Klaus Frobel

Prolonged endothelin blockade prevents hypertension and cardiac hypertrophy in stroke-prone spontaneously hypertensive rats

The cardiovascular consequences of endothelin (ET) blockade with the ETA-receptor antagonist FR 139317 were evaluated by determining the long-term effects of the drug on hemodynamic, hormonal, renal and structural parameters in stroke-prone spontaneously hypertensive rats (SHR-SP). Young SHR-SP on a high-sodium diet develop malignant hypertension accompanied by renovascular and cerebrovascular lesions. In control SHR-SP the systolic blood pressure increased from 196 +/- 3 to 260 +/- 4 mm Hg, whereas in animals treated with FR 139317 (20 mg/kg intraperitoneally, twice daily) it increased only from 196 +/- 4 to 212 +/- 3 mm Hg during a treatment period of 6 weeks. There was also an increase in heart weight. At the end of the experiment the plasma levels of atrial natriuretic peptide and brain natriuretic peptide were significantly lower in the group treated with FR 139317 than in the controls. The endothelin plasma levels were significantly higher and the plasma renin activity was lower in the group treated with the endothelin receptor antagonist. These data indicate that endothelin is involved in the maintenance of high blood pressure and cardiac hypertrophy in malignant hypertension, as exemplified by SHR-SP.

Prolonged endothelin blockade reduces hypertension and cardiac hypertrophy in SHR-SP.

Summary: The cardiovascular consequences of endothelin (ET) blockade with the ETA receptor antagonist FR 139317 were evaluated by determining long-term effects of the drug on hemodynamic, hormonal, and structural parameters in stroke-prone spontaneously hypertensive rats (SHR-SP). Young SHR-SP on a high-sodium diet develop malignant hypertension accompanied by renovascular and cerebrovascular lesions. In control SHR-SPs the systolic blood pressure increased from 196 ± 3 to 260 ± 4 mm Hg, whereas in animals treated with FR 139317 (20 mg/kg, i.p., b.i.d.) blood pressure increased only from 196 ± 4 to 212 ± 3 mm Hg during a treatment period of 6 weeks. The increase in heart weight was also delayed. At the end of the experiment, the plasma levels of ANP and BNP were significantly lower in the group treated with FR 139317 than in the controls. The plasma ET levels were significantly higher and the plasma renin activity was lower in the group treated with the ET receptor antagonist. These data indicate that ET is involved in the maintenance of high blood pressure and cardiac hypertrophy in malignant hypertension, as exemplified by an SHR-SP rat model.