Lovastatin protects mithochondrial and renal function in kidney ischemia-reperfusion in rats / Lovastatina protege a função renal e mitocondrial na isquemia/reperfusão renal em ratos

PURPOSE: To investigate the effect of lovastatin on renal ischemia followed by reperfusion. METHODS: Thirty one Wistar rats submitted to left renal ischemia for 60 minutes followed by contralateral nephrectomy were divided into two groups: A (n =17, control, no treatment), and B (n=14, lovastatin 15 mg/kg/day p.o. ten days before ischemia). The animals were sacrificed at the end of ischemia, after 24 hours and at seven days after reperfusion. Survival, serum urea and creatinine levels and renal mitochondrial function were evaluated. RESULTS: Mortality was 29.4% in group A and 0.7% in group B. Urea and creatinine levels were increased in both groups, but the values were significantly lower in group B. Mitochondrial function showed decoupling in 83.4% of group A, as opposed to 38.4/% of group B. CONCLUSIONS: The result shows a protective action of renal function by lovastatin administered before ischemia/reperfusion. Since most of the mitochondrial fraction presented membranes with the ability to maintain ATP production in group B, stabilization of the mitochondrial membrane should be considered as part of the protective action of lovastatin on renal function in ischemia/reperfusion.

OBJETIVO: Investigar a ação da lovastatina na isquemia renal seguida de reperfusão. MÉTODOS: Trinta e um ratos Wistar submetidos à isquemia renal esquerda durante 60 minutos, seguida da nefrectomia contralateral, foram distribuídos em dois grupos: A (n=17, controle, sem tratamento) e B (n=14, recebendo 15 mg/Kg/dia de lovastatina via oral), durante os dez dias que antecederam a isquemia. Os animais foram mortos ao final da isquemia, e com 24 horas e sete dias após a reperfusão. Foram avaliadas a sobrevida, os valores séricos de uréia e creatinina e a função mitocondrial renal. RESULTADOS: A mortalidade foi 29,4% no grupo A e 0,7% no grupo B. Os níveis de uréia e creatinina elevaram-se nos dois grupos, mas foram significativamente menores no grupo B. No grupo A a função mitocondrial renal ficou desacoplada em 83,4% dos ensaios, enquanto que no grupo B isto ocorreu em apenas 38,4% dos ensaios. CONCLUSÕES: Os resultados mostram que a administração de lovastatina antes do episódio de isquemia protege a função renal. No grupo B, como a maior parte da fração mitocondrial isolada apresentou função acoplada à produção de ATP, deve-se também considerar a estabilização da membrana mitocondrial como parte da ação protetora da lovastatina na função renal durante isquemia e reperfusão.

Efeitos da metformina na disfunção endotelial da circulação renal induzida pela hiperglicemia em coelhos não diabéticos / Effects of metformin on endothelial dysfunction of the renal circulation resulting from acute hyperglycemia in non-diabetic rabbits

OBJETIVO: Avaliar o efeito da metformina (Met) na disfunção endotelial da circulação renal de coelhos não diabéticos induzida por concentrações de glicose usualmente observadas em pacientes com diabetes tipo 2 (DM2) em tratamento ambulatorial. METODOLOGIA: Rins isolados de coelhos não diabéticos foram expostos por 3h a concentrações normais (100mg/dl) e elevadas (270mg/dl) de glicose na presença ou ausência de Met (100µM). Os níveis de glicose utilizados correspondem à mediana da glicemia pós-prandial (270mg/dl) obtida 2h após o café da manhã em 780 pacientes com DM2 atendidos em nosso serviço. A reatividade vascular (RV) dependente do endotélio (DE) foi avaliada com acetilcolina (ACh) e independente do endotélio (IE) com nitroprussiato de sódio (NPS). RESULTADO: Houve redução significativa na vasodilatação DE no grupo com infusão elevada de glicose em comparação ao controle (redução máxima na pressão de perfusão de respectivamente 25 ± 3 vs. 41 ± 3 por cento; p< 0,01). No grupo de infusão com concentrações elevadas de glicose associada à infusão contínua de Met, a resposta vasodilatadora DE foi restaurada sem haver diferença significativa com o grupo controle (redução da pressão de perfusão respectivamente de 43 ± 1,5 por cento e 41 ± 3 por cento, p> 0,05). A Met não alterou a vasodilatação induzida pela ACh na presença de níveis normais de glicose. Finalmente, a vasodilatação renal induzida por NPS não foi modificada pela infusão conjunta de glicose e Met. CONCLUSÃO: Níveis de glicose observados em pacientes com DM2 em tratamento ambulatorial são capazes de provocar alterações agudas na RV no modelo experimental estudado, sendo estes efeitos totalmente abolidos pela Met. Os mecanismos envolvidos nesta ação protetora da Met merecem investigações específicas.

Effects of Magnesium Sulfate on Supraceliac Aortic Unclamping in Experimental Dogs

Intravascular administration of magnesium (Mg) causes vasodilation and increases renal blood flow. The aim of this study was to investigate the renal effect of Mg following unclamping of the supraceliac aorta. Mongrels were divided into two groups, control (group C, n=7) and Mg group (group Mg, n=7). In group Mg, 30 mg/kg MgSO4 was injected as a bolus immediately prior to unclamping the supraceliac aorta and thereafter as an infusion (10 mg/kg/hr). The group C received an equivalent volume of saline solution. Systemic hemodynamics, renal artery blood flow, renal cortical blood flow (RCBF), renal vascular resistance, and renal function were compared. Following the aortic unclamping, cardiac output and RCBF were less attenuated, and the systemic and renal vascular resistance was elevated to a lesser degree in the group Mg compared to the group C. There was no significant difference in the plasma renin activity, serum creatinine and Cystatin-C between the two groups. The present study shows that Mg infusion improves systemic hemodynamics and RCBF after aortic unclamping. However, we did not observe any improvement in renal function when Mg was administered after supraceliac aortic unclamping.

Acute hypercalcemia-induced hypertension: the roles of calcium channel and alpha-1 adrenergic receptor.

OBJECTIVE: To study the mechanism(s) of acute hypercalcemia-induced hypertension in dogs. MATERIAL AND METHOD: Adult male mongrel dogs were intravenously infused with: 1) normal saline solution, 2) CaCl2 solution, 3) CaCl2 + calcium channel blocker (verapamil), 4) CaCl2 + selective alpha-1 adrenergic receptor blocker (prazosin), or 5) CaCl2 + verapamil + prazosin. Either verapamil or prazosin treatment was started at forty minutes before CaCl2 infusion and then was co-administered throughout the three-hour experimental period. Systemic and renal hemodynamics parameters were determined. RESULTS: Infusion of CaCl2 caused increases in mean arterial blood pressure (p < 0.01), total peripheral resistance (p < 0.001), and renal vascular resistance (p < 0.001). Prior treatment with either verapamil or prazosin lowered baseline blood pressure (p < 0.01) and could prevent hypercalcemia-induced hypertension. This occurred accompanying regaining to near normal values of abnormal systemic hemodynamics parameters. Combination of both drugs showed more profound effects, particularly on lowering renal vascular resistance. CONCLUSION: Acute hypercalemic hypertension is caused by an increase in vascular resistance mediated via the direct effect of calcium on vascular smooth muscle as well as the indirect effect of calcium induced hypercatecholaminemia. The stimulatory effect of hypercalcemia on renal vascular resistance is more prominent than that on peripheral vascular resistance.

Mechanism of action of the cisapride-induced vasodilatation in renal vasculature of rat.

BACKGROUND & OBJECTIVES: Cisapride is a prokinetic agent with cholinomimetic and 5-HT4 receptor agonistic properties. It has been proposed that cisapride-induced hypotension is partly mediated by cholinergic system. The aim of this study was to investigate the mechanism of cisapride-induced dilatation in the rat isolated perfused kidney. METHODS: Left kidneys of Wistar rats were isolated and perfused via renal artery and the perfusion pressure was recorded. Cisapride given as bolus injections (10(-10)-3x10(-5) mol/l) produced dose-dependent dilatations. Perfusion of antagonists or inhibitors was started 30min before the onset of phenylephrine perfusion. RESULTS: 4-Diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP; blocker of M1, and M3 muscarinic receptors; 10(-7) mol/l) inhibited the responses to the lower doses of cisapride while, dextran (10(-7) mol/l), glibenclamide (inhibitor of ATP-sensitive potassium channels; 10(-5) mol/l) and capsaicin (for neuromediator depletion; 10(-6) mol/l) inhibited those to the higher doses. Dilatations induced by most of the doses of cisapride were inhibited by atropine (non-selective muscarinic receptor antagonist; 10(-7) mol/l), methylene blue (inhibitor of soluble guanylate cyclase; 10(-5) mol/l), 1H-[1,2,4] oxadiazolo-[4,3-a] Quinoxalin-1-One (ODQ; inhibitor of soluble guanylate cyclase; 10(-5) mol/l), and NG-nitro-L-arginine (L-NOARG; NO synthase inhibitor; 10(-4) mol/l). Inhibition induced by L-NOARG was reversed by L-arginine (10(-3) mol/l). The dilatation induced by cisapride was not affected by GR113808 (5-HT4 receptor antagonist; 10(-7) mol/l) and indomethacin (cyclooxygenase inhibitor; 10(-5) mol/l). INTERPRETATION & CONCLUSION: The findings indicated that cisapride caused vasodilatation through the release of nitric oxide (NO) as a result of the release of a substance acting on muscarinic receptors, in the renal vascular bed of the rat. The role of 5-HT4 receptors and prostanoids seemed unlikely.

Role of nitric oxide in the pathogenesis of diabetic nephropathy in streptozotocin-induced diabetic rats

OBJECTIVES: Several reports suggest that enhanced generation or actions of nitric oxide (NO) have been implicated in the pathogenesis of glomerular hyperfiltration and hyperperfusion that occurs in early diabetes. However, the precise role of altered NO generation in the pathogenesis of diabetic nephropathy is unclear. The present study was aimed at investigating the role of nitric oxide in the pathogenesis of glomerular hyperfiltration and hyperperfusion in streptozotocin-induced diabetic rats. METHODS: To evaluate the role of NO in diabetic hyperfiltration, we measured plasma and urine concentrations of NO2-/NO3-, stable metabolic products of NO and protein expressions of three isoforms of nitric oxide synthase (NOS) in streptozotocin-induced diabetic rats. We also investigated renal hemodynamic changes, such as glomerular filtration rate (GFR) and renal plasma flow (RPF), in responses to acute and chronic administration of NO synthesis inhibitor, nitro-L-arginine methyl ester (L-NAME), in diabetic and control rats. RESULTS: Diabetic rats exhibited significantly elevated plasma and urinary NO2-/NO3- levels at 28 days after streptozotocin injection, and total excretion of NO2-/NO3- was approximately five-fold higher in diabetic rats than controls. Insulin and L-NAME treatment prevented the increases in plasma and urinary NO2-/NO3- concentrations in diabetic rats, respectively. The three isoforms of NOS (bNOS, iNOS, and ecNOS) were all increased in the renal cortex, whereas they remained unaltered in the renal medulla at day 28. GFR and RPF were significantly elevated in diabetic rats, and acute and chronic inhibition of NO synthesis by L-NAME attenuated the renal hemodynamic changes (increases in GFR and RPF) in diabetic rats, respectively. CONCLUSIONS: NO synthesis was increased due to enhanced NOS expression in diabetic rats, and chronic NO blockade attenuated renal hyperfiltration and hyperperfusion in diabetic rats. In addition, diabetic rats exhibited enhanced renal hemodynamic responses to acute NO inhibition and excreted increased urinary NO2-/NO3-. These results suggest that excessive NO production may contribute to renal hyperfiltration and hyperperfusion in early diabetes.

Renal vascular and excretory resistance to atrial natriuretic peptide in pre-cirrhotic, bile-duct ligated rats

Renal response to atrial natriuretic peptide in chronic cholestasis was studied in anaesthetized rats and in their isolated perfused kidneys. Cholestasis was induced by bile duct section after ligature, while controls were sham operated. Three weeks after surgery, cholestatic rats showed moderate arterial hypotension, elevated diuresis and no differences in urinary sodium, glomerular filtration rate (GFR) and fractional sodium excretion (FENa), when compared to controls. Isolated kidneys of cholestatic rats had equal basal diuresis and less natriuresis than the controls. Cholestatic rats presented blunted natriuretic and diuretic responses to iv injections of atrial natriuretic peptide (ANP 0.5 microgram), associated with reduced increments in GFR and FENa, when compared with controls. Similarly, the diuretic-natriuretic response of isolated kidneys to ANP (3.5 x 10(-9) M) was greatly attenuated in this group. ANP did not increase perfusion pressure in cholestatic rats, as it did in controls. These results indicate that animals with chronic cholestasis present refractoriness to ANP, which might be mediated by a direct impairment at the renal vascular and tubular sites for ANP action

Intrarenal hemodynamic abnormality in severe form of glomerulonephritis: therapeutic benefit with vasodilators.

Intrarenal hemodynamic and tubular function has been assessed in 16 patients who presented clinically with hypertension, hematuria and severe renal functional impairment. Twelve of these 16 patients had histopathologic classification as DPGN (3 cases), MPGN (3 cases) and FSGS (6 cases). The initial assessment of intrarenal hemodynamics in 11 patients revealed strikingly increased afferent (RA) and efferent arterioles (RE), filtration fraction (FF), intraglomerular capillary hydrostatic pressure (PG), whereas, there was marked reduction in renal plasma flow (RPF), in ultrafiltration coefficient (KFG) and in glomerular filtration rate (GFR). Tubular transporting defect as being reflected by enhanced fractional excretions of solutes was also observed. Both enhanced TXB2 production and diminished PGI2 may be in part responsible for the marked reduction of RPF and elevated intrarenal resistance. In light of the preceding intrarenal hemodynamics alteration, therapeutic intervention with vasodilators consisting of dipyridamole, calcium channel blocker and angiotensin convertase inhibitor has been accomplished with clinical improvement in glomerular and tubular functions following the improvement in intrarenal hemodynamics. Thus, this abnormal intrarenal hemodynamics renders a supportive view of the hemodynamically mediated glomerulo-tubulo-interstitial injury to be central to the pathogenetic mechanism.

Acute effects of dobutamine and dopamine on renal and respiratory functions in patients on prolonged mechanical ventilation

Its is known that positive pressure mechanical ventilation (PPMV) decreases diuresis and increases extravascular water, thereby impairing pulmonary gas exhange. Sympathomimetic amines are commonly used to relieve these effects. To compare the effects of dobutamine (DT) and dopamine (DP) on renal and pulmonary function, we studied 30 patients submitted to continuous PPMV for a least 72 h. All were in stable hemodynamic conditions.patients had pulmonary insufficiency of different etiology. The drugs were randomly administered by continuous intravenous infusion at the dose of 4 to 6 *g kg-1 min-1 for 3 h. An interval of 60 min was allowed to elapse between treatments. A significant increases in arterial pressure and heart rate occurred with both drugs (P,0.05). DP increased urinary flow by 93.7% (1.6ñ0.1 to 3.1 ñ0.4 ml/min; P,0.05) and Na excretion fraction (NaEF) by 35.5% (P,0.05).In contrast, DT reduced NaEF by 58.9%(P,0.05) and had effect on urinary flow. Neither drug altered cretinine clearance.The alveolo-arterial O2 difference (a-aO2D), which was 370ñ20 mmHg during the control period, increased to 394 ñ 20 mmHg after DP and decreased to 355 ñ 22 mmHg after DT, the difference being statistically significant (P,0.05). Pulmonary shunt (%) and the venous pO2 (mmHg) did not change during the infusion of DP or DT.In conclusion, an acute increase in salt and water excretion does not necessarily lead to an immediate reduction in pulmonary "shunt". DT deserves further investigation since it may increase paO2 in the absence of ventricular failure

Functional and histopathological renal changes induced in rats by Bothrops jararaca venom

1. Ninety-eight female rats were injected with 14 microng/g B. jararaca venom intraperitoneally to determine functional and histopathological renal changes. 2. Glomerular filtrataion rate, renal plasma flow, filtration fractional, osmolar clearance, water transportation in collecting ducts, urinary sodium excretion, fractional sodium excretion, albuminuria, urinalysis, plasma creatinine, urinary output and mean arterial pressure were sstudied before and 24 and 48 h after venom administration. Light microscope examination of the kidneys was carried out in another group of rats before and 2,5 and 24h after venom administration. 3. Treated animals developed acute renal failure characterized by a decrease in glomerular filtration rate, osmolar clearance, and fractionalal and urinary sodium excretion, and by an increase in plasma creatinine. There was also a decrease in renal plasma flow and mean arterial pressure. Histopathological examination of the kidneys indicated mild proliferation of the mesangial matrix and degenerative changes of the tubules characterized by loss of brush border and cytoplasmic vacuolation. 4. the hemodynamic changes probably played and important role in the pathogenesis of the functional and histopathological renal changes developed by the animals after venon injection

Probable interrelación de las prostaglandinas con los efectos natriurético y vasodilatador renal de la furosemida / Probable interrelation of prostaglandins with the natriuretic effects and renal vasodilator of furosemide

La furosemida es una droga natriurética y vasodilatadora renal que además, tiene la capacidad de aumentr los niveles de prostaglandinas renales. La relación entre los efectos renales de la furosemida y su capacidad de estimular al sistema de las prostaglandinas es controvertida. En el presente trabajo se estudió dicha interrelación mediante un inhibidor de la síntesis de prostaglandinas, la indometacina. En los perros pretratados con indometacina la furosemida no aumentó el flujo plasmático renal efectivo (depuración plasmática de Hippuran 131I), pero sí lo hizo en los animales no tratados con indometacina. En cuanto al efecto natriurético de la furosemida, si bien la indometacina redujo la excreción fraccional de Na, la administración posterior de la furosemida la elevó a un valor similar al obtenido por la infusión de furosemida en los perros no tratados con indometacina. En conclusión el presente trabajo sugiere que el efecto vasodilatador renal de la furosemida, pero no el natriurético, requiere para producirse una síntesis normal de prostaglandinas

The effects of sodium orthovanadate, noradrenaline and angiotensin II on isolated perfused rat kidney glomerular-tuft diameter.

The effects of sodium orthovanadate, angiotensin II (A II) and noradrenaline (NA) were studied on the isolated perfused rat kidney (IPRK) and on the diameter of the glomerular capsule and tuft. Vanadate (4.5 microM), A II (20 nM) and NA (17.3 microM) increased the total resistance of the IPRK. There was a simultaneous increase in glomerular filtration rate with vanadate and A II, but a decrease with NA. The glomerular tuft/capsule diameter ratio decreased significantly from 0.85 (control) to 0.81, 0.81 and 0.78 for vanadate, A II, and NE treated kidneys, respectively. The decrease in ratio was associated with an increase in diameter of the glomerular capsule for A II and NE. This finding accompanied with simultaneous rise in TPR and GFR in the case of vanadate and A II, indicates that the post capillary efferent arteriolar vasoconstriction is a component in the mechanism of action with A II and vanadate. Evidence for such a component is less clear for NA because GFR decreases and TPR increases. Vanadate may affect both with a predominance on the efferent arteriole. The data indicate that histological measurements of glomerular size lead to a better understanding of the mechanisms of vasoactive drugs acting on the kidney.