Hormonal factors in the control of heart rate in normoxaemic and hypoxaemic fetal, neonatal and adult sheep

The relationship of plasma levels of adrenaline, noradrenaline, arginine vasopressin (AVP) and plasma renin activity (PRA) to heart rate were studied in normoxaemic and hypoxaemic fetal, neonatal and adult sheep. The mean heart rate response of fetuses at the end of a 30 minute period of 10% oxygen delivery to the maternal ewe was tachycardia. However bradycardia, usually of a transient nature, was observed in 9 of the 12 fetuses (P less than 0.05). Multiple regression analysis was used to determine the contribution of blood gas, blood pressure and plasma hormone levels to the variance in heart rate in the perinatal sheep. 22% of the variance in fetal heart rate was provided by PRA and age from conception (P less than 0.001). Tachycardia was the invariable heart rate response of the neonates and adults to hypoxaemia. 61% of the variance in neonatal heart rate was contributed by PaO2, PaCO2, AVP, PRA and systolic blood pressure (SBP, P less than 0.001). PaO2 and plasma levels of adrenaline were significantly related to adult heart rate (P less than 0.001). Those fetuses which developed bradycardia had lower PaO2 but higher AVP and PRA during hypoxaemia than those which did not develop bradycardia. The major determinant of the area of the fetal bradycardia response was found, by multiple regression analysis, to be plasma adrenaline concentration (P less than 0.05). Thus different hormonal factors may play a role in the regulation of heart rate in normoxaemic and hypoxaemic fetal, neonatal and adult sheep.     

Systemic arterial pressure response to two weeks of Tempol therapy in SHR: involvement of NO, the RAS, and oxidative stress

The roles of nitric oxide (NO) and plasma renin activity (PRA) in the depressor response to chronic administration of Tempol in spontaneously hypertensive rats (SHR) are not clear. The present study was done to determine the effect of 2 wk of Tempol treatment on blood pressure [mean arterial pressure (MAP)], oxidative stress, and PRA in the presence or absence of chronic NO synthase inhibition. SHR were divided into four groups: control, Tempol (1 mmol/l) alone, nitro-L-arginine methyl ester (L-NAME, 4.5 mg x g(-1).day(-1)) alone, and Tempol + L-NAME or 2 wk. With Tempol, MAP decreased by 22%: 191 +/- 3 and 162 +/- 21 mmHg for control and Tempol, respectively (P < 0.05). L-NAME increased MAP by 16% (222 +/- 2 mmHg, P < 0.01), and L-NAME + Tempol abolished the depressor response to Tempol (215 +/- 3 mmHg, P < 0.01). PRA was not affected by Tempol but was increased slightly with L-NAME alone and 4.4-fold with L-NAME + Tempol. Urinary nitrate/nitrite increased with Tempol and decreased with L-NAME and L-NAME + Tempol. Tempol significantly reduced oxidative stress in the presence and absence of L-NAME. In conclusion, in SHR, Tempol administration for 2 wk reduces oxidative stress in the presence or absence of NO, but in the absence of NO, Tempol is unable to reduce MAP. Therefore, NO, but not changes in PRA, plays a major role in the blood pressure-lowering effects of Tempol. These data suggest that, in hypertensive individuals with endothelial damage and chronic NO deficiency, antioxidants may be able to reduce oxidative stress but not blood pressure.     

Dopamine does not limit fetal cerebrovascular responses to hypoxia.

Dopamine is used clinically to stabilize mean arterial blood pressure (MAP) in sick infants. One goal of this therapeutic intervention is to maintain adequate cerebral blood flow (CBF) and perfusion pressure. High-dose intravenous dopamine has been previously demonstrated to increase cerebrovascular resistance (CVR) in near-term fetal sheep. We hypothesized that this vascular response might limit cerebral vasodilatation during acute isocapnic hypoxia. We studied nine near-term chronically catheterized unanesthetized fetal sheep. Using radiolabeled microspheres to measure fetal CBF, we calculated CVR at baseline, during fetal hypoxia, and then with the addition of an intravenous dopamine infusion at 2.5, 7.5, and 25 microg.kg(-1).min(-1) while hypoxia continued. During acute isocapnic fetal hypoxia, CBF increased 73.0 +/- 14.1% and CVR decreased 38.9 +/- 4.9% from baseline. Dopamine infusion at 2.5 and 7.5 microg.kg(-1).min(-1), begun during hypoxia, did not alter CVR or MAP, but MAP increased when dopamine infusion was increased to 25 microg.kg(-1).min(-1). Dopamine did not alter CBF or affect the CBF response to hypoxia at any dose. However, CVR increased at a dopamine infusion rate of 25 microg.kg(-1).min(-1). This increase in CVR at the highest dopamine infusion rate is likely an autoregulatory response to the increase in MAP, similar to our previous findings. Therefore, in chronically catheterized unanesthetized near-term fetal sheep, dopamine does not alter the expected cerebrovascular responses to hypoxia.     

Adenosine A(2A) receptors mediate cardiovascular responses to hypoxia in fetal sheep

Nonselective adenosine (ADO) receptor antagonists block hypoxia-induced bradycardia and hypertension in fetal sheep. This study was designed to determine the ADO receptor subtype that is involved in these cardiovascular responses. In chronically catheterized fetal sheep (>0.8 term), fetal hypoxemia was induced by having the ewe breathe a hypoxic gas mixture (9% O(2)-3% CO(2)-88% N(2)) for 1 h. Intra-arterial infusion of ZM-241385, an antagonist highly selective for ADO A(2A) receptors, to eight fetuses during normoxia significantly increased mean arterial pressure (MAP) from 42.5 +/- 2.0 to 46.1 +/- 2.0 mmHg without altering heart rate (HR). Infusion of a selective antagonist of ADO A(1) receptors [1, 3-dipropyl-8-cyclopentylxanthine (DPCPX)] elevated MAP and HR only after the infusion was terminated, although administration of the vehicle for ZM-241385 or DPCPX had no effect on MAP or HR. Isocapnic hypoxia with infusion of DPCPX or the vehicle for DPCPX or ZM-241385 produced a transient fall in HR, a rise in MAP, and a decrease in plasma volume. In contrast, ADO A(2A) receptor blockade abolished the hypoxia-induced bradycardia and hypertension and blunted the decline in plasma volume. We conclude that fetal ADO A(2A) receptors: 1) modulate AP during normoxia, and 2) mediate cardiovascular responses during acute O(2) deficiency.     

Thyroid hormone modulates renin and ANG II receptor expression in fetal sheep

Fetal renin-angiotensin system (RAS) activity is developmentally regulated, increasing in late gestation toward term. At the same time, fetal hemodynamic parameters change, with blood pressure increasing and heart rate decreasing. During this period, fetal plasma thyroid hormone concentrations also increase significantly. In this study we utilized the technique of thyroidectomy (TX), which removes thyroid hormone from the circulation, to investigate the importance of thyroid hormone on the developmental changes in the RAS (in plasma, kidney, heart, and lung) and hemodynamic regulation in fetal sheep. TX was performed at 120 days of gestational age (dGA), and control fetuses were sham operated. Immediately before necropsy ( approximately 137 dGA), fetuses were infused with isoproterenol and the hemodynamic responses were noted. TX significantly decreased plasma thyroid hormone concentrations and renal renin mRNA and renal active renin levels but did not change fetal plasma active renin levels. TX decreased both angiotensin II receptor subtype 1 (AT1) mRNA and protein levels in kidney and lung but not in the left ventricle. TX also was associated with increased ANG II receptor subtype 2 (AT2) mRNA and protein at the 44-kDa band in kidney, whereas AT2 protein was decreased at the 78-kDa level in kidney and lung tissue only. TX fetuses had significantly lower basal mean arterial blood pressures (MAP) and heart rates than controls. Isoproterenol infusion decreased MAP in TX fetuses. These findings support the hypothesis that thyroid hormone is important in modulating maturation of RAS and cardiovascular function in the late-gestation fetal sheep.     

Angiotensin II potentiates the effect of ACTH on the production of cyclic AMP by bovine adrenal cells in primary culture

The effect of Angiotensin II (AII) on ACTH-induced cyclic AMP production was studied in bovine adrenocortical cells cultured in a chemically defined serum-free medium. Immediately after collagenase dispersion, AII did not modify either the basal or the ACTH-induced cAMP production by the isolated cells. During cell culture, AII alone did not affect cAMP production. But 2 days after plating, AII increased significantly the ACTH-induced cAMP production by the culture. This potentiating effect increased with the age of culture. Sar1Ala8AII (Saralasin), a potent AII antagonist, inhibited the AII potentiating effect indicating an AII specific action.     

Mitogen-activated protein kinase activation and regulation in the pressure-loaded fetal ovine heart

The mitogen-activated protein (MAP) kinase signaling pathways help to mediate the hypertrophic response of the pressure-loaded adult heart, although their importance in fetal myocardium is less known. The goal of this study was to determine the role the MAP kinase signaling pathways play in regulating the response of the fetal heart to a pressure load. Aortic (Ao) and pulmonary artery (PA) bands were placed in 132-day fetal sheep for 7 days. Protein levels of the total and active (phosphorylated) terminal MAP kinases extracellular signal-regulated kinase (ERK/P-ERK), c-Jun NH(2)-terminal kinase (JNK/P-JNK), and p38/P-p38 and the MAP kinase phosphatases MKP-1, MKP-2, and MKP-3 were made in the right and left ventricular (RV and LV) free walls. In both Ao- and PA-banded animals, total heart weight normalized to body weight was significantly increased, largely due to an increase in RV free wall mass in the Ao-banded animals and an increase in septal mass in the PA-banded fetuses. Total protein levels of the three terminal kinases and of P-ERK and P-JNK remained stable in both groups of banded animals. However, P-p38 was significantly increased in RV and LV of Ao- and PA-banded fetuses. Whereas MKP-1 and MKP-2 protein levels were unchanged following Ao- and PA-banding, MKP-3 protein levels were significantly increased in the RV of the PA-banded animals. These findings indicate that the MAP kinase signaling pathways are active in the fetal heart and help to modulate the response of prenatal myocardium to a pressure load.     

Programming of glucose-insulin metabolism in adult sheep after maternal undernutrition

The present study examines the effects of late vs. early gestation undernutrition on adult glucose-insulin homeostasis in sheep and investigates whether the lower birth weight of twins alters glucose-insulin handling in adult life. Pregnant sheep were fed to requirement (100% intake) from day 0 of gestation to term [ approximately 147 days of gestation (dGA), control singles (CS) n = 5; control twins (CT) n = 5] or to 50% requirement from days 0-30 dGA [nutrient restricted during early gestation (NRE); n = 5] or day 110-term [NR during late nutrition (NRL); n = 4]. At all other times, NR sheep received 100% intake. All sheep lambed naturally; offspring were weaned at 10 wk and were reared on pasture until 1 yr of age. At this time, indwelling catheters were inserted, and 2-4 days later, basal metabolic and endocrine status and responses to an intravenous glucose tolerance test (IVGTT) and feeding were assessed. Adipose and skeletal muscle were then sampled after humane euthanasia and were analyzed for expression of insulin-signaling proteins and GLUT4. Between groups, birth weight of singletons was similar and increased relative to twins. At 1 yr of age, weights were similar between groups. The areas under the curve for glucose and insulin during the IVGTT were greater in NRL vs. other groups, indicating glucose intolerance. This was associated with reduced adipose, but not muscle, GLUT4, and increased adipose tissue mass. Adult glucose-insulin homeostasis in sheep was unaffected by fetal number. In conclusion, prenatal undernutrition, specifically during late gestation, affects adult offspring intermediary metabolism, and, in particular, glucose-insulin homeostasis.     

Pressor responsiveness to endothelin is not attenuated in gravid rats

The aim of this study was to evaluate the effect of synthetic human/porcine endothelin (ET-1) on mean arterial blood pressure (MAP) in pregnant and non-pregnant rats and to compare this to the effects of two well characterized agonists, angiotensin II (AII), and vasopressin (VP). On day 14 of gestation (parturition day 22) polyethylene catheters were chronically implanted in the abdominal aorta for monitoring of MAP and in the vena cava for administration of drugs. Pressor responsiveness was measured in conscious freely moving animals on day 20 and again on the 7th day post-partum. All three agonists increased MAP in a dose related manner. However, whereas the sensitivity of pregnant rats (P) to AII and VP was significantly blunted compared to postpartal (PP) measurements, the MAP responses to ET-1 were the same in both groups. Moreover, the combined administration of ET-1 at a subpressor dose (0.05 pmol/100 g bw) and AII or VP at effective doses significantly potentiated (particularly in P) the pressor effects of AII and VP. These results demonstrate that ET-1 and possibly other vasoactive substances of endothelial origin, override the compensatory mechanism of normal pregnancy with respect to the blunted responsiveness to AII and VP. Such a mechanism may be of particular relevance in the evolution of pregnancy-induced hypertension.     

Pressor responsiveness to angiotensin in soy-fed spontaneously hypertensive rats

Dietary soy may attenuate the development of arterial hypertension. In addition, some soy-containing foods exhibit angiotensin-converting enzyme (ACE) inhibitory properties. Accordingly, we tested the hypothesis that ACE inhibition contributes to the antihypertensive effect of dietary soy. Mean arterial blood pressure (MAP) was recorded from conscious spontaneously hypertensive rats (SHR) at least 24 h after the implantation of catheters. Cumulative dose-response curves to intravenous angiotensin I (AI) (5-100 ng x kg(-1) x min(-1)) and angiotensin II (AII) (1-20 ng x kg(-1) x min(-1)) were constructed for male, sham-operated female, and ovariectomized female (OVX) SHR that were maintained on either casein or soy diets. The soy diet was associated with a significant reduction in baseline MAP in the OVX SHR (approximately 20 mmHg, 1 mmHg = 133.322 Pa). AI and AII infusions caused graded increases in MAP in all groups. However, there was no significant attenuation of the pressor responses to AI in the soy-fed SHR. Conversely, we observed a significant rightward displacement of the AII dose-response curves in the soy-fed sham-operated and OVX SHR. We conclude that ACE inhibition does not account for the antihypertensive effect of dietary soy in mature SHR.     

Stimulation of cardiac sympathetic nerve activity by central angiotensinergic mechanisms in conscious sheep

Central actions of angiotensin play an important role in cardiovascular control and have been implicated in the pathogenesis of hypertension and heart failure. One feature of centrally or peripherally administered angiotensin is that the bradycardia in response to an acute pressor effect is blunted. It is unknown whether after central angiotensin this is due partly to increased cardiac sympathetic nerve activity (CSNA). We recorded CSNA and arterial pressure in conscious sheep, at least 3 days after electrode implantation. The effects of intracerebroventricular infusions of ANG II (3 nmol/h for 30 min) and artificial cerebrospinal fluid (CSF) (1 ml/h) were determined. The response to intracerebroventricular hypertonic saline (0.6 M NaCl in CSF at 1 ml/h) was examined as there is evidence that hypertonic saline acts via angiotensinergic pathways. Intracerebroventricular angiotensin increased CSNA by 23 +/- 7% (P < 0.001) and mean arterial pressure (MAP) by 7.6 +/- 1.2 mmHg (P < 0.001) but did not significantly change heart rate (n = 5). During intracerebroventricular ANG II the reflex relation between CSNA and diastolic blood pressure was significantly shifted to the right (P < 0.01). Intracerebroventricular hypertonic saline increased CSNA (+9.4 +/- 6.6%, P < 0.05) and MAP but did not alter heart rate. The responses to angiotensin and hypertonic saline were prevented by intracerebroventricular losartan (1 mg/h). In conclusion, in conscious sheep angiotensin acts within the brain to increase CSNA, despite increased MAP. The increase in CSNA may account partly for the lack of bradycardia in response to the increased arterial pressure. The responses to angiotensin and hypertonic saline were losartan sensitive, indicating they were mediated by angiotensin AT-1 receptors.     

Developmental changes in the expression of genes involved in cholesterol biosynthesis and lipid transport in human and rat fetal and neonatal livers

Cloned cDNAs encoding a number of enzymes involved in cholesterol biosynthesis as well as extracellular and intracellular lipid transport were used to compare the developmental maturation of these biologic functions in the fetal and neonatal rat and human liver. The results of RNA blot hybridization analyses indicate that steady-state levels of rat HMG-CoA synthase, HMG-CoA reductase and prenyl transferase mRNAs are highest in late fetal life and undergo precipitous (up to 80-fold) co-ordinate reductions immediately after parturition. These changes reflect the ability of the fetal rat liver to produce large quantities of cholesterol as well as the repression of this function during the suckling period in response to exogenous dietary cholesterol. Striking co-ordinate patterns of HMG-CoA synthase, reductase and prenyl-transferase mRNA accumulation were also observed in four extrahepatic rat tissues (brain, lung, intestine and kidney) during the perinatal period. The concentrations of all three mRNAs in the 8-week-old human fetal liver are similar to those observed throughout subsequent intrauterine development with less than 2-fold changes noted between the 8th through 25th weeks of gestation. Analysis of the levels of human apo AI, apo AII, apo B and liver fatty acid binding protein mRNAs during this period and in newborn liver specimens also indicated less than 2-3-fold changes. These observations suggest that the 8-week human liver has achieved a high degree of biochemical differentiation with respect to functions involved in lipid metabolism/transport which may be comparable to that present in 19-21 day fetal rat liver. Further analysis of human and rat fetal liver RNAs using cloned cDNAs should permit construction of a developmental time scale correlating hepatic biochemical differentiation to be constructed between these two mammalian species.     

Effects of continuous angiotensin I-converting enzyme blockade on blood pressure, sympathetic activity and renin-angiotensin system in stroke-prone spontaneously hypertensive rats

The purpose of this study was to examine the effects of continuous angiotensin converting enzyme (ACE) blockade in stroke-prone spontaneously hypertensive rats (sp-SHR) on the renin-angiotensin system and on sympathetic activity. The pressor response to angiotensin II (AII) and norepinephrine (NE) were also examined after chronic blockade of ACE and compared to that of saline-treated controls. Captopril treatment had no effect on body weight. Serum ACE was significantly reduced on day 1; an effect that persisted through day 6 and day 10. Plasma renin activity (PRA) was elevated significantly on day 1 and remained at this high level throughout the 10 day observation period. Plasma NE was not altered by the chronic ACE blockade except on day 1, where there was a slight elevation of plasma NE in both groups. Pressor responses to AII and NE were not changed after chronic captopril treatment. It is observed that chronic inhibition of the renin-angiotensin system with captopril in sp-SHR resulted in a reduction of blood pressure, reduced serum ACE activity and elevated PRA. The constant plasma NE levels suggest that chronic inhibition of the renin-angiotensin system does not affect sympathetic activity. This study also indicates that long term inhibition of ACE does not alter pressor responses to either AII or NE.     

Plasma catecholamines and their physiologic thresholds during the first ten days of life in sheep

We studied serial plasma catecholamine levels in healthy newborn sheep over the first ten days of life. The results show that plasma norepinephrine values in newborn sheep are 3-4 fold higher, and plasma epinephrine values are two-fold higher than values in term fetal sheep. These elevations are sustained over the first 10 days of life. Cardiovascular (heart rate and blood pressure) and metabolic parameters (glucose and free fatty acids) are also significantly elevated above fetal levels. We performed graded catecholamine infusions in newborn animals and adult ewes to determine the minimum plasma catecholamine concentrations necessary for discernible physiologic effects. In response to step-wise increases in epinephrine or norepinephrine infusion rates, there were immediate increases in blood pressure and other physiologic responses. This pattern was seen in both newborn and adult animals, and differed from previous observations in fetal sheep where log-linear, dose response curves characteristic of a threshold response were seen. These results suggest that during the first two weeks of life plasma catecholamine levels are elevated above the threshold value for physiologic responses. These sustained elevations in circulating catecholamines are important in the maintenance of physiologic homeostasis.     

Role of the pituitary in the effects of tonin on adrenal secretion of the rat

Chronically catheterized conscious rats were infused intravenously with tonin at 2.4 and 12 micrograms x kg-1 x min-1 for 2 h. Plasma aldosterone concentration (PAC) at the end of the experiment was 11.2 +/- 2.4 ng% in controls, 8.5 +/- 2.8 ng% in rats infused with tonin at the lower rate, and 26.2 +/- 3.6 ng% (p less than 0.01 vs. controls) in rats infused at the higher rate. Plasma corticosterone (PC) was significantly higher (p less than 0.05) in the group infused at the high rate while plasma renin activity (PRA) was significantly reduced in this group of rats. Plasma angiotensin II (AII) concentration was similar in all three groups. PAC was elevated after tonin infusion in the presence of AII blockade. PAC in conscious sodium-depleted rats infused with tonin was not significantly changed, but PRA was significantly reduced (p less than 0.01). In chronically hypophysectomized rats, PAC remained unchanged by tonin infusion. The failure of tonin to stimulate aldosterone in hypophysectomized animals indicates a role of a pituitary hormone (probably ACTH) in the effect of tonin on adrenal secretion.     

Effect of maternal undernutrition in early gestation on ovine fetal blood pressure and cardiovascular reflexes

Human epidemiological and animal experimental studies suggest that maternal undernutrition during pregnancy may alter cardiovascular development of the offspring. The extent to which these effects involve changes in fetal cardiovascular function and whether they are necessarily linked to reduced fetal growth is unknown. In sheep, we investigated the effect of a 15% reduction in maternal global nutrition for the first 70 days of gestation (term = 147 days) on fetal blood pressure development, baroreflex control of fetal heart rate (FHR), and cardiovascular responses to acute hypoxemia in late gestation. Basal mean arterial pressure (P < 0.05), systolic blood pressure (P < 0.05), diastolic blood pressure (P < 0.05), and rate-pressure product (P < 0.001) were significantly lower in fetuses of nutritionally restricted ewes (R) compared with controls (C). FHR was not altered. The operating point for the fetal baroreflex was significantly lower in R fetuses compared with C (P < 0.01), but there was no difference between the groups in the cardiovascular response to hypoxemia. We conclude that mild maternal undernutrition alters fetal cardiovascular development, producing low blood pressure and resetting of baroreflex control mechanisms. This effect occurs without any changes in fetal growth or blood gas status.     

Time-dependent changes in cardiovascular regulation caused by chronic tobacco smoke exposure

The purpose of this study was to determine whether chronic tobacco smoke exposure for less than 2 mo alters cardiovascular regulation. One group of male Sprague-Dawley rats was administered tobacco smoke from low-nicotine cigarettes (group A, 1 mg/cigarette) for 4-6 wk, while a second group (B) served as a sham control by receiving only puffs of room air. Reflex adjustments in mean arterial blood pressure (MAP) after bilateral common carotid occlusion (BCCO) were compared between the two groups. In the anesthetized control state, no significant difference existed for the cardiovascular parameters measured in the two groups. However, MAP increases after BCCO were significantly greater in the smoke-treated animals (P less than 0.05) compared with the sham-treated group. At 10, 20, 30, and 40 s after BCCO, MAP increases above preocclusion values were 66, 45, 42, and 38% for group A and 35, 26, 24, and 22% for group B, respectively. Additionally, the time required to reach maximum MAP after BCCO was significantly less (P less than 0.05) for the smoke-treated vs. sham-treated animals (8.5 +/- 0.2s for group A, 11.2 +/- 0.3s for group B). MAP changes during BCCO were significantly different (P less than 0.05) between the treatment groups after cervical vagotomy. It is concluded that chronic tobacco smoke exposure in experimental animals for periods as short as 4-6 wk alters the reflex regulation of the cardiovascular system.     

Analysis of angiotensin-stimulated sodium transport in cultured smooth muscle cells from rat aorta

Angiotensin peptides (AI, AII, AIII) increased the rate of Na+ accumulation by smooth muscle cells (SMC) cultured from rat aorta. The stimulatory effect of AII on Na+ uptake was observed when Na+ exodus via the Na+/K+ pump was blocked either by ouabain or by the removal of extracellular K+. AII was at least ten times more potent than AIII and about 100 times more potent than AI in stimulating Na+ uptake. Saralasin had little effect on Na+ uptake by itself but almost completely blocked the increase caused by AII. The stimulation of net Na+ entry by AI, but not AII, was prevented by protease inhibitors. The stimulation of Na+ uptake was almost completely blocked by amiloride. Tetrodotoxin, which prevented veratridine from increasing Na+ uptake, had no effect on the response to AII. Angiotensin increased the rate of ouabain-sensitive 86Rb+ uptake (Na+/K+ pump activity) but had no effect on ouabain-sensitive ATPase activity in frozen-thawed SMC or in microsomal membranes isolated from cultured SMC. The stimulation of ouabain-sensitive 86Rb+ uptake by AII was blocked by saralasin. Omitting Na+ from the external medium prevented AII from increasing 86Rb+ uptake. AII had no effect on cell volume or cyclic AMP levels in the cultured SMC. These results suggest that angiotensin peptides activate an amiloride-sensitive Na+ transporter which supplies the Na+/K+ pump with more Na+, its rate-limiting substrate.     

Exaggerated sympathetic mediated responses to behavioral or pharmacological challenges following antenatal betamethasone exposure

Glucocorticoid administration to women at risk for preterm delivery is standard practice to enhance neonatal survival. However, antenatal betamethasone exposure (β-exposure) increases mean arterial pressure (MAP) in adult sheep (1.8 yr old) and results in impaired baroreflex sensitivity (BRS) for control of heart rate (HR). In the current studies we tested the hypothesis that enhanced sympathetic nervous system and hypothalamo-pituitary-adrenal (HPA) axis-mediated responses are evident at an early age in β-exposed sheep. Pregnant ewes were administered betamethasone (0.17 mg/kg twice over 24 h) or vehicle (Veh-control) on the 80th day of gestation, and offspring were delivered at full term. Female β-exposed and control offspring instrumented at age 42 ± 3 days for conscious continuous recording of MAP and HR had similar resting values at baseline. However, BRS was ~45% lower in β-exposed offspring. β-Exposed lambs allowed to suckle for 10 min had a greater elevation in MAP than Veh-control lambs (19 ± 1 vs 12 ± 2 mmHg; n = 4-5, P < 0.05). MAP was reduced by 20% from baseline via sodium nitroprusside infusion (SNP) over 10 min, which triggered a rebound increase in MAP only in β-exposed lambs. HR increased with the reduction in MAP during SNP infusion in Veh-control lambs, whereas there was no change in HR with the reduction in MAP in β-exposed lambs. Combined vasopressin-CRF injection caused greater increases in MAP in the β-exposed lambs. Cortisol and ACTH responses were higher in response to SNP hypotension in the β-exposed lambs. The data reveal enhanced sympathetic and HPA axis responses associated with impaired BRS preceding differences in resting MAP in preweanling female lambs exposed in utero to glucocorticoids. The consequences of these alterations at an early age include eventual development of higher blood pressure in this ovine model of fetal programming.