TY - JOUR
T1 - Perinatal growth restriction decreases diuretic action of furosemide in adult rats
AU - Dubois, Barent N.
AU - Pearson, Jacob
AU - Mahmood, Tahir
AU - Nguyen, Duc
AU - Thornburg, Kent
AU - Cherala, Ganesh
N1 - Funding Information:
The authors also acknowledge the intramural funding from the College of Pharmacy, Oregon State University/Oregon Health & Science University ; undergraduate research support from the Heart Research Center, Oregon Health & Science University ; and extramural funding from the Office of Research in Women׳s Health and the National Institute of Child Health and Human Development ( 2K12HD043488-11 ).
PY - 2014/4/5
Y1 - 2014/4/5
N2 - Perinatal growth restriction programs higher risk for chronic disease during adulthood via morphological and physiological changes in organ systems. Perinatal growth restriction is highly correlated with a decreased nephron number, altered renal function and subsequent hypertension. We hypothesize that such renal maladaptations result in altered pharmacologic patterns for life. Maternal protein restriction during gestation and lactation was used to induce perinatal growth restriction in the current study. The diuretic response of furosemide (2 mg/kg single i.p. dose) in perinatally growth restricted rats during adulthood was investigated. Diuresis, natriuresis and renal excretion of furosemide were significantly reduced relative to controls, indicative of decreased efficacy. While a modest 12% decrease in diuresis was observed in males, females experienced 26% reduction. It is important to note that the baseline urine output and natriuresis were similar between treatment groups. The in vitro renal and hepatic metabolism of furosemide, the in vivo urinary excretion of the metabolite, and the expression of renal drug transporters were unaltered. Creatinine clearance was significantly reduced by 15% and 19% in perinatally growth restricted male and female rats, respectively. Further evidence of renal insufficiency was suggested by decreased uric acid clearance. Renal protein expression of sodium-potassium-chloride cotransporter, a pharmacodynamic target, was unaltered. In summary, perinatal growth restriction could permanently imprint pharmacokinetic processes affecting drug response.
AB - Perinatal growth restriction programs higher risk for chronic disease during adulthood via morphological and physiological changes in organ systems. Perinatal growth restriction is highly correlated with a decreased nephron number, altered renal function and subsequent hypertension. We hypothesize that such renal maladaptations result in altered pharmacologic patterns for life. Maternal protein restriction during gestation and lactation was used to induce perinatal growth restriction in the current study. The diuretic response of furosemide (2 mg/kg single i.p. dose) in perinatally growth restricted rats during adulthood was investigated. Diuresis, natriuresis and renal excretion of furosemide were significantly reduced relative to controls, indicative of decreased efficacy. While a modest 12% decrease in diuresis was observed in males, females experienced 26% reduction. It is important to note that the baseline urine output and natriuresis were similar between treatment groups. The in vitro renal and hepatic metabolism of furosemide, the in vivo urinary excretion of the metabolite, and the expression of renal drug transporters were unaltered. Creatinine clearance was significantly reduced by 15% and 19% in perinatally growth restricted male and female rats, respectively. Further evidence of renal insufficiency was suggested by decreased uric acid clearance. Renal protein expression of sodium-potassium-chloride cotransporter, a pharmacodynamic target, was unaltered. In summary, perinatal growth restriction could permanently imprint pharmacokinetic processes affecting drug response.
KW - Fetal programming
KW - Furosemide
KW - In utero growth restriction
KW - Perinatal growth restriction
KW - Pharmacokinetics
KW - Renal insufficiency
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U2 - 10.1016/j.ejphar.2014.01.056
DO - 10.1016/j.ejphar.2014.01.056
M3 - Article
C2 - 24508521
AN - SCOPUS:84896709525
SN - 0014-2999
VL - 728
SP - 39
EP - 47
JO - European Journal of Pharmacology
JF - European Journal of Pharmacology
IS - 1
ER -