EFFECT OF PHOSPHORAMIDON (ENDOTHELIN-CONVERTING ENZYME-INHIBITOR) AND BQ-123 (ENDOTHELIN RECEPTOR SUBTYPE-A ANTAGONIST) ON BLOOD-PRESSURE IN HYPERTENSIVE RATS

We reported previously that the endothelin converting enzyme (ECE) inhibitor phosphoramidon lowers mean arterial pressure (MAP) when infused in conscious, spontaneously hypertensive rats (SHRs). In this study we determined the dose-response relationship for this action in SHRs and in a high-renin hypertensive model, the renal artery-ligated rat. We also determined whether the ETA receptor antagonist BQ-123 (cyclo [D-Trp-D-Asp-Pro-D-Val-Leu]) might lower MAP in hypertensive rats. Phosphoramidon lowered MAP by 9 +/- 4, 31 +/- 4, and 40 +/- 4 mm Hg after 5 h when infused in SHRs at 10, 20, and 40 mg/kg/h. This lowering of MAP was associated with dose-related inhibition of the pressor response to a bolus intravenous injection of big ET (1-39) at 1 nmol/kg. BQ-123 also lowered MAP in SHRs (by 25 +/- 3 mm Hg), but only at a very high dose (50 mg/kg/h for 5 h). At this dose, BQ-123 blocked the pressor response to a bolus intravenous injection of ET-1 (1 nmol/kg), but the blockade was incomplete. Phosphoramidon infused in conscious, renal hypertensive rats lowered MAP by 31 +/- 9,46 +/- 8, and 54 +/- 1 mm Hg after 5 h at 10, 20, and 40 mg/kg/h, respectively. This lowering of MAP was associated with blockade of the pressor response to big ET (1-39). BQ-123 did not lower MAP in renal hypertensive rats when infused at 30 mg/kg/h for 5 h. The antihypertensive effect of phosphoramidon in both SHRs and renal hypertensive rats could not be attributed to inhibition of other metalloproteases, ie, angiotensin converting enzyme (ACE) or neutral endopeptidase 24.11 (NEP) since: 1) ACE was not inhibited after infusion of phosphoramidon; and 2) kelatorphan, a compound which is equipotent to phosphoramidon as an NEP inhibitor, but does not inhibit ECE, did not lower blood pressure in SHRs or renal hypertensive rats at high doses. Our data suggests that blocking the biological effects of endothelin, either by inhibition of ECE or endothelin receptor antagonism, could be a new therapeutic strategy in the treatment of hypertension.