L-arginine reduces tubular cell injury in acute post-ischaemic renal failure

Background. The pathophysiology of renal ischaemia, resulting in tubular cell injury and leading to acute renal failure (ARF), remains unclear. An ever-increasing number of investigations focus on a possible role of nitric oxide (NO) in regulating circulation during ARF. In this context, we investigated the influence of chronic stimulation or inhibition of NO synthesis, or both, on haemodynamic parameters, histology and plasma renin activity (PRA) after ischaemia-reperfusion injury of rat kidneys. Methods, Experiments were performed on adult, male Wistar rats. Before induction of ARF, a group of animals was treated with a NO synthesis inhibitor (L-NAME) and another group was treated with a precursor of NO synthesis (L-arginine). The animals received those substances for 4 weeks. Control groups received the same amount of tap water for 4 or 8 weeks and were divided into groups with ARF (4 weeks-ARF group and 8 weeks-ARF group) and a sham-operated group. Another group of rats was treated first with L-NAME and then with L-arginine in their drinking water, for 4 weeks for each of these two substances. All parameters were evaluated 24 h after the induction of ischaemic ARF or the sham operation. Results, Our results show that such long-term stimulation of NO release by L-arginine improved renal haemodynamics in the ischaemic form of ARF. Renal blood Bow (RBF) increased by 96% in the L-arginine-treated rats with ARF compared with the group with ARF alone. Inhibition of NO synthesis worsens renal haemodynamics after ARF. However, this aggravation can be reversed by L-arginine. The rate of water reabsorption was reduced in all groups with ARF, but this reduction was least in the group treated with L-arginine. The rate of Na+ reabsorption was reduced in all groups 24 h after renal ischaemia, but a significant decrease was observed after the inhibition of NO synthesis. Histological examination of the kidney specimens showed that morphological changes were least in the rats treated with L-arginine, when compared with all other groups with ARF. Nevertheless, the lesions were most prominent in the L-NAME + ARF group. In this group, the areas of corticomedullar necrosis were more widespread in comparison with other groups, especially the L-arginine group where only swelling of the proximal tubular cells was observed. Treatment with L-NAME was not accompanied by any significant alteration in the plasma concentration of angiotensin I (ANG I), while in the group treated with L-arginine ANG I had a tendency to decrease. Conclusions. Acute post-ischaemic renal failure may be alleviated by administering the NO substrate (L-arginine). NO acts cytoprotectively on tubular epithelial cells in ischaemia-reperfusion injury of rat kidney. Evidence of this comes from both histopathological findings and increased tubular water and sodium reabsorption. However, inhibition of NO synthesis (provoked by L-NAME) worsens renal haemodynamics and aggravates morphological changes after ARF. These aggravations can, however, be reversed by L-arginine

Relative roles of endothelin-1 and angiotensin II in experimental post-ischaemic acute renal failure

Background. The relative roles of endothelin (ET)-1 and angiotensin (ANG) II in post-ischaemic acute renal failure (ARF) have not been fully established so far. With the aim of contributing to this goal, we assessed in this study the effect of ANG II and ET-1 blockade on the course of post-ischaemic-ARF. Methods. Anaesthetized Wistar rats received i.v. either bosentan (a dual ET receptor antagonist; 10 mg/kg body weight) or losartan [ANG II type 1 (AT(1)) receptor antagonist; 5 or 10 mg/kg body weight] or both, 20 min before, during and 20 min after ischaemia. Rats in the control group received the vehicle via the same route. Survival and renal function were monitored up to 8 days after the ischaemic challenge, while haemodynamic parameters were measured 24 h after ARF. Results. Our results demonstrate that bosentan treatment has a more beneficial effect on experimental ARF than losartan. The survival rate was remarkably higher in bosentan-treated rats than in both rat groups treated with losartan. In the ARF group treated with bosentan, renal blood flow (RBF) was increased by 129% in comparison with the untreated ARF group, whereas in the losartan-treated ARF groups, RBF was only similar to35 or 38% higher than in control ARF rats. The glomerular filtration rate was markedly higher in bosentan-treated rats than in all other ARF groups on the first and second day after ischaemia. Tubular cell injury was less severe in bosentan-treated rats than in the control ARF rats, but in losartan-treated groups it was similar to that in the ARF group. Concurrent blockade of both ET and AT(1) receptors did not improve ARF because this treatment induced a marked decrease in blood pressure. Conclusions. These results suggest that ET-1 blockade is more efficient in improving the early course of post-ischaemic renal injury than ANG II inhibition, and that blockade of ET-1 might be effective in prophylaxis of ischaemic ARF

Reduced progression of adriamycin nephropathy in spontaneously hypertensive rats treated by losartan

Background. The aim of the study was to investigate the antihypertensive effects of angiotensin II type-1 receptor blocker, losartan, and its potential in slowing down renal disease progression in spontaneously hypertensive rats (SHR) with adriamycin (ADR) nephropathy. Methods. Six-month-old female SHR were randomly selected in six groups. Two control groups (SH(6), SH(12)) received vehicle. Groups ADR(6), ADR+LOS(6) and ADR(12), and ADR+LOS(12) received ADR (2 mg/kg/b.w. i.v.) twice in a 3-week interval. Group ADR+LOS(6) received losartan (10 mg/kg/b.w./day by gavages) for 6 weeks and group ADR+LOS(12) for 12 weeks after second injection of ADR. Animals were killed after 6 or 12 weeks, respectively. Haemodynamic measurements were performed on anaesthetized animals, blood and urine samples were taken for biochemical analysis and the left kidney was processed for morphological studies. Results. Short-term losartan treatment, besides antihypertensive effect, improved glomerular filtration rate and ameliorated glomerulosclerosis resulting in decreased proteinuria. Prolonged treatment with losartan showed further reduction of glomerulosclerosis associated with reduced progression of tubular atrophy and interstitial fibrosis, thus preventing heavy proteinuria and chronic renal failure. Losartan reduced uraemia and increased urea clearance in advanced ADR nephropathy in SHR. Histological examination showed that losartan could prevent tubular atrophy, interstitial infiltration and fibrosis in ADR nephropathy. Conclusion. Losartan reduces the rate of progression of ADR-induced focal segmental glomerulosclerosis to end-stage renal disease in SHR

The mechanisms of the antihypertensive action of heparin in spontaneously hypertensive rats

The aim of this study was to examine the effects of heparin on blood pressure in spontaneously hypertensive rats (SHR). Chronic subcutaneous administration of heparin consistenly lowers blood pressure in hypertensive rats. This antihypertensive effect is related at least in part to a concomitant decrease in hematocrit. Spontaneously hypertensive rats were treated with subcutaneous heparin (700U/day) for 6 weeks. At the end of this period we determined cardiac output and total peripheral resistance. Weekly determinations of systolic blood pressure (tail-cuff) and hematocrit were done. Peripheral plasma renin activity, plasma aldosterone, plasma prostaglandins, and urinary kallikrein were measured. Blood pressure responses of acute and chronic heparin treatment to vasoconstrictor substances, including angiotensin I, angiotensin II and norepinephrine, were determined. Heparin produced a significant decrease in hematocrit and a parallel decrease in blood pressure. A significant increase in plasma renin activity was found in heparin treated SHR, but plasma aldosterone level significantly decreased. Plasma prostaglandins and urinary kallikrein levels were not different among the groups. The blood pressure responses to vasoactive substances were similar among the heparin treated and control groups. The results suggest that a reduced aldosterone level contributes to the antihypertensive mechanism of heparin

Nitric Oxide Supplementation in Postischemic Acute Renal Failure: Normotension Versus Hypertension

Nitric oxide (NO) has been suggested to play a pivotal role in ischemic acute renal failure (ARF) but there are controversies about its role in hypertensive and non hypertensive ischemic kidney. Multiple strategies including administration of exogenous NO donors have been shown to protect the kidney against toxic or ischemic injury, suggesting endothelial dysfunction as impaired NO generation due to ischemia. However, in postischemic kidney, NO derived from inducible nitric oxide synthase (iNOS) has been considered to enhance the tissue damage while iNOS inhibition decreased the tubular damage. It is well known decrease in basal production of NO in essential hypertension and that long lasting hypertension damages medium size and small-size blood vessels, therefore predisposes nephroangiosclerosis patients to ARF. Many studies have shown that long term stimulation of NO release in normotension improves renal haemodymnamics and kidney function in ischemic form of ARF. On the other hand, there are studies that have shown that NO synthesis stimulation has no effect or even worsens tubular damage in postischemic hypertensive kidney. Therefore, it seems likely that NO supplementation plays different role in postischemic renal damage development, beneficial in well preserved normotensive kidney and limited in postischemic hypertensive kidney due to disturbed tubuloglomerular response, vasoreactivity and kidney vascular structure

Uticaji blokade endotelinskih receptora na TDK postishemične eksperimentalne akutne bubrežne insuficijencije

The main goal of this study was to examine the efficacy of endothelin (ET) receptor blockade in the course of experimental postischaemic acute renal failure (ARF). Experiments were performed on male adult Wistar rats. The right kidney was removed before renal ischaemia (by clamping the left renal artery for 45 minutes). The experimental groups received either bosentan (ETA/ETB-receptor antagonist; 10mg/kg/b.m) or vehicle (saline) in the femoral vein 20 minutes before, during and 20 minutes after ischaemia. All parameters were measured 24 hours after reperfusion. The obtained results clearly demonstrate that bosentan yields beneficial effect on ARF. Bosentan improves both renal haemodynamic and functional parameters after ARF, while lesions of tubular epithelial cells, the principal targets of injury in ARF are less serious in bosentan-treated rats than in the control ARF rats. This strongly suggests that endothelins have an important role in the development of ischaemia/'reperfusion injury and contributes to the promotion of bosentan in future clinical practice.Uticaji blokade receptora endotelinskih peptida na tok postishemične eksperimentalne akutne bubrežne insuficijencije (ABI), predstavljali su glavni cilj naših istraživanja. Eksperimenti su izvođeni na odraslim pacovima Wistar soja. Urađena je netrektomija desnog bubrega, a leva bubrežna arterija je klemovana u trajanju od 45 minuta. Eksperimentalne grupe su prekofemoralne vene primale Hi bpsentan (antagonist ETA/ETB-receptora) Hi fiziološki rastvor, kontinuirano, 20 minuta pre, tokom i 20 minuta posle perioda ishemije. Svi parametri su mereni 24 časa nakon perioda ishemije. Dobijeni rezultati jasno pokazuju da bozentan iskazuje povoljne uticaje na tok ABI. Bozentan poboljšava bubrežne hemodinamske i funkcionalne parametre, a lezije epitelnih ćelija tubula (glavnih mesta oštećenja u ABI), su manje izražene kod pacova tretiranih bosentanom, negp kod kontrolnih životinja sa ABI. Sve to navodi na zaključak da endotelini imaju uticaja u razvoju ishemično/reperfuzionih oštećenja u ABI i da bosentan poseduje potencijal za primenu u kliničkoj praksi