Effects of SCH 42495, a neutral endopeptidase inhibitor, on cardiac function and mass in rats after repeated hyperbaric exposures

Abstract

The aim of the present study was to investigate the effects of inhibition of neutral endopeptidase on left ventricular hypertrophy (LVH), myocardial necrosis and haemodynamic changes, previously shown in rats after repeated hyperbaric exposures to 5 bar, by using the novel neutral endopeptidase inhibitor SCH 42495. Ten test rats underwent chamber dives daily for 40 consecutive days, and 10 control rats were exposed in the same chamber for an equivalent period of time, but in air at 1 bar. The rats received SCH 42495 orally (30 mg/kg twice a day) for 40 days. After 40 days, the body mass was identical in the two groups. Test rats and control rats had equal heart mass (both totally and left ventricular myocardium, including the ventricular septum/100 g), thus indicating that long-term treatment with SCH 42495 inhibits hyperbarically induced LVH. The left ventricular pressure (LVP) and the maximal velocity of LVP increase and decrease (+/- dP/dt) were similar in the test rats compared to the control rats at 1 bar. Previously, we found a higher LVP and dP/dt in non-treated test rats in otherwise identical experiments. This indicates that SCH 42495 "normalizes" the cardiac function of test rats after repeated hyperbaric exposures. The systolic arterial pressure, heart rate (HR) and respiratory frequency (RF) were similar in the two groups throughout the experiments. However, treatment with SCH 42495 lowered the blood pressure compared to previously non-treated rats. In conclusion, long-term administration of the neutral endopeptidase inhibitor SCH 42495 prevented previously shown changes in cardiac function as well as myocardial mass after 40 consecutive exposures to 5 bar.

Deletion of neutral endopeptidase exacerbates intestinal inflammation induced byClostridium difficiletoxin A

“…Inhibitors of neuropeptide processing are widely used and effective drugs. Angiotensin-converting enzyme (ACE) inhibitors are effective for treatment of congestive heart failure and hypertension, and NEP inhibitors have been evaluated in patients with heart failure (12,14,40). Mixed ACE and NEP inhibitors are also under development.…”