Interaction of non-guanylate cyclase-linked atriopeptin receptor ligand and endopeptidase inhibitor in conscious rats

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 249; no. 1; pp. 172 - 176
• Main Authors: Koepke, J P, Tyler, L D, Trapani, A J, Bovy, P R, Spear, K L, Olins, G M, Blaine, E H
• Format: Journal Article
• Language: English
• Published: United States American Society for Pharmacology and Experimental Therapeutics 01.04.1989
• Subjects: Animals; Atrial Natriuretic Factor - immunology; Atrial Natriuretic Factor - metabolism; Atrial Natriuretic Factor - pharmacology; blood pressure; Blood Pressure - drug effects; Diuresis - drug effects; Guanylate Cyclase - analysis; Male; Natriuresis - drug effects; Peptide Fragments - pharmacology; Protease Inhibitors - pharmacology; Rabbits; Rats; Rats, Inbred Strains; Receptors, Atrial Natriuretic Factor; Receptors, Cell Surface - drug effects; sodium; Structure-Activity Relationship; thiorphan; Thiorphan - pharmacology
• ISSN: 0022-3565; 1521-0103

We examined the interaction of SC-46542 [des(Phe106, Gly107, Ala115, Gln116)-AP(103-126)], a non-guanylate cyclase-linked atriopeptin (AP) binding site ligand, with thiorphan, an inhibitor of endopeptidase 24.11, on mean arterial pressure, urine flow, urinary sodium excretion and plasma AP immunoreactivity in conscious rats. The coadministration of SC-46542 (16 micrograms/kg/min) and thiorphan (30 mg/kg i.v. bolus) produced a greater diuresis and natriuresis (but had no effect on mean arterial pressure) than administration of either compound alone; plasma APir increased 2-fold during coadministration of SC-46542 and thiorphan (from 325 +/- 46 to 676 +/- 86 pg/ml). Administration of SC-46542 or thiorphan alone had small or no effects on mean arterial pressure, urine flow, urinary sodium excretion or plasma APir. Converting enzyme inhibition did not contribute to the effects of thiorphan since coadministration of captopril plus SC-46542 produced effects similar to SC-46542 alone. When a near threshold infusion of AP(103-126) was combined with the coadministration of SC-46542 and thiorphan, there was a potentiation of the depressor, diuretic and natriuretic responses. Neither SC-46542 nor thiorphan alone had these effects. SC-46542 potentiated the depressor but not diuretic or natriuretic responses to low dose AP(103-126) infusion; thiorphan had little or no effect on the responses to low dose AP(103-126). We conclude that blockade of non-guanylate cyclase-linked AP binding sites with SC-46542 combined with inhibition of AP degradation by endopeptidase 24.11 with thiorphan increases diuresis and natriuresis more than inhibition of either system alone.