Determinants of natriuretic, diuretic, and kaliuretic effects of diuretics: Sex and administration time

Sex differences in renal function and blood pressure have been widely described across many species. Blood pressure dips during sleep and peaks in the early morning. Similarly, glomerular filtration rate, filtered electrolyte loads, urine volume, and urinary excretion all exhibit notable diurnal rhythms, which reflect, in part, the regulation of renal transporter proteins by circadian clock genes. That regulation is sexually dimorphic; as such, sex and time-of-day are not two independent regulators of kidney function and blood pressure. The objective of this study is to assess the effect of sex and administration time on the natriuretic and diuretic effects of loop, thiazide, and K+-sparing diuretics, which are common treatment for hypertension. Loop diuretics inhibit NKCC2 on the apical membrane of the thick ascending limb, thiazide diuretics inhibit NCC on the distal convoluted tubule, and K+-sparing diuretics inhibit ENaC on the connecting tubule and collecting duct. We simulate Na+ transporter inhibition using our sex- and time-of-day-specific computational models of mouse kidney function. Simulations results highlight significant sex and time-of day differences in drug response. Loop diuretics induce larger natriuretic and diuretic effects during the active phase. The natriuretic and diuretic effects of thiazide diuretics exhibit sex and time-of-day differences, whereas these effects of K+-sparing diuretics exhibit significant time-of-day difference in females only. Kaliuretic effect depends on the type of diuretics and time of administration. The present computational models can be a useful tool in chronotherapy, to tailor drug administration time to match the body’s diurnal rhythms to optimize the drug effect.