Phosphodiesterase 5 inhibitor ameliorates renal resistance to atrial natriuretic peptide associated with obesity and hyperleptinemia.
BACKGROUND
Abnormal neurohormonal regulation of renal sodium handling plays an important role in obesity-associated hypertension. We investigated the effect of experimental obesity on renal response to atrial natriuretic peptide (ANP).


METHODS
The effect of ANP was studied in three groups of rats: (1) lean controls, (2) animals made obese by a highly palatable diet, (3) rats treated with adipose tissue hormone, leptin, for 7 days to reproduce hyperleptinemia observed in obesity.


RESULTS
ANP administered at a dose of 50 pmol/kg min(-1) induced about a 3-fold lower increase in Na+ and cGMP excretion in obese and leptin-treated rats than in the control group. ANP decreased Na+,K+-ATPase activity in the renal medulla only in the control group. Natriuretic effect of exogenous cGMP was also impaired in obese and leptin-treated rats. In contrast, hydrolysis-resistant cGMP derivative, 8-bromo-cGMP exerted comparable natriuretic effects in all groups. Neutral endopeptidase inhibitor, phosphoramidon, and ANP clearance receptor antagonist, C-ANP, increased urinary ANP excretion in all groups to a similar level, but their natriuretic effect was impaired in obese and leptin-treated groups. A specific inhibitor of cGMP-degrading phosphodiesterase, zaprinast, had comparable natriuretic and Na+,K+-ATPase-lowering effects in all groups and restored normal sensitivity to ANP.


CONCLUSIONS
(1) Dietary-induced obesity is accompanied by impaired natriuretic effect of ANP, (2) ANP resistance in obesity may be accounted for by increased leptin level, (3) accelerated degradation of cGMP may contribute to ANP resistance associated with obesity and hyperleptinemia, suggesting that inhibiting cGMP-specific phosphodiesterases may be useful in the treatment of obesity-associated hypertension.
Beltowski
Jerzy
J
Department of Pathophysiology, Medical University, Lublin, Poland. jerzybel@hotmail.com
Jamroz-Wisniewska
Anna
A
Borkowska
Ewelina
E
Marciniak
Andrzej
A
D015106:3',5'-Cyclic-GMP Phosphodiesterases; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000494:pharmacology* / Q000652:urine; D006152:Cyclic GMP / Q000652:urine; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D004351:Drug Resistance / Q000187:drug effects*; D006949:Hyperlipidemias / Q000139:chemically induced / Q000150:complications / Q000503:physiopathology*; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D009765:Obesity / Q000150:complications / Q000503:physiopathology*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D012964:Sodium / Q000378:metabolism
D010726:Phosphodiesterase Inhibitors; D009320:Atrial Natriuretic Factor; D012964:Sodium; D010727:Phosphoric Diester Hydrolases; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517384:Pde5a protein, rat; D006152:Cyclic GMP