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.(ABSTRACT TRUNCATED AT 250 WORDS)
McMahon
E G
EG
Department of Cardiovascular Diseases Research, G.D. Searle and Co., St. Louis, Missouri 63167.
Palomo
M A
MA
Brown
M A
MA
Bertenshaw
S R
SR
Carter
J S
JS
D000595:Amino Acid Sequence; D000803:Angiotensin I / Q000494:pharmacology; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D001794:Blood Pressure / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D000072396:Endothelin-Converting Enzymes; D016232:Endothelins / Q000494:pharmacology; D006020:Glycopeptides / Q000494:pharmacology*; D006973:Hypertension / Q000503:physiopathology*; D006977:Hypertension, Renal / Q000503:physiopathology; D008297:Male; D008666:Metalloendopeptidases; D008969:Molecular Sequence Data; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D010456:Peptides, Cyclic / Q000494:pharmacology*; D011498:Protein Precursors / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D017207:Rats, Sprague-Dawley
D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D016232:Endothelins; D006020:Glycopeptides; D010456:Peptides, Cyclic; D011498:Protein Precursors; D000803:Angiotensin I; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D015260:Neprilysin; D000072396:Endothelin-Converting Enzymes; C072247:cyclo(Trp-Asp-Pro-Val-Leu); C008890:phosphoramidon