Trophoblast-induced spiral artery remodelling and uteroplacental haemodynamics in pregnant rats with increased blood pressure induced by heme oxygenase inhibition.

INTRODUCTION: The aim of the present study was to determine the contribution of the heme oxygenase (HO) system to the adaptation of the uteroplacental circulation to pregnancy in the rat, and its relationship with the maintenance of blood pressure during late gestation. METHODS: The HO inhibitor, stannous mesoporphyrin (SnMP), or vehicle were administered intraperitoneally to virgin and midpregnant rats. Mean arterial pressure (MAP) was measured before and after the treatment, in the conscious rats. Uterine and radial arteries blood flow velocities were obtained from pregnant rats at days 14 and 19 of gestation using high frequency ultrasonography. Trophoblast invasion and spiral arteries remodelling were analyzed in the mesometrial triangle of pregnant rats by immunohistochemistry. RESULTS: HO activity inhibition during late gestation induced a significantly increase in the MAP of pregnant rats (114 ± 1 mmHg vs 100 ± 2 mmHg, p < 0.05) but it did not affect this parameter in virgin rats (121 ± 2 mmHg vs 124 ± 3 mmHg). MAP elevation was associated with marked (p < 0.05) decreases in the systolic and diastolic flow velocities in uterine and radial arteries, as compared with pregnant control rats. Furthermore, spiral arteries of pregnant rats treated with SnMP showed lower (p < 0.001) proportion of lumen circumference covered by trophoblast (21 ± 3%) and a higher (p < 0.05) proportion of vascular smooth muscle (33 ± 5%) than control pregnant rats (59 ± 5% and 16 ± 5%, respectively) DISCUSSION: These data indicate that HO system play an important role in the adaptation of the uteroplacental circulation to pregnancy and in the blood pressure regulation during late gestation.

Magnetic field homogeneity of a conical coaxial coil pair.

An analytical study of the magnetic field created by a double-conical conducting sheet is presented. The analysis is based on the expansion of the magnetic field in terms of Legendre polynomials. It is demonstrated analytically that the angle of the conical surface that produces a nearly homogeneous magnetic field coincides with that of a pair of loops that fulfills the Helmholtz condition. From the results obtained, we propose an electric circuit formed by pairs of isolated conducting loops tightly wound around a pair of conical surfaces, calculating numerically the magnetic field produced by this system and its heterogeneity. An experimental setup of the proposed circuit was constructed and its magnetic field was measured. The results were compared with those obtained by numerical calculation, finding a good agreement. The numerical results demonstrate a significant improvement in homogeneity in the field of the proposed pair of conical coils compared with that achieved with a simple pair of Helmholtz loops or with a double solenoid. Moreover, a new design of a double pair of conical coils based on Braunbek's four loops is also proposed to achieve greater homogeneity. Regarding homogeneity, the rating of the analyzed configurations from best to worst is as follows: (1) double pair of conical coils, (2) pair of conical coils, (3) Braunbek's four loops, (4) Helmholtz pair, and (5) solenoid pair.

Wrist skin temperature, motor activity, and body position as determinants of the circadian pattern of blood pressure.

Although the circadian blood pressure (BP) pattern has been extensively studied, the determinants of this rhythm are not fully understood. Peripheral vasodilatation is a regulatory mechanism for BP maintenance. However, it remains to be established whether the increase of nocturnal distal skin temperature associated with heat loss could also reflect the dipping status. For the first time, this paper investigates the relationship between BP and skin wrist temperature (WT), to evaluate whether the WT circadian rhythm can serve as screening procedure to detect dipping/non-dipping BP patterns. In addition, the authors compare the relationship between WT and other variables previously described as determinants of the BP pattern, such as physical activity and body position. Measurements of WT, motor activity, and body position for 5 d, plus ambulatory BP for 24-h during that span, were obtained from 28 diurnally active normotensive volunteers. WT was negatively correlated, whereas activity and body position were positively correlated, with systolic and diastolic BPs. However, these relationships were stronger during the rest than activity phase. In addition, a 78.6% concordance was detected between the observed dips in BP and the predicted BP pattern calculated based on the WT rhythm. Thus, these results suggest that the increase in WT produced by heat loss during the rest phase through peripheral skin blood vessels is the result of blood vessel vasodilatation reflexes in response to a shift from a standing to a supine position, together with shift in the circadian sympathetic/parasympathetic balance (nocturnal parasympathetic activation). In conclusion, WT could be considered as a potential new screening procedure to implement the diagnosis of non-dipping BP pattern.

Adenocarcinoma cervical de células claras no relacionado con exposición a dietilestilbestrol. Reto diagnóstico / Clear cell adenocarcinoma of the cervix without diethylstilbestrol exposure. A diagnostic challenge

Los adenocarcinomas del cérvix uterino son un tipo de tumor raro, representan alrededor del 5–10% del total de tumores en esa localización y, dentro de todos éstos, los de células claras suponen el 4–9%. El factor pronóstico más importante es el estadio tumoral, por lo que un diagnóstico precoz influye de manera notoria en la supervivencia de las pacientes; por ello, solventar los problemas diagnósticos que esta entidad ofrece se convierte en algo esencial. Presentamos un caso de adenocarcinoma de células claras de cérvix, no relacionado con exposición intrauterina a dietilestilbestrol, cuyo proceso diagnóstico conviene tener en cuenta (AU)

Cervical adenocarcinomas are rare, representing 5–10% of all cervical malignancies. Among this type of malignancy, clear cell adenocarcinomas account for 4–9%. The most important prognostic factor is tumoral stage, and consequently early diagnosis is essential due to its impact on patient survival. We report a case of clear cell cervical adenocarcinoma without diethylstilbestrol exposure and describe the diagnostic process (AU)

Characterization of manures from fish cage farming in Chile.

This study aims to characterize salmonid manures and to determine their potential use in agricultural soils. Sampling was carried out below salmon and trout cages in farms located in lakes and in the sea in the South of Chile during 2002-2003. Manure was analyzed for macronutrients, micronutrients and heavy metals. Results showed a high variability between samples and differences between sea and lake manure. Dry matter contents were low averaging c. 12-15%. Manures showed low OM contents with values

Importancia de la ciclooxigenasa-2 en la regulación de la hemodinámica renal durante la gestación en ratas conscientes / Role of COX-2 in regulating renal hemodynamics during gestation in conscious rats

Objetivo. Determinar la importancia de la ciclooxigenasa-2 (COX-2) en la regulación de la hemodinámica renal durante la gestación en ratas. Material y método. En primer lugar se determinó la expresión renal de la COX-2 a lo largo de la gestación mediante la técnica de western blot. La expresión de la COX-2 fue analizada en los siguientes grupos de ratas: ratas vírgenes (n = 6), ratas en los días 6 (n = 6), 13 (n = 6) y 20 de gestación (n = 6) y ratas en el día 4 después del parto (n = 6). El análisis densitométrico de los diferentes western blot demostró que los niveles de la proteína aumentaron (p < 0,05) un 41 % en la segunda semana de gestación con respecto a los observados en ratas vírgenes. En segundo lugar se determinó el efecto de la inhibición específica de la COX-2 sobre los cambios en la hemodinámica renal observados durante la mitad de la gestación. Los experimentos se realizaron en ratas vírgenes (n = 10) y ratas gestantes (n = 10) tratadas con vehículo (salino isotónico) o con el inhibidor específico de la COX-2 (rofecoxib). El inhibidor de la COX-2 fue administrado por vía oral durante tres días (10 mg/kg/día). Las medidas de presión arterial media (PAM), flujo plasmático renal (FPR) y tasa de filtración glomerular (TFG) fueron realizadas en el día 14 de gestación. Resultados. De acuerdo con estudios previos, la resistencia vascular renal (RVR) fue menor (p < 0,05) en el grupo de ratas gestantes (35 ± 3 mmHg/ml · min­1 · g­1) que en el grupo de ratas vírgenes tratadas con vehículo (46 ± 5 mmHg/ml · min­1 · g­1). Del mismo modo, la TFG fue mayor (p < 0,05) en las ratas gestantes (1,43 ± 0,16 ml/min/g) que en las ratas vírgenes tratadas con vehículo (0,99 ± 0,06 ml/min/g). La administración oral de rofecoxib no alteró la TFG ni la PAM en ninguno de los dos grupos de animales. Por el contrario, el tratamiento con el inhibidor específico de la COX-2 provocó una disminución significativa (p < 0,05) en la RVR en el grupo de ratas preñadas (27 ± 2 mmHg/ml · min­1 · g ­1), sin afectar la RVR en el grupo de ratas vírgenes (49 ± 4 mmHg/ ml · min­1 · g­1). Conclusión. Los resultados de este estudio sugieren que la COX-2 está implicada en la regulación de la hemodinámica renal durante la gestación en ratas conscientes

Objective. The purpose of this study was to determine the role of cyclooxygenase-2 (COX-2) in regulating renal hemodynamics during mid-gestation in the rat. Material and methods. Renal COX expression was determined by western blot analysis in kidneys from virgin rats (n = 6), pregnant rats at days 6 (n = 6), 13 (n = 6) and 20 (n = 6) of pregnancy and rats at day 4 postpartum (n = 6). Protein levels at day 13 of gestation were 41 % higher than in virgin rats. To evaluate whether the increase in COX-2 expression was involved in regulating renal hemodynamics during midpregnancy in the rat, we also tested the effects of a specific inhibitor of COX-2 (rofecoxib) on renal vascular resistance (RVR) and glomerular filtration rate (GFR) in virgin and mid-pregnant rats. Studies were conducted in four experimental groups: virgin rats + vehicle (n = 10), virgin rats + rofecoxib (n = 10), pregnant rats + vehicle (n = 10) and pregnant rats + rofecoxib (n = 10). Rofecoxib was administered by gavage over 3 days, at a dose of 10 mg/kg/day. Mean arterial pressure (MAP), renal plasma flow (RPF) and GFR were determined at day 14 of gestation. Results. Consistent with earlier reports, midterm pregnant rats showed a significantly (p < 0.05) lower RVR (35 ± 3 mmHg/ml · min­1 · g­1) than virgin controls (46 ± 5 mmHg/ ml · min­1 · g­1). Baseline GFR for gravid rats was significantly (p < 0.05) higher (1.43 ± 0.16 ml/min/g) than in virgin rats (0.99 ± 0.06 ml · min­1 · g­1). COX-2 inhibition with rofecoxib reduced RVR in pregnant rats (27 ± 2 mmHg/ml · min­1 · g­1), whereas it had not effect on RVR in virgin controls (49 ± 4 mmHg/ml · min­1 · g ­1). Conclusion. These data suggest that COX-2 is involved in regulating renal hemodynamics during gestation in conscious rats

Nitrogen budgets for three cropping systems fertilised with cattle manure.

A field plot experiment was set up on a sandy loam soil of SW England in order to determine the efficiency of nitrogen use from different cattle manures. The manure treatments were low and high dry matter cattle slurries and one farmyard manure applied at a target rate of 200 kg total N ha(-1)year(-1), and an untreated control. There were three different cropping systems: ryegrass/clover mixture, maize/rye and maize/bare soil, which were evaluated during 1998/99 and 1999/00. Measurements were made of N losses, N uptake and herbage DM yields. Result showed that manure type had a significant effect on N utilisation only for maize. N balances were negative in maize (approximately -247 to -10 kg N) compared to grass (approximately 5-158 kg N). Agronomic management was more important than manure type in influencing N losses, where soil cultivation appeared to be a key factor when comparing maize and grass systems.

Role of cyclooxygenase-2 in the control of renal haemodynamics and excretory function.

AIM: The available evidence supporting the importance of cyclooxygenase-2 (COX-2) in the regulation of renal haemodynamics and excretory function is summarized. Cyclooxygenase-2-derived metabolites play a very important role in regulating renal haemodynamics when sodium intake is low whereas it plays a minor role in the control of cortical blood flow when sodium intake is normal or elevated. The importance of COX-2 in the regulation of renal haemodynamics seems to be dependent on the endogenous production of other vasoactive products such as nitric oxide (NO) or noradrenaline. The activation of COX-2 in response to a decrease in NO may represent a mechanism aimed at defending the renal vasculature in the face of a decrease in NO levels. CONCLUSION: Contrary to the important role of COX-2 in the long-term regulation of renal haemodynamics, the metabolites derived from COX-2 seem to be only involved in the acute regulation of renal excretory function.

Role of COX-2-derived metabolites in regulation of the renal hemodynamic response to norepinephrine.

The objective of this study was to examine the role of cylcooxygenase (COX)-2-derived prostaglandins (PG) in modulating the renal hemodynamic effects of norepinephrine (NE) during low or normal sodium intake. The relative contribution of each COX isoform in producing the PG that attenuate the renal NE effects during normal sodium intake was also evaluated. The renal response to three doses of NE (50, 100, and 250 ng. kg(-1). min(-1)) was evaluated in anesthetized dogs pretreated with vehicle, a selective COX-2 inhibitor (nimesulide), or a nonselective COX inhibitor (meclofenamate). Intrarenal infusion of the two lower doses of NE in vehicle-pretreated dogs with normal sodium intake (n = 8) elicited an increase in renal vascular resistance (RVR; 21 and 34%) without inducing changes in glomerular filtration rate (GFR). The highest dose of NE in this group induced a further increment in RVR (113%) and a decrease in GFR (33%). Pretreatment with nimesulide in dogs with normal sodium intake (n = 7) did not modify the NE-induced increments in RVR but enhanced the decreases in GFR induced by the three NE doses (12, 26, and 64%). The renal hemodynamic response to NE in meclofenamate-pretreated dogs with normal sodium intake (n = 7) was similar to that found in dogs pretreated with nimesulide. Infusion of the lowest dose of NE to vehicle-pretreated dogs with low sodium intake (n = 6) did not modify GFR and elicited an increase in RVR (42%). Infusion of the second and third doses of NE led to a decrease in GFR (35 and 91%) and a rise in RVR (82 and 587%). Infusion of the first two doses of NE in nimesulide-pretreated dogs with low sodium intake (n = 5) induced a fall in GFR (64 and 92%) and an increase in RVR (174 and 2,293%) that were greater (P < 0.05) than those induced by NE in vehicle-pretreated dogs. The elevation in the urinary excretion rates of PGE(2) and 6-keto-PGF(1alpha) elicited by NE was prevented in the nimesulide-pretreated dogs. Our results show that COX-2 inhibition potentiates the renal hemodynamic effects of NE and propose that the PG involved in modulating them are mainly derived from COX-2 activity.

High doses of gonadotrophins combined with stop versus non-stop protocol of GnRH analogue administration in low responder IVF patients: a prospective, randomized, controlled trial.

Recent evidence suggests that early cessation of gonadotrophin releasing hormone analogue (GnRHa) administration may offer some benefit to low responder patients undergoing IVF. A prospective, randomized controlled trial was designed to evaluate whether early cessation of GnRHa in an ovarian stimulation regimen is more beneficial than just increasing the doses of gonadotrophins. Seventy low responder patients (less than three mature follicles in a previous cycle) with normal basal follicle stimulating hormone concentrations and a previous cancelled IVF cycle were randomly allocated into two protocols: (i) non-stop protocol: long GnRHa suppression with high doses of gonadotrophins, and (ii) stop protocol, in which GnRHa administration is stopped with the onset of menses, while gonadotrophin doses remained similar to the non-stop protocol. A significantly higher number of mature oocytes were obtained in the study group (stop protocol) compared to the control group (non-stop protocol) (8.7 +/- 0.9 versus 6.2 +/- 0.7, P: = 0. 027). The stop protocol reduced the number of ampoules of gonadotrophins required (56.6 +/- 2.7 versus 68.0 +/- 3.5, P: = 0. 013). Both protocols resulted in a similar cancellation rate (2.7 versus 5.8%) (with no cycles cancelled due to ovulation), pregnancy rate (14.3 versus 18.7%), and implantation rate (12.1 versus 8.8%). The early cessation of GnRHa combined with high doses of gonadotrophins permitted the retrieval of a significantly higher number of oocytes.

Release of nitric oxide after acute hypertension.

We have shown that NO production, assessed by measuring changes in plasma nitrate concentration, is down-regulated when blood pressure falls. This study intended to determine first, whether NO-derived plasma nitrate varies in response to increases in blood pressure induced by different mechanical and pharmacologic stimuli, including angiotensin II and catecholamines; and second, specifically to study the interaction between angiotensin II and NO production. An intravenous infusion (4-10 min) of norepinephrine (7.5 microg/kg/min), phenylephrine (30 microg/kg/min), or angiotensin II (0.3 and 3 microg/kg/min) caused hypertension accompanied by an increase in plasma nitrate, as assessed by high-performance capillary electrophoresis. Mechanical hypertension elicited by aortic occlusion also was accompanied by an increase in plasma nitrate. Angiotensin II (0.03, 0.3, and 3 microg/kg/min, 10 min) dose-dependently increased blood pressure. The intermediate and high dose, but not the low dose, of angiotensin II increased plasma nitrate concentration. N(G)-nitro-L-arginine methyl ester (L-NAME) lowered the basal concentration of plasma nitrate, abolished the increase in plasma nitrate elicited by angiotensin II and norepinephrine, and potentiated the pressor effect of the low dose of angiotensin II, although this dose did not increase NO production. L-NAME also potentiated the pressor effects of the intermediate dose of angiotensin II. This study demonstrates that an augmented systemic production of NO, measured as an increase in plasma nitrate, takes place after acute hypertension. The results of this study suggest that an increase in NO generation occurs when angiotensin II hypertension exceeds a certain limit, below which the basal production of NO is sufficient to compensate the vasoconstriction.

Role of cyclooxygenase-2-derived metabolites and nitric oxide in regulating renal function.

The aim of this study was to examine the relative contribution of both cyclooxygenase (COX) isoforms in producing the prostaglandins (PG) involved in the regulation of renal function, when nitric oxide (NO) synthesis is reduced. In anesthetized dogs with reduction of NO synthesis, the renal effects of a nonisozyme-specific COX inhibitor (meclofenamate) were compared with those elicited by a selective COX-2 inhibitor (nimesulide) before and during an extracellular volume expansion (ECVE). Intrarenal N(G)- nitro-L-arginine methyl ester (L-NAME) infusion (1 microg x kg(-1) x min(-1); n = 6) did not elicit renal hemodynamic changes and reduced (P < 0.01) the renal excretory response to ECVE. Intravenous nimesulide (5 microg x kg(-1) x min(-1); n = 6) did not modify renal hemodynamic and reduced (P < 0. 05) sodium excretion before ECVE. Simultaneous L-NAME and nimesulide infusion (n = 7) elicited an increment (37%) in renal vascular resistance (RVR; P < 0.05) before ECVE and no hemodynamic changes during ECVE. The reduced excretory response elicited by L-NAME and nimesulide was similar to that found during L-NAME infusion. Finally, simultaneous L-NAME and meclofenamate infusion (10 microg x kg(-1) x min(-1); n = 7) induced an increase in RVR (91%, P < 0.05), a decrease in glomerular filtration rate (35%, P < 0.05), and a reduction of the renal excretory response to ECVE that was greater (P < 0.05) than that elicited by L-NAME alone. The results obtained support the notion that PG involved in regulating renal hemodynamic and excretory function when NO synthesis is reduced are mainly dependent on COX-1 activity.

Renal changes induced by a cyclooxygenase-2 inhibitor during normal and low sodium intake.

Cyclooxygenase-2 (COX-2) has been identified in renal tissues under normal conditions, with its expression enhanced during sodium restriction. To evaluate the role of COX-2-derived metabolites in the regulation of renal function, we infused a selective inhibitor (nimesulide) in anesthetized dogs with normal or low sodium intake. The renal effects elicited by nimesulide and a non-isozyme-specific inhibitor (meclofenamate) were compared during normal sodium intake. In ex vivo assays, meclofenamate, but not nimesulide, prevented the platelet aggregation elicited by arachidonic acid. During normal sodium intake, nimesulide infusion (n=6) had no effects on arterial pressure or renal hemodynamics but did reduce urinary sodium excretion, urine flow rate, and fractional lithium excretion. In contrast, nimesulide administration increased arterial pressure and decreased renal blood flow, urine flow rate, and fractional lithium excretion during low sodium intake (n=6). COX-2 inhibition reduced urinary prostaglandin E(2) excretion in both groups but did not modify plasma renin activity in dogs with low (8.1+/-1.1 ng angiotensin I. mL(-1). h(-1)) or normal (1.8+/-0.4 ng angiotensin I. mL(-1). h(-1)) sodium intake. Meclofenamate infusion in dogs with normal sodium intake (n=8) induced a greater renal hemodynamic effect than nimesulide infusion. These results suggest that COX-2-derived metabolites (1) are involved in the regulation of sodium excretion in dogs with normal sodium intake, (2) play an important role in the regulation of renal hemodynamic and excretory function in dogs with low sodium intake, and (3) are not involved in the maintenance of the high renin levels during a long-term decrease in sodium intake.

Renal effects of prolonged cyclooxygenase inhibition when angiotensin II levels are elevated.

We examined the renal functional and hemodynamic changes induced by prolonged cyclooxygenase (COX) inhibition when angiotensin II levels are elevated during several consecutive days. The effects induced by the infusion of either initially subpressor or pressor angiotensin II doses (1 and 5 ng/kg/min) were examined in dogs with or without the simultaneous infusion of meclofenamate (5 microg/kg/min). Experiments were performed in conscious permanently instrumented dogs. Infusion of the lower angiotensin II dose alone (n = 6) caused a late 12+/-2% increase in arterial pressure, a 25+/-6% decrease in renal blood flow (RBF), and a transitory decrease in urinary sodium excretion. COX inhibition reduced the hypertension and renal vasoconstriction, but enhanced the sodium retention, induced by the lower dose angiotensin II infusion (n = 6). The higher angiotensin II dose (n = 6) caused a 25+/-4% increase in arterial pressure, a 24+/-5% decrease in RBF, and a transitory decrease in urinary sodium excretion. Finally, COX inhibition did not modify the renal effects elicited by the higher angiotensin II dose (n = 6). The results of this study suggest that endogenous prostaglandins play an important role in the regulation of the renal and systemic changes induced by prolonged administration of initially subpressor angiotensin II doses. It has also been demonstrated that prolonged COX inhibition does not modify the renal functional and hemodynamic changes elicited by the long-term infusion of a pressor angiotensin II dose.

Role of nitric oxide and prostaglandins in the long-term control of renal function.

Previous studies have reported evidence of an important interaction between nitric oxide (NO) and prostaglandins in the acute regulation of renal function. The objective of this study was to determine in conscious dogs whether the renal effects of the prolonged administration of a cyclooxygenase inhibitor are enhanced when NO synthesis is reduced. Meclofenamate infusion (5 microg x kg(-1) x min(-1)) during 4 consecutive days (n=8) elicited a continuous decrease (P<0.05) in renal blood flow and plasma renin activity and a transitory decrease in sodium excretion. NG-Nitro-L-arginine methyl ester (L-NAME) infusion (5 microg x kg(-1) x min(-1)) during 6 days (n=8) produced a significant increase in arterial pressure and a transitory decrease (P<0.05) in both renal blood flow and plasma renin activity. The simultaneous inhibition of NO and prostaglandin synthesis (n=7) led to an increase in arterial pressure and a decrease in renal blood flow similar to those observed during the administration of either L-NAME or meclofenamate. In contrast, this simultaneous inhibition produced a decrease in glomerular filtration rate, which was not observed in the previous groups, and also induced an increase in renal vascular resistance and a decrease in sodium excretion greater (P<0.05) than those found during the inhibition of either NO or prostaglandins. Only a transitory decrease in plasma renin activity was found during meclofenamate infusion in this group. The results of this study present new evidence that the renal vasoconstrictor and antinatriuretic effects induced by the prolonged infusion of a cyclooxygenase inhibitor are significantly enhanced when NO synthesis is reduced. These results suggest that renal function may be more sensitive to the prolonged administration of a cyclooxygenase inhibitor in situations where NO production is reduced.

Renal changes induced by nitric oxide and prostaglandin synthesis reduction: effects of trandolapril and verapamil.

The benefits of the simultaneous administration of low doses of a calcium antagonist and a converting enzyme inhibitor in the treatment of hypertension and renal vasoconstriction are well established. The objective of this study was to evaluate whether the administration of low doses of a calcium antagonist and a converting-enzyme inhibitor have beneficial effects in treating the renal alterations induced by the acute administration of a cyclooxygenase inhibitor when nitric oxide synthesis is reduced. These effects were examined in anesthetized dogs before and during an acute sodium load. It was found that the intrarenal infusion of meclofenamate (5 microg x kg[-1] x min[-1]), simultaneously with a low dose of NG-nitro-L-arginine methyl ester (1 microg x kg[-1] x min[-1]), produced a 40% decrease of renal blood flow and glomerular filtration rate and a reduction in the renal excretory response to the sodium load. In a second group of dogs, intrarenal verapamil (0.5 microg x kg[-1] x min[-1]) was effective in blocking the effects of nitric oxide and prostaglandin synthesis inhibition on sodium excretion and glomerular filtration rate but did not modify the effects on renal blood flow. An intrarenal infusion of trandolapril (0.3 microg x kg[-1] x min[-1]) was effective in a third group of dogs in reducing the renal hemodynamic effects but not in preventing the antinatriuretic effect observed in the first group. Finally, in a fourth group, the simultaneous administration of verapamil and trandolapril was effective in treating all the renal changes induced by the cyclooxygenase inhibitor when nitric oxide synthesis was reduced. These results suggest that the combination of low doses of trandolapril and verapamil has additive effects in treating the renal vasoconstriction and antinatriuresis induced by the acute administration of a cyclooxygenase inhibitor, when nitric oxide synthesis is reduced.

Effects of renal perfusion pressure on renal interstitial hydrostatic pressure and Na+ excretion: role of endothelium-derived nitric oxide.

The purpose of this study was to examine the role of endothelium-derived nitric oxide in modulating the effect of renal perfusion pressure (RPP) on renal interstitial hydrostatic pressure (RIHP) and urinary Na+ excretion (UNaV). The effects of RPP on renal hemodynamics, RIHP, and Na+ and Li+ excretions were determined in control Sprague-Dawley rats, in Sprague-Dawley rats pretreated with intravenous infusion of NG-nitro-L-arginine methyl ester (L-NAME) at doses of 1, 5, and 50 microg/kg/min, and in rats pretreated with L-NAME (5 microg/kg/min) plus L-arginine (10 mg/kg/min). The RPP was changed from 95 to 135 mm Hg by an electronically servo-controlled aortic occluder above the renal arteries in all groups. Increasing RPP in control rats from 95 to 135 mm Hg increased RIHP (from 4.4 +/- 0.5 to 8.7 +/- 1.2 mm Hg), UNaV (from 2.37 +/- 0.61 to 8.29 +/- 1.59 microEq/min), and fractional excretion of Li+ (from 38.0 +/- 2.5 to 51.4 +/- 6.0%). In rats pretreated with L-NAME (5 microg/kg/min), increases in RPP from 95 to 135 mm Hg had no effect on RIHP (from 1.6 +/- 0.4 to 2.2 +/- 0.6 mm Hg) or fractional excretion of Li+ and markedly attenuated pressure-natriuresis relationship (from 1.84 +/- 0.50 to 2.88 +/- 0.65 microEq/min). Although L-NAME did reduce renal plasma flow and glomerular filtration rate, the autoregulatory responses to RPP were maintained. In rats pretreated with L-NAME plus L-arginine, RIHP, UNaV, and fractional excretion of Li+ responses to RPP were similar to the control rats. The results of this study indicate that endothelium-derived nitric oxide plays an important role in modulating the effect of RPP on Na+ excretion by enhancing the transmission of RPP into the renal interstitium.

Comparative effects of nitric oxide synthesis inhibition and catecholamine treatment in a rat model of endotoxin shock.

Catecholamines and volume repletion are currently used for the treatment of septic shock. However, the prognosis of patients suffering from this condition is very poor. An overproduction of nitric oxide (NO) seems to be related to the hypotension and tissue damage of endotoxin shock. Thus, treatment with NO synthase inhibitors has been proposed. Using a rat model of septic shock we have studied the effects of noradrenaline or the NO synthase inhibitor, NG-nitro-L-arginine methylester (L-NMMA) on arterial pressure, tissue damage and NO production. Anaesthetized rats treated with Salmonella typhosa showed a decrease in blood pressure accompanied by an increase in the plasma concentration of cytosolic enzymes (transaminases and lactate dehydrogenase, markers of cell disruption) and nitrite plus nitrate (NO2-/NO3-, markers of NO production). A large proportion of these animals (40%) died before the end of the experiment. Co-treatment with noradrenaline resulted in temporary maintenance of arterial pressure followed by a decline, despite the dose being increased progressively. No differences were observed in plasma cytosolic enzymes, NO2-/NO3- or mortality compared with animals treated with lipopolysaccharide (LPS) alone. In contrast, administration of L-NMMA (10 mg kg-1) to septic animals prevented the fall in blood pressure and death caused by endotoxin. This treatment markedly diminished cell disruption, as measured by the plasma levels of necrosis enzymes, and partially, but significantly, reduced the production of NO as assessed by plasma NO2-/NO3-. We conclude that tissue damage in septic shock is related to the overproduction of NO and not exclusively to the hypotension that follows this increased production. Thus, maintenance of blood pressure with catecholamines fails to improve cellular damage. Instead, partial inhibition of NO generation is sufficient to ameliorate the haemodynamic and tissue-damaging effects of septic shock and improves survival in this model of endotoxaemia.