Preferential COX-2 inhibitor, meloxicam, compromises renal perfusion in euvolemic and hypovolemic rats

Nonsteroidal anti-inflammatory drugs can impair renal perfusion through inhibition of cyclooxygenase (COX)-mediated prostaglandin synthesis. We investigated the influence of the preferential COX-2 inhibitor, meloxicam (MELO), on renal hemodynamics in eu- and hypovolemic rats compared to the nonselective COX inhibitor indomethacin (INDO). The hypovolemic state was obtained in rats by three daily injections of furosemide (2 mg/kg i.p.) followed by a sodium-deficient diet for 7 days. In euvolemic rats (n = 6) neither INDO (5 mg/kg i.v.) nor MELO (1 or 2 mg/kg i.v.) influenced mean arterial blood pressure (MAP) or impaired renal (RBF) and cortical blood flow (CBF). Medullary blood flow (MBF) decreased after INDO (18%; p<0.05), and dose-dependently after MELO (1 mg, 10%; 2 mg, 18%; p<0.05). In hypovolemic rats (n = 6) INDO and MELO had no effect on MAP. RBF and CBF were reduced after INDO (11 or 20%; p<0. 05), but showed no changes after MELO. INDO induced a decrease in MBF (22%; p<0.05) which was less pronounced after MELO (12%; p <0.05). In conclusion the preferential COX-2 inhibitor MELO compromized renal perfusion in the outer medulla both in eu- and hypovolemic animals.     

Effects of tezosentan, a dual endothelin receptor antagonist, on the cardiovascular and renal systems of neonatal piglets during endotoxic shock

Background/Purpose: Endothelin is a potent mediator of the cardiovascular and renal systems. Studies have found that endothelin has an important role in regulating cardiac function and renal perfusion in neonates who are suffering from endotoxic shock. The authors believe that blockade of the endothelin response during endotoxemia will have a beneficial effect on neonatal cardiac and renal functions. In this study the authors have examined the effects of tezosentan, a dual endothelin-receptor antagonist, on the cardiovascular and renal systems of neonatal piglets during endotoxemia. Methods: Thirteen piglets were subjected to endotoxic shock and divided into a fluid-therapy group that received 0.9% normal saline and a group that received tezosentan (1 mg/kg/h). Mean arterial pressure (MAP), heart rate (HR), and glomerular filtration rate (GFR) were plotted at baseline, 1, 2, and 3 hours. Cardiac index (CI), renal blood flow (RBF), systemic vascular resistance (SVR), and renal vascular resistance (RVR) were obtained at baseline, 1, and 3 hours after baseline. Results: (P [lt ] .05 for 3 hours versus baseline and tezosentan versus fluid). Although fluid therapy in endotoxemia had no significant effect on MAP and RVR, it significantly increased HR (139 [plusmn] 17 to 246 [plusmn] 17 beats/min) and SVR (0.08 [plusmn] 0.05 to 0.33 [plusmn] 0.09 mm Hg/mL/min) and decreased CI (407 [plusmn] 208 to 98 [plusmn] 13 mL/min/kg), RBF (1.84 [plusmn] 0.38 to 0.97 [plusmn] 0.34 mL/min/kg kidney), and GFR (0.20 [plusmn] 0.05 to 0.11 [plusmn] 0.04 mL/min/kg) at 3 hours. The use of tezosentan also significantly increased HR (130 [plusmn] 14 to 220 [plusmn] 31 beats/min), but unlike in the fluid therapy group, there was a significant fall in MAP (77 [plusmn] 10 to 54 [plusmn] 9 mm Hg) and RVR (1.92 [plusmn] 0.44 to 1.77 [plusmn] 0.64 mm Hg/mL/min) and a less severe decrease in CI (482 [plusmn] 188 to 176 [plusmn] 67 mL/min/kg) at 3 hours. SVR, RBF, and GFR were maintained. Conclusions: Endotoxic shock affected cardiac and renal functions in both treatment groups. Fluid therapy alone could not prevent a statistically significant fall in CI, RBF, and GFR or prevent the increase in HR and SVR. Endothelin antagonism with tezosentan resulted in a statistically significant fall in MAP and RVR from baseline, not seen in the fluid-therapy group. CI and RBF were significantly higher, and MAP, SVR, and RVR were significantly lower when compared with the fluid-therapy group at 3 hours. GFR also was maintained at baseline with tezosentan. During endotoxemia, endothelin antagonism maintained renal and cardiac functions better than with fluid therapy alone.     

Endothelin-1 produces no renal vasoconstriction in conscious newborn lambs

Experiments were carried out to investigate the effects of endothelin-1 (ET-1) on renal vascular tone during development under physiological conditions in conscious lambs. Renal blood flow (RBF), renal vascular resistance (RVR), mean arterial pressure (MAP), and heart rate (HR) were measured in conscious, chronically instrumented lambs aged approximately 1 week and 6 weeks before and after intra-arterial (i.a.) injection of 0, 100, 200, and 400 ng/kg body weight of ET-1. In addition, plasma levels of ET-1 were measured in 39 sheep aged 5-85 days. In 6-week-old lambs, i.a. injection of ET-1 was associated with a rapid dose-dependent decrease in RBF that resulted from a dose-dependent increase in RVR. In 1-week-old lambs, there was no renal vasoconstriction observed after ET-1 administration, even at the highest dose tested. In response to i.a. injection of ET-1 to 1-week-old and 6-week-old lambs, MAP increased and there was a concomitant decrease in HR; these effects were dose dependent but not age dependent. Plasma levels of ET-1 were 10.7+/-4.2 pg/ml at 5-10 days, and remained constant throughout the first 3 months of life in conscious sheep. We conclude that ET-1 is not a renal vasoconstrictor agent in the immediate newborn period, and that the effects of ET-1 on renal vascular tone appear to be developmentally regulated.     

Effect of cyclosporine administration on renal hemodynamics in conscious rats

The effect of acute and chronic administration of cyclosporine on systemic and renal hemodynamics was studied in conscious rats. Infusion of cyclosporine in a dose of 20 mg/kg (Cy 20) resulted in a significant fall in renal blood flow (RBF) (3.4 vs. 6.5 ml/min/g, P less than 0.05) and a rise in renal vascular resistance (RVR) (36.9 vs. 20.6 mm Hg/ml/min/g, P less than 0.05). Infusion of cyclosporine at a dose of 10 mg/kg (Cy 10) did not result in a significant change in RBF or RVR. Both doses of cyclosporine resulted in stimulation of plasma renin activity (PRA) from control values of 5.6 +/- 0.8 ng/ml/hr to 11.6 +/- 2.0 with 10 mg/kg and 26.7 +/- 5.6 with 20 mg/kg. Urinary 6-keto-PGF1 alpha excretion increased from control values of 14.0 +/- 2.0 ng/6 hr to 22.7 +/- 2.2 with 10 mg/kg and 25.0 +/- 2.0 with 20 mg/kg. Similar effects on RBF, RVR, PRA, and 6-keto-PGF1 alpha excretion were seen after chronic administration of cyclosporine (20 mg/kg i.p. for 7 days). Pretreatment of animals with captopril did not prevent the fall in RBF after cyclosporine, suggesting that the vasoconstriction was not mediated by angiotensin II. Animals treated with meclofenamate demonstrated reduction in RBF with 10 mg/kg cyclosporine (4.3 vs. 7.0 ml/min/g, P less than 0.05), suggesting that prostaglandins protect against the vasoconstrictor effect of cyclosporine. Administration of phenoxybenzamine after cyclosporine improved RBF (5.0 vs. 3.4 ml/min/g) and restored RVR to normal. Similarly, renal denervation dramatically reduced the fall in RBF after cyclosporine (innervated right kidney 3.6 vs. denervated left kidney 6.0 ml/min/g, P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of tacrolimus and cyclosporine on renal microcirculation and nitric oxide production

OBJECTIVES: Cyclosporine (CSA) and tacrolimus (TAC) frequently induce nephrotoxicity and similar pathologic changes. Acute CSA-induced nephrotoxicity has been reported to be mediated by activation of vasoconstrictors such as endothelin. The purpose of the present study was to investigate the acute effects of TAC and CSA on the renal microcirculation and upon a vasodilator such as nitric oxide (NO) production. METHODS: Renal blood flow (RBF) in the microcirculation was measured by a Laser Doppler flow meter in uninephrectomised rats. RBF, mean arterial pressure (MAP), and renal vascular resistance (RVR) were measured in the following groups: (a) TAC (0.1 to 2.0 mg/kg/h, n = 3 approximately 6); CSA (20 and 50 mg/kg/h, n = 5); (b) L-NAME (10 mg/kg), an NO synthase inhibitor, 8 minutes prior to TAC (0.5 and 1.5 mg/kg/h, n = 5), or CSA (20 and 50 mg/kg/h, n = 5). Stable NO end-products, serum NO(2) and NO(3), were measured by the Griess method (n = 5). RESULTS: None of the parameters were changed by TAC alone, whereas TAC with L-NAME significantly reduced RBF (-28 +/- 7%) and increased RVR (46 +/- 17%) in a dose-dependent manner. CSA alone significantly reduced RBF (-37 +/- 6%) and increased RVR (69 +/- 22%) without any changes in MAP. The effects of CSA were enhanced by L-NAME. Serum concentration of NO(2) + NO(3) was significantly reduced by both L-NAME alone and CSA (50 mg/kg) (P < .05), while there were no changes with TAC (1.5 mg/kg). CONCLUSIONS: Blockade of NO production enhance the vasoconstrictive effect of CSA, and unmasked such an effect of TAC. These results suggest that the nephrotoxicity of CSA and TAC may involve the NO system.     

Plasma renin activity and the renal response to nitric oxide synthesis inhibition.

Inhibition of systemic endothelium-derived relaxing factor (EDRF) synthesis with L-Nw-nitroarginine (L-NAME) results in decreased RBF, which can be reversed by acute blockade of angiotensin II (AII). Because AII is particularly elevated in the renal circulation, it was hypothesized that the degree of renal vasoconstriction produced by L-NAME in Inactin-anesthetized rats is related to PRA. To test this, PRA was chronically increased or suppressed by the manipulation of dietary sodium (eating 0.03% sodium chow or deoxycorticosterone acetate plus drinking 1% NaCl, respectively). After 10 days, rats were anesthetized for determination of blood pressure (BP) and RBF before and after L-NAME (10 mg/kg body wt). In rats with high PRA (61.6 +/- 10.4 ng of angiotensin I [Al]/mL/h; N = 8), L-NAME increased BP by 29 +/- 2 mm Hg (from 110 +/- 4 to 139 +/- 5 mm Hg; P < 0.001), decreased RBF by 27% (from 7.9 +/- 0.3 to 5.8 +/- 0.3 mL/min/g kidney wt; P < 0.001), and increased renal vascular resistance (RVR) by 67% (from 14.5 +/- 0.9 to 24.2 +/- 1.1 resistance units [RU]; P < 0.001). When rats with high PRA (N = 8) were treated with 10 mg/kg body wt of DuP 753, on AII receptor antagonist, L-NAME similarly increased BP by 30 +/- 5 mm Hg (from 81 +/- 3 to 111 +/- 5; P < 0.001) but RBF did not change and RVR increased by only 31% (from 10.9 +/- 0.8 to 13.3 +/- 0.7 RU; P < 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)     

Studies of renal autoregulation in pancreatectomized and streptozotocin diabetic rats

We studied renal autoregulation in pancreatectomized Munich-Wistar diabetic rats and in their sham-operated controls. In a second experiment we studied renal autoregulation in untreated and insulin treated streptozotocin diabetic Munich-Wistar rats and their nondiabetic controls. In the first experiment the diabetic rats had higher baseline renal blood flows (RBF). There was a fall in renal vascular resistance (RVR) and sustained RBF in both diabetic and control rats as renal perfusion pressures (RPP) was reduced from 130 and 110 mm Hg. As RPP was reduced from 110 and 80 mm Hg, there was no significant Change in RVR in control rats and RBF began to fall. Below RPP of 80 mm Hg RVR rose and RBF fell sharply in these rats. In contrast, there was a progressive fall in RVR as RPP was lowered to 60 mm Hg in the diabetic rats and, thus, RBF was much better sustained in these animals. In the second experiment the plasma glucose level was 502 +/- 52 mg/dl (X +/- SD) in the untreated diabetic rats and only modestly reduced to 411 +/- 49 mg/dl in the insulin treated animals. Untreated streptozotocin diabetic rats had moderately reduced and insulin-treated diabetic rats had mildly reduced baseline RVR and RBF. However, in these animals as in the pancreatectomized rats the increases in RVR noted in control rats at subautoregulatory RPPs were not seen. Thus, regardless of whether baseline RBFs were increased or decreased, diabetic rats sustained RBF at markedly reduced RPPs far more efficiently than did nondiabetic rats. The pathogenesis of these abnormalities in diabetic rats was not learned in these studies.(ABSTRACT TRUNCATED AT 250 WORDS)     

Interlobular arterial resistance: influence of renal arterial pressure and angiotensin II

Pressure in the distal third of the interlobular arteries (Pila) was measured in anesthetized rats by micropuncture through corticotomy. Control Pila was 83.9 (SD 11.9) mm Hg at a renal arterial pressure (RAP) of 113.1 (SD 12.8) mm Hg. Reduction of RAP by 20 mm Hg caused no consistent change of total renal blood flow (RBF) or Pila. Relative interlobular arterial resistance, Rila = (RAP - Pila)/RBF, fell by 40 to 50%, and then remained practically unchanged at further reduction of RAP. Blood flow measured by radiolabeled microspheres (10.7 micron) showed similar values in intact cortex and in the tissue beneath the corticotomy, both varying in proportion to RBF. Intravenous infusion of angiotensin II (AII) 40 to 90 ng/min reduced RBF by 29% and increased RAP by 19 mm Hg. Pila rose by only 8 mm Hg and Rila increased to 209% of control. Reduction of RAP to control level during continued AII infusion did not change RBF, while Rila fell to 131% of control. We conclude that: dilatation and constriction of the interlobular arteries contribute importantly to autoregulation of outer cortical blood flow, probably through a myogenic mechanism (Bayliss); the constriction of interlobular arteries elicited by i.v. AII reflects mainly an autoregulatory response to increased arterial pressure, and to a smaller extent, a direct constrictor effect of AII.     

Effects of prostaglandin E1 on renal hemodynamics

The glomerular filtration rate (GFR), renal plasma flow (RPF), renal blood flow (RBF), filtration fraction (FF), and the ratio of mean arterial pressure (MAP) to RBF (MAP/RBF), reflecting renal vascular resistance (RVR) were determined to investigate the effects of intravenously administered prostaglandin E₁ (PGE₁) on renal hemodynamics in humans. PGE₁ produced no significant changes in GFR, but did cause significant increases in RPF and RBF and significant decreases in FF and MAP/RBF. The relationships between MAP and GFR, MAP and RBF, and MAP and MAP/RBF were investigated. PGE₁ suppressed the increase of MAP/RBF along with the increase of MAP, increased the RBF along with the increase of MAP, and kept the GFR constant, regardless of MAP. Also, the effects of PGE₁ on renal pericapillary vessels were simulated. According to this simulation, PGE₁ had a vasodilator action on both preglomerular and postglomerular capillaries.     

Impaired renal blood flow autoregulation in two-kidney, one-clip hypertensive rats is caused by enhanced activity of nitric oxide

Increases in renal perfusion pressure will induce shear stress-mediated nitric oxide (NO) release, which could oppose autoregulation of renal blood flow (RBF). Although cardiac, cerebral, and mesenteric autoregulation is enhanced during nitric oxide (NO) synthesis inhibition, this has not been reported for renal autoregulation of blood flow. In the present study, the lower limit and efficiency of RBF autoregulation (as assessed by the degree of compensation) were studied before and during NO inhibition in normotensive Sprague Dawley rats (control; n = 9) and in the non-clipped kidney of two-kidney, one-clip Goldblatt hypertensive animals (2K1C; n = 9; 3 wk; 0.25-mm silver clip). In both groups, renal autoregulation curves were obtained before and during infusion of N(G) -nitro-L-arginine (L-NNA) (bolus 1.5 mg/kg intravenously, infusion 10 microg/kg per min intravenously), using a transit-time flow probe around the left renal artery. In control rats, mean arterial pressure (MAP) increased, RBF decreased, and renal vascular resistance (RVR) increased in response to L-NNA infusion. The lower limit of autoregulation in control animals did not significantly change during L-NNA infusion (78 +/- 3 to 70 +/- 2 mmHg). The degree of compensation in these rats slightly increased during L-NNA infusion, however, this was only significant below 90 mmHg. The 2K1C rats had elevated MAP under baseline conditions. L-NNA infusion resulted in a decrease in RBF and an increase in MAP and RVR. During L-NNA infusion, RVR in 2K1C rats greatly exceeded RVR in control rats. A significant decrease was observed in the lower limit of autoregulation from 85 +/- 3 to 72 +/- 5 mmHg (P < 0.05). In the contralateral kidney of 2K1C rats, the degree of compensation was lower than in control rats under baseline conditions. L-NNA infusion resulted in significantly higher degrees of compensation compared to baseline. In conclusion, the contralateral kidney displayed a high NO dependency, as RBF greatly decreased and RVR dramatically increased in response to L-NNA infusion. The contralateral kidney of 2K1C rats exhibited impaired RBF autoregulation, which was improved by NO inhibition, as judged from a decrease in the lower limit of autoregulation and an increase in the degree of compensation. This study indicates that perfusion pressure-dependent NO release can oppose autoregulation in the kidney. However, the enhanced influence of NO on pressure-dependent RBF may facilitate the preservation of renal function in the nonclipped kidney of 2K1C rats.     

Effects of nifedipine on renal cortical and medullary blood flow in two-kidney, one-clip renovascular hypertension in rabbits

The effects of nifedipine, a calcium antagonist, on blood pressure and renal regional blood flow were investigated in two-kidney, one-clip renovascular hypertensive rabbits. At 1 week after left renal artery constriction, in the constricted group, systemic blood pressure (BP) significantly rose with the elevation of plasma renin activity (PRA). In both kidneys, renal vascular resistance (RVR on the constricted group was significantly increased as compared to that in the control group. In the clipped kidney, total renal blood flow (RBF) and renal cortical blood flow (RCBF) of the constricted group were significantly decreased, while renal medullary blood flow (RMBF) remained at the control value. In the nonclipped kidney, RBF and RCBF of the constricted group did not significantly change, and RMBF was significantly increased as compared to that of the control group. After administration of nifedipine for 1 week (1.0 mg/kg/day), BP in the constricted group was decreased to the control level and PRA in both groups was increased. The percent change of BP in the constricted group was significantly decreased and the percent change of PRA in the constricted group was significantly increased as compared to those in the control group. Nifedipine increased RBF, RCBF and RMBF and decreased RVR of both kidneys in each group. In the nonclipped kidney, the percent change of RBF, RCBF and RMBF of the constricted group was significantly increased and the percent change of RVR was significantly decreased as compared to those of the control group. In the clipped kidney, only the percent change of RBF of the constricted group was significantly lower than that in the control group.(ABSTRACT TRUNCATED AT 250 WORDS)     

Maintenance of renal vascular reactivity contributes to acute renal failure during endotoxemic shock

Septic shock is characterized by hypotension and decreased systemic vascular resistance and impaired vascular reactivity. Renal vasoconstriction markedly contrasts with sepsis-induced generalized systemic vasodilation, which is strongly dependent on nitric oxide. Whether maintained renal vascular reactivity to vasoconstrictors contributes to the decrease in renal blood flow (RBF) and GFR observed during LPS-induced sepsis was tested by assessment of the acute effects of pressor agents on mean arterial pressure (MAP) and renal hemodynamics in endotoxemic and control mice. LPS-injected mice displayed lower MAP, RBF, and GFR than controls (P < 0.001). Despite a lower MAP, basal renal vascular resistance (RVR) was higher during endotoxemia (P < 0.02). Angiotensin II infusion produced a weaker MAP response in septic mice (24 versus 37%; P < 0.005), suggesting impaired vasoconstriction and hyporeactivity. A similar MAP increase was observed between groups during norepinephrine (NE) infusion. The MAP increase to nitric oxide synthase inhibition by N(G)-nitro-L-arginine methyl ester (L-NAME) was much greater in LPS-treated mice (41 versus 15%, P = 0.01), indicating a strong influence of nitric oxide in sepsis. In contrast, the RBF and RVR responses to angiotensin II, NE, or L-NAME were similar in both groups. Moreover, vasopressin produced greater changes in MAP, RBF, and RVR in septic mice than in controls. Among the vasoconstrictor challenges, only NE ameliorated the decrease in GFR 14 h after LPS injection. The in vivo results demonstrate that the renal microvasculature displays a normal or enhanced reactivity to constrictor agents as compared with nonrenal circulatory beds. Such responsiveness may contribute to reduced RBF and GFR during endotoxemia.     

Haemodynamic and renal effects of endothelin receptor antagonism in patients with chronic kidney disease.

BACKGROUND: Endothelin-1 (ET-1) has been implicated in the pathophysiology of chronic kidney disease (CKD) and ET receptor blockade has shown renoprotective effects in animals. We examined the haemodynamic and renal effects of an ET receptor antagonist, TAK-044, in patients with CKD. METHODS: Seven patients with CKD (mean arterial pressure 103 mmHg; mean plasma creatinine 3.5 mg/dl) received three 15 min intravenous infusions, each separated by at least 7 days, of either placebo or TAK-044 (100 or 750 mg) in a randomized, double blind crossover study. Systemic and renal haemodynamics, and plasma immunoreactive ET-1, big ET-1 and C-terminal fragment concentrations, were determined before and after the infusions of placebo and drugs. RESULTS: Compared with placebo, TAK-044 reduced mean arterial pressure (MAP) (100 mg: 7.4 +/- 1.9 mmHg, 750 mg: 8.4 +/- 2.3 mmHg, P < 0.01) and systemic vascular resistance index (100 mg: 650 +/- 140 dyne.s.cm(-5).m(-2), 750 mg: 829 +/- 141 dyne.s.cm(-5).m(-2), P < 0.01) at both doses. TAK-044 increased cardiac index and heart rate to a similar degree at both doses. With regards to renal haemodynamics, TAK-044 had no significant effect on the glomerular filtration rate at either dose but tended to increase renal plasma flow (100 mg: 9.6 +/- 5.0 ml/min, 750 mg: 25.3 +/- 19.5 ml/min) and decreased the effective filtration fraction (100 mg: 3.6 +/- 1.1%, 750 mg: 4.7 +/- 1.7%, P < 0.01), in a dose-dependent manner. TAK-044 had no significant effect on sodium or lithium clearance, or on fractional excretion of sodium and lithium. Plasma ET-1 concentrations rose more than two-fold after 750 mg TAK-044 while big ET-1 and C-terminal fragment concentrations were unchanged. CONCLUSIONS: These findings suggest an important role for ET-1 in controlling systemic and renal haemodynamics in patients with CKD. The antihypertensive and potentially renoprotective actions of ET receptor antagonists shown in this study may prove useful in slowing the progression of CKD. Clinical trials are now needed to address these key questions for CKD.     

Influence of acute selective endothelin-receptor-A blockade on renal hemodynamics in a rat model of chronic allograft rejection

We have recently demonstrated up-regulation of renal endothelin (ET) synthesis in a rat model of chronic renal allograft rejection. Treatment with a selective ET-A receptor antagonist improved survival and reduced functional and morphological kidney damage. However, the underlying mechanisms have not yet been elucidated, as ET exhibits both hemodynamic and inflammatory properties. Therefore, in the present study we investigated acute hemodynamic effects of the selective ET-A receptor antagonist LU 302146 (LU) on chronic renal allograft rejection in rats. Experiments were performed in the Fisher-to-Lewis model of chronic renal allograft rejection. Lewis-to-Lewis isografts served as controls. After 2, 12, and 24 weeks, hemodynamic measurements were performed on anesthetized animals. Measurement of mean arterial pressure (MAP) was performed via a catheter in the femoral artery. Renal blood flow (RBF) was measured by an ultrasonic flow probe placed around the renal transplant artery. Medulla blood flow (MBF) and cortex blood flow (CBF) were determined with laser Doppler probes. Hemodynamic response upon intravenous bolus injection of LU (50 mg/kg) was investigated. The application of LU was followed by a decline in MAP that reached statistical significance only in isografts (ISOs) after 12 weeks and allografts (ALLOs) after 24 weeks. RBF slightly decreased in all groups; however, without reaching statistical significance. MBF showed a small increase in ALLO12 and ALLO24 whereas CBF slightly decreased in all groups. Acute ET-A receptor blockade does not induce important hemodynamic effects in kidneys undergoing chronic rejection. The lack of response to ET-A receptor blockade suggests that the beneficial effect of ET receptor antagonists in this model is likely to be due to improvement of renal morphology.     

Systemic and regional hemodynamics in cyclosporin A hypertension in the rat

SUMMARY: This study examined the hemodynamic effects of 21 days oral administration of cyclosporin A (CyA) in the male Wistar rat. Forty rats were randomly divided into four groups ( n =10). Group 1: Sham (olive oil 1 mL/kg/day by gavage ) with cardiac output (CO) measurement. Group 2: CyA (CyA 15 mg/kg/day in olive oil by gavage ) with CO measurement. Group 3: Sham as for group 1 with regional flow measurements. Group 4: CyA as for group 2 with regional flow measurements. Systolic blood pressure was measured every fourth day. After 21 days mean arterial blood pressure was measured by intra-arterial cannulation, and CO, and renal, mesenteric, and hindquarter blood flows (RBF, MBF, and HBF) were determined using transonic small animal flowmeters. Total peripheral resistance (TPR) and regional resistances were calculated. Oral CyA produced a sustained rise in systolic blood pressure. Olive oil did not affect blood pressure. CyA increased TPR ( P <0.05), renal vascular resistance (RVR, P <0.01) and MBF ( P <0.01), decreased RBF ( P <0.01), but did not change CO, HBF, mesenteric or hindquarter vascular resistance. We conclude that chronic oral administration of CyA produces hypertension with a hemodynamic profile characterized by rises in TPR and RVR without changes in CO or mesenteric or hindquarter vascular resistances in the Wistar rat.     

Early renal pathophysiology in an acute model of cyclosporine nephrotoxicity in rats

We have recently described a rat model of acute cyclosporine nephrotoxicity characterized by rapid onset of reproducible mild to moderate renal failure. In the present studies, we have examined early pathophysiologic events and morphologic changes in this model. Following acute intraperitoneal administration of 60 mg/kg of parenteral cyclosporine, renal blood flow (RBF) fell 24% from baseline. Intraperitoneal administration of an oral cyclosporine preparation (60 mg/kg) also reduced RBF (25%), as did administration of an equivalent volume of parenteral cremophore (23%). Renal vascular resistance (RVR) increased significantly in all these groups. In contrast, intraperitoneal administration of mineral oil or olive oil oral vehicle produced no significant change in RBF (4% fall from baseline), and RVR actually decreased in these control animals. Following 2 daily doses of these agents, RBF remained significantly lower in rats given parenteral cyclosporine (5.10 mL/min vs 8.54 mL/min in cremophore rats and 7.28 mL/min in oil control rats) and renal vascular resistance remained high. Systemic blood pressure was also significantly lower in cyclosporine-treated rats at 2 days, and GFR was depressed. Morphologic studies revealed a correlation at 2 days between tubular vacuolation and renal blood flow and renal vascular resistance in cyclosporine-treated rats.     

Losartan increases renal blood flow during isoflurane anesthesia in sheep

BACKGROUND: Inhaled anesthetics cause a transient reversible depression of renal function by direct renal effects or indirectly by changes in neurohumoral systems or cardiovascular performance. When the sympathetic nervous activity is decreased during anesthesia, other vasoactive systems like vasopressin (AVP) and particularly the renin angiotensin system (RAS) are of importance for blood pressure maintenance. Little is known about how the renal circulation is affected by angiotensin receptor blockade during isoflurane anesthesia. METHODS: The study was performed on isoflurane anesthetized sheep equipped with flow probes (placed around a femoral and a renal artery) and a pulmonary artery catheter. During stable conditions the sheep were given one or more of the following substances: isotonic saline (NaCl); losartan (LOS) 10 mg x kg(-1); prazosin (PRAZ) 0.2 mg x kg(-1) and a vasopressin V1-receptor antagonist (AVP-a) 10 microg x kg(-1). RESULTS: LOS and AVP-a did not affect mean arterial pressure (MAP), whereas PRAZ lowered MAP significantly (from 98+/-12 to 65+/-7 mmHg). Renal blood flow (RBF) increased after LOS treatment (148+/-34 to 222+/-33 ml x min(-1)). The other substances were without effect on RBF. Femoral blood flow remained unchanged after all treatments. CONCLUSION: We conclude that the sympathoadrenal system is still the major determinant for blood pressure maintenance during isoflurane anesthesia in sheep. The apparently increased activity of the renin angiotensin system in this situation causes a reduction in renal blood flow, which is counteracted by angiotensin II AT1-receptor blockade.     

Thromboxane receptor mediates renal vasoconstriction and contributes to acute renal failure in endotoxemic mice

Sepsis is a major cause of acute renal failure (ARF) and death. Thromboxane A2 (TxA(2)) may mediate decreases of renal blood flow (RBF) and/or GFR associated with LPS-induced sepsis. This study tested whether TxA(2) receptor blockade, with the use of TxA(2) receptor knockout (TP-KO) mice or a selective TP receptor antagonist (SQ29,548), would alleviate LPS-induced renal vasoconstriction and ARF. Under basal conditions, anesthetized TP-KO mice displayed a lower mean arterial pressure than wild-type (WT) mice (102 versus 94 mmHg; P < 0.05). RBF, renal vascular resistance (RVR), GFR, and urine flow did not differ among groups under basal conditions, suggesting little tonic influence of TxA(2) on renal TP receptors in health. In endotoxemic WT mice, 14 h after LPS (Escherichia coli LPS 8.5 mg/kg intraperitoneally), mean arterial pressure was reduced to 85 mmHg (P < 0.001), as were RBF (5.0 versus 9.3 ml/min per g kidney wt; P < 0.001) and GFR (0.38 versus 1.03 ml/min per g kidney wt; P < 0.001). Heart rate and RVR (71 versus 47 mmHg/ml per min; P < 0.05) increased. The decreases in RBF and GFR after LPS were attenuated in TP-KO mice versus WT mice (both P < 0.05). In both TP-KO and TP antagonist-treated mice, RVR remained stable in response to LPS versus WT mice that did not receive LPS. Delayed TP-antagonist treatment (12 h after LPS injection) ameliorated RBF and RVR but did not restore GFR. In other WT animals, TP-antagonist treatment for 2 h before intravenous LPS abolished the early renal vasoconstriction and alleviated the decrease in GFR. These results demonstrate that renal vasoconstriction during endotoxemic shock induced by LPS is mediated by TP receptors as indicated by pharmacologic blockade and genetic disruption of TP receptors.     

Systemic hemodynamics in nephrotoxic acute renal failure

Cardiac output (CO) and renal blood flow (RBF) were simultaneously evaluated (microsphere method) in awake rats, 3, 6, and 24 h after induction of acute renal failure by mercuric chloride (HgCl2; 4.7 mg/kg body weight). 3 h after injection of HgCl2, CO and RBF decreased to 77 and 72% of respective control values of 32.0 +/- 2.4 and 4.65 +/- 0.44 ml/min/100 g. Renal vascular resistance (RVR) and total peripheral resistance (TPR) were significantly increased compared to control at this time. Similar results were observed 6 h after administration of HgCl2. Volume expansion with plasma (2% of body weight) restored CO, RBF, TPR, and RVR to normal 3 h after injection of HgCl2. Despite significantly elevated blood urea nitrogen 24h after injection of HgCl2 (103.7 mg%), all hemodynamic parameters were within control range. Plasma volume was normal 3 h after HgCl2 but was significantly elevated compared to control 24 h after HgCl2 (4.73 vs. 3.92 ml/100 g, p less than 0.01). These findings indicate that factors other than preferential renal vasoconstriction may be involved in the transient renal ischemia of HgCl2-induced acute renal failure.     

Effects of aortic stenosis on renal renin, angiotensin receptor, endothelin and NOS gene expression in rats

BACKGROUND/AIMS: Published data regarding the effects of common cardiovascular diseases, i.e. aortic stenosis on renal regulation of major vasoconstrictive (renin, endothelins) and vasodilatory systems (NO) are controversial. Therefore we aimed to evaluate the effects of chronic aortic stenosis on the renal renin-angiotensin, endothelin and NO systems. METHODS: Experimental supravalvular aortic stenosis was induced by using silver clips with a 0.6 mm internal diameter on the ascending aorta of weanling rats. Renal endothelin-1 (ET-1), endothelin-3 (ET-3), renin, AT(1a), AT(1b), eNOS, and bNOS gene expression were assessed by RNase protection assay. RESULTS: Renal renin gene expression increased twofold in rats with aortic stenosis. In contrast, renal ET-1, ET-3, eNOS, bNOS, and AT(1a), AT(1b) gene expression were unchanged in rats with aortic stenosis. CONCLUSION: Our study demonstrates that in rats with severe experimental supravalvular aortic stenosis only renal renin gene expression is stimulated. This contrasts with severe heart failure where endothelins and NO synthases are also upregulated. Different patterns of regulation of renal vasoactive mediators may be of importance for the extent of the renal impairment associated with aortic stenosis, and may be correlated with the severity of congestive heart failure.