HS-142-1, a potent antagonist of natriuretic peptides in vitro and in vivo.
To determine whether HS-142-1 (HS), a potent atrial natriuretic peptide (ANP) receptor antagonist, also inhibits the effects of brain natriuretic peptide (BNP), urodilatin (URO), and C-type natriuretic peptide, in vitro studies were carried out, demonstrating that HS inhibited production of cGMP by rat fetal lung fibroblast cells induced by ANP, BNP, URO, and C-type natriuretic peptide. Acute clearance studies were conducted in euvolemic Munich-Wistar rats under inactin anesthesia to characterize the effects of HS in vivo. In response to ANP, BNP, or URO (4 micrograms/kg priming dose plus 0.5 micrograms/kg per minute for 20 min), urine flow, absolute sodium excretion rates, and fractional sodium excretion exhibited similar increases (four- to fivefold) in vehicle-treated rats; these responses were, however, completely abolished by prior HS treatment. The tendency for GFR to rise during the infusion of natriuretic peptides (NP) was also blocked after HS. By contrast, HS did not block the renal effects of L-arginine, a precursor of nitric oxide, or of furosemide. Furthermore, the inhibition of endogenous NP by HS was associated with small but significant reductions in GFR and absolute and fractional sodium excretion in normal rats under euvolemic but not hydropenic conditions. These studies provide evidence that the observed effects of HS in vivo and in vitro are mediated exclusively by receptors of NP. Together, these data support the view that HS is a highly specific ligand for NP receptors, capable of antagonizing the renal effects not only of exogenous ANP, but also those of BNP and URO.
Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115.
P L
PL
Zhang
W
W
Jiménez
H S
HS
Mackenzie
J
J
Guo
J L
JL
Troy
J
J
Ros
P
P
Angeli
V
V
Arroyo
B M
BM
Brenner
D000818:Animals; D001120:Arginine / Q000494:pharmacology; D009320:Atrial Natriuretic Factor / Q000037:antagonists & inhibitors*; D002460:Cell Line; D006152:Cyclic GMP / Q000096:biosynthesis; D005665:Furosemide / Q000494:pharmacology; D005919:Glomerular Filtration Rate / Q000187:drug effects; D008297:Male; D009318:Natriuresis / Q000187:drug effects; D020097:Natriuretic Peptide, Brain; D020098:Natriuretic Peptide, C-Type; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors; D010446:Peptide Fragments / Q000037:antagonists & inhibitors; D011134:Polysaccharides / Q000494:pharmacology*; D011506:Proteins / Q000037:antagonists & inhibitors; D051381:Rats; D017208:Rats, Wistar; D017461:Receptors, Atrial Natriuretic Factor / Q000037:antagonists & inhibitors
C072551:HS 142-1; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; D011134:Polysaccharides; D011506:Proteins; D020097:Natriuretic Peptide, Brain; D020098:Natriuretic Peptide, C-Type; C056452:Ularitide; D005665:Furosemide; D009320:Atrial Natriuretic Factor; D001120:Arginine; D017461:Receptors, Atrial Natriuretic Factor; D006152:Cyclic GMP