Background: Leptin concentrations are increased during late pregnancy, and leptin receptors are expressed in placental and fetal tissues, suggesting a role for leptin in placental and/or fetal growth, or both. In humans, leptin concentrations in adulthood are inversely related to body weight at birth, independent of adult adiposity, and correlate with fasting insulin. Glucocorticoids and insulin regulate leptin secretion. Excessive exposure to glucocorticoids during late fetal development in the rat causes intrauterine growth retardation (IUGR), together with hypertension and hyperinsulinaemia in adulthood. Leptin may have a role in the development of some forms of hypertension. Objective: To determine whether IUGR induced by maternal glucocorticoid treatment during the last third of pregnancy in the rat is associated with modulation of either maternal or fetal leptin concentrations, the placental expression of leptin or the short form of the leptin receptor (ObR-S), or combinations thereof, and to evaluate whether hypertension or hyperinsulinaemia in the earlygrowth-retarded adult progeny of dexamethasone-treated dams is associated with altered leptin concentrations. Design and Methods: Dexamethasone was administered to pregnant rats from day 15 to day 21 of gestation via a chronically implanted subcutaneous osmotic minipump. Protein expression of leptin and ObR-S in the placenta at day 21 of pregnancy was measured by western blotting. Plasma leptin and insulin concentrations were determined by radioimmunoassay and ELISA respectively. Systolic hypertension was measured by tail cuff plethysmography. Results: Dexamethasone administration during the last third of pregnancy decreased placental mass and fetal body weight at day 21 of gestation, caused maternal hyperleptinaemia but fetal hypoleptinaemia, and suppressed placental leptin protein expression whilst up-regulating placental protein expression of ObR-S. The male and female offspring of dexamethasone-treated dams were hypertensive from 12 weeks of age. One-year-old offspring of dexamethasone-treated dams exhibited signi®cant hyperleptinaemia compared with age-matched controls, an effect associated with hyperinsulinaemia in the male, but not female, offspring. Conclusions: The rat model of maternal dexamethasone treatment is established as a paradigm of programmed' hypertension in man. Our data show modi®cation of placental leptin and leptin receptor protein expression by dexamethasone treatment during the last third of pregnancy. We also show that leptin concentrations are suppressed during fetal life but increased in adulthood in this rat model of programmed hypertension. Our data do not necessarily establish a causal relationship between fetal hypoleptinaemia and impaired fetal growth during early life, or between hyperleptinaemia and hypertension in adulthood. Nevertheless, they suggest that hyperleptinaemia may be a component of the cluster of metabolic abnormalities seen in the insulin resistance syndrome in man. They also suggest that excessive...

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1 Radioligand binding and contractility studies were undertaken to determine the subtype/s of muscarinic receptors present in uteri of oestrogen-treated and late pregnant rats. 2 Competition binding studies with uterine membrane preparations and [ 3 H]-QNB (quinuclidinyl benzilate) provided negative log dissociation constants (pK i ) for each antagonist as follows; oestrogentreated ± atropine (7.98)5himbacine (7.83)4methoctramine (7.52)5hexahydrosiladiphenidol (HHSiD; 7.32)55,11]benzodiazepin-6-one (AF-DX 116, 6.77)4pirenzepine (6.17); late pregnant ± atropine (8.05)5methoctramine (7.95)5himbacine (7.71)5HHSiD (7.52)5AF-DX 384 (7.34)4AF-DX 116 (6.72)4pirenzepine (6.18). 3 The potency of carbachol in causing uterine contraction was similar in preparations from pregnant and non-pregnant animals (pD 2 =5.57 and 5.46, respectively). Each muscarinic antagonist caused parallel, rightward shifts of carbachol concentration-response curves. The pA 2 estimates were: oestrogentreated ± atropine (9.42)4himbacine (8.73)5HHSiD (8.68)5methoctramine (8.49)5AF-DX 384 (7.91)5AF-DX 116 (7.36)5pirenzepine (7.26); late pregnant ± atropine (9.48)4himbacine (8.37)5HHSiD (8.22)5methoctramine (8.01)5AF-DX 116 (7.73)5AF-DX 384 (7.44)5pirenzepine (6.92). 4 The relative pK i estimates for antagonists obtained in membrane preparations from oestrogen-treated rats suggest the presence of muscarinic M 2 subtypes. In functional studies pA 2 values indicated the additional presence of muscarinic M 3 receptor or, possibly an atypical receptor subtype. The similarity between pK i and pA 2 estimates obtained in uteri from oestrogen-treated and pregnant animals, respectively, indicates that pregnancy does not a ect myometrial muscarinic receptors in the rat.

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