Neutral metalloendopeptidase inhibitors as ANF potentiators: sites and mechanisms of action.
Inhibition of the enzyme neutral metalloendopeptidase potentiates responses to atrial natriuretic factor and elicits reductions of blood pressure in desoxycorticosterone acetate sodium hypertensive rats. The present study evaluated the role of atrial natriuretic factor and bradykinin in the antihypertensive response to neutral metalloendopeptidase inhibition through the use of antibodies and antagonists, respectively. In addition, the pharmacokinetic mechanism by which neutral metalloendopeptidase inhibition interferes with atrial natriuretic factor metabolism was explored. The antihypertensive response to the neutral metalloendopeptidase inhibitor SCH 34826 was abruptly reversed by i.v. injection of a polyclonal antiserum to atrial natriuretic factor. In contrast, the antihypertensive response to SCH 34826 was unaffected by injection of the bradykinin antagonist Thi5,8-D-Phe7 bradykinin. The renal response to atrial natriuretic factor, SCH 34826, and phosphoramidon was inhibited by the bradykinin antagonist. The NEP inhibitor SCH 39370 significantly delayed the disappearance of TCA precipitable radioactivity from plasma following i.v. bolus dosing with 125I-labelled ANF 99-126. The effects were enhanced in the presence of the C receptor ligand. The results indicate that atrial natriuretic factor, but not bradykinin, plays an important role in the antihypertensive response to SCH 34826. Bradykinin plays a permissive role in the diuretic responses to atrial natriuretic factor and inhibitors of neutral metalloendopeptidase. Lastly, neutral metalloendopeptidase inhibition significantly alters the clearance and metabolism of tracer quantities of atrial natriuretic factor.
Sybertz
E J
EJ
Department of Pharmacology, Schering Plough Research, Bloomfield, NJ 07003.
Chiu
P J
PJ
Watkins
R W
RW
Vemulapalli
S
S
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D009320:Atrial Natriuretic Factor / Q000378:metabolism / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D001920:Bradykinin / Q000037:antagonists & inhibitors / Q000502:physiology; D003900:Desoxycorticosterone; D004148:Dioxolanes / Q000037:antagonists & inhibitors / Q000494:pharmacology; D004151:Dipeptides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D004357:Drug Synergism; D006973:Hypertension / Q000139:chemically induced / Q000188:drug therapy; D007457:Iodine Radioisotopes; D007705:Kinins / Q000037:antagonists & inhibitors; D008297:Male; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D051381:Rats; D011919:Rats, Inbred Strains; D015244:Thiorphan / Q000494:pharmacology
D000959:Antihypertensive Agents; D004148:Dioxolanes; D004151:Dipeptides; D007457:Iodine Radioisotopes; D007705:Kinins; C056319:Sch 34826; D003900:Desoxycorticosterone; D009320:Atrial Natriuretic Factor; D015244:Thiorphan; D008666:Metalloendopeptidases; D001920:Bradykinin