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1 Department of Gastrosurgical Research, Institute of Surgical Sciences, Sahlgrenska Academy at Göteborg University, PO Box 750 38, SE 400 36 Gothenburg, Sweden
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(Received 21 June 2005;
accepted after revision 13 October 2005; first published online 1 November 2005)
Corresponding author S. Ewert: Department of Gastrosurgical Research, Institute of Surgical Sciences, Sahlgrenska Academy at Göteborg University, PO Box 750 38, SE 400 36 Gothenburg, Sweden. Email: sara.ewert{at}lthalland.se
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Introduction |
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It is well established that the main effector of the RAS, the octapeptide angiotensin II (Ang II), exerts its effects via two receptors, the Ang II type 1 receptor (AT1R) and Ang II type 2 receptor (AT2R; de Gasparo et al. 2000). Recently, we reported that AT1R and AT2R have counteracting influences on DMAS in anaesthetized Sprague–Dawley rats (S–D); activation of AT1R prolongs sympathoadrenergic inhibition of DMAS, whereas AT2R mediates stimulation of this secretion (Johansson et al. 1997, 2001).
The latter effect was recently further investigated using the AT2R agonist CGP42112A and was shown to involve activation of the bradykinin type 2 (BK2) receptor (Ewert et al. 2003a). These studies also demonstrated that the cells expressing AT2R are situated in the villus lamina propria (Johansson et al. 2001), whereas BK2 receptors are located on the cryptal epithelial cells (Ewert et al. 2003a). When these pharmacological experiments were resumed, however, CGP42112A surprisingly did not stimulate DMAS. Since the animal care unit had changed supplier of S–D, we hypothesized that the lack of response to CGP42112A could be due to a lower expression of AT2R in the duodenal tissue of the new line of S–D compared to animals used in the previous studies. This assumption was based on the observation that the AT2R has a rather dynamic pattern of expression in the adult organism and is upregulated in pathological conditions when tissue integrity is challenged, such as following stroke (Zhu et al. 2000), nerve injury (Gallinat et al. 1998), myocardial infarction (Jugdutt, 2001) and during skin wound healing (Kimura et al. 1992; Viswanathan & Saavedra, 1992). Since duodenal tissue biopsies had been saved from both the previous and the new S–D line, it was possible to make a ‘retrospective’ examination concerning the expression of angiotensin II receptors in relation to the secretory response to CGP42112A. We can now report that the new S–D line exhibited a low AT2R expression, which explains the absence of response to the AT2R agonist. In order to further prove this association, we tested whether, in the new line of S–D with confirmed low baseline expression of AT2R, induction of duodenal AT2R expression was related to the appearance of a secretory response to the agonist CGP42112A.
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Anaesthesia and surgical procedures
All experiments were performed on non-fasted male Sprague–Dawley rats weighing 250–400 g delivered by either Møllegard A/S, Denmark (previous line) or B-K Universal, Sweden (new line). Anaesthesia was induced with methohexitone (60 mg kg–1
I.P.) and maintained with 
-chloralose (bolus I.V. of 50 mg kg–1 followed by infusion I.V. 25 mg kg–1 h–1) or by pentobarbitone (60 mg kg–1
I.P. followed by 10 mg kg–1 h–1). Lack of response to interdigital reflex stimuli confirmed an adequate anaesthetic condition. A thermostatically controlled heating pad and a lamp kept the body temperature at 38°C measured by rectal probe. Free airways were ensured by a catheter inserted into the trachea. The right femoral vein and artery were catheterized for drug infusions and measurement of arterial blood pressure (using a Statham P23Dc pressure transducer and a computer to obtain averages over 5 min periods), respectively. To avoid acidosis and to compensate for basal needs and fluid losses due to the surgical trauma, an isotonic buffered glucose (2.5%) solution was infused intra-arterially (3 ml kg–1 h–1) throughout the experiments.
Recording of duodenal mucosal alkaline secretion. A mid-line laparotomy was performed. The common bile duct was catheterized 5 mm proximal to the papilla of Vateri, and secretions of bile and pancreatic juice were collected outside the animal to avoid contamination of the duodenal perfusate. A duodenal segment (length 1.5 cm, proximal end 0.5 cm distal to the pylorus) was isolated between two glass tubes connected to a reservoir enclosed by a water jacket for maintenance of 38°C. Saline solution (150 mM NaCl) was perfused and recirculated through the reservoir and duodenal segment by means of a gas lift (air, 150 ml min–1). Alkaline secretion into the luminal perfusate was titrated to pH 7.40 by automatic infusion of isotonic HCl using a pH-stat equipment (Flemstrom et al. 1982).
Western blot for AT1R and AT2R
Duodenal specimens of full wall thickness were collected immediately after the laparotomy incision, snap frozen in liquid nitrogen and subsequently stored at –70°C. Specimens were thawed and homogenized on ice (Polytron, Kinematica AG, Switzerland) in buffer A (10% glycerol, 20 mmol l–1 Tris-HCl pH 7.3, 100 mmol l–1 sodium chloride, 2 mmol l–1 phenylmethylsulphonyl fluoride, 2 mmol l–1 EDTA, 2 mmol l–1 EGTA, 10 mmol l–1 sodium orthovanadate, 10 mg ml–1 leupeptin and 10 mg ml–1 aprotinin; Ozono et al. 1997). Centrifugation was performed at 30 000g for 30 min at 4°C. The pellet was resuspended in buffer B (1% NP 40 (Sigma) in buffer A) and subsequently stirred at 4°C for 1 h before centrifugation at 30 000g for 30 min at 4°C. The supernatant was analysed for protein content by the method of Bradford (Bradford, 1976) and stored at –70°C for further analysis. Samples were diluted in SDS-buffer and heated at 70°C for 10 min before they were loaded on a NuPage 10% Bis-Tris gel and the electrophoresis run with a Mops buffer (Invitrogen AB, Sweden). One lane of each gel was loaded with SeeBlue prestained molecular weight standards (Invitrogen AB) and two lanes on each gel were loaded with KNRK (for AT2) and PC-12 (for AT1) whole cell lysate (Santa Cruz, CA, USA), serving as positive controls. These positive controls were used for intergel standardization when necessary. After the electrophoresis the proteins were transferred to a polyvinyldifluoride membrane (Amersham, UK) which was incubated with polyclonal specific antibodies of rabbit origin directed to the AT1R and AT2R (Santa Cruz). An alkaline phosphatase-conjugated goat antirabbit IgG antibody (Santa Cruz), with CDP-Star (Tropix, Bedford, MA, USA) as a substrate, was used to identify immunoreactive proteins by chemiluminescense. Images were captured by a LAS-100 cooled CCD camera, and semiquanification was performed using the software Gauge 3.3 (Fujifilm, Tokyo, Japan).
Real-time PCR
The tissue was homogenized and total RNA obtained using phenol–chloroform extraction and ethanol precipitation. The RNA concentration was quantifed by absorbance measurement at 260 nm and the integrity was assessed by absorbance measurement at 280 nm. Reverse transcription from 5 µg of total RNA was carried out using the SUPERSCRIPTTM First-Strand Synthesis System (Invitrogen AB) with Oligo (dT) primers (Life Technologies, Taby, Sweden) according to the manufacturers instructions. cDNA was stored at –20°C until use. Lightcycler Q-PCR (Roche Diagnostics AB, Sthlm, Sweden) performed the PCR reaction in a volume of 20 ml using the FastStart DNA Master SYBR Green I (Roche Diagnostics AB) according to the manufacturer's instructions. The MgCl2 concentration was optimized to 4 mM to obtain the highest signal intensity and lowest background. The primer concentrations were 500 nM in each reaction. Specific primer sequences, concentrations and PCR conditions and references are shown in Table 1. Sample concentration was determined from a standard curve for each pair of primers. The quantification was performed by the software supplied by Roche Diagnostics (Mannheim, Germany). Data on AT1aR and AT2R RNAs are given in relation to a housekeeper gene (GAPDH) or as a ratio of AT1R to AT2R.
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Comparison of previous and new S–D lines. Duodenal secretion and mean arterial pressure were monitored according to a standardized protocol (Johansson et al. 2001). After 60 min recovery from surgery, baseline recordings were made over 30 min, after which drugs were administered; CGP42112A (or saline vehicle) infusion intravenously at a rate of 0.1 µg kg–1min–1 for 45 min or prostaglandin E2 (PGE2) 10–5 M intraluminally. The end-point variable was the net drug-induced response expressed as a percentage of the individual baseline. Net change was defined as the difference between an average of the last 15 min period of drug administration and basal conditions. In a subset of animals, antemesenteric duodenal specimens of full wall thickness (corresponding to the part used in secretion experiments) were collected immediately after the abdominal incision. Subsequently the animals were killed by a lethal dose of anestetic (I.V.) followed by cardiac inscision.
Dose-finding experiments. AT2R expression has previously been reported to be stimulated by Ang II in vitro or following chronic administration in vivo (Zahradka et al. 1998; Ruiz-Ortega et al. 2003; Yayama et al. 2004). Few data exist on the effects of acute administration of Ang II in vivo, and a dose-finding study was first performed using 120 min Ang II treatment. Animals were distributed into three groups that received intravenously saline vehicle (150 mM NaCl), Ang II at 2.5 µg kg–1 h–1 or Ang II at 10 µg kg–1 h–1 for 120 min. Mean arterial pressure was continuously recorded. After treatment, a mid-line laparotomy was performed and duodenal full wall biopsies were collected.
AT2R expression versus secretory response. Based on the dose-finding experiments, Ang II infusion was prolonged to 240 min at a rate of 10 µg kg–1 h–1. To minimize handling bias, parallel experiments using infusion of isotonic saline were simultaneously performed. After cessation of the intravenous infusion, a laparotomy was performed and the duodenum was instrumented for alkaline secretion measurements as described above. In association with the surgical preparation, duodenal full wall biopsies were collected. The alkaline secretion was monitored over a 30 min baseline period and 60 min of CGP42112A treatment at 0.1 µg kg–1 min–1 (a dose previously reported to stimulated DMAS by AT2R selective activation; Johansson et al. 2001).
Drugs
Pentobarbital sodium (Apoteksbolaget, Umea, Sweden). methohexitone (BrietalTM, Lilly Inc., Indianapolis, IN, USA), CGP42112A (peptidergic AT2-receptor agonist; Neosystem, Strasbourg, France), and angiotensin II (Sigma, St Louis, MO, USA) were dissolved in saline solution (150 mM NaCl). -Chloralose (Kebo Laboratory, Spanga, Sweden) was dissolved in tetraborate decahydrate (Merck, Darmstadt, Germany) and titrated to pH 7.40. Prostaglandin E2 (Sigma) was dissolved in ethanol and isotonic saline.
Statistics
Changes in alkaline secretion and mean arterial pressure were analysed by ANOVA for repeated measurements and Student's unpaired t test. Receptor expression datasets were analysed by Kruskal–Wallis or Mann–Whitney U test. Data are presented as means (S.E.M.). P < 0.05 was considered significant.
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Results |
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In the previous line, mean basal DMAS was 10.5 (0.8) µeq ch–1 h–1 (n = 21) and ranged from 5 to 19 µeq ch–1 h–1. In relation to individual baseline secretion, the AT2R agonist CGP42112A (infused intravenously at a rate of 0.1 µg kg–1 min–1) elicited a significant and quite evenly distributed secretory increase with a group mean (S.E.M.) of 45 (8)% (n = 9). Animals recieving only vehicle lacked response (n = 6; Fig. 1). In the new line, a similar dose of CGP42112A did not elicit any change in DMAS (n = 11), which was similar to animals recieving vehicle (n = 10; Fig. 1). Intraluminal administration of the secretagogue PGE2 (10–5 M, ethanol less than 2%) elicited a significant 91 (22)% (n = 6) and 92 (33)% (n = 6) net increase of the duodenal mucosal alkaline secretion in the new and the previous line, respectively (Fig. 1). The baseline mean arterial pressure was 123 (2) mmHg (n = 44) and neither changed over time during the protocol in any group nor differed between groups.
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The ability of a 120 min systemic administration of angiotensin II to influence the relation AT1R to AT2R expression was tested. Two infusion rates of Ang II (2.5 and 10 µg kg–1 h–1) were employed and compared to saline vehicle (150 mM NaCl). Mean arterial pressure increased dose dependently in the Ang II-treated groups but remained at the baseline level in the group receiving saline (Table 2). The individual ratios between AT1R and AT2R analyses were used as indicators of changes in RNA and protein expression. Regardless of the Ang II infusion rate, protein expression was similar to the group receiving saline (data not shown). The AT1aR to AT2R RNA ratio, however, was significantly lower in the group receiving 10 µg kg–1 h–1 Ang II than in the saline-infused control group (Fig. 4).
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Based on the dose-finding experiment results, an infusion rate of 10 µg kg–1 h–1 of Ang II was used, but administration was prolonged to 4 h. As expected, mean arterial pressure increased significantly during Ang II infusion, but remained unchanged in control animals (Table 2).
Following the 4 h infusion protocol, AT1R protein expression did not differ significantly between the Ang II-administered group and the time controls receiving saline. AT2R expression, however, was significantly higher in the Ang II-treated S–D rats (Fig. 5).
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Discussion |
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The investigation demonstrates a clear relation between the effect of CGP42112A on duodenal mucosal alkaline secretion and the expression of Ang II receptors in the rat duodenum. Lower expression of AT2R relative to AT1R, as demonstrated by analyses of both RNA and protein expression, was associated with a lack of response in duodenal mucosal alkaline secretion. In the previous experiments, however, which represented the conditions reported by Johansson et al. (2001), AT2R was expressed at a higher level and administration of CGP42112A induced a marked secretory response. It should be stressed that the reference stimulation by intraluminal administration of the secretagogue PGE2 was of a similar order of magnitude in both settings. PGE2 has a main point of action in the secreting surface epithelium that is clearly separated from the postulated location of the AT2R (Johansson et al. 2001; Morrow & Roberts, 2001; Ewert et al. 2003a). The preserved effect of PGE2 strongly indicates that the mucosal secretory capacity per se did not differ between the two rat lines.
It is interesting to note that the two lines responded differently to the AT2R agonist although both were of the Sprague–Dawley genotype. The reason for this phenotypic difference is obscure, but may be because the two lines were raised at separate locations and in different environments. The AT2Rs are markedly expressed during fetal development in most tissues, but decline after birth. In adult tissues, AT2R expression has been shown to exist, for example, in the adrenal glands, the uterus and the heart (de Gasparo et al. 2000). AT2R expression is markedly upregulated during pathological conditions with challenged tissue integrity, such as skin wound healing (Kimura et al. 1992), myocardial infarction (Jugdutt, 2001) and cerebral infarction areas (Zhu et al. 2000). Low AT2R expression should also be possible to trace in other organ systems. These tissues, however, were not saved from the previous line and the analysis could therefore not be performed. Thus, it may be that environmental factors directly influence receptor expression in the intestinal tissue.
The previous S–D line (with a higher level of AT2R expression) had been subject to relapsing viral infections in our animal housing. The RAS is involved in regulating inflammatory conditions at several levels (Ruiz-Ortega et al. 2001a,b). It is well known that the AT2R is involved in apoptosis and release of NO (Berry et al. 2001), which in the intestine could to be of importance for the host defence against intestinal infections. Although speculative, it may be that the better general health of the new S–D line had led to less stimulation of duodenal mucosal AT2R expression.
Other confounding factors possibly influencing AT2R expression could be the habitat for the experimental animals, e.g. the environment in which the animals were housed, the spaciousness of the cages, possibilities of exercise and the social environment. Most rats housed for experimental reasons receive standard rat chow, but differences may exist between the food they receive during development at the breeder's premises. The renal AT2R expression has been shown to be induced by dietary sodium depletion in the adult rat (Ozono et al. 1997), and a high-salt diet has been shown to inhibit AT2R expression in mesenteric resistance arteries (Gonzalez et al. 2005). These factors were not possible to control retrospectively, but ought to be focused on in future studies.
The compound CGP42112A is often used as an AT2R agonist, but its receptor selectivity and efficacy can been questioned. In some experimental systems in vitro, CGP42112A has been ascribed properties of a partial agonist and at high concentrations it has been shown to act as an antagonist at both the AT1R and the AT2R (Macari et al. 1993, 1994). It follows that effects of CGP42112A attributed to actions via AT2R have to be confirmed in each in vivo model used, by showing sensitivity to a selective AT2R antagonist, preferably compound PD123319. Such a pharmacological pattern has accordingly been demonstrated with regard to rat DMAS by Johansson et al. (2001). The present observed finding of a positive association between duodenal AT2R expression and pharmacological effect strengthens the previous conclusion that CGP42112A is a selective AT2R agonist in rat small intestine (Jin et al. 1998, 1999; Johansson et al. 2001). But then again, concerning the usefulness of CGP42112A as a pharmacological tool in investigating AT2R in vivo actions, we want to stress the necessity to investigate the presence of Ang II receptor populations and the CGP42112A receptor-specific effects in each in vivo model.
In order to demonstrate a receptor-specific relation to DMAS convincingly, it was considered of great value to induce AT2R expression in the new line of S–D rats, which had confirmed low expression of receptor in baseline conditions, and then to demonstrate a secretory response to CGP42112A. Several authors have reported that the natural ligand Ang II influences AT2R expression (Ouali et al. 1997; Zahradka et al. 1998; Bonnet et al. 2001). The present dose-finding procedure showed an altered transcription of Ang II receptor genes rapidly, after 2 h of intravenous infusion of Ang II at an infusion rate which raised the mean arterial pressure. Not surprisingly, however, a 2 h infusion did not induce changes in Ang II receptor protein expression as assessed. When the Ang II infusion was prolonged to 4 h, the AT2R protein expression increased significantly compared to the saline-infused control group. Furthermore, in this situation, pharmacological stimulation of the AT2R by CGP42112A was associated with a secretory response, which demonstrated that the receptors were functional.
The question whether Ang II causes AT2R gene transcription via interaction with Ang II receptors, directly or indirectly via, e.g. aldosterone, or whether it is a secondary effect brought about, for example, by the rise in MAP is still to be determined (Bonnet et al. 2001; Yayama et al. 2004; Gonzalez et al. 2005).
In summary, the present study demonstrates a differential RNA and protein expression of Ang II receptors in rat duodenal tissue and a related difference in AT2R agonist-induced duodenal mucosal alkaline secretion. These differences are confined to separate lines of experimental animals. We conclude that both the AT2R RNA and protein expression differed significantly between the two S–D lines, which probably explained the presence or absence of response to the AT2R agonist CGP42112A. This interpretation was strongly supported by the observation that pharmacological induction of AT2R was associated with the appearance of a functional secretory response. The present study highlights the difficulty of using in vivo models and the importance of taking many biological factors into consideration, e.g. the level of expression for a regulatory system under study.
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