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(Hypertension. 1995;26:634-641.)
© 1995 American Heart Association, Inc.

Articles

Atrial Natriuretic Peptide in Chronically Hypertensive Dogs

Andrea A. Seymour; Magdi M. Asaad; Jeffrey H. Sheldon; Patricia L. Smith; W. Lynn Rogers

From the Departments of Pharmacology and Biochemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ.

Correspondence to Andrea A. Seymour, PhD, Bristol-Myers Squibb Pharmaceutical Research Institute, PO Box 4000, Princeton, NJ 08543-4000. E-mail Seymour Andrea aprilvms3@msmail.bms.com.

Abstract We determined the renal and depressor activities of 10, 50, and 100 pmol/kg per minute IV 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. In conclusion, dogs with chronic one-kidney, one clip hypertension and mild proteinuria were hyporesponsive to the renal activity of atrial natriuretic peptide, presumably because of renal receptor downregulation and possible defects in cGMP signal transduction.

Key Words: atrial natriuretic factor • hypertension • cGMP • sodium