AJP - Regu Track the topics, authors and articles important to you
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Am J Physiol Regul Integr Comp Physiol 294: R842-R850, 2008. First published December 26, 2007; doi:10.1152/ajpregu.00691.2007
0363-6119/08 $8.00
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
294/3/R842    most recent
00691.2007v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Abassi, Z.
Right arrow Articles by Hoffman, A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Abassi, Z.
Right arrow Articles by Hoffman, A.

RENAL HEMODYNAMICS AND CARDIORENAL INTEGRATION

Adverse effects of pneumoperitoneum on renal function: involvement of the endothelin and nitric oxide systems

Zaid Abassi,1,2 Bishara Bishara,3 Tony Karram,2 Samer Khatib,4 Joseph Winaver,1 and Aaron Hoffman2

1Department of Physiology and Biophysics, Ruth & Bruce Rappaport Faculty of Medicine, Technion, Israel Institute of Technology, and 2Department of Vascular Surgery and Kidney Transplantation, 3Department of General Surgery "A", and 4Department of Anesthesiology, Rambam Human Health Care Campus, Haifa, Israel

Submitted 25 September 2007 ; accepted in final form 22 December 2007


   ABSTRACT
TOP
 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Increased intra-abdominal pressure (IAP) during laparoscopy adversely affects kidney function. The mechanism underlying this phenomenon is largely unknown. This study was designed to investigate the involvement of endothelin (ET)-1 and nitric oxide (NO) systems in IAP-induced renal dysfunction. Rats were subjected to IAP of 14 mmHg for 1 h, followed by a deflation for 60 min (recovery). Four additional groups were pretreated with 1) ABT-627, an ETA antagonist; 2) A-192621, an ETB antagonist; 3) nitroglycerine; and 4) NG-nitro-L-arginine methyl ester, a NO synthase inhibitor, before IAP. Urine flow rate (V), absolute Na+ excretion (UNaV), glomerular filtration rate (GFR), and renal plasma flow (RPF) were determined. Significant reductions in kidney function and hemodynamics were observed when IAP was applied. V decreased from 8.1 ± 1.0 to 5.8 ± 0.5 µl/min, UNaV from 1.08 ± 0.31 to 0.43 ± 0.10 µeq/min, GFR from 1.84 ± 0.12 to 1.05 ± 0.06 ml/min (–46.9 ± 2.7% from baseline), and RPF from 8.62 ± 0.87 to 3.82 ± 0.16 ml/min (–54 ± 3.5% from baseline). When the animals were pretreated with either ABT-627 or A-192621, given alone or combined, the adverse effects of IAP on GFR, RPF, V, and UNaV were significantly augmented. When the animals were pretreated with nitroglycerine, the adverse effects of pneumoperitoneum on GFR and RPF were substantially improved. In contrast, pretreatment with NG-nitro-L-arginine methyl ester remarkably aggravated pneumoperitoneum-induced renal dysfunction. In conclusion, decreased renal excretory function and hypofiltration are induced by increased IAP. These effects are related to impairment of renal hemodynamics and could be partially ameliorated by pretreatment with nitroglycerine and aggravated by NO and ET blockade.

rat; intra-abdominal pressure

PNEUMOPERITONEUM AT PRESSURE above 10 mmHg during laparoscopic surgery has been shown to produce transient oliguria and reduced glomerular filtration rate (GFR) and renal blood flow (RBF) (3, 9, 16, 33, 34). Despite much research in this field, the systemic physiological consequences of CO2 pneumoperitoneum and the mechanisms underlying its adverse effects on renal hemodynamics and excretory function are not fully understood (9). However, there is compelling experimental evidence that the adverse renal effects induced by pneumoperitoneum are affected by the level of intra-abdominal pressure (IAP), volume status, degree of hypercarbia, positioning, and individual hemodynamic and renal reserves (9, 10). Additional factors that may affect renal function during pneumoperitoneum include direct compression of the renal parenchyma and renal vein (4, 17), increased resistance in the renal vasculature (47), and release of vasoconstrictors, such as vasopressin, angiotensin II, catecholamines, and endothelin (ET)-1 (1, 13). The latter is a very potent natural mammalian vasoconstrictor agent (25), acting on the cardiovascular and renal systems and other target organs by binding to two major types of receptors, ETA and ETB (2, 25, 36). High abundance of ETA receptors has been detected in the aorta, heart, and kidney, whereas ETB receptors are expressed mainly in the endothelium and tubular epithelial cells of the collecting duct (24, 25, 26, 40). Activation of ETA receptors on vascular smooth muscle cells (VSMC) increases intracellular Ca2+ levels, leading to prolonged vasoconstriction and cell proliferation (31, 35, 41). In contrast, activation of ETB receptors, present on endothelial cells, induces the release of nitric oxide (NO) and prostaglandins, thus provoking transient vasodilation (41, 43, 44). While it is accepted that ETA and ETB receptors mediate vasoconstriction and vasodilation, respectively, several studies have demonstrated that ETB receptors present on VSMC can elicit vasoconstriction (6–8, 19–21). Thus differences in tissue-specific expression and density of the two receptor subtypes, the tissue concentration of the ET-1, and the preexisting state of the vascular bed determine the type and magnitude of vascular response (vasoconstriction or vasodilation) of this peptide (35).

The kidney is both a target organ and a major source of ET-1 production (25, 35). The highest concentrations of immunoreactive ET-1 in the body have been detected in the renal medulla (23). In addition, gene expression and immunoreactive peptides of ET-1 and its receptors have been demonstrated in the renal tissue, especially in the medullary region (23, 26, 40, 42, 45). Interestingly, in vivo studies revealed that administration of ET-1 resulted in reduced renal hemodynamics and kidney dysfunction, similar to those found during pneumoperitoneum (9). For instance, whole organ studies in intact rats have demonstrated that a shortlasting infusion of ET-1 into the renal artery decreases renal plasma flow (RPF), GFR, and urine volume (5, 22, 38, 46). Similarly, a long-term infusion of ET-1 into conscious dogs results in increased renal vascular resistance and decreased GFR and RPF (5, 46). Hence, it is proposed that activation of the ET system may be involved in pneumoperitoneum-induced renal dysfunction. In line with this assumption, high plasma levels of ET-1 were measured in dogs, subjected to 5 h of elevated IAP, within 20 min of insufflation (15). Similarly, an elevation in local renal ET-1 expression has recently been reported in experimental pneumoperitoneum (1). Unfortunately, these studies did not examine thoroughly the effects of selective ET receptor antagonists on renal dysfunction associated with elevated IAP.

An additional autocrine/paracrine system within the kidney that also influences the vascular and tubular function and may interact with the actions of the ET system is NO. In this regard, several studies have demonstrated that medullary NO plays a pivotal role in the regulation of renal medullary hemodynamics and excretory function (27, 28, 30). Previously, our laboratory (14, 18) and others (48) have shown that the renal vasodilatory actions of ETB, as well as its stimulatory effects on water and sodium excretion, are mediated through generation of NO. Similarly, Mattson et al. (32) have demonstrated that chronic intravenous administration of the NO synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) selectively decreases renal medullary blood flow, causes sodium and water retention, and leads to hypertension. Similar manifestations were noticed in rats with collecting duct-specific knockout to the ETB receptor (12). Taken together, these findings appeal to the notion that alterations in the endogenous NO system may contribute to the altered renal hemodynamics and kidney function seen in pneumoperitoneum.

Therefore, the present study was designed to explore the effects of acute blockade of the ETA and ETB receptors and the involvement of the NO system on renal hemodynamics and function in rats with pneumoperitoneum at a pressure of 14 mmHg.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Studies were conducted on male Sprague-Dawley rats (Harlan Laboratories, Jerusalem, Israel) weighing 290–320 g. The animals were fed standard rat chow containing 0.5% NaCl and tap water ad libitum. All experiments were approved by, and performed according to the guidelines of, the committee for the supervision of animal experiments, Technion, IIT.

Rats were anesthetized with Inactin (100 mg/kg ip), placed on a thermoregulated (37°C) surgical table, and prepared for hemodynamic and clearance studies (11). After tracheotomy, polyethylene tubes (PE50) were inserted into the carotid artery and jugular vein for blood pressure monitoring and infusion of various solutions, respectively. The abdomen was opened by a small, midline incision, and the urinary bladder was catheterized with PE-50 for urine collection. A solution of 2% of inulin and 0.5% p-aminohippurate (PAH) in 0.9% saline was continuously infused at a rate of 1.0–1.5% of body weight per hour throughout the experiment. Mean arterial blood pressure (MAP) was continuously monitored with a pressure transducer (model 156PC05GWL; Microswitch, Freepoint, IL) connected to the carotid arterial line.

Experimental Model of Pneumoperitoneum

A small incision in the lower third between the xiphoid and pubis was made, through which a regular Veress needle was inserted into the abdominal cavity. A pneumoperitoneum of 14 mmHg was established with CO2 gas supply to maintain IAP at the desired level using a special insufflator (Aesculap, Tuttlingen, Germany) connected to the Veress needle. The muscle layer and skin layer of the abdominal wall were closed separately by silk sutures in an airtight manner. This IAP pressure (14 mmHg) was chosen based on preliminary experiments in which incremental increases in IAP from 0 to 7 and 14 mmHg were applied. While the latter was effective in causing renal dysfunction, IAP of 7 mmHg did not affect kidney function and hemodynamics (data not shown). Moreover, IAP of ~14 mmHg is the pressure utilized by surgeons during laparoscopic surgery (9).

Clearance Studies

Rats were prepared for clearance studies as described above. After a 60-min equilibration period, two baseline clearance periods of 30 min each were obtained (IAP = 0). The rats were then subjected to one of the following experimental protocols.

Group A. Seven rats were subjected to IAP of 14 mmHg over 1 h, followed by deflation period of 1 h (recovery). Two clearance periods were obtained during baseline, vehicle/drug treatment, IAP, and recovery period. Blood samples were obtained in the midst of every second clearance period (Fig. 1). The two collection periods during baseline, drug treatment, and recovery were averaged and combined.


Figure 1
View larger version (9K):
[in this window]
[in a new window]

  		Fig. 1. Group A experimental protocol. B1–B4, blood samples; U1–U8, clearance periods. NTG, nitroglycerine; IAP, intra-abdominal pressure. See MATERIALS AND METHODS for details.

 
Group B. Six or seven rats were pretreated with 1) ABT-627, an antagonist of ETA receptor (1.0 mg·kg–1·h–1 iv), and 2) A-192621, an antagonist of ETB receptor (3.0 mg·kg–1·h–1 iv), given alone or combined, beginning 60 min before the application of 14-mmHg insufflation pressure for 1 h, followed by desufflation to 0 mmHg (recovery). Two clearance periods were obtained during ET antagonists infusion alone, ET antagonists + IAP of 14 mmHg, and the recovery period. Previous studies from our laboratory have demonstrated that these blockers are highly selective at the applied doses (11).

Group C. Seven additional rats were pretreated with a nondepressor dose of nitroglycerine (NTG) (prime 1.5 µg/kg and sustained infusion of 15 µg·kg–1·h–1 iv), beginning 60 min before the application of 14-mmHg insufflation pressure for 1 h, followed by desufflation to 0 mmHg (recovery). Two clearance periods were obtained during baseline, NTG infusion alone, NTG + IAP of 14 mmHg, and the recovery period. Blood samples were obtained in the midst of every second clearance period.

Group D. Six additional rats were pretreated with L-NAME (100 mg/l) added to drinking water for 4 days before the experiment. On the 5th day, two basal clearance periods were obtained before rats were subjected to IAP of 14 mmHg over 1 h, followed by a deflation period of 1 h (recovery). Two clearance periods were obtained during baseline, insufflation, and recovery periods. Blood samples were obtained in the midst of every second clearance period (Fig. 2).


Figure 2
View larger version (6K):
[in this window]
[in a new window]

  		Fig. 2. Group D experimental protocol. L-NAME, NG-nitro-L-arginine methyl ester. See MATERIALS AND METHODS for details.

 
Chemical Analysis

Urine volume was determined gravimetrically. Plasma samples were separated by centrifugation, and the concentrations of sodium in plasma and urine were determined by a flame photometer (model IL 943, Instrumentational Laboratory). Concentrations of inulin and PAH, in plasma and urine samples, were measured by the colorimetric anthrone method. RPF and GFR were estimated as the clearance of the infused PAH and inulin, respectively.

Statistical Analysis

One-way ANOVA for repeated measures, followed by the Dunnett test, was used for comparison of treatment values with baseline in each group or with corresponding values in the control group. A value of P ≤ 0.05 was considered statistically significant. Data are presented as means ± SE.


   RESULTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Effects of Short-term Increase in IAP on Renal Clearance Parameters and Renal Hemodynamics

Figure 3 depicts urinary flow rate (V), and absolute and fractional Na+ excretion (UNaV), of rats that underwent incremental increases in IAP from 0 to 14 mmHg. Significant reductions in these parameters were observed when IAP of 14 mmHg was applied for 60 min. V decreased from 8.1 ± 1.0 to 5.8 ± 0.5 µl/min (P ≤ 0.05; –19.6 ± 17.1% from baseline), and UNaV from 1.08 ± 0.31 to 0.43 ± 0.10 µeq/min (P < 0.05; –26.0 ± 26.7% from baseline). These alterations in excretory functions were associated with a maximal decline in GFR from 1.84 ± 0.12 to 1.05 ± 0.06 ml/min (P < 0.05; –46.9 ± 2.7% from baseline), and RPF from 8.62 ± 0.87 to 3.82 ± 0.16 ml/min (P < 0.05; –54 ± 3.5% from baseline) (Fig. 4), without a significant change in MAP [from 110.2 ± 4.6 to 107.8 ± 6.4 mmHg; P = not significant (NS)] (Table 1). Both the excretory parameters and renal hemodynamics returned to baseline values following a deflation period of 1 h (recovery) (Figs. 3 and 4). The current findings indicate that IAP of 14 mmHg significantly decreased GFR and RBF, in association with impairment of urine output and UNaV.


Figure 3
View larger version (24K):
[in this window]
[in a new window]

  		Fig. 3. Effects of 14-mmHg insufflations with CO2 on urinary flow (V; A and B) and urinary sodium excretion (UNaV; C and D) in the presence and absence of ABT-627, an endothelin (ET)A antagonist (1.0 mg·kg–1·h–1 iv), or A-192621, an ETB antagonist (3.0 mg·kg–1·h–1 iv) (n = 6–7). Untreated animals served as controls (n = 7). Data are expressed as absolute values (A and C) and as %change from baseline values (B and D). Baseline data represent the 1-h vehicle/antagonist collection period. *P < 0.05 vs. baseline; #P < 0.05 vs. untreated pneumoperitoneum.

 

Figure 4
View larger version (27K):
[in this window]
[in a new window]

  		Fig. 4. Effects of 14-mmHg insufflations with CO2 on glomerular filtration rate (GFR; A and B) and renal plasma flow (RPF; C and D) in the presence and absence of ABT-627, an ETA antagonist (1.0 mg·kg–1·h–1 iv), or A-192621, an ETB antagonist (3.0 mg·kg–1·h–1 iv) (n = 6–7). Untreated animals served as controls (n = 7). Data are expressed as absolute values (A and C) and as %change from baseline values (B and D). Baseline data represent the 1-h vehicle/antagonist collection period. *P < 0.05 vs. baseline; #P < 0.05 vs. untreated pneumoperitoneum.

 

View this table:
[in this window]
[in a new window]

  		Table 1. Mean arterial blood pressure in the different experimental groups

 
Effects of ETA and ETB Antagonists on Kidney Function and Renal Hemodynamic Response to Pneumoperitoneum

To further elucidate possible involvement of the ET system in the pathogenesis of pneumoperitoneum-induced renal dysfunction, studies were repeated with rats pretreated with either ABT-627 or A-192621, given alone or combined.

ETA antagonist. Pretreatment with ABT-627 aggravated the adverse effects of elevated IAP on V and UNaV. V decreased from 17.0 ± 4.5 to 3.7 ± 0.4 µl/min (P < 0.05; –68.8 ± 6.4% from baseline), and UNaV from 0.83 ± 0.48 to 0.08 ± 0.04 µeq/min (P < 0.05; –73.0 ± 9.6% from baseline) (Fig. 3). Besides its effects on renal excretory function, ABT-627 worsened the influence of pneumoperitoneum on renal perfusion. GFR decreased from 1.5 ± 0.17 to 0.47 ± 0.07 ml/min (P < 0.05; –67.9 ± 4.8% from baseline), and RPF from 6.0 ± 0.7 to 2.16 ± 0.58 ml/min (P < 0.05; –67 ± 4.9% from baseline) (Fig. 4). Treatment with ABT-627 produced a slight decrease in MAP from 113.8 ± 2.9 to 105.8 ± 2.1 mmHg (P = NS) 60 min after the elevation of IAP (Table 1). It should be emphasized that the magnitude of these decreases in V, UNaV, GFR, and RPF, calculated as percent change from baseline, was significantly greater compared with that of untreated rats that underwent identical insufflation (Figs. 3 and 4). Notably, both GFR and RPF substantially increased during the recovery period, yet V and UNaV were decreased or unchanged, respectively. These results suggest that the recovery of renal hemodynamics is faster than the recovery of the tubular function, which is known to be very sensitive to hypoperfusion.

ETB antagonist. Similar to ABT-627, pretreatment with A-192621 aggravated the adverse effects of pneumoperitoneum on V and UNaV. V decreased from 33.3.0 ± 9.0 to 8.8 ± 0.4 µl/min (P < 0.05) (–75 ± 6.1% from baseline), and UNaV from 1.52 ± 0.53 to 0.35 ± 0.02 µeq/min (P < 0.05; –77.3 ± 4.3% from baseline) (Fig. 3). In addition, A-192621 augmented the adverse influence of pneumoperitoneum on renal perfusion. GFR decreased from 2.5 ± 0.3 to 0.61 ± 0.09 ml/min (P < 0.05; –76.0 ± 7.4% from baseline), and RPF from 7.8 ± 0.6 to 2.6 ± 0.8 ml/min (P < 0.05; –82.8 ± 4.0% from baseline) (Fig. 4). Treatment with A-192621 significantly increased MAP from 119.7 ± 2.4 to 131.1 ± 4.0 and 138.7 ± 4.3 mmHg (P < 0.05) 30 and 60 min after the elevation of IAP, respectively (Table 1). The magnitude of these decreases in V, UNaV, GFR, and RPF, calculated as percent change from baseline, was significantly greater compared with that of untreated rats that underwent identical insufflation (Figs. 3 and 4).

ETA + ETB antagonists. Coadministration of both ABT-627 and A-192621 resulted in aggravation of renal excretory function and renal hemodynamics caused by elevated IAP. V decreased from 14.8. ± 1.6 to 3.8 ± 1.0 µl/min (P < 0.05; –68.8 ± 6.4% from baseline), and UNaV from 2.44 ± 0.48 to 0.34 ± 0.12 µeq/min (P < 0.05; –86.3 ± 4.3% from baseline), GFR decreased from 1.65 ± 0.17 to 0.27 ± 0.08 ml/min (P < 0.05; –81.0 ± 5.6% from baseline), and RPF from 12.64 ± 3.3 to 2.2 ± 0.8 ml/min (P < 0.05; –86.4 ± 5.4% from baseline) (Figs. 3 and 4), without significantly affecting MAP (Table 1). The magnitude of these decreases in V, UNaV, GFR, and RPF, calculated as percent change from baseline, was comparable to those obtained when each antagonist was administered alone (Fig. 4). Similar to rats treated with ETA antagonist, treatment with combined ETA and ETB antagonists resulted in remarkable increase in GFR (but not RPF) during the recovery period, yet V and UNaV were decreased or unchanged, respectively.

Effects of NO Donor or NO Synthase Inhibition on Renal Hemodynamic Response to Pneumoperitoneum

This protocol was designed to investigate the involvement of the NO system in the pathogenesis of pneumoperitoneum-induced renal dysfunction.

Administration of a nondepressor dose of NTG maintained V and UNaV during IAP of 14 mmHg (Fig. 5). However, both V and UNaV still decreased relative to the NTG-enhanced basal values. V decreased from 16.8 ± 1.1 to 8.9 ± 0.9 µl/min (–51.3 ± 7.1%; P < 0.05), and UNaV decreased from 1.7 ± 0.4 to 1.14 µeq/min (–33.2 ± 27.0%; P < 0.05), after 60 min of insufflations (Fig. 5), without a significant change in MAP (107.6 ± 2.7 to 108.4 ± 4.2 mmHg) (Table 1).


Figure 5
View larger version (28K):
[in this window]
[in a new window]

  		Fig. 5. Effects of pretreatment with NTG (15 µg·kg–1·h–1 iv) on pneumoperitoneum-induced (IAP = 14 mmHg) renal excretory dysfunction. A and B: V; C and D: UNaV (n = 7). Untreated animals served as controls (n = 7). Data are expressed as absolute values (A and C) and as %change from baseline values (B and D). Baseline data represent the 1-h vehicle/NTG collection period. *P < 0.05 vs. baseline; #P < 0.05 vs. untreated pneumoperitoneum.

 
In line with its beneficial renal excretory effects during pneumoperitoneum, NTG significantly attenuated the decrease in renal hemodynamics after 60 min, but not 30 min, of insufflation. GFR decreased from 1.84 ± 0.08 to 1.14 ± 0.2 ml/min (–40.6 ± 8.7%; P < 0.05) and 1.48 ± 0.14 ml/min (–23.8 ± 7.2%; P < 0.05), 30 and 60 min after insufflation, respectively (Fig. 6). Similarly, RPF decreased from 9.59 ± 1.0 to 4.73 ± 0.9 ml/min (–34.9 ± 15.4%; P < 0.05) and 6.84 ± 0.7 ml/min (–16.7 ± 11%; P = NS), at 30 and 60 min, respectively. It should be emphasized that the magnitude of the decreases in GFR and RPF during the second 30 min of insufflation, calculated as percent change from baseline, was significantly lower compared with untreated rats that underwent identical insufflations (Fig. 6). Despite the beneficial effects of NTG on renal hemodynamics, both GFR and RBF still dropped by 25–40% during increased IAP compared with baseline values. Both the excretory parameters and renal hemodynamics returned to values above normal following a deflation period of 1 h (recovery).


Figure 6
View larger version (30K):
[in this window]
[in a new window]

  		Fig. 6. Effects of pretreatment with NTG (15 µg·kg–1·h–1 iv) on pneumoperitoneum-induced (IAP = 14 mmHg) renal hemodynamic changes. A and B: GFR; C and D: RPF (n = 7). Untreated animals served as controls (n = 7). Data are expressed as absolute values (A and C) and as %change from baseline values (B and D). Baseline data represent the 1-h vehicle/NTG collection period. *P < 0.05 vs. baseline; #P < 0.05 vs. untreated pneumoperitoneum.

 
These results suggest that NO plays a beneficial role in maintaining renal function during pneumoperitoneum. In agreement with this notion, pretreatment with L-NAME remarkably aggravated the renal excretory function, as well as hypoperfusion and hypofiltration associated with pneumoperitoneum. V decreased from 13.0 ± 0.85 to 3.4 ± 0.7 µl/min (–70 ± 8.5%; P < 0.05), and UNaV from 0.37 ± 0.16 to 0.12 ± 0.08 µeq/min (–55.7 ± 5.6%; P < 0.05), after 60 min of insufflations (Fig. 7). As expected, basal MAP was significantly higher in L-NAME-treated animals compared with controls (137.0 ± 5.0 vs. 110.2 ± 4.6 mmHg; P < 0.05) (Table 1). Besides aggravating the adverse effects of pneumoperitoneum on renal excretory function, L-NAME remarkably worsened the pneumoperitoneum-induced hypoperfusion/hypofiltration. GFR decreased from 1.70 ± 0.15 to 0.42 ± 0.13 ml/min (–73.8 ± 7.7%; P < 0.05) and 0.62 ± 0.2 ml/min (–58.8 ± 14.0%; P < 0.05), 30 and 60 min, respectively, after abdominal insufflation of L-NAME-pretreated rats (Fig. 8). RPF decreased from 5.41 ± 0.35 to 1.27 ± 0.35 ml/min (–74.3 ± 8.87%; P < 0.05) and 1.8 ± 0.6 ml/min (–50.3 ± 11.9%; P < 0.05), at 30 and 60 min, respectively (Fig. 8). Notably, the magnitude of these decreases in GFR and RPF, calculated as percent change from baseline, was significantly higher in L-NAME-treated animals compared with untreated rats that underwent identical insufflations (Fig. 8).


Figure 7
View larger version (24K):
[in this window]
[in a new window]

  		Fig. 7. Effects of pretreatment with L-NAME (100 mg/l in drinking water) on pneumoperitoneum-induced (IAP = 14 mmHg) renal excretory dysfunction. A and B: V; C and D: UNaV (n = 6). Untreated animals served as controls (n = 7). Data are expressed as absolute values (A and C) and as %change from baseline values (B and D). *P < 0.05 vs. baseline; #P < 0.05 vs. untreated pneumoperitoneum.

 

Figure 8
View larger version (28K):
[in this window]
[in a new window]

  		Fig. 8. Effects of pretreatment with L-NAME (100 mg/l in drinking water) on pneumoperitoneum-induced (IAP = 14 mmHg) renal hemodynamic changes. A and B: GFR; C and D: RPF (n = 6). Untreated animals served as controls (n = 7). Data are expressed as absolute values (A and C) and as %change from baseline values (B and D). *P < 0.05 vs. baseline; #P < 0.05 vs. untreated pneumoperitoneum.

 

   DISCUSSION
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The findings of the present study provide novel information on the effects of pneumoperitoneum on kidney function and renal perfusion and the mechanisms underlying the adverse physiological consequences of this surgical procedure.

As expected, we demonstrated that rats subjected to 14 mmHg of pneumoperitoneum show reductions in both renal hemodynamics and excretory function. Selective ETA or ETB blockers, given separately or combined, aggravated these effects. Similarly, NO inhibition enhanced the pneumoperitoneum-induced renal dysfunction, whereas pretreatment with nondepressor doses of NTG significantly ameliorated the adverse effects of IAP on GFR and RPF. Although NTG maintained V and UNaV during IAP of 14 mmHg, both V and UNaV still decreased relative to the NTG-enhanced basal values. These findings suggest that both ET and NO systems play an important beneficial role in maintaining renal hemodynamic and kidney function during pneumoperitoneum.

A role of ET-1 in the pathogenesis of the adverse renal effects of pneumoperitoneum has been suggested, based on the following findings: first, Hamilton and colleagues (15) reported that plasma levels of ET-1 are elevated in dogs, subjected to 5 h of elevated IAP, within 20 min of insufflation. Moreover, Ambrose and colleagues (1) demonstrated increased expression of ET-1 gene in the renal vasculature and proximal tubule of rats subjected to 30 min of tissue pneumoperitoneum. In addition, infusion of ET-1 into the kidney produced decreases in RBF, GFR, and V, similar to those found during pneumoperitoneum (25). Collectively, this suggests that upregulation of the ET system could play a part in the renal dysfunction associated with pneumoperitoneum and that blockade of this system might improve kidney function. In line with this notion, preliminary data in a rat pneumoperitoneum model indicate that administration of Ro 61–0612, a nonselective ETA- and ETB-receptor antagonist, before and during insufflation, improved kidney function and renal hemodynamics during pneumoperitoneum (1, 39). To the best of our knowledge, the present study is the first one that examines whether selective ETA or ETB blockade can alter the changes in kidney function and renal hemodynamics caused by pneumoperitoneum. In line with its physiological vasodilatory action (14, 19, 25), blockade of ETB receptor aggravated the fall in GFR and RPF during pneumoperitoneum. This observation is further supported by our laboratory's previous findings that ETB receptor is preferably expressed in the outer and inner medulla, mainly in the vasa recta, thick ascending limb of Henles' loop, and collecting duct (11). Moreover, our finding that ETB blockade worsened the oliguria characterizing pneumoperitoneum supports the role of tubular ETB receptors in mediating the diuretic effect of ET-1 under physiological conditions (11, 18, 25).

Unexpectedly, ETA blockade did not prevent the decline in V, UNaV, GFR, and RPF induced by pneumoperitoneum, rather it caused significant decreases in these parameters, comparable to those obtained with ETB antagonist. Taking into account the diuretic action of the ETB receptor, these effects are unexpected and could not be explained by changes in blood pressure, since MAP declined slightly and insignificantly following the administration of ETA blocker. Moreover, one may expect that blockade of ETA, which predominantly localized to the peritubular capillaries and mediates vasoconstriction, should result in an increase in RPF and GFR. Although the bulk of evidence supports a vasodilatory function of ETB receptors, few studies revealed that, in some vascular beds, ET-1 elicits constriction through both receptor subtypes (8, 19, 20). Activation of ETB receptor with selective agonists such as sarafotoxin 6c produced transient depressor response followed by a longer pressor phase (7). Similarly, BQ3020, an ETB agonist, is a potent constrictor of renal and mesenteric vasculature beds (21). Based on these contradictory results, it is widely believed that the endothelial ETB receptor mediates dilatation and the smooth muscle cell ETB receptor mediates constriction (6, 19, 37).

Dual blockade of ETA and ETB resulted in aggravation of the renal excretory function and renal hypoperfusion caused by elevated IAP. However, the magnitude of these decreases in V, UNaV, GFR, and RPF was only slightly higher than those obtained when each antagonist was administered alone, suggesting that blockade of the ET system, either at the ETA or ETB level, is sufficient to eliminate the beneficial effects of this system during pneumoperitoneum. These results are at odds with those reported that administration of Ro 61-0612, a mixed ETA and ETB blocker, attenuated the fall in GFR and oliguria during pneumoperitoneum (1, 39). It should be emphasized that these authors applied similar IAP and drug infusion protocol; however, the pneumoperitoneum was established for only 15 min, which most likely produced less profound insult to renal function compared with the 60 min applied in the present study.

Because endothelium-derived NO is important in the regulation of RBF and kidney function (28, 29), we tested the hypothesis of whether altered activity of the NO system may be involved in the pathogenesis of the reduced RBF and kidney function characterizing pneumoperitoneum. Indeed, the most prominent finding in the present study was the effects of NO modulations on the adverse renal effects of elevated IAP. In that respect, rats that received NTG displayed attenuated renal vasoconstrictive response to pneumoperitoneum, whereas rats pretreated with L-NAME displayed a higher sensitivity to this surgical procedure, suggesting a greater dependence of the kidney on NO as a beneficial counterregulatory system during pneumoperitoneum. This conclusion is compatible with the notion that NO plays a prominent role in the control of renal hemodynamics and tubular function (28, 29). NO is constitutively produced from its precursor, L-arginine, by the enzyme endothelial NO synthase and acts on adjacent smooth muscle cells to exert vasodilatory tone on the renal microvasculature, primarily the afferent arteriole. In addition, NO affects renal function by modulating tubuloglomerular feedback and renin release and by altering tubular salt reabsorption (28, 29). These actions are thought to be mediated by NO generated in vascular endothelial cells, mesangial cells, macula densa, and epithelial tubular cells.

Perspective and Significance

Our study demonstrates for the first time the involvement of the NO system in the adaptive changes in renal hemodynamics and kidney function during the induction of pneumoperitoneum. While blockade of ET or NO systems aggravates the pneumoperitoneum-induced renal hypoperfusion and oliguria, pretreatment with NTG substantially attenuates the adverse effects of elevated IAP on kidney function and renal hemodynamics. Our data may have potential therapeutic implications and suggest that pretreatment with NO donor may be beneficial in the setting of laparoscopic surgery. Future studies are requested to evaluate the effects of pneumoperitoneum on the expression of the various NO synthase isoforms and production of NO in the renal tissue.


   FOOTNOTES
 

Address for reprint requests and other correspondence: Z. Abassi, Dept. of Physiology & Biophysics, Faculty of Medicine, Technion, IIT, P.O. Box 9649, Haifa, 31096, Israel (e-mail: abassi{at}tx.technion.ac.il)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


   REFERENCES
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Ambrose JA, Onders RP, Stowe NT, Simonson MS, Robinson AV, Wilhelm S, Schulak JA. Pneumoperitoneum upregulates preproendothelin-1 messenger RNA. Surg Endosc 15: 183–188, 2001.[CrossRef][Medline]
  2. Arai H, Hori S, Aramori I, Ohkubo H, Nakanishi S. Cloning and expression of a cDNA encoding an endothelin receptor. Nature 348: 730–732, 1990.[CrossRef][Medline]
  3. Chang DT, Kirsch AJ, Sawczuk IS. Oliguria during laparoscopic surgery. J Endourol 8: 349–352, 1994.[Medline]
  4. Chiu AW, Azadzoi KM, Hatzichristou DG, Siroky MB, Krane RJ, Babayan RK. Effects of intra-abdominal pressure on renal tissue perfusion during laparoscopy. J Endourol 8: 99–103, 1994.[Web of Science][Medline]
  5. Clavell AL, Stingo AJ, Margulies KB, Brandt RR, Burnett JC Jr. Role of endothelin receptor subtypes in the in vivo regulation of renal function. Am J Physiol Renal Fluid Electrolyte Physiol 268: F455–F460, 1995.[Abstract/Free Full Text]
  6. Clozel M, Gray GA. Are there different ETB receptors mediating constriction and relaxation? J Cardiovasc Pharmacol 26, Suppl 3: S262–S264, 1995.[Web of Science][Medline]
  7. Clozel M, Gray GA, Breu V, Löffler BM, Osterwalder R. The endothelin ETB receptor mediates both vasodilation and vasoconstriction in vivo. Biochem Biophys Res Commun 186: 867–873, 1992.[CrossRef][Web of Science][Medline]
  8. Davenport AP, Maguire JJ. Is endothelin-induced vasoconstriction mediated only by ETA receptors in humans. Trends Pharmacol Sci 15: 9–11, 1994.[CrossRef][Medline]
  9. Demyttenaere S, Feldman LS, Fried GM. Effect of pneumoperitoneum on renal perfusion and function: a systematic review. Surg Endosc 21: 152–160, 2007.[CrossRef][Medline]
  10. Demyttenaere SV, Feldman LS, Bergman S, Gholoum S, Moriello C, Unikowsky B, Fraser S, Carli F, Fried GM. Does aggressive hydration reverse the effects of pneumoperitoneum on renal perfusion?. Surg Endosc 2: 274–280, 2006.
  11. Francis B, Winaver J, Karram T, Hoffman A, Abassi Z. Renal and systemic effects of chronic blockade of ETA or ETB receptors in normal rats and animals with experimental heart failure. J Cardiovasc Pharmacol 44: S54–S58, 2004.[CrossRef][Medline]
  12. Ge Y, Bagnall A, Stricklett PK, Strait K, Webb DJ, Kotelevtsev Y, Kohan DE. Collecting duct-specific knockout of the endothelin B receptor causes hypertension and sodium retention. Am J Physiol Renal Physiol 291: F1274–F1280, 2006.[Abstract/Free Full Text]
  13. Gudmundsson FF, Viste A, Myking OL, Bostad L, Grong K, Svanes K. Role of angiotensin II under prolonged increased intraabdominal pressure (IAP) in pigs. Surg Endosc 17: 1092–1097, 2003.[CrossRef][Web of Science][Medline]
  14. Gurbanov K, Rubinstein I, Hoffman A, Abassi Z, Better OS, Winaver J. Differential regulation of renal regional blood flow by endothelin-1. Am J Physiol Renal Fluid Electrolyte Physiol 271: F1166–F1172, 1996.[Abstract/Free Full Text]
  15. Hamilton BD, Chow GK, Inman SR, Stowe NT, Winfield HN. Increased intra-abdominal pressure during pneumoperitoneum stimulates endothelin release in a canine model. J Endourol 12: 193–197, 1998.[Web of Science][Medline]
  16. Harman PK, Kron IL, McLachlan HD, Freedlender AE, Nolan SP. Elevated intra-abdominal pressure and renal function. Ann Surg 196: 594–597, 1982.[Web of Science][Medline]
  17. Ho HS, Saunders CJ, Gunther RA, Wolfe BM. Effector of hemodynamics during laparoscopy: CO2 absorption or intra-abdominal pressure? J Surg Res 59: 497–503, 1995.[CrossRef][Web of Science][Medline]
  18. Hoffman A, Abassi ZA, Brodsky S, Ramadan R, Winaver J. Mechanisms of big endothelin-1-induced diuresis and natriuresis : role of ET(B) receptors. Hypertension 35: 732–739, 2000.[Abstract/Free Full Text]
  19. Honoré JC, Fecteau MH, Brochu I, Labonté J, Bkaily G, D'Orleans-Juste P. Concomitant antagonism of endothelial and vascular smooth muscle cell ETB receptors for endothelin induces hypertension in the hamster. Am J Physiol Heart Circ Physiol 289: H1258–H1264, 2005.[Abstract/Free Full Text]
  20. Inscho EW, Imig JD, Cook AK, Pollock DM. ETA and ETB receptors differentially modulate afferent and efferent arteriolar responses to endothelin. Br J Pharmacol 146: 1019–1026, 2005.[CrossRef][Web of Science][Medline]
  21. Just A, Olson AJ, Arendshorst WJ. Dual constrictor and dilator actions of ET(B) receptors in the rat renal microcirculation: interactions with ET(A) receptors. Am J Physiol Renal Physiol 286: F660–F668, 2004.[Abstract/Free Full Text]
  22. Katoh T, Chang H, Uchida S, Okuda T, Kurokawa K. Direct effects of endothelin in the rat kidney. Am J Physiol Renal Fluid Electrolyte Physiol 258: F397–F402, 1990.[Abstract/Free Full Text]
  23. Kitamura K, Tanaka T, Kato J, Ogawa T, Eto T, Tanaka K. Immunoreactive endothelin in rat kidney inner medulla: marked decrease in spontaneously hypertensive rats. Biochem Biophys Res Commun 162: 38–44, 1989.[CrossRef][Web of Science][Medline]
  24. Kohan DE, Hughes AK, Perkins SP. Characterization of endothelin receptors in the inner medullary collecting duct of the rat. J Biol Chem 267: 12336–12340, 1992.[Abstract/Free Full Text]
  25. Kohan DE. Endothelins in the normal and diseased kidney. Am J Kidney Dis 29: 2–26, 1997.[Web of Science][Medline]
  26. Kohzuki M, Johnston CI, Chai SY, Casley DJ, Mendelsohn FAO. Localization of endothelin receptors in rat kidney. Eur J Pharmacol 160: 193–194, 1989.[CrossRef][Web of Science][Medline]
  27. Kone BC. Nitric oxide in renal health and disease. Am J Kidney Dis 30: 311–333, 1997.[Web of Science][Medline]
  28. Kone BC, Baylis C. Biosynthesis and homeostatic roles of nitric oxide in the normal kidney. Am J Physiol Renal Physiol 272: F561–F578, 1997.[Abstract/Free Full Text]
  29. Kone BC. Nitric oxide synthesis in the kidney: isoforms, biosynthesis, and functions in health. Semin Nephrol 4: 299–315, 2004.
  30. Lahera V, Salom Miranda-Guardiola F MG, Moncada S, Romero JC. Effects of NG-nitro-L-arginine methyl ester on renal function and blood pressure. Am J Physiol Renal Fluid Electrolyte Physiol 261: F1033–F1037, 1991.[Abstract/Free Full Text]
  31. Marsen TA, Schramek H, Dunn MJ. Renal actions of endothelin: linking cellular signaling pathways to kidney disease. Kidney Int 45: 336–344, 1994.[Web of Science][Medline]
  32. Mattson DL, Lu S, Cowley AW Jr. Role of nitric oxide in the control of the renal medullary circulation. Clin Exp Pharmacol Physiol 24: 587–590, 1997.[Web of Science][Medline]
  33. Nishio S, Takeda H, Yokoyama M. Changes in urinary output during laparoscopic adrenalectomy. BJU Int 83: 944–947, 1999.[CrossRef][Medline]
  34. Richards WO, Scovill W, Shin B, Reed W. Acute renal failure associated with increased intra-abdominal pressure. Ann Surg 197: 183–187, 1983.[Web of Science][Medline]
  35. Rubanyi GM, Polokoff MA. Endothelins: molecular biology, biochemistry, pharmacology, physiology, and pathophysiology. Pharmacol Rev 46: 325–415, 1994.[Web of Science][Medline]
  36. Sakurai T, Yanagisawa M, Takuwa Y, Miyazaki H, Kimura S, Goto K, Masaki T. Cloning of a cDNA encoding a nonisopeptide-selective subtype of the endothelin receptor. Nature 348: 732–735, 1990.[CrossRef][Medline]
  37. Schneider MP, Boesen EI, Pollock DM. Contrasting actions of endothelin ET(A) and ET(B) receptors in cardiovascular disease. Annu Rev Pharmacol Toxicol 47: 731–59, 2007.[CrossRef][Web of Science][Medline]
  38. Stacy DL, Scott JW, Granger JP. Control of renal function during intrarenal infusion of endothelin. Am J Physiol Renal Fluid Electrolyte Physiol 258: F1232–F1236, 1990.[Abstract/Free Full Text]
  39. Stowe N, Sung G, Sable J, Gill IS. Pretreatment with an endothelin antagonist attenuates the fall in GFR during laparoscopic surgery in a rat model (Abstract). J Am Soc Nephrol 9: 658A, 1998.
  40. Terada Y, Tomita K, Nonoguchi H, Marumo F. Different localization of two types of endothelin receptor mRNA in microdissected rat nephron segments using reverse transcription and polymerase chain reaction assay. J Clin Invest 90: 107–112, 1992.[Web of Science][Medline]
  41. Tirapelli CR, Casolari DA, Yogi A, Montezano AC, Tostes RC, Legros E, D'Orléans-Juste P, de Oliveira AM. Functional characterization and expression of endothelin receptors in rat carotid artery: involvement of nitric oxide, a vasodilator prostanoid and the opening of K+ channels in ETB-induced relaxation. Br J Pharmacol 146: 903–912, 2005.[CrossRef][Web of Science][Medline]
  42. Ujiie K, Terada Y, Nonoguchi H, Shinohara M, Tomita K, Marumo K. Messenger RNA expression and synthesis of endothelin-1 along rat nephron segments. J Clin Invest 90: 1043–1048, 1992.[Web of Science][Medline]
  43. Warner TD, Allcock GH, Corder R, Vane JR. Use of the endothelin antagonists BQ-123 and PD 142893 to reveal three endothelin receptors mediating smooth muscle contraction and the release of EDRF. Br J Pharmacol 110: 777–782, 1993.[Web of Science][Medline]
  44. Warner TD, Battistini B, Allcock GH, Vane JR. Endothelin ETA and ETB receptors mediate vasoconstriction and prostanoid release in the isolated kidney of the rat. Eur J Pharmacol 250: 447–453, 1993.[CrossRef][Web of Science][Medline]
  45. Wilkes BM, Ruston AS, Mento P, Girardi E, Hart D, Vander Molen M, Barnett R, Nord EP. Characterization of endothelin 1 receptor and signal transduction mechanisms in rat medullary interstitial cells. Am J Physiol Renal Fluid Electrolyte Physiol 260: F579–F589, 1991.[Abstract/Free Full Text]
  46. Wilkins FC Jr, Alberola A, Mizelle HL, Opgenorth TJ, Granger JP. Systemic hemodynamics and renal function during long-term pathophysiological increases in circulating endothelin. Am J Physiol Regul Integr Comp Physiol 268: R375–R381, 1995.[Abstract/Free Full Text]
  47. Zacherl J, Thein E, Stangl M, Feussner H, Bock S, Mittlbock M, Erhardt W, Siewert JR. The influence of periarterial papaverine application on intraoperative renal function and blood flow during laparoscopic donor nephrectomy in a pig model. Surg Endosc 17: 1231–1236, 2003.[CrossRef][Web of Science][Medline]
  48. Zou AP, Cowley AW Jr. Nitric oxide in renal cortex and medulla: an in vivo microdialysis study. Hypertension 29: 194–198, 1997.[Abstract/Free Full Text]




This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
294/3/R842    most recent
00691.2007v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Abassi, Z.
Right arrow Articles by Hoffman, A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Abassi, Z.
Right arrow Articles by Hoffman, A.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Visit Other APS Journals Online
Copyright © 2008 by the American Physiological Society.