Prolonged Inhibition of Neutral Endopeptidase 24.11 by Sinorphan in Stroke-Prone Spontaneously Hypertensive Rats.

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Abstract
The cardiovascular consequences of inhibition of the neutral endopeptidase 24.11 (NEP) with the orally active NEP inhibitor sinorphan were evaluated by determining long-term effects of the drug on hemodynamic, hormonal and structural parameters in stroke-prone spontaneously hypertensive rats (SHR-SP). Systolic blood pressure increased in young SHR-SP from 194 +/- 2 to 266 +/- 7 mmHg, whereas in sinorphan (30 mg/kg p.o. bid) treated animals systolic blood pressure increased only from 193 +/- 4 to 229 +/- 4 mmHg during the treatment period of 9 weeks. The increase in relative heart weight was also delayed. Plasma ANP was higher in the sinorphan group than in the controls. The results of a second study demonstrate a substantial improvement of cardiac pump function and ventricular hypertrophy in old SHR-SP with compromised cardiac function by long-term inhibition of NEP. Thirteen-month-old SHR-SP were treated with sinorphan (30 mg/kg p.o. bid) for two weeks. At the end of experiment, the increase in ANP plasma levels did not reach statistical significance, whereas plasma cGMP was higher in sinorphan treated animals than in controls. Left ventricular end-diastolic pressure was markedly elevated in controls and significantly lower in sinorphan treated animals. In addition, sinorphan reduced cardiac hypertrophy in these old SHR-SP. In conclusion, the results of the present studies demonstrate that long-term NEP inhibition with sinorphan has inhibitory effects on malignant hypertension and associated cardiac hypertrophy in young SHR-SP on a high-sodium diet. NEP inhibition substantially improves cardiac pump function and reduces ventricular hypertrophy of old SHR-SP with compromised cardiac function.

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