Influence of administration time and sex on natriuretic, diuretic, and kaliuretic effects of diuretics.

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 the present study was 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 treatments for hypertension. Loop diuretics inhibit Na+-K+-2Cl- cotransporters on the apical membrane of the thick ascending limb, thiazide diuretics inhibit Na+-Cl- cotransporters on the distal convoluted tubule, and K+-sparing diuretics inhibit epithelial Na+ channels on the connecting tubule and collecting duct. We simulated Na+ transporter inhibition using sex- and time-of-day-specific computational models of mouse kidney function. The simulation results highlighted significant sex and time-of-day differences in the drug response. Loop diuretics induced larger natriuretic and diuretic effects during the active phase. The natriuretic and diuretic effects of thiazide diuretics exhibited sex and time-of-day differences, whereas these effects of K+-sparing diuretics exhibited a significant time-of-day difference in females only. The kaliuretic effect depended 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.NEW & NOTEWORTHY Sex influences cardiovascular disease, and the timing of onset of acute cardiovascular events exhibits circadian rhythms. Kidney function also exhibits sex differences and circadian rhythms. How do the natriuretic and diuretic effects of diuretics, a common treatment for hypertension that targets the kidneys, differ between the sexes? And how do these effects vary during the day? To answer these questions, we conducted computer simulations to assess the effects of loop, thiazide, and K+-sparing diuretics.

Pairwise comparison of hydrochlorothiazide and chlorthalidone responses among hypertensive patients.

This study conducted a pairwise comparison of antihypertensive and metabolic effects of hydrochlorothiazide (HCTZ) and chlorthalidone (CTD) at 25 mg/day in the same individuals to address the clinical dilemma on preferred thiazide for hypertension (HTN) management. We included 15 African American (AA) and 35 European American (EA) patients with HTN treated with HCTZ and CTD as part of the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) and PEAR-2 trials, respectively. Mean reduction in systolic/diastolic blood pressure (SBP/DBP) with HCTZ versus CTD was 8/5 versus 16/8 mmHg among EA patients (p < 1.0e-5 SBP, p = 0.002 DBP) and 11/8 versus 20/11 mmHg among AA patients (p = 0.03 SBP, p = 0.22 DBP). While CTD showed clinically meaningful benefit over HCTZ in two-thirds of participants with respect to SBP reduction and half of EA patients with respect to DBP reduction, a majority of AA patients (53%) showed similar DBP reduction with both thiazides. Sixty percent of AA patients and 29% of EA patients attained blood pressure (BP) <140/90 mmHg with both thiazides. Mean potassium (K+) reduction was greater with CTD compared to HCTZ both in EA patients (mean difference = 0.35, p = 0.0002) and AA patients (0.49, p = 0.043). While 31% of AA patients developed severe hypokalemia on CTD, <5% of others developed severe hypokalemia. Although 46% of AA patients on CTD required K+ supplementation, only 6%-11% of others required supplementation. Overall, in the majority of EA patients, CTD was superior to HCTZ, whereas among AA patients, it was superior in a minority, and was associated with significant potassium-related risk, suggesting that guideline preferences for CTD over HCTZ are reasonable in EA patients but may be less reasonable in AA patients, particularly if the target is <140/90 mmHg.

Evaluation of diuretic activity of Amaranthus spinosus Linn. aqueous extract in Wistar rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Traditional Siddha medicine literature claims that the Amaranthus spinosus Linn. (family: Amaranthaceae) whole plant possesses diuretic property. AIM OF THE STUDY: To evaluate the diuretic potential of Amaranthus spinosus aqueous extract (ASAE) in rats. MATERIAL AND METHODS: Different concentrations of ASAE (200, 500, 1000, 1500mg/kg), thiazide (10mg/kg) and vehicle were orally administered to rats (n=6 animals per group) and their urine output was collected after 24h. Volume, pH, Na(+), K(+) and Cl(-) concentrations of urine were estimated. RESULTS: ASAE produced increase in Na(+), K(+), Cl(-) excretion, caused alkalinization of urine, showed strong saluretic activity and carbonic anhydrase inhibition activity. These effects were observed predominantly at 500mg/kg dose and there was no dose-response relationship. CONCLUSION: Our study strongly suggests that the Amaranthus spinosus is acting as a thiazide like diuretic with carbonic anhydrase inhibitory activity which restates the claim as diuretic herb in Siddha medicine.

[Hypertension, CKD and bone metabolism].

The patients with "Hypertension" and "Chronic Kidney Disease (CKD) " are accompanied with an osteoporosis. In hypertension patients, excess urinary calcium secretion induces secondary parathyroidsim to increase serum calcium (Ca) level, which may lead to Ca release from bone. In this aspect, there are several reports that anti-hypertensive drugs, especially thiazides, increase bone mineral density and decrease the incidence of bone fracture. In addition, we demonstrated that renin-angiotensin system can be involved in the process of osteoporosis. Angiotensin II significantly induced the expression of RANKL (receptor activator of NF-κB ligand) in osteoblasts, leading to the activation of osteoclasts, while these effects were completely blocked by an Ang II type 1 receptor blockade. As for CKD, excess phosphorus (P) due to renal dysfunction induces secondary parathyroidism to decrease serum P level, which similarly leads to osteoporosis. Moreover, excess P can increase FGF23 expression and decrease activated vitamin D, which also resulted in progression of osteoporosis. Both "Hypertension" and "Chronic Kidney Disease (CKD) " are inducible factor to osteoporosis.

Torasemide significantly reduces thiazide-induced potassium and magnesium loss despite supra-additive natriuresis.

BACKGROUND: Resistance to high-dose loop diuretics can be overcome either by co-administration with thiazides or by treatment with medium-dose loop diuretics combined with thiazides. Combination therapy has been proven to be superior to high-dose loop diuretic monotherapy for cardiac and renal edema. However, such a strongly efficacious short-term regimen is often complicated by undesired effects, including circulatory collapse and electrolyte disturbances. The question of whether the loop diuretic/thiazide combinations are efficacious and safe when conventional doses are combined has not yet been answered. METHODS: The effects of hydrochlorothiazide (HCT) and torasemide (TO) given alone on the excretion of Na+, Cl-, K+, Mg2+, and Ca2+ were compared with the effects of combined administration of the diuretics in 12 healthy volunteers. RESULTS: The co-administration of HCT (25 mg) with TO (5 or 10 mg) strongly increased Na+ excretion. However, the combination significantly reduced K+ and Mg2+ excretion. The K+-sparing effect of the HCT/TO combination was shown to be due to a significant reduction in the HCT-induced increase in fractional K+ excretion by the loop diuretic. Total excretion of Ca2+ relative to Na+ excretion was less with the HCT/TO combination than with TO given alone. CONCLUSION: The enhancement of desired NaCl excretion by the HCT/TO combination with significant reduction of undesired loss of K+ and Mg2+ meets clinical requirements but has to be validated in long-term clinical trials.

Renal expression of parvalbumin is critical for NaCl handling and response to diuretics.

The distal convoluted tubule (DCT) plays an essential role in the reabsorption of NaCl by the kidney, a process that can be inhibited by thiazide diuretics. Parvalbumin (PV), a Ca(2+)-binding protein that plays a role in muscle fibers and neurons, is selectively expressed in the DCT, where its role remains unknown. We therefore investigated the renal phenotype of PV knockout mice (Pvalb(-/-)) vs. wild-type (Pvalb(+/+)) littermates. PV colocalized with the thiazide-sensitive Na(+)-Cl(-) cotransporter (NCC) in the early DCT. The Pvalb(-/-) mice showed increased diuresis and kaliuresis at baseline with higher aldosterone levels and lower lithium clearance. Acute furosemide administration increased diuresis and natriuresis/kaliuresis, but, surprisingly, did not increase calciuria in Pvalb(-/-) mice. NaCl supplementation of Pvalb(-/-) mice increased calciuria at baseline and after furosemide. The Pvalb(-/-) mice showed no significant diuretic response to hydrochlorothiazide, but an accentuated hypocalciuria. A decreased expression of NCC was detected in the early DCT of Pvalb(-/-) kidneys in the absence of ultrastructural and apoptotic changes. The PV-deficient mice had a positive Ca(2+) balance and increased bone mineral density. Studies in mouse DCT cells showed that endogenous NCC expression is Ca(2+)-dependent and can be modulated by the levels of PV expression. These results suggest that PV regulates the expression of NCC by modulating intracellular Ca(2+) signaling in response to ATP in DCT cells. They also provide insights into the Ca(2+)-sparing action of thiazides and the pathophysiology of distal tubulopathies.

Effects of furosemide on renal calcium handling.

Furosemide is a loop diuretic agent that has been used to treat hypercalcemia because it increases renal calcium excretion. The effect of furosemide on calcium transport molecules in distal tubules has yet to be investigated. We conducted studies to examine the effects of furosemide on renal calcium excretion and expression of calcium transport molecules in mice. Mice were administered with a single dose of furosemide (15 mg/kg) and examined 4 h later or were given twice-daily furosemide injections for 3 days. To evaluate the effects of volume depletion, drinking water was supplemented with salt. Our results showed that, in acute experiments, furosemide enhanced urinary calcium excretion, which was associated with a significant increase in mRNA levels of TRPV5, TRPV6, and calbindin-D28k but not calbindin-D9k as measured by real-time PCR (TRPV5 and TRPV6 are transient receptor potential vanilloid 5 and 6). Chronic furosemide administration induced three- to fourfold increases in urinary calcium excretion and elevated mRNA levels of TRPV5, TRPV6, calbindin-D28k, and calbindin-D9k without or with salt supplement. Similar upregulation of calcium transport molecules was observed in mice with gentamicin-induced hypercalciuria. Coadministration of chlorothiazide decreased furosemide-induced calciuria, either acutely or chronically, although still accompanied by upregulation of these transport molecules. Immunofluorescent staining studies revealed comparably increased protein abundance in TRPV5 and calbindin-D28k. We conclude that furosemide treatment enhances urinary calcium excretion. Increased abundance of calcium transport molecules in the distal convoluted tubule represents a solute load-dependent effect in response to increased calcium delivery and serves as a compensatory adaptation in the downstream segment.