Atrial natriuretic peptide in chronically hypertensive dogs.
We determined the renal and depressor activities of 10, 50, and 100 pmol/kg per minute i.v. of human atrial natriuretic peptide-(99-126) in conscious one-kidney, one clip dogs with chronic hypertension and modest renal dysfunction, as indicated by mild proteinuria. Atrial natriuretic peptide increased fractional sodium excretion by 0.009 +/- 0.002, 0.042 +/- 0.005, and 0.049 +/- 0.007, respectively; urinary excretion of atrial natriuretic peptide by -0.4 +/- 0.8, 3.3 +/- 1.4, and 15.8 +/- 7.4 fmol/min; and cGMP excretion by 0.65 +/- 0.06, 1.65 +/- 0.08, and 4.88 +/- 0.85 nmol/min in one-kidney shams. The changes in fractional sodium excretion were significantly attenuated in the hypertensive dogs (0.005 +/- 0.002, 0.018 +/- 0.003, and 0.022 +/- 0.004, respectively) despite exaggerated increases in atrial natriuretic peptide excretion (3.3 +/- 1.6, 22.0 +/- 5.0, and 46.6 +/- 10.8 fmol/min) and cGMP excretion (0.96 +/- 0.47, 4.51 +/- 1.27, and 7.06 +/- 1.38 nmol/min). The slope of the line relating urinary atrial natriuretic peptide to cGMP was significantly suppressed in the hypertensive dogs, suggesting a downregulation of the guanylate cyclase-linked receptors. The slope of the relationship between cGMP excretion and the natriuretic response was also depressed in the hypertensive dogs, indicating possible impairment of cGMP signal transduction. The differences between sham and hypertensive dogs were diminished when urinary levels of atrial natriuretic peptide were maximized by prior treatment with SQ 28603, an inhibitor of neutral endopeptidase EC 3.4.24.11. Atrial natriuretic peptide caused comparable decreases in mean arterial pressure and increases in glomerular filtration rate in sham and hypertensive dogs, suggesting similar vascular reactivity.(ABSTRACT TRUNCATED AT 250 WORDS)
Seymour
A A
AA
Departments of Pharmacology and Biochemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ, USA.
Asaad
M M
MM
Sheldon
J H
JH
Smith
P L
PL
Rogers
W L
WL
D000409:Alanine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D002908:Chronic Disease; D004232:Diuretics / Q000494:pharmacology*; D004285:Dogs; D005260:Female; D006801:Humans; D006978:Hypertension, Renovascular / Q000503:physiopathology*; D007275:Injections, Intravenous; D007668:Kidney / Q000187:drug effects / Q000503:physiopathology; D008297:Male; D015260:Neprilysin / Q000037:antagonists & inhibitors; D010446:Peptide Fragments / Q000494:pharmacology*
D004232:Diuretics; D010446:Peptide Fragments; C065359:SQ 28603; D009320:Atrial Natriuretic Factor; D015260:Neprilysin; D000409:Alanine