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Symposium-Related Papers |
1 Department of Physiology, University of Cambridge, Cambridge CB2 3EG, UK
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Abstract |
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335 days). At least 5 days after surgery, pressor, vasoconstrictor and cardiac chronotropic responses to exogenous bolus doses of phenylephrine, angiotensin II and arginine vasopressin were recorded. Fetal cardiac baroreflex slopes were obtained using the peak pressor and heart rate responses to increasing doses of phenylephrine. Fetal treatment with phenylephrine, angiotensin II and vasopressin produced significant changes in arterial blood pressure, hind limb vascular resistance and heart rate. Pressor and vasopressor responses to all agonists were greater at 0.9 than at 0.6 of gestation; however, fetal cardiac baroreflex sensitivity decreased with advancing gestational age. Correlation analysis revealed that fetal plasma cortisol rather than gestational age was a greater determinant of pressor and vasopressor reactivity. In contrast, gestational age rather than cortisol better determined heart rate and baroreflex responsiveness in the equine fetus. The data show that development of cardiovascular function in the equine fetus occurs via cortisol-dependent and -independent pathways.
(Received 18 January 2006;
accepted after revision 7 February 2006;
first published online 9 February 2006)
Corresponding author D. A. Giussani: Department of Physiology, University of Cambridge, Cambridge CB2 3EG, UK. Email: dag26{at}cam.ac.uk
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Introduction |
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In all species studied to date, there is also an increase in circulating glucocorticoid concentration in the fetus as term approaches (Fowden et al. 1998). In sheep, several findings support a role for the fetal prepartum surge in cortisol to mediate maturation of fetal cardiovascular function as term approaches. The ontogenic increase in arterial blood pressure is strongly correlated to prepartum increases in plasma cortisol concentration (Forhead et al. 2000a) and it is abolished when the fetal cortisol surge is prevented by fetal adrenalectomy (Unno et al. 1999). Conversely, treatment of immature fetal sheep with cortisol or with synthetic glucocorticoids promotes changes in cardiovascular function towards those seen in fetuses at term. These include elevations in arterial blood pressure and hind limb vascular resistance, enhanced pressor responses to exogenous vasoconstrictor agents and resetting of the cardiac baroreflex towards the maintenance of an elevated resting arterial blood pressure (Wood et al. 1987; Tangalakis et al. 1992; Derks et al. 1997; Anwar et al. 1999; Docherty et al. 2001a; Koenen et al. 2000; Fletcher et al. 2002).
In the horse, fetal plasma cortisol rises much closer to term and much more abruptly than in other species (Fowden & Silver, 1995). Relative to other species, marked changes in the maturation of the cardiovascular system may therefore occur towards term in the horse. The comparatively late development of the cardiovascular system in equids may account, in part, for the increased incidence of cardiovascular complications associated with prematurity in newborn foals (Webb et al. 1984). In the horse fetus during late gestation, it is known that arterial blood pressure and plasma concentrations of vasoconstrictor agents increase in close temporal association with the delayed increase in fetal plasma cortisol (Forhead et al. 2000b; O'Connor et al. 2002; Giussani et al. 2005). However, it remains unknown whether there are parallel changes in other components regulating cardiovascular function during late gestation in the equine fetus. In addition, there is no information about developmental changes in fetal hind limb vascular reactivity in vivo for any species. Hence, the aims of this study were to determine developmental changes in cardiac baroreflex responses and in hind limb vascular reactivity at 0.6 and 0.9 of gestation, in relation to changes in fetal plasma cortisol concentration, in the horse fetus.
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Methods |
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Gestational age was determined from known mating dates and confirmed by ultrasound scan and the measurement of aortic diameter (Renaudin et al. 2000). Welsh Pony mares (n= 13) carrying fetuses of known gestational ages between 0.6 (218 ± 10 days, mean ±S.E.M., estimated fetal weight 5 kg, Fowden et al. 2000) and 0.9 (301 ± 7 days; estimated fetal weight 15 kg, Fowden et al. 2000) of gestation were used (term is 330 days; estimated fetal body weight at term is 20 kg, Fowden et al. 2000). The ponies were housed in individual stables and were fed 500 g concentrates (Horse Stud Mix; Moulton's Feed Supplies, Lincolnshire, UK) twice a day with access to hay and water ad libitum. On the day preceding surgery, mares were moved into an indoor horsebox within the main animal facility. Food, but not water, was withdrawn 18 h prior to surgery and the cyclooxygenase inhibitor, meclofenamic acid (2 mg kg–1; Arquel, Pharmacia & Upjohn, Sussex, UK) was given orally the night before surgery and again the morning after surgery to reduce endogenous prostaglandin production associated with fasting and surgery in this species (Silver et al. 1979). On the morning of surgery, mares were given by intravenous injection through a jugular catheter 20 µg kg–1 acepromazine (ACP; C-Vet, Leyland, UK), 20 µg kg–1 butorphanol (Torbugesic; Fort Dodge, Southampton, UK) and 10 µg kg–1 detomidine (Domosedan; Pfizer, Sandwich, UK). Thirty minutes after premedication, anaesthesia was induced with a further 10 µg kg–1 detomidine I.V., followed 5 min later by 2 mg kg–1 ketamine I.V. (Vetalar; Pharmacia & Upjohn, Corby, UK). The trachea was intubated with a cuffed endotracheal tube (Portex Ltd; Hythe, Kent, UK) as soon as the pony became recumbent, and 100% oxygen was supplied via a to-and-fro rebreathing system (Fluotec; Ohmeda, Hatfield, UK). General anaesthesia was maintained in the recumbent position with I.V. infusion of propofol (Rapinovert; Schering Plough, Harefield, UK) (Taylor et al. 2001) and ketamine (Baker et al. 1999). The first abdominal incision was made paramedially. The uterus was palpated to manoeuvre the fetal hind limbs such that they could be exposed through a small uterine incision. Vascular catheters (Portex Translucent PVC Tubing, Thin Walled, ref. 800/010/125/800) were inserted into the fetal dorsal aorta and caudal vena cava via the metatarsal vessels. In addition, an ultrasonic flow transducer (Transonic Systems Inc., NY, USA) was implanted around the contralateral fetal metatarsal artery, and a further catheter was secured to the hind limb to monitor amniotic fluid pressure. The hind limbs were then returned into the uterine cavity, the fetal membranes were tied tightly and the uterine incision was closed in layers. Following I.V. administration of ampicillin (25 mg kg–1 estimated bodyweight; Penbritin; Beecham Animal Health, Brentford) and gentamycin (5 mg kg–1 estimated bodyweight; Frangen-100; Biovet Ltd, Mullingar) to the fetus, all catheters were filled with heparinized saline (50 i.u. heparin ml–1 in 0.9% NaCl), plugged with brass pins, and were exteriorized with the flow probe lead through a key hole incision in the maternal flank and secured in a plastic pouch sutured to the maternal skin. The maternal abdominal and skin incisions were closed. Ampicillin (1 g, I.V.) was administered to the mare at surgery and for a further 5 days.
During post-operative recovery, and throughout the experimental period, daily fetal blood samples were taken for analyses of arterial blood gases (measurements corrected to 38.5°C), percentage saturation of O2 in haemoglobin, haemoglobin concentration, and pH using an ABL5 blood gas analyser and OSM2 haemoximeter (Radiometer, Copenhagen, Denmark). Daily blood glucose and lactate concentrations were also measured using an automated analyser (Yellow Springs 2300 Stat Plus glucose/lactate analyser; YSI, Farnborough, UK).
Experimental protocol
Six fetuses were classified as 0.6 of gestation (mean ±S.E.M., 218 ± 10 days) and seven fetuses were classified as 0.9 of gestation (mean 301 ± 7 days) at the time of the experimental procedures. All fetuses were studied at least 5 days after surgery. On the day of study, the fetal arterial and amniotic catheters were attached to pressure transducers (COBE; Argon, TX, USA) and the metatarsal flow probe was connected to a flow box (T201 or T206; Transonics Systems Inc., Ithaca, NY, USA). Output signals from the analog pressure and flow amplifiers were channelled through a custom-built electronic switch box (Cambridge University, Cambridge, UK) to an analog–digital data acquisition system (DAS) card (NIDAQ; National Instruments, Austin, TX, USA) which sampled signals at 500 Hz. Pulsatile analog outputs from the Transonic flow meter and arterial blood pressure amplifiers were used to trigger a heart rate meter. Values for fetal blood pressure, heart rate, and hind limb blood flow were logged at 1 s intervals using DAS software running on a PC. Arterial blood pressure was corrected for amniotic pressure and hind limb vascular resistance was calculated using Ohm's principle by dividing supra-amniotic arterial blood pressure by metatarsal blood flow.
Prior to any manipulation of cardiovascular function, arterial blood (4 ml) was collected during basal condition into a chilled K+-EDTA tube (L.I.P. Ltd) and immediately centrifuged (4 min, 4000 r.p.m. [1789 g] at 4°C). Aliquots of plasma were transferred to PVC tubes and were frozen to –20°C until analysis of plasma cortisol concentration.
Pressor, vasoconstrictor and chronotropic responses to exogenously administered bolus doses (in 1 ml isotonic saline) of phenylephrine (Sigma-Aldrich Co. Ltd, UK; 12.5, 25, 50, 100 µg), angiotensin II (CIBA Laboratories, Horsham, West Sussex, UK; 400, 800, 1200, 1600 ng) and arginine vasopressin (Bachem Ltd, Saffron Walden, Essex, UK; 120, 200, 400, 800 ng) were recorded. Suitable dose ranges for each agonist were derived either from pilot studies or, where possible, from previous studies reported in the literature in the sheep fetus (Tangalakis et al. 1992; Fletcher et al. 2002). Bolus doses were infused down the caudal vena cava catheter over 2–3 s followed by 5 ml of saline to clear the dead space. Cardiovascular variables were allowed to return to stable baseline values before subsequent doses were administered. The dose–response protocols were typically carried out over 2 days.
All procedures underwent local ethical approval and were performed under license by the UK Home Office, under the Animals (Scientific Procedures) Act, 1986. Following the conclusion of the experimental protocol, foals that delivered live and all mares were discharged from the Act and re-homed following veterinary approval.
Data and biochemical analyses
During the dose–response protocol, baseline data for all the measured cardiovascular variables were obtained by averaging values for each variable over the 2 min preceding the administration of the bolus dose. Baseline data for all the measured cardiovascular variables were similar between different doses of the same agonist and between agonists. The maximum deviation from baseline for all cardiovascular variables was then determined, and all responses were expressed as absolute increments or decrements from baseline for each dose of each agonist. The corresponding changes in arterial blood pressure and heart rate to increasing bolus doses of phenylephrine were used to construct two baroreflex function curves, one representing the mean correlates of blood pressure and heart rate for all animals, and the other showing raw correlates for each individual animal.
Plasma concentrations of cortisol were measured by radioimmunoassay (RIA) using methods previously validated for use with equine plasma (Rossdale et al. 1982). The minimum detectable quantity of cortisol in the assay was 1 ng ml–1. The intra-assay coefficient of variation was 2.7% for a mean value of 29.5 ng ml–1. The interassay coefficients of variation for two plasma pools (mean concentrations: 10.7 and 29.5 ng ml–1) were 9.4 and 7.8%, respectively. The cross-reactivities of the antiserum at 50% binding with other cortisol-related compounds were: 0.5% cortisone; 2.3% corticosterone; 0.3% progesterone; 4.6% deoxycortisol.
Statistical analyses
Data are expressed as means ±S.E.M. throughout unless otherwise indicated. Basal variables were compared using the Student's t test for paired or unpaired data. Changes from baseline for each dose and agonist were assessed using the significance of a single mean calculation. Comparisons of dose–responses within and between gestational age groups were determined using either one-way or two-way ANOVA with repeated measures and the Tukey post hoc test. The slope of the mean cardiac baroreflex (calculated as the change in heart rate divided by the change in arterial blood pressure) was compared between 0.6 and 0.9 of gestation by the method of Armitage et al. (2002). Relationships between cardiovascular variables and either the prevailing cortisol concentrations or gestational age were determined by the Pearson Product Moment correlation (Jandel SigmaStat statistical software version 2.0; Jandel Corp., San Rafael, CA, USA). Partial correlation analysis, which considers the relative strength of correlation between cardiovascular variables, cortisol concentrations, and gestational age was determined using StatView 4.02. For all comparisons, statistical significance was accepted when P < 0.05.
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Results |
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Significant increases in basal arterial blood pressure, hind limb blood flow, haemoglobin and plasma cortisol concentration occurred from 0.6 to 0.9 of gestation (P < 0.05, Table 1). In contrast, a significant fall in heart rate occurred at 0.9 compared with 0.6 of gestation (P < 0.05, Table 1).
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Phenylephrine. At both 0.6 and 0.9 of gestation, fetuses showed a dose-related pressor response to increasing bolus doses of phenylephrine (Fig. 1Ai). Throughout the dose range, the pressor response tended to be greater at 0.9 than 0.6 of gestation but was only significantly greater at the 25 µg dose. All fetuses showed a decrement in heart rate in response to phenylephrine, which was dose dependent only at 0.6 of gestation (Fig. 1Aii). The difference in the decrement in heart rate became significant between the age groups at the 100 µg dose (Fig. 1Aii). Phenylephrine had no effect on metatarsal blood flow or vascular resistance at 0.6 of gestation (Fig. 1Aiii and iv). In contrast, at 0.9 of gestation in response to phenylephrine, there were pronounced reductions in blood flow and dose-dependent increases in vascular resistance in the metatarsal circulation, which became significant between the age groups by the 100 µg dose (Fig. 1Aiii and iv).
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Arginine vasopressin. Significant increments in fetal blood pressure were obtained in response to bolus doses of vasopressin at all gestational ages studied (Fig. 1Ci). These increments in blood pressure were dose dependent at 0.6 of gestation between 120 and 200 ng but peaked at greater doses (Fig. 1Ci). Fetuses at 0.6 and 0.9 of gestation showed opposite chronotropic responses to treatment with vasopressin. While significant dose-related increments in heart rate occurred at 0.6 of gestation, significant dose-related decrements in heart rate were obtained at 0.9 of gestation (Fig. 1Cii). At 0.6 of gestation there were no significant changes in hind limb blood flow and hind limb vascular resistance in response to vasopressin at any dose (Fig. 1Ciii and iv). In contrast, at 0.9 of gestation, vasopressin evoked significant falls in flow and significant increments in vascular resistance in the metatarsal circulation (Fig. 1Ciii and iv). The increase in metatarsal vascular resistance was significantly greater at the highest dose of vasopressin in the older group of fetuses (Fig. 1Civ).
Baroreflex. Analysis of the fetal cardiac baroreflex, by comparison of the slopes derived from the relationship between arterial blood pressure and heart rate changes to increasing bolus doses of phenylephrine for all individual animals, revealed a significant decrease in the slope of the relationship at 0.9 compared with at 0.6 of gestation (Fig. 2).
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Discussion |
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Previous studies have shown that fetal arterial blood pressure increases and fetal heart rate decreases with advancing gestational age in a number of species, including the horse (Reeves et al. 1972; Boddy et al. 1974; Dawes et al. 1980; Macdonald et al. 1983; Kitanaka et al. 1989; Forhead et al. 2000a; Giussani et al. 2005). However, there is no information about developmental changes in fetal hind limb vascular reactivity in vivo for any species. Using Transonic flowmetry, the current study addressed developmental changes in hind limb vascular reactivity to classical vasoconstrictors, such as phenylephrine and angiotensin II, and less well investigated agonist systems in the fetus, such as vasopressin. The data show that developmental changes in arterial blood pressure and heart rate in the equine fetus occur in parallel with changes in hind limb vascular reactivity and baroreflex function. At 0.6 of gestation, despite significant changes in arterial blood pressure to the agonist dose–responses, there was no change in hind limb blood flow or hind limb vascular resistance to any of the increasing doses of constrictor agonists. Therefore, the changes in arterial blood pressure to the agonists at 0.6 of gestation probably represent changes in vascular resistance in peripheral circulations other than those represented by the metatarsal circulation in the horse (e.g. the placental circulation for angiotensin II). In addition, since heart rate increased siginificantly in response to angiotensin II and vasopressin at 0.6 of gestation, the pressor responses at this gestational age may also reflect changes in cardiac output. At 0.9 of gestation, there were marked pressor and hind limb constrictor responses to phenylephrine, angiotensin II and vasopressin in the horse fetus. The greater constrictor responses at 0.9 of gestation occurred in spite of the same exogenous doses of the agonists used in fetuses estimated to be three times heavier than at 0.6 of gestation (see Fowden et al. 2000), emphasizing the difference in the sensitivity of the hind limb vasculature between the ages. These findings are consistent with previous observations that intravenous injections of angiotensin II increase mean arterial blood pressure to greater values in neonatal than in fetal sheep (Scroop et al. 1986). Developmental changes in the expression of vascular AT1 receptors and of renal V1 receptors have been observed in fetal sheep and fetal rats, respectively (Ostrowski et al. 1993; Wintour et al. 1999; Cox & Rosenfeld, 1999; Burrell et al. 2001). Additional in vitro experiments have shown that the maximum vasoconstrictor responses to potassium, noradrenaline and endothelin-1 also increase with advancing gestational age in small branches of femoral arteries isolated from baboon and sheep fetuses (Anwar et al. 2001; Docherty et al. 2001b).
Much more is known about the effects of glucocorticoids on fetal hind limb vascular reactivity. In vivo studies in sheep have shown that treatment of fetal sheep at 0.8 of gestation with cortisol or dexamethasone can enhance the pressor response to exogenous angiotensin II and phenylephrine (Tangalakis et al. 1992; Fletcher et al. 2002). Other in vivo studies in sheep have shown that maternal or fetal treatment with dexamethasone augments the femoral vasoconstrictor response to acute hypoxaemia in fetuses at 0.8 of gestation (Fletcher et al. 2003; Jellyman et al. 2005). In vitro studies using wire myography have reported enhanced vasoconstrictor function in isolated hind limb vessels of sheep exposed antenatally to synthetic glucocorticoids (Anwar et al. 1999; Docherty et al. 2001a). In the present study, hind limb vascular reactivity to phenylephrine, angiotensin II and vasopressin was related to the fetal plasma cortisol concentration in the equine fetus. Taken together, these observations suggest that glucocorticoids have an important role in the developmental regulation of hind limb vascular reactivity.
The fall in heart rate during stimulation of the cardiac baroreflex by phenylephrine in both fetal and adult animals is mediated by the combined effects of an increase in vagal discharge with sympathetic outflow withdrawal (Fritsch & Eckberg, 1989; Segar et al. 1992; Brooks et al. 1993; Hogan et al. 1999; Yu & Lumbers, 2000; Fletcher et al. 2002). In the present study, the magnitude of the phenylephrine-induced bradycardia was greater at 0.6 than at 0.9 of gestation, suggesting changes in the sensitivity of baroreflex function in the horse fetus as term approaches. Analysis of corresponding changes in heart rate to changes in arterial blood pressure in response to increasing bolus doses of phenylephrine in individual horse fetuses showed that the slope of the heart rate–blood pressure relationship was shallower and, thereby, the sensitivity or gain of the cardiac baroreflex was diminished, at 0.9 than at 0.6 of gestation. Similarly, in the sheep fetus it has been reported that the sensitivity of the baroreflex is greatest during early fetal life, and that it decreases with advancing gestational age, and into postnatal life (Blanco et al. 1988; Segar, 1997). The fall in heart rate in response to phenylephrine is also smaller at 2 weeks than at 1 week of postnatal life in newborn foals (O'Connor et al. 2005). The developmental decrease in baroreflex sensitivity may therefore accommodate the ontogenic increase in basal arterial blood pressure during the perinatal period in the horse, as occurs in other species.
The positive chronotropic effects of angiotensin II have long been established (Machado et al. 1987; Machado & Salgado, 1990). However, the mechanisms mediating angiotensin II-induced tachycardia are not well understood. While some investigators favour a systemic effect of angiotensin II secondary to either enhanced release of catecholamines (Feldberg & Lewis, 1964; Butler et al. 1994; Shetty & Delgrande, 2000) and/or inhibition of acetylcholine release from cardiac parasympathetic terminals (Du et al. 1998), others support a central role of the peptide in altering the relative outflow of sympathetic and parasympathetic influences on heart rate (Lumbers et al. 1979; Lee et al. 1980; Guo & Abboud, 1984; Potter & Reid, 1985; Bealer, 2002). In the present study, angiotensin II-induced tachycardia in the horse fetus was similar at 0.6 and 0.9 of gestation suggesting that either central or peripheral actions of angiotensin II on the heart are already established by mid-gestation in the horse.
By contrast, fetal treatment with vasopressin induced tachycardia at 0.6 of gestation, but bradycardia at 0.9 of gestation in the horse fetus. A fall in heart rate in response to exogenous vasopressin has been reported previously in fetal sheep at 0.8–0.9 of gestation (Rurak, 1978; Tomita et al. 1985; Irion et al. 1990; Fletcher et al. 2002); however, there have been no studies on the cardiac effects of vasopressin earlier in gestation in the ovine fetus. Several mechanisms mediate chronotropic effects of vasopressin, including baroreflex-mediated modulation of the autonomic nervous system, central effects involving the prostanoids and adenosine, and direct effects on cardiac tissue (Wiriyathian et al. 1983; Tomita et al. 1985; Wood, 1995). These effects are dose- and receptor-dependent, with differential chronotropic responses obtained with low and high doses of vasopressin administered centrally (Diamant & De Wied, 1993), and with V1 receptors playing a greater role in promoting bradycardia than V2 receptors (Walker et al. 1988). The switch in the heart rate response to exogenous vasopressin in the fetal horse during late gestation from tachycardia to bradycardia may thus include developmental changes in the interplay of all these influences. In the present study, partial correlation analysis revealed that advancing gestation was a greater determinant of the chronotropic effects of vasopressin than plasma cortisol in the horse fetus. This again supports the idea that mechanisms in addition to the prepartum surge in plasma cortisol may mediate developmental changes in the responsiveness to stimuli of the equine fetal heart with advancing gestation.
In conclusion, the data show that there are developmental changes in hind limb vascular reactivity and baroreflex function in the horse fetus in the second half of gestation. While developmental increases in fetal hind limb vascular reactivity may contribute to elevations in fetal basal arterial blood pressure, developmental decreases in the gain of baroreflex function may allow the increasing resting arterial blood pressure with advancing gestation in this species.
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BP, i), heart rate (
designates difference between groups; different letters designate difference within groups (two-way ANOVA plus Tukey test, P < 0.05).