Antihypertensive activity during inhibition of neutral endopeptidase and angiotensin converting enzyme.
The specific neutral endopeptidase (NEP) inhibitor, SQ 29,072 (7-[2-(mercaptomethyl)-1-oxo-3-phenylpropyl]amino]heptanoic acid), was studied in conscious spontaneously hypertensive rats (SHRs) and in DOCA/salt hypertensive rats during inhibition of angiotensin-converting enzyme (ACE) activity with captopril or SQ 27,519 (the free acid of fosinopril). In the SHR, the maximal depressor responses to the combination of SQ 29,072 and SQ 27,519 (-44 +/- 4 mm Hg) were greater than the responses to any of the inhibitors given alone (-26 +/- 5, -40 +/- 10, and -28 +/- 6 mm Hg for SQ 29,072, captopril, and SQ 27,519, respectively). In contrast, the maximal antihypertensive activities of SQ 29,072 were the same in conscious DOCA/salt hypertensive rats infused with saline, captopril, or SQ 27,519 (-54 +/- 10, -51 +/- 8, and -58 +/- 11 mm Hg, respectively), indicating a lack of synergism in this model. In agreement, SQ 28,133 [N-[2-(mercaptomethyl)-1-oxo-3-phenylpropyl]-L-leucine], a compound that inhibits both NEP and ACE, elicited significant depressor activities in both SHR and DOCA/salt hypertensive rats. In conclusion, a selective NEP inhibitor enhanced the depressor activity of ACE inhibitors in the conscious SHR, indicating that these agents may be effectively combined for treatment of some types of hypertension.
Seymour
A A
AA
Department of Pharmacology, Squibb Institute for Medical Research, Princeton, New Jersey 08540.
Swerdel
J N
JN
Abboa-Offei
B
B
D000596:Amino Acids / Q000494:pharmacology*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D002216:Captopril / Q000494:pharmacology; D017328:Fosinopril / Q000031:analogs & derivatives*; D006973:Hypertension / Q000503:physiopathology; D008297:Male; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D009943:Organophosphorus Compounds / Q000494:pharmacology; D011392:Proline / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D011919:Rats, Inbred Strains; D013438:Sulfhydryl Compounds / Q000494:pharmacology*
D000596:Amino Acids; D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D009943:Organophosphorus Compounds; D013438:Sulfhydryl Compounds; C060193:SQ 29072; D011392:Proline; D002216:Captopril; D015260:Neprilysin; D017328:Fosinopril; C046965:fosinoprilat