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1 Departments of Physiology and Biophysics/Medicine, University of Calgary, Calgary, Alberta, Canada T2N 4N1
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Abstract |
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(Received 15 June 2005;
accepted after revision 3 August 2005; first published online 9 August 2005)
Corresponding author F. G. Smith: Department of Physiology and Biophysics, Faculty of Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, Canada T2N 4N1. Email: fsmith{at}ucalgary.ca
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Introduction |
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During the perinatal period, the renin–angiotensin system is activated, with increased plasma levels of renin and ANG II before birth and a further increase following the transition to newborn life; as postnatal maturation proceeds, renin and ANG II levels decline (Trimper & Lumbers, 1972; Broughton Pipkin et al. 1974; Pelayo et al. 1981; Rosenfeld et al. 2003; Monument & Smith, 2003). In addition, the expression of AT1 and AT2 receptors is developmentally regulated, with AT2 receptors predominating in the brain, adrenal gland and kidney of fetal and newborn rats, fowl, rabbits, sheep and humans (Millan et al. 1991; Gröne et al. 1992; Bensoussan et al. 1993; Ciuffo et al. 1993; Robillard et al. 1994; Robillard et al. 1995; Arens et al. 1998; Wintour et al. 1998; Kaiser et al. 1998; Wintour et al. 1999; Burrell et al. 2001; Bagby et al. 2002a,b; Kintscher & Unger, 2003). Apart from umbilical VSM cells, the AT2 receptor is the primary receptor subtype expressed in systemic arterial VSM cells of near-term fetal sheep and newborn lambs (Cox & Rosenfeld, 1999). After 2 weeks of postnatal life, there is a transition from AT2 to AT1 receptors that is complete by 3 months of age in sheep (Kaiser et al. 1998; Cox & Rosenfeld, 1999). This is similar for major blood vessels of the developing swine (Bagby et al. 2002b). However to date, the physiological impact of (a) elevated ANG II levels, and (b) increased AT2 receptor expression early in life is poorly understood.
The present experiments were designed to test the hypothesis that AT2 receptors buffer the vasoconstrictor response to AT1 receptor activation by ANG II, in an age-dependent manner, therefore making the vasculature of newborns less sensitive to ANG II. To test this hypothesis, dose-dependent effects of acute administration of ANG II on systemic and renal haemodynamics were measured in lambs aged 
1 week when circulating levels of renin (Monument & Smith, 2003; Thomsen & Smith, 2004) and ANG II (Wilson et al. 1981b; Rosenfeld et al. 2003) as well as the expression of AT2 receptors in VSM cells (Kaiser et al. 1998; Cox & Rosenfeld, 1999) are high, and 6 weeks when renin (Monument & Smith, 2003; Thomsen & Smith, 2004) and ANG II levels (Wilson et al. 1981b; Rosenfeld et al. 2003) as well as AT2 receptors in VSM cells (Kaiser et al. 1998; Cox & Rosenfeld, 1999) are lower. In additional experiments, to determine whether responses to ANG II are mediated by activation of AT1 or AT2 receptors, application of ANG II at the EC50 value was also tested in the presence of the specific ANG II AT1 receptor antagonist, ZD 7155, the specific AT2 receptor antagonist, PD 123319, and vehicle.
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Methods |
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1 (n
= 14) and 6 weeks (n
= 28). Details of the animals studied are shown in Table 1. Lambs were obtained from a local source (Woolfitt Acres, Olds, Alberta, Canada) and housed with their mothers in individual pens in the vivarium of the Health Sciences Centre, except during training, surgery and experiments. All surgical and experimental procedures described herein were carried out according to the ‘Guidelines for the Care and Use of Laboratory Animals’ provided by the Canadian Council on Animal Care, and were approved by the Animal Care Committee of the University of Calgary.
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Surgery was performed on lambs using sterile techniques, as previously described (Smith & Abraham, 1995). Briefly, anaesthesia was induced with halothane (3–4%) in oxygen via a mask, the trachea was intubated and anaesthesia was maintained with halothane (1–1.5%) in a mixture of nitrous oxide and oxygen (3 : 1). The femoral veins were cannulated (PE 160, Intramedic) and the catheters advanced to the inferior vena cava for intravenous (I.V.) infusions during experiments and for measurements of mean venous pressure. The left femoral artery was also cannulated (PE 160) and the catheter advanced to the abdominal aorta for measurement of arterial pressure during experiments. Catheters were tunnelled subcutaneously to exit the lamb on the right and left flanks. Through a left flank incision to expose the left kidney, a precalibrated ultrasonic flow transducer (3–6 mm, Transonics Systems Inc.) was placed around the left renal artery for measurement of RBF during experiments, as previously described (de Wildt & Smith, 1997). All incisions were sutured, and the catheters and flow transducer cable were secured in pouches on a body jacket (Lomir Inc.), for safe storage. Lambs were allowed to recover from the effects of surgery and anaesthesia in a critical care unit for small animals (Shor-line, Schroer Manufacturing Co.) with adjustable oxygen supply and, when standing, were returned to their mothers in the vivarium. Antibiotics (Synergistin, sulbactam benzathine 3.3 mg kg–1/ampicillin trihydrate 6.6 mg kg–1) were administered intramuscularly on the day before surgery and at 24-h intervals during the recovery period, for an additional 48 h. During the recovery period, lambs were trained for at least 60 min daily to rest quietly in a supportive sling in the laboratory environment.
Experimental details
On the day of an experiment, the lamb was removed from the vivarium and placed in the same supportive sling in the laboratory environment for 60 min. During this equilibration period, an I.V. infusion of 5% dextrose and 0.9% sodium chloride was started and continued throughout the experiment at 4.17 ml h–1 kg–1, to assist in maintaining fluid balance during experiments. Catheters were connected to pressure transducers (Statham, P23XL) for pressure measurements; the flow transducer was connected to a flowmeter (T101, Transonics Systems Inc.) for measurement of RBF. Pressures and RBF were recorded onto a polygraph (Grass Instruments, Model 7) and simultaneously digitized at 200 Hz using the data acquisition and analysis software package, PolyVIEW (AstroMed Inc.). After experiments were completed, lambs were killed with a lethal dose of sodium pentobarbitone. Placement of catheters and the flow transducer was confirmed by post-mortem inspection, and the zero offset of the flow transducer was determined; both kidneys were removed and immediately weighed.
Detailed protocols
Protocol I.
Experiments consisted of haemodynamic measurements for 10 s before (Control) and for 60 s after administration of one of 11 doses of ANG II (0, 0.39, 0.78, 1.56, 3.125, 6.25, 12.5, 25, 50, 100 and 200 ng kg–1). Each dose was administered twice, in random order, with 5–7 min between each dose (based upon the known half-life of ANG II of 20 s measured in sheep; Rosenfeld et al. 1995), and to allow the haemodynamic variables to return to control levels between each dose. For each experiment, all doses were administered in the same volume (0.03–0.04 ml kg–1) and infused I.V. over 10 s using a microprocessor-controlled syringe pump (Model 100, Stoelting, KD Scientific). This protocol was used to select the EC50 dose for the ANG II-dependent MAP response for protocol II.
Protocol II. Responses to the EC50 dose of ANG II, calculated from protocol I, were measured. This was followed by I.V. administration of 400 µg kg–1 of the specific ANG II AT1 receptor antagonist, ZD 7155, 400 µg kg–1 of the specific ANG II AT2 receptor antagonist, PD 123319, or vehicle. (Doses of ZD 7155 and PD 123319 were selected from preliminary dose–response studies). ZD 7155 or PD 123319 were administered only once and separate animals were used for each experiment. For each dose of ZD 7155 or PD 123319, as well as for vehicle, the same volume was administered (0.48–1.33 ml kg–1) over 2 min using a microprocessor-controlled syringe pump (Model 100, Stoelting, KD Scientific). After 30 min, the MAP and RBF responses to ANG II at the EC50 were again measured. MAP and RBF were continuously digitized at 200 Hz during the experimental period.
Drugs
ANG II (Sigma-Aldrich Canada Ltd) was dissolved in a sterile solution of 0.9% sodium chloride to make a stock solution of 1 mg ml–1. Doses of ANG II were made by serial dilution, and stored at –20°C in 1-ml aliquots. Both ZD 7155 (5,7-diethyl-3,4-dihydro-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1,6-napthyridin-2(1H)-one hydrochloride) and PD 123319 (1-[[4-(dimethylamino)-3-methylphenyl]methyl]-5-(diphenylacetyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylic acid trifluoroacete) were manufactured by Tocris Cooksons Ltd (Bristol, UK). On the morning of each experiment, ZD 7155 and PD 123319 were weighed and immediately dissolved in a sterile solution of 0.9% sodium chloride, as required. The same volume of 0.9% sodium chloride was used as vehicle.
Selection of drugs
We selected ZD 7155 because it is a potent, highly selective and reversible antagonist for the AT1 receptor that does not generate an active metabolite, as is the case for losartan. It was also considered better than EXP 3174, which has non-competitive antagonistic effects on the AT1 receptor (Timmermans et al. 1993). ZD 7155 is 10-fold more potent than losartan in antagonizing ANG II-induced pressor effects in conscious rats (Junggren et al. 1996), and it readily displaces [125I]-ANG II in a concentration-dependent manner from its binding sites on guinea-pig adrenal gland membranes (Wong et al. 1992). PD 123319 is a highly selective, reversible antagonist for the AT2 receptor and therefore a suitable drug choice for haemodynamic measurements in conscious animals (Siragy & Carey, 2001).
Data analyses
Systolic arterial pressure (SAP), diastolic arterial pressure (DAP), and MAP were determined for each experiment using the analyses component of PolyVIEW. RBF measured in the two age groups was normalized per gram of kidney weight. Renal vascular resistance (RVR) was calculated as: (MAP – MVP)/RBF, where MVP refers to mean venous pressure. Statistical tests were carried out using Sigmastat Version 3.0 (Jandel Scientific) and a confidence interval of 95%; normality of distribution was confirmed prior to testing. All data are expressed as mean ± one standard deviation.
Protocol I. Data were averaged over the 10-s control period to one control measurement. Using the analyses component of PolyVIEW, the maximum response to ANG II, as well as the time to maximum response after application of ANG II, was determined for each trial at each dose; the two trials at each dose were averaged and the data pooled. Dose–response relationships were constructed for ANG II dose–MAP response and ANG II dose–RBF response in both age groups. The EC100 was measured for both variables for both age groups as well as the time to peak response; the EC50 was calculated as the dose that elicited a half-maximal change in MAP or RBF. Statistical differences were evaluated using two-way ANOVA, factors being age and dose. Where the F-value was significant, Holm-Sidak multiple comparison procedures (Ludbrook, 1991) were applied to determine where the significant differences occurred.
Protocol II. MAP and RBF responses to ANG II measured before and after application of ZD 7155, PD 123319 or vehicle, were evaluated using ANOVA with factors, age (1 week, 6 weeks), treatment (vehicle, ZD 7155, PD 123319) and time (Control, 30 min). Where the F-value was significant, Holm-Sidak multiple comparison procedures were applied to determine where significant differences occurred (Ludbrook, 1991). Comparisons between baseline variables were made using non-paired t tests.
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Results |
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Table 1 shows demographics of conscious lambs studied in protocol I. MAP was lower at 1 week (71 ± 7 mmHg) compared to 6 weeks (77 ± 8 mmHg; P < 0.001); RBF was also lower at 1 week (2.8 ± 0.8 ml min–1 g–1) compared to 6 weeks (3.25 ± 1.1 ml min–1 g–1; P = 0.024).
There was an effect of dose (F = 122.8, P < 0.001) and age (F = 47.4, P < 0.001) on the MAP response to ANG II as well as an interaction between dose and age (F = 4.2, P < 0.001). Administration of ANG II was associated with a dose-dependent increase in MAP to the EC100 value of 100 ng kg–1 in lambs aged both 1 and 6 weeks (Fig. 1). The increase in MAP was significantly greater than zero for doses of 12.5 ng kg–1 at 1 week and 3.125 ng kg–1 at 6 weeks. Details of MAP responses at EC100 value of ANG II are shown in Table 2. Changes in MAP resulted from age- and dose-dependent increases in both SAP and DAP, the profiles of which mirrored the MAP responses to ANG II in both age groups.
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Protocol II
Administration of ZD 7155, but not PD 123319 or vehicle, abolished by 100% the MAP and RBF responses to ANG II in both age groups of lambs measured at 30 min compared to Control (Figs 3 and 4).
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Discussion |
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During fetal life, the renin–angiotensin system is activated, thus levels of renin and ANG II are high near-term (Trimper & Lumbers, 1972; Broughton Pipkin et al. 1974; Pelayo et al. 1981; Rosenfeld et al. 2003). The transition from fetal to newborn life is associated with a further activation of the renin–angiotensin system (Lumbers & Reid, 1977; Davidson, 1987); after birth, renin and ANG II levels decline (Broughton Pipkin et al. 1974; Pelayo et al. 1981; Rosenfeld et al. 2003; Monument & Smith, 2003) Binder & Anderson (1992) demonstrated a negative correlation between plasma renin activity (PRA) and arterial pressure measured in fetal sheep near term, and in newborn lambs in the 24 h after delivery by caesarean section and during the first week of postnatal life. In developing sheep, PRA decreases from 15.7 ± 8.4 ng ANG I ml–1 h–1 at 1 week to 2.7 ± 1.6 ng ANG I ml–1 h–1 at 6 weeks, and to adult levels of 1.6 ± 1.5 ng ANG I ml–1 h–1 at 12 weeks (Monument & Smith, 2003). During this 12 week period, arterial pressure increases slightly, while renal vascular resistance decreases dramatically.
Except for in umbilical VSM cells, the AT2 receptor is the primary receptor subtype expressed in systemic arterial VSM cells of near-term fetal sheep and newborn lambs (Cox & Rosenfeld, 1999). After 2 weeks of postnatal life, there is a transition from AT2 to AT1 receptors that is complete by 3 months of age in sheep (Kaiser et al. 1998; Cox & Rosenfeld, 1999). This is similar for major blood vessels of the developing swine (Bagby et al. 2002b). AT2 receptor expression is also present at the onset of kidney development and decreases during gestation in developing sheep (Butkus et al. 1997; Gimonet et al. 1998), as in other species (Shanmugam et al. 1994; Kakucki et al. 1995). In sheep, however, where nephrogenesis is complete before birth, AT2 receptor mRNA expression is almost undetectable after 120 days of gestation; in mouse and rat, AT2 mRNA persists until nephrogenesis is complete in the weeks after birth. AT1 mRNA expression is also present during fetal life in sheep (Robillard et al. 1994; Butkus et al. 1997; Gimonet et al. 1998), as in other species (Tufro-McReddie et al. 1993; Shanmugam et al. 1994; Kakucki et al. 1995), yet persists after nephrogenesis is complete. Furthermore, it is localized in differentiated structures (Gimonet et al. 1998) suggesting more of a functional role in contributing to mesangial and/or smooth muscle cell formation.
In previous studies, blood pressure responses to exogenous administration of ANG II have been measured in fetal and newborn animals (Iwamoto & Rudoph, 1981; Siegel, 1981; Wilson et al. 1981a,b; Velaphi et al. 2002; Shi et al. 2004). For example, in 
-chloralose-anaesthetized lambs, infusion of ANG II at a rate of 0.1 µg kg–1 min–1 over several minutes increased blood pressure by 40% (Goetzman & Bennett, 1991). Davidson (1987) infused 0.1–2.3 µg min–1 of ANG II for 2 min to conscious lambs in the hours after birth and observed an increase in blood pressure which correlated with plasma ANG II. In lambs and ewes studied 48 h after catheter placement under local anaesthetic, Siegel (1981) measured blood pressure responses to ANG II infused over 30 min. Ten times the concentration of ANG II was required in lambs to raise blood pressure to the same extent as in ewes, providing evidence that the pressor response to ANG II is reduced early in life. This is similar to our present observations that MAP responses to ANG II were greater at 6 than at 1 week of postnatal life in conscious lambs. Velaphi et al. (2002) also measured blood pressure responses to four doses of ANG II ranging from 0.04 to 0.4 µg kg–1 min–1, each infused I.V. over 7 min at three postnatal ages in conscious lambs. A dose-dependent increase in arterial pressure that was similar across the three age groups was reported. This confirms results from a previous study by Wilson et al. (1981b) in which blood pressure increased following 30-min ANG II infusions, also in a dose-dependent manner; the effects were similar in lambs aged between 1 and 7 weeks. However, responses to such longer-term ANG II infusions maybe complicated by factors other than the acute, direct effects of ANG II. For example, an increased circulating level of ANG II is associated with stimulation of other vasoactive factors, such as prostaglandins, nitric oxide or kinins, inhibition of renin release, activation of the sympathetic nervous system, direct cardiac effects and alterations in CNS control of the baroreceptor reflex, as well as secondary effects of ANG II centrally on other systems such as arginine vasopressin (Breuhaus & Chimoskey, 1990; Lüscher, 1990; Butler et al. 1994; Brooks, 1997; Dendorfer et al. 1998; de Gasparo, 2002).
Effects of endogenously produced ANG II have also been evaluated in developing animals. For example, in anaesthetized newborn pigs, angiotensin converting enzyme (ACE) inhibition following administration of enalaprilat, is associated with a reduction in arterial pressure as well as RBF (Nilsson & Friberg, 2000). In previous studies in conscious, chronically instrumented 3-week-old lambs (de Wildt & Smith, 1997; Smith et al. 1997), we showed that ACE inhibition by administration of captopril was associated with a decrease in DAP and MAP, and an increase in heart rate, as well as a decrease in RBF. More recently, we administered captopril to conscious lambs, aged 1 and 6 weeks, to assess the cardiovascular effects of endogenously produced ANG II during postnatal development (Monument & Smith, 2003). A decrease in MAP and an increase in heart rate occurred after ACE inhibition; these effects were greater in lambs aged 1 week compared with lambs aged 6 weeks. The fact that the pressor and renal vascular responses to ANG II were not significantly altered by administration of PD 123319 in the present study is not surprising as AT2-dependent vasodilatation after exposure to exogenous ANG II involves bradykinin B2 receptor activation (Siragy, 2000). Widdop et al. (1992) measured blood pressure as well as flow to kidney, mesentery and hindquarters using Doppler shift in conscious Long-Evans rats and assessed the effects of ANG II before and after administration of the AT1 receptor antagonist, EXP 3174, and the AT2 receptor antagonist, PD 123319. EXP 3174, but not PD 123319, inhibited the pressor and haemodynamic responses to ANG II. This is in keeping with our present observations in conscious developing lambs. Scheuer & Perrone (1993) first described a role for AT2 receptors in modulating the blood pressure responses to ANG II. In that study, ANG II injected into anaesthetized rats at doses of 100–1000 ng kg–1 elicited a dose-dependent depressor response 1–4 min after the initial pressor response. Blockade of the pressor responses to ANG II by the selective AT1 receptor antagonist, losartan, unmasked a more consistent depressor response which was abolished by combined AT1 and AT2 receptor blockade. In the present study in conscious lambs, the depressor response observed by Scheuer & Perrone (1993) in the minutes following high doses of ANG II was not seen even at the highest doses tested. This may have been due either to differences in species (sheep versus rat), experimental conditions (anaesthetized versus conscious) and/or dose (0–200 versus 100–1000 ng kg–1). Inhibition of AT1 receptors would also increase circulating renin and ANG II levels which might in turn activate AT2 receptors. Combined AT1 and AT2 receptor antagonism may reveal such an additive effect.
In conclusion, the present experiments provide new information that acute ANG II administration to conscious lambs results in a dose-dependent increase in MAP and decrease in RBF. Effects of ANG II on both variables appear greater at 6 weeks than at 1 week of age, in conscious lambs. Furthermore, both pressor and renal vasoconstrictor effects of ANG II during the first 6 weeks of postnatal life in lambs are elicited by activation of AT1 but not AT2 receptors. In addition, effects of endogenously produced ANG II on blood pressure and renal vascular tone appear to be modulated exclusively by activation of AT1 receptors soon after birth. A physiological role for AT2 receptors in the immediate newborn period remains to be determined. Part of this work has been reported previously in abstract form (Chappellaz & Smith, 2004, 2005).
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P < 0.05 compared to 1 week; 
EC100.
