Perinatal growth restriction decreases diuretic action of furosemide in adult rats

Abstract

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 (2mg/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 was 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 was 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.

Furosemide Pharmacokinetics in Adult Rats become Abnormal with an Adverse Intrauterine Environment and Modulated by a Post‐Weaning High‐Fat Diet

“…In our previous study, using 2 mg/kg furosemide i.p. dose, we found a significant decrease in renal excretion and diuresis . A higher 10 mg/kg i.p.…”

“…Determination of in vitro glucuronidation of furosemide. The in vitro formation of furosemide-glucuronide was measured in hepatic microsomes from previously adapted methods [11,16,17]. Briefly, microsomes were pre-incubated with alamethicin (250 lg/mg protein) on ice for 30 min.…”

“…In our model of IUGR, pregnant rats were fed a low-protein diet during gestation and lactation resulting in offspring with low birthweight and stunted postnatal growth [7][8][9][10]. The IUGR offspring had a reduced urinary excretion of the loop diuretic, furosemide, compared to rats that had a normal birthweight [11]. These experiments led to the studies reported here.…”

Lack of In Vitro–In Vivo Correlation of Adulthood Cytochrome P450 Activities in Low-Birth-Weight Rats

“…As Sohi et al point out in their discussion, other pharmacokinetic processes such as protein binding and transporters might be confounding in vitro-in vivo correlation. Preliminary data from our research group are supportive of confounding factors (Dubois et al, 2013). We could not agree more with the authors that there is a need for prospective studies to elucidate the effects of perinatal environment on pharmacokinetics during adulthood.…”

Vascular endothelial growth factor signaling is necessary for expansion of medullary microvessels during postnatal kidney development

“…The pathophysiological mechanisms are not fully understood but have been associated with impaired nephron endowment (21). The renal medulla contributes significantly to systemic blood pressure control through regulation of sodium excretion and fetal programming includes enhanced salt sensitivity of blood pressure (2,12). Normal salt excretion is a function that relies partly on the unique architecture and close tubulovascular relationship of the renal medulla (10).…”