Early developmental influences on hepatic organogenesis

Organogenesis

Volumn 4, Issue 3, 2008, Pages

  Hyatt, Melanie A ^a   Budge, Helen ^a   Symonds, Michael E ^a,b  

^a UNIVERSITY OF NOTTINGHAM   (United Kingdom)

^b NOTTINGHAM UNIVERSITY HOSPITALS NHS TRUST   (United Kingdom)

Author keywords

Development; Growth factor; Liver; Maternal constraint; Nutrition; Parity; Placental insufficiency

Indexed keywords

FIBRINOGEN; INSULIN; LOW DENSITY LIPOPROTEIN CHOLESTEROL;

APOPTOSIS; CARDIOVASCULAR DISEASE; CELL DIFFERENTIATION; CELL PROLIFERATION; CHOLESTEROL BLOOD LEVEL; FETUS LIVER; FIBRINOGEN BLOOD LEVEL; HORMONAL REGULATION; IMPAIRED GLUCOSE TOLERANCE; INSULIN SENSITIVITY; LIVER CELL; LIVER DEVELOPMENT; LIVER FUNCTION; REVIEW;

EID: 50849134859     PISSN: 15476278     EISSN: 15558592     Source Type: Journal    
DOI: 10.4161/org.4.3.6849     Document Type: Review

References (120)

1. Kinoshita T, Miyajima A. Cytokine regulation of liver development. Biochim Biophys Acta 2002; 1592:303-12.
2. Hui AY, Friedman SL. Molecular basis of hepatic fibrosis. Expert Rev Mol Med 2003; 5:1-23.
3. Fausto N, Webber EM. Control of liver growth. Crit Rev Eukaryot Gene Expr 1993; 3:117-35.
4. Kmiec Z. Cooperation of liver cells in health and disease. Adv Anat Embryol Cell Biol 2001; 161:1-151.
5. Jungermann K. Zonation of metabolism and gene expression in liver. Histochemistry 1995; 103:81-91.
6. Barker DJP, Martyn CN, Osmond C, Wield GA. Abnormal liver growth in utero and death from coronary heart disease. Br Med J 1995; 310:703-4.
7. Motta PM. The three-dimensional microanatomy of the liver. Archives of Histology: Japan 1984; 47:1-30.
8. Sasse D, Spornitz UM, Maly IP. Liver architecture. Enzyme 1992; 46:8-32.
9. Blouin A, Bolender RP, Weibel ER. Distribution of organelles and membranes between hepatocytes and non-hepatocytes in the rat parenchyma. J Cell Biol 1977; 72:441-55.
10. Ikezawa Y, Yamatani K, Ogawa A, Ohnuma H, Igarashi M, Daimon M, et al. Effects of glucagon on glycogenolysis and gluconeogenesis are region-specific in periportal and perivenous hepatocytes. J Lab Clin Med 1998; 132:547-55.
11. Quistorff B. Gluconeogenesis in periportal and perivenous hepatocytes of rat liver, isolated by a new high-yield digitonin/collagenase perfusion technique. Biochem J 1985; 22:221-6.
12. Teutsch HF. Regionality of glucose-6-phosphate hydrolysis in the liver lobule of the rat: metabolic heterogeneity of "portal" and "septal" sinusoids. Hepatology 1998; 8:311-7.
13. Panduro A, Shalaby F, Shafritz DA. Changing patterns of transcriptional and posttranscriptional control of liver-specific gene expression during rat development. Genes Dev 1987; 1:1172-82.
14. Derman E, Krauter K, Walling L, Weinberger C, Ray M, Darnell JEJ. Transcriptional control in the production of liver-specific mRNAs. Cell 1981; 23:731-9.
15. Shiojiri N, Lemire JM, Fausto N. Cell lineages and oval cell progenitors in rat liver development. Cancer Res 1991; 51:2611-20.
16. Hyatt MA, Gopalakrishnan GS, Bispham J, Gentili S, McMillen IC, Rhind SM, et al. Maternal nutrient restriction in early pregnancy programs hepatic mRNA expression of growth-related genes and liver size in adult male sheep. J Endocrinol 2007; 192:87-97.
17. Fowden AL, Li J, Forhead AJ. Glucocorticoids and the preparation for life after birth: are there long-term consequences of the life insurance? Proc Nutr Soc 1998; 57:113-22.
18. Fowden AL, Mijovic J, Silver M. The effects of cortisol on hepatic and renal gluconeogenic enzyme activities in the sheep fetus during late gestation. J Endocrinol 1993; 137:213-22.
19. Nyirenda MJ, Lindsay RS, Kenyon CJ, Burchell A, Seckl JR. Glucocorticoid exposure in late gestation permanently programs rat hepatic phosphoenolpyruvate carboxykinase and glucocorticoid receptor expression and causes glucose intolerance in adult offspring. J Clin Invest 1998; 101:2174-81.
20. Palmes D, Spiegel HU. Animal models of liver regeneration. Biomaterials 2004; 25:1601-11.
21. Kaplowitz N. Biochemical and cellular mechanisms of toxic liver injury. Semin Liver Dis 2002; 22:137-44.
22. Lemaigre F, Zaret KS. Liver development update: new embryo models, cell lineage control, and morphogenesis. Curr Opin Genet Dev 2004; 14:582-90.
23. Hata S, Namae M, Nishina H. Liver development and regeneration: from laboratory study to clinical therapy. Dev Growth Differ 2007; 49:163-70.
24. Duncan SA. Mechanisms controlling early development of the liver. Mech Dev 2003; 120:19-33.
25. Zaret KS. Liver specification and early morphogenesis. Mech Dev 2000; 92:83-8.
26. Zhao R, Duncan SA. Embryonic development of the liver. Hepatology 2005; 41:956-67.
27. Schmidt C, Bladt F, Goedecke S, Brinkmann V, Zschiesche W, Sharpe M, et al. Scatter factor/hepatocyte growth factor is essential for liver development. Nature 1995; 373:699-702.
28. Uehara Y, Mori C, Noda T, Shiota K, Kitamura N. Placental defect and embryonic lethality in mice lacking hepatocyte growth factor/scatter factor. Nature 1995; 373:702-5.
29. Alison MR. Regulation of hepatic growth. Physiol Rev 1986; 66:499-541.
30. Sanchez A, Alvarez AM, Lopez P, J.M., Roncero C, Benito M, Fabregat I. Apoptotic response to TGF-beta in fetal hepatocytes depends on their state of differentiation. Exp Cell Res 1999; 252:281-91.
31. Cruise JL, Knechtle SJ, Bollinger RR, Kuhn C, Michalopoulos GK. α1 Adrenergic effects and liver regeneration. Hepatology 1987; 7:1189.
32. Bucher NLR, Patel U, Cohen S. Hormonal factors concerned with liver regeneration. Hepatotrophic Factors Ciba Found Symp 1978; 55:95.
33. Anthony RV, Pratt SL, Liang R, Holland MD. Placental-fetal hormonal interactions: impact on fetal growth. J Anim Sci 1995; 73:1861-71.
34. Harding JE, Liu L, Evans PC, Gluckman PD. Insulin-like growth factor 1 alters fetoplacental protein and carbohydrate metabolism in fetal sheep. Endocrinology 1994; 134:1509-14.
35. Gallaher BW, Oliver MH, Eichhorn K, Kessler U, Kiess W, Harding JE, et al. Circulating insulin-like growth factor II/mannose-6-phosphate receptor and insulin-like growth factor binding proteins in fetal sheep plasma are regulated by glucose and insulin. Eur J Endocrinol 1994; 131:398-404.
36. Waters MJ, Kaye PL. The role of growth hormone in fetal development. Growth Horm IGF Res 2002; 12:137-46.
37. McMillen IC, Houghton DC, Phillips ID. Maturation of cytokine receptors in preparation for birth. Biochem Soc Trans 2001; 29:63-8.
38. Hyatt MA, Budge H, Walker D, Stephenson T, Symonds ME. Ontogeny and nutritional programming of the hepatic growth hormone-insulin-like growth factor-prolactin axis in the sheep. Endocrinology 2007; 148:4754-60.
39. Ravelli ACJ, van der Meulen JHP, Michels RPJ, Osmond C, Barker DJP, Hales CN, et al. Glucose tolerance in adults after prenatal exposure to the Dutch famine. Lancet 1998; 351:173-7.
40. Cheung CY, Bogic L, Gagnon R, Harding R, Brace RA. Morphologic alterations in ovine placenta and fetal liver following induced severe placental insufficiency. J Soc Gynecol Investig 2004; 11:521-8.
41. Ergaz Z, Avgil M, Ornoy A. Intrauterine growth restriction-eitology and consequences: what do we know about the human situation and experimental animal models? Reprod Toxicol 2005; 20:301-22.
42. Hales CN, Barker DJP. The thrifty phenotype hypothesis. Br Med Bull 2001; 60:5-20.
43. Nathanielsz PW, Hanson MA. The fetal dilemma: spare the brain and spoil the liver. J Physiol 2003; 548.2:333.
44. al-Ghazali W, Chita SK, Chapman MG, Allan LD. Evidence of redistribution of cardiac output in asymmetrical growth retardation. BJOG 1989; 96:697-704.
45. Barker DJP, Martyn CN, Osmond C, Hales CN, Fall CH. Growth in utero and serum cholesterol concentrations in adult life. Br Med J 1993; 307:1524-7.
46. Barker DJP, Meade TW, Fall CH, Lee A, Osmond C, Phipps K, et al. Relation of fetal and infant growth to plasma fibrinogen and factor VII concentrations in adult life. Br Med J 1992; 304:148-52.
47. Hannula K, Lipsanen-Nyman M, Kristo P, Kaitila I, Simola KO, Lenko HL, et al. Genetic screening for maternal uniparental disomy of chromosome 7 in prenatal and postnatal growth retardation of known cause. Pediatrics 2002; 109:441-8.
48. Cetin I, Foidart JM, Miozzo M, Raun T, Jansson T, Tsatsaris V, et al. Fetal growth restriction: a workshop report. Placenta 2004; 25:753-7.
49. Wilcox M, Gardosi J, Mongelli M, Ray C, Johnson I. Birth weight from pregnancies dated by ultrasonography in a multicultural British population. Br Med J 1993; 307:588-91.
50. Johar R, Rayburn W, Weir D, Eggert L. Birthweights in term infants. J Reprod Med 1988; 33:813-6.
51. Garite TJ, Clark RH, Elliott JP, Thorp JA. Twins and triplets: the effect of plurality and growth on neonatal outcome compared with singleton infants. Am J Obstet Gynecol 2004; 191:700-7.
52. Gluckman PD, Gunn AJ, Wray A, Cutfield WS, Chatelain PG, Guilbaud O, et al. Congenital idiopathic growth hormone deficiency associated with prenatal and early postnatal growth failure. The International Board of the Kabi Pharmacia International Growth Study. J Pediatr 1992; 121:920-3.
53. Woods KA, Camacho-Hubner C, Barter D, Clark AJ, Savage MO. Insulin-like growth factor gene deletion causing intrauterine growth retardation and severe short stature. Acta Paediatr Suppl 1996; 423:39-45.
54. Holmes R, Montemagno R, Jones J, Preece M, Rodeck C, Soothill P. Fetal and maternal plasma insulin-like growth factors and binding proteins in pregnancies with appropriate or retarded fetal growth. Early Hum Dev 1997; 49:7-17.
55. Kalanda BF, van Buuren S, Verhoeff FH, Brabin BJ. Anthropometry of fetal growth in rural Malawi in relation to maternal malaria and HIV status. Arch Dis Child Fetal Neonatal Ed 2005; 90:F161-F5.
56. Michlin R, Ottinger M, Odeh M, Koury S, Ophir E, Barak M, et al. Maternal obesity and pregnancy outcome. Isr Med Assoc J 2000; 2:10-3.
57. Clarke L, Yakubu DP, Symonds ME. Influence of maternal bodyweight on size, conformation and survival of newborn lambs. Reprod Fertil Dev 1997; 9:509-14.
58. Allen JC, Wilsher S, Turnbull C, Stewart F, Ousey J, Rossdale PD, et al. Influence of maternal size on placental, fetal and postnatal growth in the horse. Reproduction 2002; 123:445-53.
59. Walton A, Hammond J. The maternal effects on growth and conformation in the Shire horse-Shetland pony crosses. Proc Biol Sci 1938; 125:311-35.
60. Lenders CM, McElrath TF, Scholl TO. Nutrition in adolescent pregnancy. Curr Opin Pediatr 2000; 12:291-6.
61. Menacker F, Martin JA, MacDorman MF, Ventura SJ. Births to 10-14 year-old mothers, 1990-2002: trends and health outcomes. National Vital Statistics Report 2004; 53:1-18.
62. Wallace JM, Aitken RP, Milne JS, Hay WWJ. Nutritionally mediated placental growth restriction in the growing adolescent: consequences for the fetus. Biol Reprod 2004; 71:1055-62.
63. Heasman L, Clarke L, Firth K, Stephenson T, Symonds ME. Influence of restricted maternal nutrition in early to mid gestation on placental and fetal development at term in sheep. Ped Res 1998; 44:546-51.
64. Lumey LH, Stein AD. Offspring birthweight after maternal intrauterine undernutrition: a comparison within sibships. Am J Epidemiol 1997; 146:810-9.
65. Wallace JM, Bourke DA, Aitken RP, Palmer RM, Da Silva P, Cruickshank MA. Relationship between nutritionally-mediated placental growth restriction and fetal growth, body composition and endocrine status during late gestation in adolescent sheep. Placenta 2000; 21:100-8.
66. Shah NR, Bracken MB. A systemic review and meta-analysis of prospective studies on the association between maternal cigarette smoking and preterm delivery. Am J Obstet Gynecol 2000; 182:465-72.
67. Vogt Isaksen C. Maternal smoking, intrauterine growth restriction, and placental apoptosis. Pediatr Dev Pathol 2004; 7:433-42.
68. Peacock JL. Smoking in pregnancy and fetal growth. Acta Paediatr 2002; 91:263-4.
69. Gauthier TW, Drews-Botsch C, Falek A, Coles C, Brown LA. Maternal alcohol abuse and neonatal infection. Alcohol Clin Exp Res 2005; 29:1035-43.
70. Zimmet P, Alberti KG, Shaw J. Global and societal implications of the diabetes epidemic. Nature 2001; 414:782-7.
71. Wynn SW, Wynn AH, Doyle W, Crawford MA. The association of maternal social class with maternal diet and the dimensions of babies in a population of London women. Nutr Health 1994; 9:303-15.
72. Nicolaides KH, Economides DL, Soothill PW. Blood gases, pH, and lactate in appropriate-and small-for-gestational-age fetuses. Am J Obstet Gynecol 1989; 161:996-1001.
73. Owens JA, Falconer J, Robinson JS. Restriction of placental size in sheep enhances efficiency of placental transfer of antipyrine, 3-O-methyl-D-glucose but not of urea. J Dev Physiol 1987; 9:457-64.
74. Nahum GG, Stanislaw H. Relationship of paternal factors to birth weight. J Reprod Med 2003; 48:963-8.
75. McMillen IC, Robinson JS. Developmental origins of the metabolic syndrome: prediction, plasticity, and programming. Physiol Rev 2005; 85:571-633.
76. Morrison JL. Sheep models of intrauterine growth restriction: fetal adaptations and consequences. Clin Exp Pharmacol Physiol 2008; 35:730-43.
77. Barry JS, Anthony RV. The pregnant sheep as a model for the human pregnancy. Theriogenology 2008; 69:55-67.
78. Painter RC, Roseboom TJ, Bossuyt PMM, Osmond C, Barker DJP, Bleker OP. Adult mortality at age 57 after prenatal exposure to the Dutch famine. Eur J Epidemiol 2005; 20:673-6.
79. Langley-Evans SC, Jackson AA. Increased systolic blood pressure in adult rats induced by fetal exposure to maternal low protein diets. Clin Sci 1994; 86:217-22.
80. Holemans K, Aerts L, Van Assche FA. Fetal growth and long-term consequences in animal models of growth retardation. Eur J Obstet Gynecol Reprod Biol 1998; 81:149-56.
81. Edwards LJ, McMillen IC. Impact of maternal undernutrition during the periconceptional period, fetal number, and fetal sex on the development of the hypothalamo-pituitary adrenal axis in sheep during late gestation. Biol Reprod 2002; 66:1562-9.
82. Gardner DS, Pearce S, Dandrea J, Walker RM, Ramsey MM, Stephenson T, et al. Peri-implantation undernutrition programs blunted angiotensin II evoked baroreflex responses in young adult sheep. Hypertension 2004; 43:1290-6.
83. Gardner DS, Tingey K, Van Bon BWM, Ozanne SE, Wilson V, Dandrea J, et al. Programming of glucose-insulin metabolism in adult sheep after maternal undernutrition. Am J Physiol 2005; 289:R947-R54.
84. Gopalakrishnan GS, Gardner DS, Rhind SM, Rae MT, Kyle CE, Brooks AN, et al. Programming of adult cardiovascular function after early maternal undernutrition in sheep. Am J Physiol 2004; 287:R12-R20.
85. Luther J, Aitken RP, Milne JS, Matsuzaki M, Reynolds LP, Redmer DA, et al. Maternal and fetal growth, body composition, endocrinology, and metabolic status in undernourished adolescent sheep. Biol Reprod 2007; 77:343-50.
86. Hyatt MA, Budge H, Walker D, Stephenson T, Symonds ME. Effects of maternal parity and late gestational nutrition on mRNA abundance for growth factors in the liver of postnatal sheep. Am J Physiol Regul Integr Comp Physiol 2007; 292:R1934-42.
87. Hyatt MA, Butt E, Budge H, Stephenson T, Symonds ME. Effects of maternal cold exposure and nutrient restriction on the ghrelin receptor, the growth hormone - insulin like growth factor axis and metabolic regulation in the postnatal ovine liver. Reproduction 2008; 135:723-32.
88. Budge H, Dandrea J, Mostyn A, Evens Y, Watkins R, Sullivan C, et al. Differential effects of fetal number and maternal nutrition in late gestation on prolactin receptor abundance and adipose tissue development in the neonatal lamb. Ped Res 2003; 53:302-8.
89. Clarke L, Bryant MJ, Lomax MA, Symonds ME. Maternal manipulation of brown adipose tissue and liver development in the ovine fetus during late gestation. Br J Nutr 1997; 77:871-83.
90. Zhou Y, Nijland M, Miller M, Ford S, Nathanielsz PW, Brenna JT. The influence of maternal early to mid-gestation nutrient restriction on long chain polyunsaturated fatty acids in fetal sheep. Lipids 2008; 43:525-31.
91. Brameld JM, Mostyn A, Dandrea J, Stephenson TJ, Dawson JM, Buttery PJ, et al. Maternal nutrition alters the expression of insulin-like growth factors in fetal sheep liver and skeletal muscle. J Endocrinol 2000; 167:429-37.
92. Leon DA, Koupilova I, Lithell HO, Berglund L, Mohsen R, Vagero D, et al. Failure to realize growth potential in utero and adult obesity in relation to blood pressure in 50 year old Swedish men. Br Med J 1996; 312:401-6.
93. Roseboom TJ, van der Meulen JH, Osmund C, Barker DJP, Ravelli AC, Schroeder-Tanka JM, et al. Coronary heart disease after prenatal exposure to the Dutch famine. Heart 2000; 84:595-8.
94. Roseboom TJ, van der Meulen JH, Ravelli AC, Osmond C, Barker DJP, Bleker OP. Plasma fibrinogen and factor VII concentrations in adults after prenatal exposure to famine. Br J Haematol 2000; 111:112-7.
95. Ravelli AC, Van der Meulen JH, Osmund C, Barker DJP, Bleker OP. Obesity at the age of 50 y in men and women exposed to famine prenatally. Am J Clin Nutr 1999; 70:811-6.
96. Roseboom TJ, van der Meulen JH, Osmond C, Barker DJP, Ravelli AC, Bleker OP. Plasma lipid profiles in adults after prenatal exposure to the Dutch famine. Am J Clin Nutr 2000; 72:1101-6.
97. Bauer M, Breier B, Harding J, Veldhuis J, Gluckman P. The fetal somatotropic axis during long term maternal undernutrition in sheep: evidence for nutritional regulation in utero. Endocrinology 1995; 136:1250-7.
98. Edwards LJ, Symonds ME, Warnes KE, Owens JA, Butler TG, Jurisevic A, et al. Responses of the fetal pituitary-adrenal axis to acute and chronic hypoglycemia during late gestation in the sheep. Endocrinology 2001; 142:1778-85.
99. Winick M. Cellular changes during placental and fetal growth. Am J Obstet Gynecol 1971; 109:166.
100. Whorwood CB, Firth KM, Budge H, Symonds ME. Maternal undernutrition during early to midgestation programs tissue-specific alterations in the expression of the glucocorticoid receptor, 11β-hydroxysteroid dehydrogenase isoforms, and type 1 angiotensin II receptor in neonatal sheep. Endocrinology 2001; 142:2854-64.
101. Vonnahme KA, Hess BW, Hansen TR, McCormick RJ, Rule DC, Moss GE, et al. Maternal undernutrition from early- to mid-gestation leads to growth retardation, cardiac ventricular hypertrophy, and increased liver weight in the fetal sheep. Biol Reprod 2003; 69:133-40.
102. Magnus P, Berg K, Bjerkedal T. The association of parity and birthweight: testing the sensitisation hypothesis. Early Hum Dev 1985; 12:49-54.
103. Wilcox MA, Chang AM, Johnson IR. The effects of parity on birthweight using successive pregnancies. Acta Obstet Gynecol Scand 1996; 75:459-63.
104. Meikle A, Kulcsar M, Chilliard Y, Delavaud C, Cavestany D, Chilibroste P. Effects of parity and body condition at parturition on endocrine and reproductive parameters of the cow. Reproduction 2004; 127:727-37.
105. Town SC, Patterson JL, Pereira CZ, Gourley G, Foxcroft GR. Embryonic and fetal development in a commercial dam-line genotype. Anim Reprod Sci 2005; 85:301-16.
106. Gardner DS, Buttery PJ, Daniel Z, Symonds ME. Factors affecting birth weight in sheep: maternal environment. Reproduction 2007; 133:297-307.
107. Bradford GE. The role of maternal effects in animal breeding. VII. Maternal effects in sheep. J Anim Sci 1972; 35:1324-34.
108. Ong KKL, Preece MA, Emmett PM, Ahmed ML, Dunger DB. Size at birth and early childhood growth in relation to maternal smoking, parity and infant breast-feeding: Longitudinal birth cohort study and analysis. Ped Res 2002; 52:863-7.
109. Parsons TJ, Power C, Manor O. Fetal and early life growth and body mass index from birth to early adulthood in 1958 British cohort: longitudinal study. Br Med J 2001; 323:1331-5.
110. Forsen T, Eriksson JG, Tuomilehto J, Osmond C, Barker DJP. Growth in utero and during childhood among women who develop coronary heart disease: longitudinal study. Br Med J 1999; 319:1403-7.
111. Adair LS, Cole TJ. Rapid child growth raises blood pressure in adolescent boys who were thin at birth. Hypertension 2003; 41:451-6.
112. Khong TY, Adema ED, Erwich JJHM. On an anatomical basis for the increase in birth weight in second and subsequent born children. Placenta 2003; 24:348-53.
113. Owens JA, Falconer J, Robinson JS. Effect of restriction of placental growth on umbilical and uterine blood flows. Am J Physiol 1986; 250:R427-34.
114. Godfrey K, Robinson S, Barker DJP, Osmond C, Cox V. Maternal nutrition in early and late pregnancy in relation to placental and fetal growth. Br Med J 1996; 312:410-4.
115. Edwards MJ, Walsh DA, Li Z. Hyperthermia, teratogenesis and the heat shock response in mammalian embryos in culture. Int J Dev Biol 1997; 41:354-8.
116. Eran E, Iddo ZBD, Yami S, Nilli D, Ruth A, Daniel S, et al. Acute Hepatitis A Infection in Pregnancy Is Associated With High Rates of Gestational Complications and Preterm Labor. Gastroenterology 2006; 130:1129-34.
117. Regnault TR, Orbus RJ, Battaglia FC, Wilkening RB, Anthony RV. Altered arterial concentrations of placental hormones during maximal placental growth in a model of placental insufficiency. J Endocrinol 1999; 162:433-42.
118. Dreiling CE, Carman FS, III, Brown DE. Maternal Endocrine and Fetal Metabolic Responses to Heat Stress. J Dairy Sci 1991; 74:312-27.
119. Thureen PJ, Trembler KA, Meschia G, Makowski EL, Wilkening RB. Placental glucose transport in heat-induced fetal growth retardation. Am J Physiol Regul Integr Comp Physiol 1992; 263:R578-85.
120. Wallace JM, Regnault TRH, Limesand SW, Hay WW, Jr., Anthony RV. Investigating the causes of low birth weight in contrasting ovine paradigms. J Physiol 2005; 565:19-26.