BACKGROUNDThe association of an angiotensin-converting enzyme inhibitor (ACEI) with a neutral endopeptidase inhibitor (NEPI) has potent blood pressure (BP) lowering action, but is associated with side-effects. We evaluated the effects of combining an angiotensin II type 1 (AT1) receptor blocker (ARB, valsartan) and a NEPI (CGS 25354) in comparison with a dual ACEI/NEPI (CGS 30440) in stroke-prone spontaneously hypertensive rats (SHRSP).METHODS AND RESULTSTen-week-old SHRSP were treated with valsartan (10 mg/kg per day), valsartan + CGS 25354 (100 mg/kg per day), CGS 25354, CGS 30440 (10 mg/kg per day) or hydralazine (25 mg/kg per day) for 10 weeks. Mesenteric resistance arteries were studied on a pressurized myograph, whereas cardiac effects were assessed by histology and immunohistochemistry. BP of SHRSP was lowered by combined valsartan/NEPI and ACEI/NEPI slightly more than valsartan, whereas NEPI was ineffective. Valsartan, valsartan/NEPI and ACEI/NEPI normalized resistance artery relaxation responses to acetylcholine, and significantly decreased media/lumen ratio and collagen deposition. All treatments decreased vascular NAD(P)H oxidase-mediated superoxide production. Valsartan/NEPI and ACEI/NEPI decreased media/lumen ratio of intramyocardial coronary arteries, while valsartan alone had no effect. Valsartan/NEPI and ACEI/NEPI increased vascular matrix metalloproteinase-2 activity, and decreased tissue inhibitors of metalloproteinase-2 activity and macrophage infiltration.CONCLUSIONCombined valsartan/NEPI was almost as effective as a dual ACEI/NEPI in lowering BP and improving vascular remodeling in SHRSP. These findings suggest the potential therapeutic value of combining ARB and NEPI in the treatment of hypertension.

01 Jul 1998·Journal of Cardiovascular PharmacologyQ4 · MEDICINE

Protective Effects of CGS 30440, a Combined Angiotensin-Converting Enzyme Inhibitor and Neutral Endopeptidase Inhibitor, in a Model of Chronic Renal Failure

Q4 · MEDICINE

Article

Author: Graybill, Suzanne R. ; Mathis, Janice E. ; Wosu, N. Jonathan ; Cohen, David S. ; Dotson, Ronald A.

The purpose of these studies was to compare the effects of CGS 30440 (CGS), a dual angiotensin-converting enzyme inhibitor (ACEI)/neutral endopeptidase inhibitor (NEPI) to benazepril (BZ), an ACEI, in a model of five-sixths nephrectomy. The doses of BZ and CGS 30440 tested were 6.5 micromol/kg/day and 2.2 micromol/kg/day. Drugs or vehicle (V) were administered subcutaneously for 6 weeks with dosing initiated 1 week after renal mass reduction. At 6 weeks of receiving drug (7 weeks after five-sixths nephrectomy), CGS/6.5 and BZ/6.5 and CGS/2.2 maintained systolic blood pressures (SBP) at presurgical values. BZ/2.2 did not reduce SBP and was similar to the V group. Urinary protein excretion increased >10-fold in the V-treated group. BZ, at either dose, reduced the proteinuria slightly. CGS/6.5 and CGS/2.2 caused significant (p < 0.05) reductions in proteinuria. Creatinine clearance (Cr(cl)), was reduced by 82% in V, 65 and 61% in the CGS/6.5 and CGS/2.2 groups, and by 69 and 74% in the BZ/6.5 and BZ/2.2 groups, respectively. Both CGS treatments improved the fractional excretion of Na+ (%FE(Na)) significantly from the BZ and V groups. The %FE(Na) for BZ at either dose did not differ from that of V. Elevated urinary cyclic guanosine monophosphate (cGMP), an indicator suggesting increased intrarenal levels of atrial natriuretic peptide (ANP), was observed only in the CGS groups. Histologic examination indicated that BZ/6.5 reduced glomerular sclerosis and the extent of tubular dilation, whereas BZ/2.2 had little effect. CGS, especially at the high dose, virtually normalized the glomerular and tubular pathology. Compared with BZ, CGS 30440 treatment further diminished tubular dilation and proteinaceous cast formation. These tubular effects are consistent with some of the renal actions of ANP. The results from these studies indicate that CGS 30440, a combined ACEI/NEPI, conferred a greater renal protective effect than did ACE inhibition alone.

01 Mar 1998·The Journal of pharmacology and experimental therapeutics

Antihypertensive and natriuretic effects of CGS 30440, a dual inhibitor of angiotensin-converting enzyme and neutral endopeptidase 24.11.

Article

Author: Lappe, R W ; Odorico, L M ; Ghai, R D ; Fink, C A ; De Lombaert, S ; Chatelain, R E ; Trapani, A J ; Dardik, B N

Dual angiotensin-converting enzyme (ACE)/neutral endopeptidase (NEP) inhibitors, by decreasing angiotensin-II production and by preventing the degradation of atrial natriuretic peptide (ANP), may be useful for the treatment of hypertension and congestive heart failure. The thiol dipeptide CGS 30440 (prodrug of CGS 30008, IC50: ACE/NEP = 19/2 nM) administered to rats (10 mg/kg p.o.) inhibited lung tissue ACE activity by 98% and 61% at 1 and 24 hr (P < .001) and inhibited the angiotensin-I pressor response by 75 to 90% for more than 6 hr. Renal tissue NEP activity was reduced by 80% at 1 hr and 73% at 24 hr (P < .001). In rats supplemented with exogenous ANP, CGS 30440 (1 mg/kg p.o.) elevated the concentration of circulating ANP (133%, P < .025) for 4 hr and increased the excretion of urine (300%, P < .001), sodium (194%, P < .025) and cyclic GMP (238%, P < .005). CGS 30440 (10 mg/kg p.o.) administered to hypertensive rats with aortic ligation between the renal arteries (mean arterial blood pressure, 209 +/- 4 mm Hg) produced a 48 mm Hg blood pressure reduction (P < .001) within 4 hr. CGS 30440 given to cynomolgus monkeys at 2 mg/kg inhibited plasma ACE activity by 96% within 1 hr (P < .001), and this inhibition was maintained for 7 and 21 days in monkeys receiving the compound orally at 2.5 mg/kg b.i.d. These studies demonstrate that CGS 30440 is an orally active agent which produces tissue ACE and NEP inhibition in rats and plasma ACE inhibition in primates and suggest that the compound may be useful in the treatment of hypertension and congestive heart failure.

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Indication	Highest Phase	Country/Location	Organization	Date
Hypertension	Discovery	US	Ciba-Geigy Corp.	-

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