Modulation of exogenous and endogenous atrial natriuretic peptide by a receptor inhibitor.
Atrial natriuretic peptide is an important peptide hormone of cardiac origin that functions to regulate cardiac preload via the regulation of sodium excretion. This natriuretic action occurs through activation of the particulate guanylyl cyclase-linked natriuretic peptide-A receptor. HS-142-1 is a newly discovered antagonist of the natriuretic peptide-A receptor that permits insight into the functional role of atrial natriuretic peptide in cardiorenal homeostasis. The first objective of this study was to define for the first time the intrarenal action of HS-142-1 on exogenous atrial natriuretic peptide-mediated natriuresis in anesthetized normal dogs. In group 1 (n = 6), which received intravenous atrial natriuretic peptide at 100 ng/kg per minute, intrarenal HS-142-1 (0.5 mg/kg bolus) attenuated atrial natriuretic peptide-induced increases in glomerular filtration rate, urine flow, sodium excretion, and renal cyclic GMP generation and decreases in distal tubular sodium reabsorption. The second objective was to determine whether endogenous atrial natriuretic peptide participates in the regulation of basal sodium excretion. In group 2 (n = 6), intrarenal HS-142-1 alone decreased both absolute and fractional sodium excretion and renal cyclic GMP generation and increased distal tubular sodium reabsorption. These studies demonstrate that HS-142-1 markedly attenuates exogenous atrial natriuretic peptide-mediated natriuresis via enhancement of distal tubular reabsorption and blunting of increases in glomerular filtration rate. Second, the current studies support a functional role for endogenous atrial natriuretic peptide in the regulation of basal sodium excretion.
Stevens
T L
TL
Division of Cardiovascular Diseases, Mayo Clinic and Foundation, Rochester, Minn 55905.
Wei
C M
CM
Aahrus
L L
LL
Heublein
D M
DM
Kinoshita
M
M
Matsuda
Y
Y
Burnett
J C
JC
D000818:Animals; D009320:Atrial Natriuretic Factor / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D006152:Cyclic GMP / Q000096:biosynthesis; D004285:Dogs; D006439:Hemodynamics / Q000187:drug effects; D007668:Kidney / Q000187:drug effects; D008297:Male; D011134:Polysaccharides / Q000494:pharmacology*; D017461:Receptors, Atrial Natriuretic Factor / Q000037:antagonists & inhibitors*; D012083:Renin / Q000097:blood
C072551:HS 142-1; D011134:Polysaccharides; D009320:Atrial Natriuretic Factor; D012083:Renin; D017461:Receptors, Atrial Natriuretic Factor; D006152:Cyclic GMP