-independent model of hypertension.