HS-142-1, a novel nonpeptide atrial natriuretic peptide (ANP) antagonist, blocks ANP-induced renal responses through a specific interaction with guanylyl cyclase-linked receptors.
HS-142-1, a novel microbial product, blocked 125I-labeled rat atrial natriuretic peptide (rANP) (= ANF(99-126)) binding to bovine adrenocortical membranes, where guanylyl cyclase-containing receptors are predominantly expressed. However, HS-142-1 only slightly inhibited [125I]rANP binding to bovine lung membranes where only a small portion of binding sites are coupled to guanylyl cyclase. Further, HS-142-1 only recognized the 135 kDa ANP receptor, which is considered to be the guanylyl cyclase-containing receptor based on the results obtained in affinity cross-linking studies with bovine adrenocortical and lung membranes. Under identical conditions, Atriopeptin I selectively recognized guanylyl cyclase-free receptors both in binding and affinity cross-linking experiments. When injected intravenously (1 mg/kg) to anesthetized rats, HS-142-1 abolished ANP-induced diuresis and natriuresis. These results suggest that HS-142-1 works in vivo through a specific interaction with the ANP functional receptor, and that HS-142-1 will be a powerful tool for understanding the physiological roles of ANP in distinction from its pharmacological effects.
Tokyo Research Laboratories, Kyowa Hakko Kogyo Co., Ltd., Japan.
Y
Y
Morishita
T
T
Sano
H
H
Kase
K
K
Yamada
T
T
Inagami
Y
Y
Matsuda
D000311:Adrenal Glands / Q000187:drug effects / Q000378:metabolism; D000758:Anesthesia; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D002417:Cattle; D003432:Cross-Linking Reagents / Q000494:pharmacology; D006162:Guanylate Cyclase / Q000378:metabolism*; D066298:In Vitro Techniques; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008970:Molecular Weight; D010446:Peptide Fragments; D011134:Polysaccharides / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D017461:Receptors, Atrial Natriuretic Factor; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors* / Q000187:drug effects; D012964:Sodium / Q000652:urine; D014563:Urodynamics / Q000187:drug effects
D003432:Cross-Linking Reagents; C072551:HS 142-1; D010446:Peptide Fragments; D011134:Polysaccharides; D011956:Receptors, Cell Surface; D009320:Atrial Natriuretic Factor; C062522:atrial natriuretic factor prohormone (103-123); D012964:Sodium; D006162:Guanylate Cyclase; D017461:Receptors, Atrial Natriuretic Factor