A peptide released by pepsin from kininogen domain 1 is a potent blocker of ANP-mediated diuresis-natriuresis in the rat.
A 20-amino acid peptide, KYEIKEGDCPVQSGKTWQDC (PU-D1), released by pepsin hydrolysis of LMW kininogen domain 1 was tested for its ability to antagonize the diuretic and natriuretic effect of ANP(103-125) in anesthetized rats. A single dose of 10.8 or 21.6 pmol (25 or 50 ng) PU-D1 given intravenously or into the duodenal lumen suppressed the diuresis-natriuresis induced by 209 pmol (500 ng) ANP by 43% to 59% and 69% to 96%, respectively. None of the doses tested (2.16 to 432 pmol, 5 ng to 1 microg) modified systemic blood pressure. Strikingly, a single IV dose of 10.8 pmol PU-D1 blocked the action of ANP for more than 3 hours. ANP blockade by PU-D1 was annulled completely by the bradykinin (BK) B2 receptor inhibitor Hoe 140. On a molar basis, PU-D1 is more effective than BK and kinins of 15, 16, and 18 amino acids for blocking the ANP-mediated diuresis-natriuresis. As with BK and other kinins, the inhibitory effect of Pu-D1 on ANP is obtained only within a small range of picomol doses. A single dose of 2.16 or 4.32 pmol PU-D1 or 47 pmol (50 ng) BK is ineffective against ANP if injected alone. However, when both substances are administered concomitantly at these subthreshold doses, they totally suppress ANP-induced diuresis-natriuresis. These results raise the question of whether PU-D1, released from kininogen domain 1, either alone or associated with BK, may interact with ANP in the regulation of urinary water and electrolyte excretion in physiological and pathological conditions.
Croxatto
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Departamento de Ciencias Fisiológicas, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago. mboric@genes.bio.puc.cl
Silva
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Figueroa
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Albertini
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Roblero
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Boric
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D000595:Amino Acid Sequence; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000037:antagonists & inhibitors / Q000502:physiology*; D001920:Bradykinin / Q000031:analogs & derivatives / Q000494:pharmacology; D004231:Diuresis / Q000187:drug effects* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004386:Duodenum; D005260:Female; D007267:Injections; D007275:Injections, Intravenous; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D007704:Kininogens / Q000378:metabolism / Q000494:pharmacology*; D008969:Molecular Sequence Data; D009318:Natriuresis / Q000187:drug effects* / Q000502:physiology; D010434:Pepsin A / Q000494:pharmacology*; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats
D007704:Kininogens; C117937:PU-D1 peptide; D010446:Peptide Fragments; C065679:icatibant; D009320:Atrial Natriuretic Factor; D010434:Pepsin A; D001920:Bradykinin