Effect of crude extract of Stevia rebaudiana on renal water and electrolytes excretion.

To evaluate the effect of crude extract of Stevia rebaudiana on renal water, Na+ and K+ excretion, male Wistar rats (250-350 g each) under antidiuresis or water diuresis conditions, were evaluated. During intravenous infusion of the extract (0.05 mg/min/100 g) no significant differences were detected in mean arterial pressure or renal hemodynamics parameters. In contrast, fractional water and sodium excretion and solute clearance increased significantly, in both groups of animals. In antidiuresis rats the extract significantly increased reabsorption of water by the collecting duct and in water diuresis animals the extract significantly increased free water clearance. The data suggest preferential action of the extract in the proximal tubular cells involved with salt transport mechanism.     

Intrahepatic adenosine-mediated activation of hepatorenal reflex is via A1 receptors in rats

Previous studies have shown that intrahepatic adenosine is involved in activation of the hepatorenal reflex that regulates renal sodium and water excretion. The present study aims to determine which subtype of adenosine receptors is implicated in the process. Mean arterial pressure, portal venous pressure and flow, and renal arterial flow were monitored in pentobarbital anesthetized rats. Urine was collected from the bladder. Intraportal administration of 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), a selective adenosine A1 receptor antagonist, increased urine flow by 24%, 89%, and 143% at the dose of 0.01, 0.03, and 0.1 mg x kg(-1), respectively; in contrast, DPCPX, when administered intravenously at the same doses, only increased urine flow by 0%, 18%, and 36%. The increases in urine flow induced by intraportal administration of DPCPX were abolished in rats with liver denervation. Intrahepatic infusion of adenosine significantly decreased urine flow and this response was abolished by intraportal administration of DPCPX. Neither intraportal nor intravenous administration of 3,7-dimethyl-1-propargylxanthine, a selective adenosine A2 receptor antagonist, showed significant influence on urine flow. Systemic arterial pressure, renal blood flow and glomerular filtration rate were unaltered by the administration of any of the drugs. In conclusion, intrahepatic adenosine A1 receptors are responsible for the adenosine-mediated hepatorenal reflex that regulates renal water and sodium excretion.     

Antiulcerogenic activity of a crude hydroalcoholic extract and coumarin isolated from Mikania laevigata Schultz Bip

The leaves of Mikania (Asteraceae) species are used in folk medicine as antispasmodic, antiulcerogenic and antirheumatic agents. Phytochemical screening of the crude hydroalcoholic 70% extract (CHE) of Mikania laevigata Shultz Bip. revealed coumarins, terpenes and organic acids. Antiulcerogenic activity of CHE was evaluated, employing different experimental models in rats, to discern the pharmacological mechanism of action. Both the antisecretory and the cytoprotection hypothesis were evaluated. The crude hydroalcoholic extract (1000 mg/kg body wt., vo) decreased the ulcerative lesion index produced by indomethacin, ethanol, stress and reserpine in rats by 85%, 93%, 82% and 50%, respectively. In the pyloric ligation model, a decrease of hydrogenionic concentration (53%) was observed, suggesting that the pharmacological mechanism has a relationship to antisecretory activity. The antisecretory mechanisms of CHE and the coumarin isolated from M. laevigata were confirmed by acid hypersecretion induced by histamine, pentagastrin and bethanechol. Duodenal administration of CHE (1000 mg/kg body wt.) and coumarin (100 mg/kg body wt.) inhibited only the gastric acid secretion produced by bethanecol. These results suggest that both CHE and coumarin may influence the secretion control mediated by the parasympathetic system.     

Effects of aspirin on renal sodium excretion, blood pressure, and plasma and extracellular fluid volume in salt-loaded rats.

The effect of aspirin administration and presumed blockade of prostaglandin synthesis on renal sodium excretion, plasma and extracellular fluid volumes, and blood pressure were examined in rats on a high sodium intake. After acute salt loading aspirin treated rats showed an impaired sodium excretion, while no changes in glomerular filtration rate were observed. In chronically loaded rats (7 weeks) administration of aspirin induced significant increases in both plasma and extracellular fluid volume, but no significant changes in blood pressures were found. The results are consistent with the hypothesis that prostaglandins mediate renal sodium excretion and therefore participate in extracellular fluid volume regulation.     

Synthesis and renal effects of Ala-Gly-[Arg8]-vasopressin

A new neurohypophyseal hormone analogue, Ala-Gly-[Arg⁸]-vasopressin, was synthesized by the stepwise solution techniques and its effect on systemic blood pressure and renal function was examined in nondiuretic Sprague-Dawley rats. Clearance of inulin was used to study glomerular filtration rate. Intravenous administration of 50 pmole/100 g. b. wt. Ala-Gly-[Arg⁸]-vasopressin caused diuresis and natriuresis without significant change of mean arterial blood pressure. The fractional excretion of sodium was increased by 225% within 10 min after the analogue administration. The present study suggests that this analogue has a direct effect on renal tubular transport of electrolyte independent of affecting systemic circulation.     

Effects of aspirin on renal sodium excretion, blood pressure, and plasma and extracellular fluid volume in salt-loaded rats

The effect of aspirin administration and presumed blockade of prostaglandin synthesis on renal sodium excretion, plasma and extracellular fluid volumes, and blood pressure were examined in rats on a high sodium intake. After acute salt loading aspirin treated rats showed an impaired sodium excretion, while no changes in glomerular filtration rate were observed. In chronically loaded rats (7 weeks) administration of aspirin induced significant increases in both plasma and extracellular fluid volume, but no significant changes in blood pressure were found. The results are consistent with the hypothesis that prostaglandins mediate renal sodium excretion and therefore participate in extracellular fluid volume regulation.     

Effects of aspirin on renal sodium excretion,blood pressure,and plasma and extracellular fluid volume in salt-loaded rats

The effect of aspirin administration and presumed blockade of prostaglandin synthesis on renal sodium excretion, plasma and extracellular fluid volumes, and blood pressure were examined in rats on a high sodium intake. After acute salt loading aspirin treated rats showed an impaired sodium excretion, while no changes in glomerular filtration rate were observed. In chronically loaded rats (7 weeks) administration of aspirin induced significant increases in both plasma and extracellular fluid volume, but no significant changes in blood pressure were found. The results are consistent with the hypothesis that prostaglandins mediate renal sodium excretion and therefore participate in extracellular fluid volume regulation.     

Influence of renal denervation on renal effects of acute nitric oxide and ETA/ETB receptor inhibition in conscious normotensive rats.

The role of renal nerves in the effects of concomitant NO synthase and non-selective ET(A/)ET(B) receptor inhibition on renal function was investigated in conscious normotensive Wistar rats. NO synthase inhibition alone (10 mg/kg b. w. i.v. L-NAME) in sham-operated rats with intact renal nerves induced an increase in systolic, diastolic and mean arterial pressure, urine flow rate, sodium, chloride and calcium excretion (p<0.05). The effect of L-NAME was markedly reduced by bosentan (10 mg/kg b.w. i.v.) and the values of urine flow rate, sodium, chloride and calcium excretions returned to control level (p<0.05). L-NAME administration one week after a bilateral renal denervation increased blood pressure to a similar extent as in sham-operated rats but decreased urine flow rate (p<0.05) and did not change electrolyte excretion. ET(A/)ET(B) receptor inhibition with bosentan during NO synthase inhibition in the renal denervated rats did not produce changes in urine flow rate or electrolyte excretion. NO synthase inhibition as well as concurrent NO synthase and ET(A/)ET(B) receptor inhibition did not change clearance of inulin or paraaminohippuric acid in sham-operated or renal denervated rats. These results indicate that renal sympathetic nerves play an important modulatory role in NO and endothelin induced effects on renal excretory function.     

Effect of lysophosphatidylcholine on renal hemodynamics and excretory function in anesthetized rats.

The effect of myristoyl-lysophosphatidylcholine (myristoyl-LPC) on renal hemodynamics, electrolyte and water excretion was examined over a 90 min period in sodium pentobarbital anesthetized male Sprague Dawley rats. Intravenous infusion of myristoyl-LPC at 13 +/- 3 pmol/min resulted in a small fall in systemic blood pressure, a 13% decrease in renal plasma flow without significantly altering glomerular filtration rate and produced a slightly greater excretion of sodium and water than vehicle controls. These results suggest that short term myristoyl-LPC administration can significantly alter renal function producing a weak natriuresis and diuresis which is not dependent on systemic blood pressure and renal hemodynamic changes.     

Synthesis and renal function study of Val-Asp-[Arg8]-vasopressin

A new neurohypophyseal hormone analogue, Val-Asp-[Arg⁸]-vasopressin (VAAVP), was synthesized by the stepwise solution techniques and its effect on systemic blood pressure and renal function was examined in nondiuretic Sprague-Dawley rats. Clearance of inulin was used to study glomerular filtration rate. Intravenous administration of 50 pmole/100g. b. wt. VAAVP caused diuresis and increase in urinary excretion of sodium and potassium without significant change of mean arterial blood pressure. The same dose of VAAVP caused a maximal increase infractional excretion of sodium by 80% although it also caused a slight increase of GFR. The present study suggests that VAAVP could be a natriuretic hormone which acts directly on kidney without affecting systemic circulation.     

The effect of nitrendipine on renal haemodynamics and tubular reabsorption and its neural control in anaesthetised rats with chronic renal failure.

This study examined the influence of a calcium channel antagonist, nitrendipine, on blood pressure and kidney function in a rat model of chronic renal failure. Additionally, the effects of low frequency renal nerve stimulation were studied in the presence and absence of nitrendipine. Male Wistar rats were fed a diet high in adenine for 4 weeks and then acutely anaesthetised and prepared for renal functional measurements. Blood pressure was elevated but renal blood flow and glomerular filtration rate were reduced, between 30 to 50%, urine flow and absolute sodium excretion were lower and fractional sodium excretion was two to three times higher than in normal rats. Nitrendipine (0.25 microg/kg/min i.v.) decreased blood pressure at 114+/-7 mm Hg, by 11% (P<0.05), increased left renal blood flow, at 1.3+/-0.2 ml/min(-1) g(-1), by 16% (P<0.01), and urine flow, absolute and fractional sodium excretions, by between 50-83% (all P<0.05). Renal nerves stimulation (0.7-1.3 Hz, 15V, 0.2 ms) decreased (P<0.02) left renal blood flow by 10% but had no effect on excretory variables, irrespective of nitrendipine administration. These results show that in renal failure rats the vascular and tubular responses to nitrendipine are preserved. However, the neural regulation of tubular reabsorption is abolished in this experimental model, irrespective of nitrendipine administration.     

Interaction between prostanoids and nitric oxide in the control of tubular function in rats with chronic bile duct ligation.

Recent work indicates that both nitric oxide and cyclooxygenase products play an important role in the renal alterations of liver cirrhosis, although the interactions between them have not been completely established. The purpose of this study was to assess the effect of simultaneous blockade of nitric oxide synthase and cyclooxygenase in rats with chronic bile duct ligation and in control, sham-operated rats. Compared with control rats, chronic bile duct ligation rats, 23-25 days after surgery, showed a decreased mean arterial pressure, natriuresis, and kaliuresis, without differences in glomerular filtration rate, and an increased urinary nitrite excretion. Nitric oxide synthesis inhibition by administration of N(G)-nitro-L-arginine methyl ester induced, in control rats, an increase in mean arterial pressure, without significant changes in natriuresis or glomerular filtration rate. In chronic bile duct ligation rats, N(G)-nitro-L-arginine methyl ester induced an increase in mean arterial pressure, natriuresis, and kaliuresis, together with a reduction in urinary nitrite excretion and an increase in prostaglandin E2 excretion. Cyclooxygenase inhibition with indomethacin induced in both experimental groups a marked inhibition in urinary prostaglandin E2 excretion without significant changes in Na+ or K+ excretion, and a significant increase in urinary nitrite excretion in control rats. N(G)-Nitro-L-arginine methyl ester in addition to indomethacin prevented the indomethacin-induced increase in nitrite excretion and dramatically reduced sodium excretion in both experimental groups. Thus, the present study suggests that both nitric oxide and cyclooxygenase products interact in the control of urinary sodium excretion and that each system is activated in the absence of the other one.     

Effect of angiotensin converting enzyme inhibition on renal response to atrial natriuretic factor in rats

Previous studies have shown that atrial natriuretic factor (ANF) inhibits renin secretion whereas cilazapril blocks angiotensin II generation via converting enzyme inhibition. Both agents enhance renal excretory function. The present study was conducted to test whether the renin-angiotension system is involved in the ANF-induced renal effects. ANF was administered to anesthetized normal rats (n = 16) with or without a simultaneous infusion of cilazapril. Single bolus injections of ANF at doses of 2.5 micrograms/kg and 5.0 micrograms/kg significantly decreased mean arterial blood pressure by 6.8 +/- 2.3% and 9.4 +/- 2.2%, respectively. The corresponding increases in glomerular filtration rate were 5.6 +/- 3.7% and 8.4 +/- 2.8%, in absolute sodium excretion were 55.0 +/- 18.5% and 105.2 +/- 39.9%, and in urine flow were 24.8 +/- 9.3% and 35.6 +/- 14.6%. Intravenous infusion of cilazapril (33 micrograms/kg.min) reduced the arterial blood pressure, elevated the glomerular filtration rate and increased sodium and water excretion. The corresponding doses of ANF administration during continuous infusion of cilazapril further decreased blood pressure by 8.3 +/- 1.9% and 10.9 +/- 5.4%, respectively. However, there were no significant changes in the glomerular filtration rate and sodium and water excretion. The failure of ANF to exhibit a renal effect was irrelevant to the lowering blood pressure induced by cilazapril. These results suggest that reduced endogenous angiotensin II generation contributes to the renal, but not the hypotensive, effect of ANF.     

Early altered renal sodium handling determined by lithium clearance in spontaneously hypertensive rats (SHR): role of renal nerves

The mechanism by which blood pressure rises in the SHR strain remains to be elucidated. Since the long-term changes in renal sodium tubule handling associated with genetic hypertension have not been examined in detail, we hypothesized that SHR hypertension development may result from sustained renal sympathetic nerve overactivity and consequently decreased urinary sodium excretion. To test this hypothesis, we assessed renal sodium handling and cumulative sodium balance for 10 consecutive weeks in unanesthetized renal-denervated SHR, performed prior to the start of the entire 10-week metabolic studies, and their age-matched normotensive and hypertensive controls. The present investigation shows that SHR excreted less sodium than Wistar-Kyoto (WKy) rats during the initial 3-week observation period (p <0.05). This tendency was reversed when SHR were 10-wk old. Fractional urinary sodium excretion (FENa+) was significantly lower in 3 and 6-wk-old SHR when compared with the WKy age-matched group, as follows: SHR3-wk-old: 0.33 +/- 0.09% and WKy3-wk-old: 0.75 +/- 0.1% (P <0.05); SHR(6-wk-old): 0.52 +/- 0.12% and WKy6-wk-old: 0.83 +/- 0.11%. The decreased FENa+ in young SHR was accompanied by a significant increase in proximal sodium reabsorption (FEPNa+) compared with the normotensive age-matched control group (P <0.01). This increase occurred despite unchanged creatinine clearance (CCr) and fractional post-proximal sodium excretion (FEPPNa+)in all groups studied. The decreased urinary sodium excretion response in SHR up to the age of 6 weeks was significantly eradicated by bilateral renal denervation of SHR3-wk-old: 0.33 +/- 0.09% and SHR6-wk-old: 0.52 +/- 0.12% to DxSHR 3-wk-old: 1.02 +/- 0.2% and DxSHR 6-wk-old: 0.94 +/- 0.2% (P <0.01), in renal denervated rats. The current data suggest that neural pathways may play an instrumental role on renal sodium reabsorption as result of sustained sympathetic nervous system overexcitability.     

Epoxyeicosatrienoic Acid inhibition alters renal hemodynamics during pregnancy

In this study we examined the expression of cytochrome P450 (CYP) 2C and CYP2J isoforms in renal proximal tubules and microvessels isolated from rats at different stages of pregnancy. We also selectively inhibited epoxyeicosatrienoic acid (EET) production by the administration of N-methanesulfonyl-6-(2-proparyloxyphenyl)hexanamide (MSPPOH 20 mg/kg/day iv) to rats during Days 14-17 of gestation and to age-matched virgin rats and determined the consequent effects on renal function. Western blot analysis showed that CYP2C11, CYP2C23, and CYP2J2 expression was significantly increased in the renal microvessels of pregnant rats on Day 12 of gestation. In the proximal tubules, CYP2C23 expression was significantly increased throughout pregnancy, while the expression of CYP2C11 was increased in early and late pregnancy and the expression of CYP2J2 was increased in middle and late pregnancy. MSPPOH treatment significantly increased pregnant rats' mean arterial pressure, renal vascular resistance, and sodium balance but significantly decreased renal blood flow, glomerular filtration rate, and urinary sodium excretion, as well as fetal pups' body weight and length. In contrast, MSPPOH treatment had no effect on renal hemodynamics or urinary sodium excretion in age-matched virgin rats. In pregnant rats, MSPPOH treatment also caused selective inhibition of renal cortical EET production and significantly decreased the expression of CYP2C11, CYP2C23, and CYP2J2 in the renal cortex, renal microvessels, and proximal tubules. These results suggest that upregulation of renal vascular and tubular EETs contributes to the control of blood pressure and renal function during pregnancy.     

Propranolol induces acute natriuresis by beta blockade and dopaminergic stimulation.

dl-Propranolol (0.8-1.6 mg/kg - h for 1 h) produced a transient two- to three-fold increase in sodium excretion in nondiuretic rats infused with Pitressin and aldosterone and in water diuretic rats. Sodium excretion increased more in rats depleted of renin by chronic Doca and salt administration than in rats maintained on a low salt diet. An angiotensin inhibitor (1,sarcosine-8,valine angiotensin II) decreased sodium excretion. Therefore the natriuresis was not mediated by antidiuretic hormone, aldosterone, or renin-angiotensin. d-Propranolol did not produce a natriuresis. Prior treatment with phenoxybenzamine did not prevent the natriuretic response but chlorisondamine pretreatment did. The natriuresis is produced by beta blockade and requires post ganglionic nerve function but is independent of alpha receptors. dl-Propranolol decreased heart rate and cardiac output but systemic pressure did not fall and renal blood flow increased. This suggests a dopamine-mediated renal vasodilation and natriuresis. Haloperidol and pimozide, both dopamine blocking agents with minimal beta blocking effects, prevented the natriuretic response. We conclude that propranolol may increase sodium excretion directly by blocking beta receptors in the distal nephron and indirectly by dopamine-mediated renal vasodilation.     

Antihypertensive and bilateral renal responses to diuretics in 2-kidney, 1-clip Goldblatt hypertensive rats

Experiments were conducted to assess the effect of furosemide or amiloride alone and a combination of both agents on each kidney in anesthetized 2-kidney, 1 clip Goldblatt hypertensive rats (n = 25). Intravenous infusion of furosemide alone (1.02 mg/kg.hr) significantly reduced the blood pressure by 14 +/- 5 mmHg. There were 6- to 10-fold increases in water, absolute sodium and fractional sodium excretions and a 2-fold increase in potassium excretion in the nonclipped kidney. A smaller but significant increase in the excretory function was also observed in the clipped kidney. There was no significant change in GFR of both kidneys. Indomethacin pretreatment (2 mg/kg) failed to significantly alter the vasodepressor and renal responses to furosemide in both hypertensive and normal rats. Removal of the renal artery clip from the hypertensive rats reduced the blood pressure by 12 +/- 3 mmHg and enhanced the function of the ipsilateral, unclipped kidney. Subsequent administration of furosemide further increased the excretory response. Administration of amiloride alone (2.4 mg/kg.hr) or with furosemide into hypertensive rats reduced the arterial pressure and increased excretion rates of urine flow and urinary sodium. Potassium excretion rate decreased bilaterally in amiloride treated rats but did not alter significantly in rats which received a combination of amiloride and furosemide. These results indicate that diuretics ameliorate the excretory function of both the stenotic kidney and the nonstenotic kidney and that the improvement of the kidney function is independent of prostaglandin. Furthermore, removal of the stenosis accentuates the beneficial effect of diuretics on the kidney.     

Inhibition of heme oxygenase augments tubular sodium reabsorption

Heme oxygenase (HO) catalyzes the degradation of heme to form iron, biliverdin, and carbon monoxide (CO). The vascular actions of CO include direct vasodilation of vascular smooth muscle and indirect vasoconstriction through inhibition of nitric oxide synthase (NOS). This study was performed to examine the effects in the kidney of inhibition of heme oxygenase alone or combined with NOS inhibition. Chromium mesoporphyrin (CrMP; 45 μmol/kg ip), a photostable HO inhibitor, was given to control rats and N(G)-nitro-l-arginine methyl ester (l-NAME)-treated hypertensive rats (50 mg·kg?1·day?1), 12 h, 4 days). In control animals, CrMP decreased CO levels, renal HO-1 levels, urine volume, and sodium excretion, but had no effect on arterial pressure, renal blood flow (RBF), plasma renin activity (PRA), or glomerular filtration rate (GFR). In l-NAME-treated hypertensive rats, CrMP decreased endogenous CO and renal HO-1 levels and had no effect on arterial pressure, RBF, or GFR but decreased sodium and water excretion in a similar manner to control animals. An increase in PRA was observed in untreated rats but not in l-NAME-infused rats, indicating that this effect is associated with an absent NO system. The results suggest that inhibition of HO promotes water and sodium excretion by a direct tubular action that is independent of renal hemodynamics or the NO system.     

Overexpression of HIF Prolyl‐Hydoxylase‐2 transgene in the renal medulla induced a salt sensitive hypertension

Renal medullary hypoxia‐inducible factor (HIF)‐1α and its target genes, such as haem oxygenase and nitric oxide synthase, have been indicated to play an important role in the regulation of sodium excretion and blood pressure. HIF prolyl hydroxylase domain‐containing proteins (PHDs) are major enzymes to promote the degradation of HIF‐1α. We recently reported that high salt intake suppressed the renal medullary PHD2 expression and thereby activated HIF‐1α‐mediated gene regulation in the renal medulla in response to high salt. To further define the functional role of renal medullary PHD2 in the regulation of renal adaptation to high salt intake and the longer term control of blood pressure, we transfected PHD2 expression plasmids into the renal medulla in uninephrectomized rats and determined its effects on pressure natriuresis, sodium excretion after salt overloading and the long‐term control of arterial pressure after high salt challenge. It was shown that overexpression of PHD2 transgene increased PHD2 levels and decreased HIF‐1α levels in the renal medulla, which blunted pressure natriuresis, attenuated sodium excretion, promoted sodium retention and produced salt sensitive hypertension after high salt challenge compared with rats treated with control plasmids. There was no blood pressure change in PHD2‐treated rats that were maintained in low salt diet. These results suggested that renal medullary PHD2 is an important regulator in renal adaptation to high salt intake and a deficiency in PHD2‐mediated molecular adaptation in response to high salt intake in the renal medulla may represent a pathogenic mechanism producing salt sensitive hypertension.     

Cadmium as hypertensive agent. Effect on ion excretion in rats

1. Sodium, K and Cl excretion and changes in blood volume were studied after parenteral injection of Cd²⁺ (1 μmol/100g body weight) in intact and adrenalectomized rats.2. The final systolic arterial pressure and mean arterial pressure of adrenalectomized rats increase significantly after Cd²⁺ administration compared with values from control group and initial systolic arterial pressure of each group.3. Cadmium administration induced a significant inhibition of Na⁺ excretion in urine and a decrease in blood volume in ADX rats compared with values from control or sham operated rats.4. The possibility that hypertension induced by Cd may be explained by inhibition of Na excretion and changes in blood volume is discussed.