Renal and depressor effects of SQ 29,072, a neutral endopeptidase inhibitor, in conscious hypertensive rats.
The depressor and renal responses to the neutral endopeptidase (NEP) inhibitor, SQ 29,072, were characterized in both the conscious spontaneously hypertensive rat (SHR) and the conscious deoxycorticosterone acetate (DOCA)/salt hypertensive rat. Inhibition of tissue NEP activity by pharmacologically active doses was also ascertained in both hypertensive models. Intravenous administration of 300 mumol/kg of SQ 29,072 significantly reduced mean arterial pressure (MAP), produced modest natriuretic and diuretic responses, and inhibited renal NEP activity by approximately 40% in conscious SHR. Doses of 100 and 300 mumol/kg of SQ 29,072 elicited greater depressor responses (-36 +/- 7 and -41 +/- 8 mm Hg, respectively) in DOCA/salt hypertensive rats than in SHR (-11 +/- 24 and -31 +/- 5 mm Hg, respectively). SQ 29,072 (300 mumol/kg, i.v.) also inhibited renal NEP activity to a greater extent (70%) in DOCA/salt hypertensive rats. Similarly, the depressor responses to exogenous ANP 99-126 (1, 3, and 10 nmol/kg, i.v.) were greater in DOCA/salt hypertensive rats (-16 +/- 4, -38 +/- 6, and -73 +/- 6 mm Hg, respectively) than in the SHR (0 +/- 6, -17 +/- 3, and -24 +/- 3 mm Hg, respectively). Finally, equidepressor doses of SQ 29,072 and ANP 99-126 both increased urine volume as well as sodium and cyclic GMP excretion in conscious DOCA/salt hypertensive rats. In conclusion, the profile of depressor and renal activities produced by SQ 29,072 was consistent with potentiation of endogenous ANP by inhibition of NEP in conscious SHR and DOCA/salt hypertensive rats.
Squibb Institute for Medical Research, Princeton, NJ 08543-4000.
A A
AA
Seymour
J A
JA
Norman
M M
MM
Asaad
S A
SA
Fennell
J N
JN
Swerdel
D K
DK
Little
C R
CR
Dorso
D000596:Amino Acids / Q000494:pharmacology*; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects*; D001920:Bradykinin; D003900:Desoxycorticosterone; D004231:Diuresis / Q000187:drug effects; D006973:Hypertension / Q000139:chemically induced / Q000503:physiopathology*; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology; D007677:Kidney Function Tests; D008297:Male; D009318:Natriuresis / Q000187:drug effects; D010446:Peptide Fragments / Q000494:pharmacology; D011480:Protease Inhibitors / Q000097:blood; D051381:Rats; D011918:Rats, Inbred SHR; D013438:Sulfhydryl Compounds / Q000494:pharmacology*
D000596:Amino Acids; D010446:Peptide Fragments; D011480:Protease Inhibitors; D013438:Sulfhydryl Compounds; C060193:SQ 29072; D003900:Desoxycorticosterone; D009320:Atrial Natriuretic Factor; D001920:Bradykinin