Inhibition by HS-142-1, a novel nonpeptide atrial natriuretic peptide antagonist of microbial origin, of atrial natriuretic peptide-induced relaxation of isolated rabbit aorta through the blockade of guanylyl cyclase-linked receptors.
HS-142-1, a specific nonpeptide antagonist for the atrial natriuretic peptide (ANP) receptor, equally blocked rat ANP (rANP)-, porcine brain natriuretic peptide-, or porcine C-type natriuretic peptide-stimulated GMP production in cultured bovine aortic smooth muscle (BASM) and bovine aortic endothelial (BAE) cells in a concentration-dependent fashion, at concentrations of 1-300 micrograms/ml. But, even at 300 micrograms/ml, HS-142-1 only weakly inhibited the specific binding of 125I-rANP to the BASM and BAE cells, where only a small portion of the binding sites are linked to guanylyl cyclase. Further, with BAE cell membranes, HS-142-1 recognized only the 135-kDa ANP receptor, which is thought from 125I-rANP affinity cross-linking studies to be the guanylyl cyclase-linked receptor. HS-142-1 also, if anything, inhibited the labeling of 135-kDa ANP receptors in the affinity cross-linking studies with BASM membranes, suggesting that a major portion of the 135-kDa ANP receptors are HS-142-1 insensitive and only a small portion of the 135-kDa ANP receptors are responsible for the blockade by HS-142-1 of GMP production in BASM cells. At a concentration of 100 micrograms/ml, HS-142-1 reversibly prevented ANP-induced relaxation of the isolated rabbit thoracic aorta induced to contract with 3 x 10(-7) M phenylephrine, but not the relaxation induced by sodium nitroprusside, isoproterenol, or papaverine. These results suggest that HS-142-1 specifically inhibits natriuretic peptide-induced vasorelaxation through the blockade of guanylyl cyclase-linked natriuretic peptide receptors. HS-142-1 thus will be a powerful tool for understanding the physiological roles, in vasculature, of natriuretic peptides, which contribute to the homeostasis of blood pressure and intravascular volume.
Tokyo Research Laboratories, Kyowa Hakko Kogyo Co., Ltd., Japan.
R
R
Imura
T
T
Sano
J
J
Goto
K
K
Yamada
Y
Y
Matsuda
D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D009320:Atrial Natriuretic Factor / Q000037:antagonists & inhibitors*; D002417:Cattle; D002478:Cells, Cultured; D003432:Cross-Linking Reagents; D006152:Cyclic GMP / Q000378:metabolism; D006162:Guanylate Cyclase / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D011134:Polysaccharides / Q000494:pharmacology*; D011817:Rabbits; D017461:Receptors, Atrial Natriuretic Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014665:Vasodilator Agents / Q000494:pharmacology*
D003432:Cross-Linking Reagents; C072551:HS 142-1; D011134:Polysaccharides; D014665:Vasodilator Agents; D009320:Atrial Natriuretic Factor; D006162:Guanylate Cyclase; D017461:Receptors, Atrial Natriuretic Factor; D006152:Cyclic GMP