COMPARATIVE INFLUENCE OF TRENTHAL AND XANTHINOL NICOTINATE ON THE FUNCTIONAL STATE OF KIDNEYS IN RATS UNDER CONDITIONS OF SALT LOADING

The aim – to investigate the comparative influence of trenthal and xanthinol nicotinateon the functional state of the rat kidneys under conditions of salt loading after a singleand durable (7 days) administration of preparations.Material and methods. Changes of excretory, water- and ion-regulating functions of thekidneys following a single and long trenthal and xanthinol nicotinate administration atdoses of 3mg/kg under conditions of salt loading with NaCl solution 0,45% were studiedin the experiments on non-linear white rats.Results. Both the rapid response of the kidneys after a single injection of trenthaland xanthinol nicotinate and more significant changes of the renal function followingrepeated (7 days) drugs’ administration under conditions of salt hydration with NaCl0.45% solution were observed. Comparative estimation of the renal action at a singleadministration has shown that xanthinol nicotinate activates water-, ion-regulating andexcretory function of kidneys more significantly than trenthal. After xanthinol nicotinateadministration the urine output in rats increased 74%, natriuresis - 66%, creatinineexcretion – 52% in comparison with the control, while following trenthal administrationthe indices under study increased only 62%, 33% and 34% correspondingly.Under conditions of salt loading water-regulating function of kidneys activated moresignificantly following durable (7 days) administration than after a single introduction ofpreparations. Under trenthal influence diuresis increased 1.8 times, xanthinol nicotinate– 1.9 times in comparison with the control. Trenthal increased endogenous creatinineexcretion – 1.4 times and xanthinol nicotinate – 1.6 times.Natriuresis increased almost 2 times, trenthal - 1.4 times under xanthinol nicotinateinfluence. The natriuretic effect of xanthinol nicotinate is 55% higher than that oftrenthal. Positive correlative relation has been established between increased urinationand natriuresis only after durable xanthinol nicotinate administration (r=0,784, p<0,05).Trenthal appeared to be more pronounced kaliurretic.Conclusions. Excretory, water- and ion-regulating renal function is activated following asingle and protracted (7 days) introduction of methylxanthine derivatives – trenthal andxanthinol nicotinate at a dose of 3mg/kg under hydration conditions with NaCl solution0,45%. Renal effects of the preparations under study is characterized by an increaseof endogenous creatinine excretion. With long-term administration of the preparationsnatriuretic effect predominates in xanthinol nicotinate, kaliuretic effect - in trenthal.

Thiazide-Sensitive NCC (Sodium-Chloride Cotransporter) in Human Metabolic Syndrome

The thiazide-sensitive sodium-chloride cotransporter (NCC;SLC12A3) is central to sodium and blood pressure regulation. Metabolic syndrome induces NCC upregulation generating sodium-sensitive hypertension in experimental animal models. We tested the role of NCC in sodium sensitivity in hypertensive humans with metabolic syndrome. Conversely, oral potassium induces NCC downregulation producing potassium-induced natriuresis. We determined the time course and magnitude of potassium-induced natriuresis compared with the natriuresis following hydrochlorothiazide (HCTZ) as a reference standard. We studied 19 obese hypertensive humans with metabolic syndrome during 13-day inpatient confinement. We determined sodium sensitivity by change in 24-hour mean systolic pressure by automated monitor from days 5 (low sodium) to 10 (high sodium). We determined NCC activity by standard 50 mg HCTZ sensitivity test (day 11). We determined potassium-induced natriuresis following 35 mmol KCl (day 13). We determined (1) whether NCC activity was greater in sodium-sensitive versus sodium-resistant participants and correlated with sodium sensitivity and (2) time course and magnitude of potassium-induced natriuresis following 35 mmol KCl directly compared with 50 mg HCTZ. NCC activity was not greater in sodium-sensitive versus sodium-resistant humans and did not correlate with sodium sensitivity. Thirty-five-millimoles KCl produced a rapid natriuresis approximately half that of 50 mg HCTZ with a greater kaliuresis. Our investigation tested a key hypothesis regarding NCC activity in human hypertension and characterized potassium-induced natriuresis following 35 mmol KCl compared with 50 mg HCTZ. In obese hypertensive adults with metabolic syndrome ingesting a high-sodium diet, 35 mmol KCl had a net natriuretic effect approximately half that of 50 mg HCTZ.

Diuretic, Kaliuretic and Anti-Natriuretic Properties of Aqueous Extract of Celosia trigyna L. (Amaranthaceae) on Wistar Rats

Aims: The purpose of this study was to determine the diuretic and electrolyte excretion properties of the aqueous extract of Celosia trigyna L. (Amaranthaceae) on female Wistar rats. Methodology: The extraction of active principles was done by macerating aerial parts of the plant. The administration of the extract and other products was done by single-dose gavage. Measurements of urinary flow rate (UFR), natriuria, kaliuria and chloruria were taken on urine collected for twenty-four hours after each product was administered. Diuretic activity (DA) and diuretic index (DI), natriuretic and saluretic effects, and carbonic anhydrase inhibition were calculated. A NaCl solution (0.9%) was used as a negative control; furosemide and aldactone were respectively used as hypokalemic and hyperkalemic positive controls. Results: We observed a significant increase in UFR, confirmed by the values of DA and DI, obtained after the administration of extract. For electrolyte excretion, we observed an increase of the kaliuria (p ˂ 0.001) and a decrease of natriuria (p ˂ 0.001) after the extract was administered; chloruria did not significantly changed. We also found a drastic anti-natriuretic dose-dependent effect while saluretic activity and carbonic anhydrase inhibition were not clearly observable. Conclusion: These results confirm the ethnobotanical data about diuretic effect of Celosia trigyna L. extract. This diuretic effect would be supported by a specific increase in K+ excretion suggesting that the extract is possibly hypokalemic. The anti-natriuretic effect suggests that extract possess an aldosterone-like properties.

A role for tubular Na+/H+ exchanger NHE3 in the natriuretic effect of the SGLT2 inhibitor empagliflozin

Inhibitors of proximal tubular Na+-glucose cotransporter 2 (SGLT2) are natriuretic, and they lower blood pressure. There are reports that the activities of SGLT2 and Na+-H+ exchanger 3 (NHE3) are coordinated. If so, then part of the natriuretic response to an SGLT2 inhibitor is mediated by suppressing NHE3. To examine this further, we compared the effects of an SGLT2 inhibitor, empagliflozin, on urine composition and systolic blood pressure (SBP) in nondiabetic mice with tubule-specific NHE3 knockdown (NHE3-ko) and wild-type (WT) littermates. A single dose of empagliflozin, titrated to cause minimal glucosuria, increased urinary excretion of Na+ and bicarbonate and raised urine pH in WT mice but not in NHE3-ko mice. Chronic empagliflozin treatment tended to lower SBP despite higher renal renin mRNA expression and lowered the ratio of SBP to renin mRNA, indicating volume loss. This effect of empagliflozin depended on tubular NHE3. In diabetic Akita mice, chronic empagliflozin enhanced phosphorylation of NHE3 (S552/S605), changes previously linked to lesser NHE3-mediated reabsorption. Chronic empagliflozin also increased expression of genes involved with renal gluconeogenesis, bicarbonate regeneration, and ammonium formation. While this could reflect compensatory responses to acidification of proximal tubular cells resulting from reduced NHE3 activity, these effects were at least in part independent of tubular NHE3 and potentially indicated metabolic adaptations to urinary glucose loss. Moreover, empagliflozin increased luminal α-ketoglutarate, which may serve to stimulate compensatory distal NaCl reabsorption, while cogenerated and excreted ammonium balances urine losses of this “potential bicarbonate.” The data implicate NHE3 as a determinant of the natriuretic effect of empagliflozin.

The Renal Extraction and the Natriuretic Action of GLP-1 in Humans Depend on Interaction With the GLP-1 Receptor

Purpose The natriuretic effect of glucagon-like peptide-1 (GLP-1) in humans is independent of changes in renal plasma flow (RPF) and glomerular filtration rate (GFR) but may involve suppression of angiotensin II (ANG II) and a significant (~45%) renal extraction of GLP-1. The current study was designed to investigate the consequences for the renal extraction and the natriuretic effect of blocking GLP-1 receptors with the specific GLP-1 receptor antagonist, Exendin 9–39 (Ex 9–39). Methods Under fixed sodium intake for 4 days before each study day, 6 healthy male participants were recruited from our recent study where GLP-1 or vehicle was infused (1). In the present new experiments, participants were examined during a 3-hour infusion of GLP-1 (1.5 pmol/kg/min) together with a 3.5-hour infusion of Ex 9–39 (900 pmol/kg/min). Timed urine collections were conducted throughout the experiments. Renal extraction of GLP-1 as well as RPF and GFR were measured via Fick’s principle after catheterization of a renal vein. Arterial plasma renin, ANG II, and aldosterone concentrations were measured. Results Co-infusion of Ex 9–39 significantly reduced renal extraction of GLP-1 to ~25% compared with GLP-1 infusion alone (~45%). Urinary sodium excretions remained at baseline levels during co-infusion of Ex 9–39 as well as vehicle. By contrast, GLP-1 infusion alone resulted in a 2-fold increase in natriuresis. Ex 9–39 abolished the GLP-1-induced decrease in arterial ANG II concentrations. RPF and GFR remained unchanged during all experiments. Conclusions Renal extraction of GLP-1 and its effect on natriuresis are both dependent on GLP-1 receptor activation in healthy humans.

The Off-Target Effects, Electrolyte and Mineral Disorders of SGLT2i

The sodium-glucose cotransporter 2 inhibitors (SGLT2i) are a relatively new class of antidiabetic drugs that, in addition to emerging as an effective hypoglycemic treatment, have been shown to improve, in several trials, both renal and cardiovascular outcomes. In consideration of the renal site of action and the associated osmotic diuresis, a negative sodium balance has been postulated during SGLT2i administration. Although it is presumable that sodium and water depletion may contribute to some positive actions of SGLT2i, evidence is far from being conclusive and the real physiologic effects of SGLT2i on sodium remain largely unknown. Indeed, no study has yet investigated how SGLT2i change sodium balance in the long term and especially the pathways through which the natriuretic effect is expressed. Furthermore, recently, several experimental studies have identified different pathways, not directly linked to tubular sodium handling, which could contribute to the renal and cardiovascular benefits associated with SGLT2i. These compounds may also modulate urinary chloride, potassium, magnesium, phosphate, and calcium excretion. Some changes in electrolyte homeostasis are transient, whereas others may persist, suggesting that the administration of SGLT2i may affect mineral and electrolyte balances in exposed subjects. This paper will review the evidence of SGLT2i action on sodium transporters, their off-target effects and their potential role on kidney protection as well as their influence on electrolytes and mineral homeostasis.