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¹ Department of Physiology & Biophysics, Faculty of Medicine, University of Calgary, Calgary, Alberta T2N 4N1, Canada

	Abstract

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Both prostaglandins (PGs) PGE₂ and PGI₂ can act as renal vasodilators, these effects being exacerbated when the renin–angiotensin system is activated. Therefore, we hypothesized that PGs would play a more predominant role in modulating renal haemodynamics in the newborn period, when the renin–angiotensin system is activated. To this end, the role of endogenously produced PGs in modulating systemic and renal haemodynamics was investigated in two groups of conscious lambs aged 1 and 6 weeks. Arterial pressure, venous pressure and renal blood flow were measured for 5 min before (control) and for 20 min after intravenous injection of vehicle (experiment 1). Twenty-four hours later, this protocol was repeated with intravenous injection of the non-selective cyclo-oxygenase inhibitor indomethacin (1 mg kg^–1, experiment 2). Heart rate was calculated from the systolic peak of the arterial pressure waveform, and renal vascular resistance (RVR) was calculated from the measured variables. In response to indomethacin but not vehicle, in both age groups of lambs there was an increase in mean arterial pressure and pulse interval, as well as a marked increase in RVR. These responses to indomethacin were, however, transient, with baseline levels being resumed within minutes. Although the hypothesis that PGs play a greater role in modulating renal haemodynamics early in life is not supported, these data do provide evidence that endogenously produced PGs modulate systemic and renal haemodynamics during postnatal maturation. It is apparent, however, that other vasoactive factors must be rapidly recruited in order to buffer the circulatory responses to removal of vasodilatory PGs in the developing newborn.

(Received 17 October 2006; accepted after revision 18 December 2006; first published online 18 January 2007)
Corresponding author F. G. Smith: Department of Physiology & Biophysics, Faculty of Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta T2N 4N1, Canada. Email: fsmith{at}ucalgary.ca

	Introduction

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Prostaglandins (PGs) are produced constitutively by many tissues in the body and are involved in a variety of physiological processes, including inflammation, gastric motility and renal function. Prostaglandins comprise a diverse family of biologically active lipids derived from the enzymatic metabolism of arachidonic acid by cyclo-oxygenase (COX) to PGG₂/H₂ followed by the generation of five primary bioactive prostanoids: PGE₂, PGI₂, PGD₂, PGF₂ and thromboxane A₂ (Breyer & Breyer, 2000a,b; Funk, 2001).

Although PG synthesis occurs in all cells and tissues, the kidney is a particularly rich source, with PGE₂ being the major prostanoid excreted in the urine. Among the COX products, PGE₂ is released in greatest abundance from all nephron segments (Bonvalet et al. 1987), both basally and when stimulated, and can also be released, along with PGI₂, from the vascular endothelium and vascular smooth muscle cells (Purdy & Arendshorst, 1999). Prostaglandin E₂ interacts with four G protein-coupled E-prostanoid receptors, designated EP_1–4. Through these receptors, PGE₂ influences a variety of physiological functions in the mammalian kidney, including glomerular ultrafiltration and tubular Na⁺ transport (Navar et al. 1996; Breyer & Breyer, 2000b). For example, PGE₂ is a potent renal vasodilator (Imig, 2000) and buffers the vasoconstrictor responses to angiotensin II and noradrenaline (Inscho et al. 1990), as well as arginine vasopressin (Seino et al. 1985). Prostaglandin I₂, through activation of the IP receptor, also promotes renal vasodilatation (Nasrallah & Hebert, 2005), although its renal vasodilatory effects are approximately one-half that demonstrated by PGE₂ (Villa et al. 1997).

The aforementioned renal vasodilatory effects of PGE₂ and PGI₂ are increased under conditions of activation of the renin–angiotensin system. Therefore, we hypothesized that PGs would play a more predominant role in modulating renal haemodynamics in the newborn period, when the renin–angiotensin system is activated (Trimper & Lumbers, 1972; Broughton Pipkin et al. 1974; Pelayo et al. 1981; Monument & Smith, 2003). To test this hypothesis, experiments were carried out to measure the effects of administration of the non-selective COX inhibitor indomethacin on systemic and renal haemodynamics at two postnatal ages in conscious, chronically instrumented lambs.

	Methods

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Animals

Experiments were performed at least 5 days after the surgery in two age groups of conscious, chronically instrumented lambs (Table 1). Lambs were obtained from a local source (Woolfit Acres, Olds, Alberta, Canada) and housed with their mothers in individual pens in the vivarium of the Health Sciences Centre of the University of Calgary, where they were provided with standard food and water, except during surgery, training and experiments. All surgical and experimental procedures were carried out in accordance with the Guide to the Care and Use of Experimental Animals provided by the Canadian Council on Animal Care and with the approval of the Animal Care Committee of the University of Calgary.

Surgery was performed using aseptic techniques as previously described (Smith & Abraham, 1995; Sener & Smith, 1999a). Briefly, anaesthesia was induced with a mask and isoflurane (4%) in oxygen, the trachea was intubated, and then anaesthesia was maintained by ventilating the lungs with isoflurane (1.5–2.5%) in a mixture of nitrous oxide and oxygen (3:2). Under sterile conditions, catheters (Tygon® Microbore Tubing i.d. 1.016 mm; o.d. 1.718 mm) were inserted into right and left femoral vessels and advanced to the aorta and inferior vena cava for later pressure measurements, as well as I.V. injections of drugs and solutions. The catheters were tunnelled subcutaneously to exit the lamb on the right and left flanks, respectively. By means of a right flank incision, the right kidney was approached, and a precalibrated ultrasonic flow transducer (size 3S–6S, Transonic Systems Inc., Ithaca, NY, USA) was placed around the right renal artery for later measurement of renal blood flow (RBF) as previously described (de Wildt & Smith, 1997). Catheters and the flow transducer cable were contained in pouches on a lamb body jacket (Lomir Inc., Montreal, Canada) for safe storage between experiments. All lambs were able to stand soon after the completion of surgery and were allowed to recover from the effects of surgery and anaesthesia in a small animal critical care unit (Shor-line, Schroer manufacturing Co., Kansas City, KS, USA) for 30–60 min, after which time they were returned to the vivarium, where they were housed with their mothers until the time of the experiment at least 5 days later. Antibiotics (Synergistin, Pfizer Canada Inc., Kirkland, Quebec City, Canada; sulbactam benzathine 3.3 mg kg^–1 and ampicillin trihydrate 6.6 mg kg^–1) were administered intramuscularly at 24 h intervals beginning on the day before surgery for a total period of 4 days. During the recovery period, animals were removed from the vivarium daily for a period of 1 h to allow them to accommodate to a supportive sling in which they were housed during experiments. This training period ensured that animals were at ease and resting quietly in the laboratory setting during experiments.

Experimental details

On the day of an experiment, each animal was removed from the vivarium at 08.00 h and placed in the same supportive sling in the laboratory environment for at least 60 min. During this equilibration period, an I.V. infusion of 5% dextrose in 0.9% sodium chloride (4.17 ml kg^–1 h^–1) was started and was continued until the end of the experiment to assist in maintaining fluid balance. The flow transducer cable was connected to a flowmeter (T101, Transonics Systems Inc.) for measuring RBF. The left femoral catheters were connected to pressure transducers (Statham, P23XL, West Warwick, RI, USA) for measuring arterial (AP) and venous pressures (VP). Renal blood flow, AP and VP were recorded onto a polygraph (Grass Instruments, model 7, West Warwick, RI, USA) and simultaneously digitized at 200 Hz using the data acquisition and analysis software package PolyVIEW^TM (Astro Medical Inc., Grass Instrument Division, West Warwick, RI, USA).

The following two experiments were carried out in each animal at a minimum interval of 24 h: vehicle (experiment 1) and indomethacin (experiment 2). (Owing to the known half-life of indomethacin in sheep of 17 h (Vinagre et al. 1998), vehicle was always administered first.) Arterial pressure, VP and RBF measurements were made for 5 min before (control) and for 20 min after I.V. injection of vehicle (0.05 M Na₂CO₃, experiment 1) and indomethacin (1 mg kg^–1 dissolved in 0.05 M Na₂CO₃, experiment 2). (This dose was selected from preliminary experiments as the minimum dose that inhibits the urinary excretion of PGs of the E series for at least 24 h.) Indomethacin (Sigma) was dissolved in a solution of 0.05 M Na₂CO₃ to prepare a stock solution of 5 mg ml^–1. Both indomethacin and vehicle were administered as a bolus I.V. injection (0.2 ml kg^–1) followed by 4 ml infusion of 0.9% saline over 20 s using a microprocessor-controlled syringe pump (model 11, Harvard Apparatus, Holliston, MA, USA).

At the end of the two experiments, lambs were killed with a lethal dose of I.V. sodium pentobarbitone and the zero offset of the flow transducer was determined. Catheters and flow transducer placement were verified by inspection post mortem. Both kidneys were removed and weighed.

Data analysis

Renal vascular resistance (RVR) was calculated as (MAP – MVP)/RBF, where MAP and MVP refer to mean arterial and venous pressures, respectively. Renal vascular resistance and RBF were normalized per gram of kidney weight to allow comparisons between the two age groups. Data were analysed and averaged over 1 min intervals and exported to a spreadsheet (Microsoft Excel), where they were consolidated. Data collected during the 5 min before indomethacin or vehicle were averaged to one control value. A two-way analysis of variance (ANOVA) procedure for repeated measures was applied to the measured and calculated variables to evaluate the effects of age (1 versus 6 weeks) and treatment (vehicle versus indomethacin), using Sigmastat (Jandel Scientific, version 3.0). Where the F value was significant, Newman–Keul's multiple comparison procedures were applied to determine where the differences occurred. Significance was accepted at the 95% confidence interval. All data are presented as means ± S.D.

	Results

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Baseline values for the measured and calculated variables are provided in Table 1. Heart rate and RVR were lower, whilst MAP, diastolic arterial pressure (DAP), MVP and RBF were higher in lambs aged 1 week compared with lambs aged 6 weeks.

There was an effect of age (F = 13.9; P < 0.001), treatment (F = 4.95; P = 0.031) and time (F = 11.95; P < 0.001) on MAP, as well as an interaction between treatment and time (F = 10.58; P < 0.001). Mean arterial pressure increased in both groups of lambs soon after administration of indomethacin, returning to control values within the next 9 min. The increase in MAP was similar in both groups of lambs (25%) and resulted from changes in both systolic (SAP) and DAP in both groups. Figure 1 shows MAP as change from control after indomethacin and vehicle.

View larger version (15K): [in this window] [in a new window]   Figure 1.  Effects of indomethacin or vehicle on mean arterial pressure (MAP) Changes in MAP from control (C) measured for 20 min after I.V. administration of indomethacin () or vehicle ().*P < 0.05 compared to C; P < 0.05 compared with vehicle.

View larger version (14K): [in this window] [in a new window]   Figure 2.  Effects of indomethacin or vehicle on heart rate (HR) Changes in HR from control (C) measured for 20 min after I.V. administration of indomethacin () or vehicle (). *P < 0.05 compared with C; P < 0.05 compared with vehicle.

View larger version (15K): [in this window] [in a new window]   Figure 3.  Effects of indomethacin or vehicle on renal vascular resistance (RVR) Changes in RVR from control (C) measured for 20 min after I.V. administration of indomethacin () or vehicle (). *P < 0.05 compared with C; P < 0.05 compared with vehicle.

View larger version (15K): [in this window] [in a new window]   Figure 4.  Effects of indomethacin or vehicle on renal blood flow (RBF) Changes in RBF from control (C) measured for 20 min after I.V. administration of indomethacin (•) or vehicle ().*P < 0.05 compared with C; P < 0.05 compared with vehicle.

	Discussion

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The present study was designed to explore the role of endogenously produced PGs in modulating resting systemic and renal haemodynamics in conscious developing lambs. Effects of the non-selective COX inhibitor indomethacin were investigated at two postnatal ages, resulting in the following novel findings. Following administration of indomethacin but not vehicle in both age groups, there was an increase in arterial pressure and pulse interval and a marked increase in RVR. These effects of indomethacin were, however, transient, with baseline levels being resumed within minutes. These findings show that under physiological conditions, endogenously produced PGs modulate both systemic and renal haemodynamics early in life. Other vasoactive factors must, however, be rapidly recruited in order to buffer the circulatory responses to the removal of vasodilatory PGs. Finally, there is little evidence to support a greater renal vasodilatory role for PGs in the newborn period, leading us to reject our hypothesis.

The role of PGs in modulating renal haemodynamics in adult mammals is well recognized (Lifschitz, 1981; Lopez et al. 2003). It is generally believed that COX-2-derived metabolites play an important role in regulating renal haemodynamics, especially under conditions of low salt intake or activation of the renin–angiotensin system. Previous studies in experimental animals have also investigated the role of PGs produced by the fetal and newborn kidney in modulating renal haemodynamics, yet the results are variable. This variability may reflect differences in experimental design, state of the animal, method of measurement of renal haemodynamics, species, choice of drug and dose. For example, Herin & Aperia (1982) showed in anaesthetized, paralysed lambs that indomethacin (2.5 mg kg^–1 bolus plus 1.0 mg kg^–1 h^–1) had no effect on RBF measured using radiolabelled microspheres. In conscious lambs, Winther et al. (1980) reported a decrease in effective RBF, calculated from the clearance of radiolabelled hippurate, at 2–4 h after administration of low-dose (0.2 mg kg^–1) as well as high-dose indomethacin (7.5 mg kg^–1). They also showed a further decrease in effective RBF at 12–14 h and again at 22–24 h after administration of high- but not low-dose indomethacin. In conscious older piglets but not newborn piglets, Osborn et al. (1980) showed that indomethacin (bolus 3.0 mg kg^–1 plus infusion of 2.0 mg kg^–1 h^–1) decreased RBF and increased the ratio of outer to inner cortical flow, as measured with radiolabelled microspheres. In these two studies, experiments were carried out immediately after surgery, which could impact upon the measured responses to indomethacin. More recently, it has been shown from studies in anaesthetized and ventilated newborn rabbits (Chamaa et al. 2000; Drukker et al. 2001) that administration of other COX inhibitors (ibuprofen and acetylsalicyclic acid) increases RVR 30–60 min later. Comparative effects of I.V. aspirin, indomethacin and ibuoprofen were also measured in anaesthetized, ventilated newborn rabbits by the same group (Guignard, 2002). All three compounds were shown to have marked effects in increasing RVR within 30–60 min. In these experiments, RVR was calculated from the measurement of effective renal plasma flow as the clearance of para-aminohippurate. In conscious, chronically instrumented fetal sheep, Stevenson & Lumbers (1992) showed using radiolabelled microspheres that high-dose indomethacin (10 mg kg^–1 to the ewe and 12 mg kg^–1 to the fetus) decreased the ratio of outer to inner cortical flow but did not alter RBF at 2 h. In the aforementioned studies in which measurements of renal haemodynamics were made at least 30 min after administration of non-steroidal anti-inflammatory drugs, early effects of removing endogenous PGs would not have been observed.

Against this background, the present experiments show that administration of indomethacin to conscious lambs has rapid effects in increasing RVR, yet this response is transient, with complete restoration of baseline renal haemodynamics within minutes. It has been known for 30 years that the non-selective COX inhibitor indomethacin is the preferred treatment for infants with symptomatic patent ductus arteriosus (PDA; Heymann et al. 1976). Effective closure of a PDA reduces the need for surgical ligation as well as the incidence of intraventricular cerebral haemorrhage, necrotizing encolitis, bronchopulmonary dysplasia and death, and is therefore considered an important therapeutic regimen. There are, however, numerous side-effects associated with indomethacin treatment, including oliguria, which if untreated can result in acute renal failure in the neonatal period (Guignard, 2002). This suggests that PGs may play an important role in promoting renal perfusion pressure in the newborn kidney. In fact, Pezzati et al. (1999) showed that there was a significant decrease in RBF velocity measured using Doppler ultrasound in mechanically ventilated preterm infants within 30 min of receiving indomethacin or ibuprofen. Our results support the notion that administration of indomethacin decreases RBF, leading to a marked increase in RVR in the newborn. However, since this rapid increase in RVR is short lived (Fig. 3), it is unlikely to have any direct impact on renal function, assuming that the autoregulatory capacity of the kidney remains intact. Beilin & Bhattacharya (1977) demonstrated that administration of indomethacin to anaesthetized dogs did not alter steady-state autoregulation of RBF, although there was a transient decrease in RBF, as observed in the present experiments. We speculate that any sustained effects of indomethacin on RVR which could impact renal function, leading to oliguria if untreated, could only occur in the absence of the rapid buffering capacity we observed in the healthy newborn animal. That is, if there was a lack of release of vasodilatory factors such as nitric oxide (NO) and/or an increased release of vasoconstrictor factors such as angiotensin II, the effects of indomethacin on RVR could be sustained, leading to more deleterious consequences for the function of the newborn kidney.

Previous studies in sheep have demonstrated the pharmacokinetics of indomethacin. Following I.V. administration of indomethacin at a dose of 1 mg kg^–1, peak concentrations are reached rapidly, plasma levels are maintained over 50 min, and its elimination half-life is 17 h (Vinagre et al. 1998). If such pharmacokinetics are similar in younger lambs, we can assume that during the period of measurement of systemic and renal haemodynamics, the level of circulating indomethacin would have been relatively constant. Despite this, rapid adjustments to the measured variables occurred within minutes. Therefore, the effects of indomethacin, and therefore removal of endogenously produced PGs, must be buffered by the local release of other vasodilatory factors. One possibility for this would be NO. In support of this postulate are our previous studies in conscious lambs showing a greater modulatory role for NO on the renal circulation early in life (Sener & Smith, 1999b, 2001b, 2002). Furthermore, we showed that a renal vasoconstrictor response to endothelin-1 is only revealed in the newborn kidney once NO has been removed (Smith et al. 2005). Additional studies are necessary to determine the mechanism(s) underlying the rapid restoration of renal haemodynamics following indomethacin and/or whether NO interacts with PGs in influencing renal vascular tone early in life.

von Euler (1936) first showed that PGs are involved in modulating arterial pressure. It is now well recognized that administration of indomethacin increases arterial pressure through an increased total systemic vascular resistance (Wennmalm, 1978). Nowak & Wennmalm (1978) demonstrated in humans that indomethacin increased renal and splanchnic vascular resistance, whilst increasing blood flow to non-visceral regions; the pulmonary vasculature does not, however, appear to be affected by indomethacin (Wennmalm, 1978). In the present study, indomethacin administration was associated with a transient increase in arterial pressure. Although there was a marked increase in RVR, suggesting an overall increase in peripheral vascular resistance, blood flow changes to other regions were not measured. In addition to the marked changes in arterial pressure and RVR, there appeared to be a greater effect of indomethacin on HR in the younger age group of animals, although the profile of the HR response between the two age groups was similar. This might suggest that PGs modulate the arterial baroreflex control of HR soon after birth. No previous studies have evaluated the role of PGs in modulating the baroreflex early in life, although it is well recognized that PGs influence the baroreflex in adult mammals. For example, Hull & Chimoskey (1984) reported a resetting of the baroreflex by intracarotid PGE₂ infusion to conscious sheep, dogs and calves, with no change in baroreflex sensitivity. McDowell et al. (1989) reported that the arterial baroreflex control of lumbar sympathetic activity was attenuated by intrasinus administration of indomethacin, and facilitated by intrasinus administration of arachidonic acid as well as PGI₂. In conscious dogs, Panzenbeck et al. (1989) showed that intracoronary administration of PGE₂ inhibits the arterial baroreflex control of HR. A paracrine role for PGI₂ in influencing baroreceptor activity has also been reported from experiments by Chen et al. (1990) in rabbits. More recently, investigations in pentobarbitone-anaesthetized rats provided evidence that NO influences baroreceptor afferent activity through a COX-dependent mechanism. Therefore, the apparently larger HR response to indomethacin observed at 1 week in the present study could be related, at least in part, to an altered effect of NO on the baroreflex soon after birth, through a COX-dependent mechanism. In previous studies, we have shown that NO modulates the arterial baroreflex control of HR in an age-dependent manner, with predominant effects seen at 1 week (Sener & Smith, 2001a). Until the effects of PGs in modulating the arterial baroreflex control of HR and/or any potential interaction between PGs and NO on the baroreflex during postnatal maturation are investigated, this remains purely speculative.

	References

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	Acknowledgements

 
This work was supported by an Operating Grant provided by the Canadian Institutes for Health Research and a Grant-in-Aid provided by the Heart & Stroke Foundation of Canada. During the tenure of these experiments, Francine G. Smith was a Heritage Medical Senior Scholar supported by the Alberta Heritage Foundation for Medical Research, and Fatemah Sharbaf Ghane was provided a 6 month research fellowship by the Government of Iran. Her current address is Mashad University of Medical Sciences, Iran. A portion of this work was presented in poster format to the 2006 annual meetings for Experimental Biology (Ebenezar, K. K., Ghane, F. S. & Smith, F. G. (2006). Effects of indomethacin on systemic and renal haemodynamics during postnatal maturation in conscious lambs. FASEB J 20, C480). The authors gratefully acknowledge the excellent assistance provided by Dr Wei Qi and Lucy Yu.

This Article Abstract Full Text (PDF) All Versions of this Article: 92/3/575    most recent expphysiol.2006.036152v1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Ebenezar, K. K. Articles by Smith, F. G. Search for Related Content PubMed PubMed Citation Articles by Ebenezar, K. K. Articles by Smith, F. G.