Maximizing the natriuretic effect of endogenous atriopeptin in a rat model of heart failure.
The effect of pharmacological manipulation of atriopeptin (AP) activity on sodium excretion and blood pressure was examined in the rat aortovenocaval (A-V) fistula model of cardiac failure. Introduction of an A-V shunt led to a marked and sustained elevation of plasma AP immunoreactivity and urinary cGMP levels. Further elevation of plasma AP levels by infusion of exogenous peptide induced modest increases in urinary sodium and cGMP excretion and a decrease in blood pressure but these responses were significantly attenuated compared to sham-operated animals. In contrast, low-dose infusion of M + B 22948 (a cGMP phosphodiesterase inhibitor) or thiorphan [a neutral endopeptidase (membrane metallo-endopeptidase, EC 3.4.24.11) inhibitor] induced a natriuresis in A-V fistula rats, which exceeded that seen in control animals given these compounds and matched the peak natriuresis produced in sham-operated animals by high doses of AP. In the doses used, these compounds had little effect on blood pressure. The greater renal efficacy of M + B 22948 in A-V fistula rats is consistent with postreceptor facilitation of AP activity. The effect of thiorphan on sodium excretion was accompanied by a pronounced increase in urinary cGMP and AP immunoreactivity excretion (and was attenuated by anti-AP monoclonal antibody) but could not be explained solely in terms of an increase in circulating AP levels. It is proposed that thiorphan allows filtered AP to reach renal tubule sites that are normally inaccessible to the peptide and are thus protected from down-regulation by high circulating AP levels. The implication of these observations for patients in cardiac failure is the potential for using pharmacological agents to maximize the response to endogenous AP without compromising cardiac function.
Wilkins
M R
MR
Department of Pharmacology, Washington University Medical School, Saint Louis, MO 63110.
Settle
S L
SL
Stockmann
P T
PT
Needleman
P
P
D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000818:Animals; D000911:Antibodies, Monoclonal; D009320:Atrial Natriuretic Factor / Q000097:blood / Q000276:immunology / Q000502:physiology*; D001794:Blood Pressure; D006152:Cyclic GMP / Q000652:urine; D004195:Disease Models, Animal; D006333:Heart Failure / Q000188:drug therapy / Q000503:physiopathology*; D008297:Male; D011688:Purinones / Q000627:therapeutic use*; D051381:Rats; D011919:Rats, Inbred Strains; D012016:Reference Values; D012964:Sodium / Q000652:urine; D015244:Thiorphan / Q000627:therapeutic use*
D000911:Antibodies, Monoclonal; D011688:Purinones; D009320:Atrial Natriuretic Factor; D012964:Sodium; D015244:Thiorphan; D015106:3',5'-Cyclic-GMP Phosphodiesterases; C011145:zaprinast; D006152:Cyclic GMP