gms | German Medical Science

Neutral endopeptidase (EC3.4.24.11, NEP or enkephalinase) is a zinc-metalloendopeptidase, cleaving a variety of substrates like natriuretic peptides, substance P, and bradykinin. A decade ago, transgenic mice lacking the enzyme NEP have been developed (Lu et al., 1995). The present study was designed to investigate the cardiovascular parameters of these NEP-knockout mice using telemetry. Seven male NEP-knockout (KO) mice and 7 controls (C) (20-weeks old) received a telemetry implant (TA11-PA20; DSI, USA) in the carotid artery. All mice were housed in individual cages in light cycles (6am-6pm) and were allowed access ad libitum to water and food. After 10 days, the mice were monitored for 7 days receiving normal diet (0.6% NaCl) followed by one-week high salt diet (8% NaCl). Interestingly, KO showed higher body weight (C: 31.4+/-0.5 g; KO: 34.6+/-0.9 g, P<0.05) but lower mean arterial pressure (MAP) compared to controls (C: 111.5+/-2.1 mmHg; KO: 102.1+/-2.1 mmHg, P<0.05). Heart rate (HR) and the locomotor activity were not altered between both groups (C: 523+/-19 mmHg; KO: 531+/-15 bpm/ C: 10+/-2.7 L; KO: 8.4+/-0.2 L). Food ingestion (normal or high salt chow) was not different between the groups. As expected, exposure to a high NaCl diet increased the average MAP in control mice (C: 123,8+/-4,6 mmHg, +12%). While HR and the locomotor activity were not significantly altered in both groups after salt diet, NEP-deficient mice presented a less pronounced MAP increase (KO: 109.5+/-1 mmHg, +6.8% P<0.05). We conclude that NEP absence promotes hypotension and body weight gain and diminished increase in blood pressure after high salt diet. One of the mechanisms involved could be the increase in natriuretic peptides and kinin levels that play a key role in the regulation of salt and water balance, cell growth, as well as blood pressure homeostasis. These data further demonstrate the potential of NEP inhibition in the treatment of hypertension and renal diseases.