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.

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

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.

Pathophysiology of hypertension during preeclampsia linking placental ischemia with endothelial dysfunction.

Studies over the past decade have provided a better understanding of the potential mechanisms responsible for the pathogenesis of preeclampsia. The initiating event in preeclampsia has been postulated to be reduced uteroplacental perfusion as a result of abnormal cytotrophoblast invasion of spiral arterioles. Placental ischemia is thought to lead to widespread activation/dysfunction of the maternal vascular endothelium that results in enhanced formation of endothelin and thromboxane, increased vascular sensitivity to angiotensin II, and decreased formation of vasodilators such as NO and prostacyclin. These endothelial abnormalities, in turn, cause hypertension by impairing renal-pressure natriuresis and increasing total peripheral resistance. The quantitative importance of the various endothelial and humoral factors in mediating the reduction in renal hemodynamic and excretory function and elevation in arterial pressure during preeclampsia are still unclear. Results from ongoing basic and clinical studies, however, should provide new and important information regarding the physiological mechanisms responsible for the elevation in arterial pressure in women with preeclampsia.

Effect of angiotensin II synthesis blockade on the hypertensive response to chronic reductions in uterine perfusion pressure in pregnant rats.

The purpose of this study was to examine the role of the renin-angiotensin system in mediating the hypertension in response to chronic reductions in uterine perfusion pressure (RUPP) in conscious chronically instrumented pregnant rats. Mean arterial pressure was significantly higher in pregnant rats with chronic RUPP (125+/-3.0 mm Hg, P<0.01, n=12) than in pregnant rats (100+/-2.3 mm Hg, n=17). Plasma renin activity in pregnant rats with chronic RUPP was 17.1+/-2.5 nmol angiotensin I. L(-1). h(-1) compared with 21.9+/-3.5 nmol angiotensin I. L(-1). h(-1) in pregnant rats. Chronic oral administration of a converting-enzyme inhibitor (enalapril, 250 mg/L for 6 days) decreased mean arterial pressure to a similar extent in pregnant rats with chronic RUPP (109+/-4.2 mm Hg, P<0.01, n=9) and in normal pregnant (81+/-1.8 mm Hg, P<0.01, n=9) rats. Blockade of the renin-angiotensin system, however, had no significant effect on the blood pressure response to chronic RUPP as differences were similar in control (Delta25 mm Hg) and converting-enzyme inhibitor-treated (Delta27 mm Hg) groups. These findings suggest that the renin-angiotensin system does not play a major role in mediating the hypertension produced by chronic RUPP in pregnant rats.

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.

Role of angiotensin II in the renal effects induced by nitric oxide and prostaglandin synthesis inhibition.

The objective of this study was to examine the renal effects of changes in intrarenal angiotensin II levels during the administration of a cyclooxygenase inhibitor, when nitric oxide synthesis is reduced. In the first group of dogs, the administration of meclofenamate and a subpressor dose of L-NAME induced an increase (P < 0.05) in arterial pressure (14 +/- 2 mm Hg), a decrease (P < 0.05) in RBF (180 +/- 13 to 111 +/- 10 mL/min) and GFR (37 +/- 3 to 24 +/- 5 mL/min), and a reduction in the renal excretory response to a sodium load. In the second group, the administration of a converting enzyme inhibitor prevented the increase in arterial pressure, the renal vasoconstriction, and the increase in the proximal but not the distal tubular sodium reabsorption induced by the inhibition of prostaglandins and nitric oxide synthesis. In the third group, it was found that a small increase in the intrarenal angiotensin II levels, which does not produce changes in renal function in control conditions, induced a significant decrease in RBF (183 +/- 14 to 71 +/- 12 mL/min) and GFR (36 +/- 3 to 13 +/- 4 mL/min) when meclofenamate was administered and nitric oxide synthesis was slightly reduced. The results of this study suggest that renal vasoconstriction and increased proximal sodium reabsorption during the reduction of nitric oxide and prostaglandin synthesis are produced by endogenous angiotensin II levels. These results also suggest that endogenous intrarenal nitric oxide and prostaglandins may serve as homeostatic mediators of angiotensin II effects when the intrarenal levels are inappropriately elevated, as occurs in salt-sensitive hypertension.

Nitric oxide synthase activity in renal cortex and medulla of normotensive and spontaneously hypertensive rats.

The medullary portion of the kidney plays a crucial role in the control of sodium and water excretion and arterial pressure. This control is anomalous in hypertension and may be related to an impaired renal nitric oxide (NO) production. We have measured the activity of NO synthase (NOS) in the renal medulla, renal cortex, heart, and aorta from normotensive Wistar Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). Enzyme activity was determined by measuring the conversion of 14C-L-arginine to 14C-L-citrulline. Ca2+-dependent NOS activity was considerably higher in the renal medulla than in the other tissues studied, both in WKY and SHR. The medulla and heart of the SHR displayed a higher Ca2+-dependent NOS activity compared to that of WKY. No differences were found in the Ca2+-independent NOS activity, except for the renal cortex of the SHR, which was higher than in the rest of the tissues. These observations indicate that the renal medulla has a high relative capacity to synthesize NO and suggest that the impaired renal medullary control of arterial pressure of genetic hypertension is not due to a reduced NO production by the kidney.

Effects of verapamil on the renal actions induced by nitric oxide and prostaglandin synthesis inhibition.

This study was designed to determine the effects of a calcium antagonist (verapamil) on the renal actions induced by nitric oxide synthesis inhibition, with and without simultaneous prostaglandin synthesis inhibition. The renal effects of verapamil (2 micrograms/kg/min) were examined in anesthetized dogs before and after an increase of extracellular volume and during the reduction of nitric oxide synthesis (1 microgram/kg/min NG-nitro-L-arginine methyl ester [L-NAME]), with and without the administration of a cyclooxygenase inhibitor (5 micrograms/kg/min meclofenamate). Nitric oxide synthesis inhibition produced an increase in proximal sodium reabsorption (lithium clearance technique) and a decrease in the excretory response to volume expansion that was prevented by the administration of verapamil. The administration of a cyclooxygenase inhibitor, during nitric oxide synthesis inhibition, elicited an increase in arterial pressure, an important renal vasoconstriction, and reduced the renal excretory response to volume expansion. The antinatriuretic effect produced by the simultaneous reduction of nitric oxide and prostaglandin synthesis, before and after the volume expansion, was abolished with the verapamil infusion. However, the increase of arterial pressure and renal vasoconstriction were only partly affected by verapamil. We found that the antinatriuretic effect secondary to the reduction of nitric oxide synthesis, during an increase in extracellular volume, is prevented by the administration of verapamil. Additionally, the administration of verapamil completely prevents the antinatriuretic, but not the vasoconstrictor, effects induced by the administration of a cyclooxygenase inhibitor when nitric oxide is slightly reduced.

Interactions between angiotensin and nitric oxide in the renal response to volume expansion.

This study examined, in anesthetized dogs, the possible interactions between nitric oxide (NO) and angiotensin II (ANG II) in mediating the renal response to an extracellular volume expansion (ECVE). It was found that the intrarenal maintenance of ANG II levels (group 1) or the intrarenal NO synthesis inhibition (group 2) did not induce changes in renal hemodynamics but reduced (P < 0.05) the ECVE-induced increments in sodium excretion and fractional lithium excretion (FeLi). In the third group, ANG II synthesis was inhibited during NO synthesis blockade. It was found in this group that the NO synthesis inhibition reduced the ECVE-induced increment in sodium excretion (P < 0.05) but did not modify the ECVE-induced increment in FeLi. These results suggest that the increase of proximal sodium reabsorption induced by the No synthesis inhibition is mediated by endogenous ANG II levels. In the fourth group, it was observed that NO synthesis inhibition, during the intrarenal maintenance of ANG II levels, induced a decrease of renal blood flow (P < 0.05) and reduced the natriuretic response to ECVE to a lower level (P < 0.05) than that observed in groups 1 and 2. The results of this group suggest that endogenous NO modulates the vasoconstrictor and antinatriuretic effects of ANG II during an ECVE. In summary, the results of this study suggest that there is an important interaction between NO and ANG II in mediating the renal response to an ECVE.

Role of prostaglandins and nitric oxide in mediating renal response to volume expansion.

The objective of the present study was to examine, in anesthetized dogs, the possible interaction between prostaglandins (PG) and nitric oxide (NO) in mediating the renal response to an extracellular volume expansion (ECVE). The renal response to ECVE was examined during 1) intrarenal infusion of a PG synthesis inhibitor, 2) intrarenal administration of a NO synthesis inhibitor, and 3) simultaneous inhibition of PG and NO synthesis in the right kidney. Compared with the control group, the ECVE-induced increments in sodium excretion and fractional excretion of lithium were not affected by the PG synthesis inhibition. The NO synthesis inhibition did not induce changes in renal hemodynamics but reduced (P < 0.05) the ECVE-induced increments in sodium excretion and fractional excretion of lithium. When PG and NO synthesis were simultaneously inhibited in the right kidney during ECVE, there were no significant differences between the renal hemodynamics of both kidneys. However, compared with the left kidney, the ECVE-induced changes in sodium excretion and fractional excretion of lithium were reduced in the right kidney. The reduction of the natriuretic response to ECVE was greater (P < 0.05) than in the dogs where only NO synthesis was inhibited. Our results suggest a major interaction between NO and PG in mediating the renal hemodynamic and excretory responses to an increase in extracellular volume.