Hormone Infusion Research Articles

Multihormonal regulation of hepatic sinusoidal Ntcp gene expression.

Bile acids are efficiently removed from sinusoidal blood by a number of transporters including the Na+-taurocholate-cotransporting polypeptide (Ntcp). Na+-dependent bile salt uptake, as well as Ntcp, are expressed twofold higher in male compared with female rat livers. Also, estrogen administration to male rats decreases Ntcp expression. The aims of this study were to determine the hormonal mechanism(s) responsible for this sexually dimorphic expression of Ntcp. We examined castrated and hypophysectomized rats of both sexes. Sex steroid hormones, growth hormone, thyroid, and glucocorticoids were administered, and livers were examined for changes in Ntcp messenger RNA (mRNA). Ntcp mRNA and protein content were selectively increased in males. Estradiol selectively decreased Ntcp expression in males, whereas ovariectomy increased Ntcp in females, confirming the importance of estrogens in regulating Ntcp. Hypophysectomy decreased Ntcp mRNA levels in males and prevented estrogen administration from decreasing Ntcp, indicating the importance of pituitary hormones. Although constant infusion of growth hormone to intact males reduced Ntcp, its replacement alone after hypophysectomy did not restore the sex differences. In contrast, thyroid hormone and corticosterone increased Ntcp mRNA in hypophysectomized rats. Sex differences in Ntcp mRNA levels were produced only when the female pattern of growth hormone was administered to animals also receiving thyroid and corticosterone. Thyroid and dexamethasone also increased Ntcp mRNA in isolated rat hepatocytes, whereas growth hormone decreased Ntcp. These findings demonstrate the essential role that pituitary hormones play in the sexually dimorphic control of Ntcp expression in adult rat liver and in the mediation of estrogen effects.

Pulsatile intravenous infusion of recombinant human luteinizing hormone under acute gonadotropin-releasing hormone receptor blockade reconstitutes testosterone secretion in young men.

The present study tests the hypothesis that iv infusion of discrete pulses of recombinant human (rh)LH after overnight GnRH-receptor blockade can restore midphysiological concentrations of testosterone (Te) in normal young men. In a pilot time-course analysis, injection of the GnRH antagonist ganirelix (2.0 mg sc) at 2200 h lowered LH concentrations (mean +/- sem) from 3.4 +/- 0.7 to 0.8 +/- 0.1 IU/liter (P < 0.01) and Te concentrations from 416 +/- 48 to 107 +/- 16 ng/dl (P < 0.01) (to convert to nmol/liter, multiply by 0.0347) at 0800 h the next morning. LH and Te concentrations remained suppressed thereafter for an additional 15 h (interval, 10-25 h after ganirelix administration) at mean values of 1.2 +/- 0.1 IU/liter and 67 +/- 10 ng/dl, respectively (P < 0.005 vs. baseline). Based on these data and earlier dose-finding studies, eight men received a single ganirelix injection followed by seven consecutive iv pulses of rhLH (15.3 IU Second International Reference Preparation) each delivered over 6 min every 2 h beginning at 0800 h. Recurrent rhLH stimuli restored mean LH concentrations (IU/liter of homologous standard) to 4.8 +/- 0.3, LH peak maxima to 7.1 +/- 0.6, incremental LH peak amplitudes to 3.7 +/- 0.4, and interpeak nadir LH concentrations to 3.3 +/- 0.3 (each P < 0.01 vs. saline infusion after ganirelix). These values were indistinguishable from the normal 95% range established in 23 young adults of comparable age. Injected LH pulses increased total Te concentrations (ng/dl) to 440 +/- 52, Te peak maxima to 552 +/- 64, incremental Te amplitudes to 188 +/- 23, and interpeak nadir Te concentrations to 366 +/- 43 (each P < 0.01 vs. saline addback; P value not significant vs. untreated men). Under combined ganirelix inhibition and pulsatile rhLH drive, Te concentrations rose from a nadir of less than 120 ng/dl to an asymptotic plateau of 611 ng/dl with an estimated half-time of 97 +/- 9.1 min. Cross-correlation analysis of paired serial LH and Te concentrations verified that infused LH pulses stimulate Te elevations within 40-70 (median 50) min (P < 0.001). Kinetic estimates of the half-life of exogenous rhLH averaged 107 +/- 3.8 min, which value exceeded that of secreted LH monitored after pharmacological GnRH stimulation (83 +/- 12 min; P = 0.012). We conclude that intermittent iv pulses of rhLH delivered over 12 h under selective GnRH-receptor blockade can restore young adult-like pulsatile LH and Te concentrations with an appropriate time delay coupling the lutropic stimulus to the steroidogenic response. Whether a comparable near-physiological paradigm can maintain human Leydig-cell testosterone production for a more extended interval is not known.

P0180 PP RELATIVE STIMULATION OF SUPERIOR MESENTERIC ARTERIAL (SMA) BLOOD FLOW BY ENTERAL NUTRITION AND GLUCAGON-LIKE PEPTIDE 2 (GLP-2) IN TOTAL PARENTERAL NUTRITION (TPN) FED NEONATAL PIGLETS

Introduction: Our previous studies in neonatal piglets showed that compared to enteral nutrition, total parenteral nutrition (TPN) leads to mucosal atrophy and reduced portal blood flow. Moreover, infusion of the trophic gut hormone, GLP-2, increases portal blood flow and prevents mucosal atrophy in TPN fed piglets. Among GI tissues, the GLP-2 trophic effect and the most abundant GLP-2 receptor expression are localized in the small intestine. Thus, we hypothesize that GLP-2 dose dependently increases SMA blood flow in TPN fed piglets. Methods: In study 1, 2-wk-old pigs (N=3) were implanted with duodenal, jugular and carotid catheters and an ultrasonic flow probe on the SMA. After recovery and 4 d of enteral feeding, pigs were fasted overnight then given 8h enteral feeding followed by 12h of TPN. In study 2, 3-d-old pigs (N=3) were implanted with jugular and carotid catheters and a SMA flow probe; flow probes were placed on the celiac artery (CA) in two separate pigs. After surgery, pigs were placed on TPN and continued for 7 d. In all pigs, SMA or CA flow was measured during a 2-h saline baseline infusion followed by 2-h GLP-2 infusions at doses ranging from physiologic (62.5 pmol/kg/hr) to pharmacologic (125, 250, 500, 1000 pmol/kg/hr). Results: Mean SMA flow during enteral feeding was 34% higher (p< 0.05) than during TPN. GLP-2 dose dependently increased SMA flow based on both 2-h area under the curve (AUC) and 1-h infusion time point. For AUC, GLP-2 stimulated SMA flow was 22%, 26%, 56%, 66%, and 103% above the saline baseline (P <0.05), respectively for each increasing GLP-2 dose. GLP-2 did not significantly increase CA flow at any dose. Conclusion: We conclude GLP-2 dose dependently increases SMA flow, but not CA arterial flow in TPN fed piglets consistent with the relative expression of GLP-2 receptor in gastrointestinal tissues. Pharmacologic doses of GLP-2 stimulate SMA flow in excess of that observed with enteral nutrition.

Plasminogen regulates pro‐opiomelanocortin processing

Plasminogen-deficient mice exhibit behavioral differences in response to stress, including a markedly reduced acoustic startle reflex response compared with wild-type (WT) littermates. The acoustic startle reflex activates the hypothalamic-pituitary axis and is modulated by these hormones. The purpose of this study was to investigate whether plasminogen plays a role in the processing of hormones in the hypothalamic-pituitary axis. In this study the concentration of plasma, pituitary, and brain hypothalamic-pituitary axis hormones and precursor processing was examined in WT and plasminogen deficient (Plg-/-) mice before and after acoustic startle reflex testing. Plasma adrenocorticotropic hormone (ACTH), beta-endorphin and alpha-melanocyte stimulating hormone were elevated after acoustic startle reflex testing in both WT and (Plg-/-) mice. However, in the Plg-/- mice, beta-endorphin values were 43, 35, and 45% lower in the plasma, pituitary, and whole brain, respectively, compared with the WT mice. Plasmin readily degraded precursor peptides, the 23-kDa precursor, beta-lipotropin, and ACTH, when presented as purified proteins or as the secretory products of mouse pituitary cells (AtT-20). The precursor peptide, 23 kDa, for beta-endorphin and alpha-melanocyte stimulating hormone was reduced in the pituitaries from the Plg-/- mice, and the mRNA for Plg was found in pituitaries from WT mice. Infusion of beta-endorphin and alpha-melanocyte stimulating hormone into the brain of Plg-/- mice increased acoustic startle reflex. The results of this study show that plasmin is involved in the processing of hormones derived from the pro-opiomelanocortin precursor in the intermediate pituitary. A deficiency of plasminogen reduces processing of beta-endorphin and alpha-melanocyte stimulating hormone, and interferes with normal brain function.

Effects of ovariectomy and steroid hormones on vaginal smooth muscle contractility.

The role of steroid hormones in regulating vaginal smooth muscle contractility was investigated. Rabbits were kept intact or ovariectomized. After 2 weeks, animals were continuously infused with vehicle or supraphysiological levels of testosterone (100 microg/day), or estradiol (200 microg/day), for an additional 2 weeks. The distal vaginal tissue was used to assess contractility in organ baths and changes in tissue structure were assessed by histology. Ovariectomized animals infused with vehicle exhibited significant atrophy of the muscularis and decreased epithelial height, resulting in thinning of the vaginal wall. Estradiol infusion increased epithelial height, comparable to that of intact animals, but only partially restored the muscularis layer. In contrast, testosterone infusion completely restored the muscularis layer, but only partially restored the epithelial height. In vaginal tissue strips contracted with norepinephrine and treated with bretylium, electrical field stimulation (EFS) caused frequency-dependent relaxation that was slightly attenuated with vehicle, significantly inhibited with estradiol and significantly enhanced with testosterone. VIP-induced relaxation was slightly attenuated in tissues from vehicle and estradiol-infused groups, but was enhanced in tissues from testosterone-infused animals. Contraction elicited by EFS or exogenous norepinephrine was not significantly altered with ovariectomy or steroid hormone infusion when data were normalized to potassium contraction. However, the tissue from testosterone-infused animals developed significantly greater contractile force to norepinephrine. These observations suggest that steroid hormones may be important regulators of vaginal tissue structure and contractility.

Dietary n-3 and n-6 Fatty Acids Alter Avian Pituitary Sensitivity

The effects of dietary saturated and polyunsaturated fatty acids (PUFAs) of the n-3 and n-6 series on avian pituitary sensitivity were investigated by infusing human growth hormone (GH) releasing hormone--fragment 1-29--and chicken luteinising hormone releasing hormone (LHRH) into catheterized broiler chickens. At 3 weeks of age three groups (n=18; six birds per group) were fed for 6 weeks isonitrogenous and isoenergetic experimental diets containing 80 g/kg of edible tallow (saturated fatty acids), fish oil (n-3 PUFAs) or sunflower oil (n-6 PUFAs). Jugular catheterisation was performed under general anaesthesia during week four of the dietary treatments and the birds allowed 7 days post surgery to recover. A bolus of LHRH (20 μg/bird) and a GH releasing hormone (12.5 μg/kg) infusion was given on different days to each chicken and serial blood samples taken over a 1 h period. Plasma luteinising hormone and GH concentrations were measured by radioimmunoassay. Pre-infusion GH concentrations were similar for the tallow, fish and sunflower oil dietary groups (5.2±3.9, 5.2±1.0 and 6.1±3.1 ng/ml, respectively), however, GH concentration in response to the GH releasing hormone infusion was elevated in the sunflower oil group (44.7±5.7 ng/ml) when compared to chicken fed tallow (33.7±9.7 ng/ml) or fish oil (21.3±5.0 ng/ml). There was a significant decrease (P<0.05) in the clearance rate of plasma GH for the birds fed the fish oil compared with those fed sunflower oil with an intermediate value being observed in the tallow fed group. Pre-infusion plasma luteinising hormone concentrations for the birds fed tallow (3.2±0.7 ng/ml) were significantly elevated (P<0.05) when compared to birds fed either the sunflower oil (0.84±0.25 ng/ml) or fish oil (0.93±0.22 ng/ml) diets. There were no significant differences between the dietary groups in either the maximal plasma luteinising concentration or its disappearance rate following the LHRH infusion. The data demonstrate that dietary fatty acids alter avian pituitary sensitivity and this modulation is determined by the nature of the dietary fat rather than the degree of saturation per se. In addition, this study also shows that dietary fats have a differential effect on pituitary cell activity and are specific to certain pituitary cell types.

Letters to the Editor

To the Editor: Deducing the physiological role of aldosterone from studies using systemic infusions of hormone is difficult because of the interdependent nature of many of the often counter-regulatory organ responses that are evoked. It is because of such general limitations that venous occlusion plethysmography (VOP), combined with intra-arterial drug infusion, has been used extensively to study (regional) human vascular physiology in vivo. Using this technique, Schmidt et al1 report rapid nongenomic effects of aldosterone …

Hypothalamic neuronal histamine in genetically obese animals: its implication of leptin action in the brain.

Leptin regulates feeding behavior and energy metabolism by affecting hypothalamic neuromodulators. The present study was designed to examine hypothalamic neuronal histamine, a recently identified mediator of leptin signaling in the brain, in genetic obese animals. Concentrations of hypothalamic histamine and tele-methylhistamine (t-MH), a major histamine metabolite, were significantly lower in obese (ob/ob) and diabetic (db/db) mice, and Zucker fatty (fa/fa) rats, leptin-deficient and leptin-receptor defective animals, respectively, relative to lean littermates (P < 0.05 for each). A bolus infusion of leptin (1.0 microg) into the lateral ventricle (ilvt) significantly elevated the turnover rate of hypothalamic neuronal histamine, as assessed by pargyline-induced accumulation of t-MH, in ob/ob mice compared with phosphate-buffered saline (PBS) infusions (P < 0.05). However, this same treatment did not affect hypothalamic histamine turnover in db/db mice. In agouti yellow (A(y)/a) mice, animals defective in pro-opiomelanocortin (POMC) signaling, normal levels of histamine, and t-MH were seen in the hypothalamus at 4 weeks of age when obesity had not yet developed. These amine levels in A(y)/a mice showed no change until 16 weeks of age, although the mice were remarkably obese by this time. Infusions of corticotropin releasing hormone (CRH), one of neuropeptide related to leptin signaling, into the third ventricle (i3vt) increased histamine turnover in the hypothalamus of Wistar King A rats (P < 0.05 versus PBS infusion). Infusion of neuropeptide Y (NPY) or alpha-melanocyte stimulating hormone (MSH), a POMC-derived peptide failed to increase histamine turnover. These results indicate that lowered activity of hypothalamic neuronal histamine in ob/ob and db/db mice, and fa/fa rats may be due to insufficiency of leptin action in the brains of these animals. These results also suggest that disruption of POMC signaling in A(y)/a mice may not impact on neuronal histamine. Moreover, CRH but neither POMC-derived peptide nor NPY may act as a signal to neuronal histamine downstream of the leptin signaling pathway.

Growth hormone and epidermal growth factor together enhance amino acid transport systems B 0,+ and A in remnant small intestine after massive enterectomy

Background. Sodium-dependent brush-border nutrient transport is decreased 2 weeks after massive enterectomy. This down-regulation is ameliorated by a 1-week infusion of parenteral growth hormone (GH) and epidermal growth factor (EGF) started 1 week after resection. We hypothesize that glutamine (GLN) transport will be enhanced by earlier and longer growth factor infusion, with differential effects on the Na +-dependent GLN transport systems A, B 0,+, and B 0/ASCT2. Materials and methods. New Zealand White rabbits underwent 70% small bowel resection then immediately received parenteral EGF, GH, both EGF and GH, or neither for 2 weeks. Na +-dependent 3H-GLN uptake by jejunal and ileal brush-border membrane vesicles was measured and the contribution of systems A, B 0,+, and B 0 was then determined by competitive inhibition. Data were analyzed using one-way analysis of variance. Results. In nonresected animals, the relative contribution of the systems was similar in jejunum (A 9%, B 0,+ 20%, and B 0 71%) and ileum (A 13%, B 0,+ 27%, and B 0 60%). Na +-dependent GLN uptake was reduced by one half in resected untreated controls, primarily because of decreased B 0 activity. EGF or GH alone did not affect Na +-dependent GLN transport, but, as a combination, there was increased uptake in the residual ileum and jejunum by 144% and 150%, respectively, over resected controls ( P < 0.05). This was twice that achieved by delayed and shorter-duration combination treatment. This augmentation was a result of a 6.1–8.2-fold increase in system A as well as a 3.8–3.9-fold enhancement of system B 0,+ activity in remnant ileum and jejunum ( P < 0.01). Conclusions. Parenteral EGF and GH, given in combination for 2 weeks immediately after massive enterectomy, synergistically enhance GLN uptake by systems A and B 0,+.

Centrally administered ghrelin suppresses sympathetic nerve activity in brown adipose tissue of rats

To clarify the functional roles of ghrelin in regulating energy balance, we investigated the effects of a central infusion of ghrelin on food intake and the activity of the sympathetic nerve innervating brown adipose tissue (BAT), the site regulating energy expenditure in rodents. A bolus infusion of ghrelin at a dose of 1 nmol/rat into the third cerebral ventricle (i3vt) increased the 4 h cumulative food intake. I3vt infusion of ghrelin (1 nmol/rat) suppressed BAT sympathetic nerve activity, followed by a gradual recovery. In contrast, i3vt infusion of growth hormone (GH) at a dose of 0.5 nmol/rat induced a gradual increase in sympathetic nerve activity. The ghrelin infusion decreased BAT temperature, which recovered gradually, but did not affect rectal temperature. In conclusion, the central administration of ghrelin suppresses energy expenditure and thermogenesis in BAT via its inhibitory effect on BAT sympathetic nerve activity. Simultaneous GH secretion induced by ghrelin treatment may modulate the temporal course of the sympathetic nerve response to ghrelin. The stimulatory and inhibitory effects of ghrelin on energy intake and expenditure, respectively, may induce a positive energy balance, which, in turn, affects adiposity and body weight.

Growth hormone and epidermal growth factor together enhance amino acid transport systems B 0,+ and A in remnant small intestine after massive enterectomy

Background Sodium-dependent brush border nutrient transport is decreased 2 weeks after massive enterectomy. This downregulation is ameliorated by a 1-week infusion of parenteral growth hormone (GH) and epidermal growth factor (EGF) started 1 week after resection. We hypothesized that glutamine (GLN) transport would be enhanced by earlier and longer growth factor infusion, with differential effects on the Na +-dependent GLN transport systems A, B 0,+, and B 0/ASCT2. Materials and methods New Zealand White rabbits underwent 70% small bowel resection then immediately received parenteral EGF, GH, both, or neither for 2 weeks. Na +-dependent 3H-GLN uptake by jejunal and ileal brush-border membrane vesicles was measured and the contribution of systems A, B 0,+, and B 0 then determined by competitive inhibition. Data were analyzed using one-way analysis of variance. Results In nonresected animals, the relative contribution of the systems was similar in jejunum (A, 9%, B 0,+, 20%; and B 0, 71%) and ileum (A, 13%; B 0,+, 27%; and B 0, 60%). Na +-dependent GLN uptake was reduced by half in resected, untreated controls, primarily because of decreased B 0 activity. EGF or GH alone did not affect Na +-dependent GLN transport, but as a combination, increased uptake in the residual ileum and jejunum by 144% and 150%, respectively, over resected controls ( P < 0.05). This was twice that achieved by delayed and shorter-duration combination treatment. This augmentation was due to a 6.1- to 8.2-fold increase in system A as well as a 3.8- to 3.9-fold enhancement of system B 0,+ activity in remnant ileum and jejunum ( P < 0.01). Conclusions Parenteral EGF and GH, given in combination for 2 weeks immediately after massive enterectomy, synergistically enhance GLN uptake by systems A and B 0,+.

LOCAL THERMAL CONTROL OF SKIN BLOOD FLOW IN DIABETES

Local temperature has an important role in the control of the skin circulation in humans, and can change skin blood flow from zero to maximal levels. Vasodilation to local warming of the skin includes important roles for sensory nerves and nitric oxide. In individuals with type 2 diabetes mellitus (DM), cutaneous vascular function is impaired, but the mechanisms are not well understood. PURPOSES To test whether local warming vasodilation is altered in type 2 DM, and to test whether hyperglycemia per se has a role in altered local control of skin blood flow in diabetes. METHODS 1. We used nonpainful local warming (42°C) of the skin in combination with laser-Doppler measurement of skin blood flow in individuals with type 2 DM and in age-matched controls. 2. In separate studies, we measured responses to similar local warming in healthy individuals during acute hyperglycemia induced by intravenous infusion of glucose with simultaneous insulin, somatostatin, glucagon and growth hormone infusions to keep all other hormones at baseline physiological levels. RESULTS Preliminary results indicate diminished vasodilation to nonpainful local warming in patients with type 2 DM compared to controls, including a decrease of ∼20% in both the initial peak (sensory nerve mediated) and final plateau (NO dependent) phases of the response. Acute hyperglycemia in healthy subjects did not alter cutaneous vasodilation to local warming. CONCLUSION Cutaneous vasodilation to nonpainful local warming is impaired in type 2 DM. Although one episode of acute hyperglycemia did not affect this response in healthy subjects, this impairment in patients may be a result of repeated episodes or higher levels of hyperglycemia in the development of the disease. Supported by NIH DK-29953, HL-63328, AR-08610 and GCRC grant RR-00585 (to the Mayo Clinic).

Chronic pulsatile infusion of growth hormone to growth-restricted fetal sheep increases circulating fetal insulin-like growth factor-I levels but not fetal growth.

Intra-uterine growth restriction (IUGR) is a major cause of perinatal mortality and morbidity. Postnatally, growth hormone (GH) increases growth, increases circulating insulin-like growth factor (IGF)-I levels, and alters metabolism. Our aim was to determine if GH infusion to IUGR fetal sheep would alter fetal growth and metabolism, and thus provide a potential intra-uterine treatment for the IUGR fetus. We studied three groups of fetuses: control, IUGR+ vehicle and IUGR+GH (n=5 all groups). IUGR was induced by repeated embolisation of the placental vascular bed between 110 and 116 days of gestation (term=145 days). GH (3.5 mg/kg/day) or vehicle was infused in a pulsatile manner from 117 to 127 days of gestation. Embolisation reduced fetal growth rate by 25% (P<0.01) and reduced the weight of the fetal liver (20%), kidney (23%) and thymus (31%; all P<0.05). GH treatment further reduced the weight of the fetal kidneys (32%) and small intestine (35%; both P<0.04), but restored the relative weight of the fetal thymus and liver (P<0.05). Embolisation decreased fetal plasma IGF-I concentrations (48%, P<0.001) and increased IGF binding protein 1 (IGFBP-1) concentrations (737%, P<0.002). GH treatment restored fetal plasma IGF-I concentrations to control levels, while levels in IUGR+vehicle fetuses stayed low (P<0.05 vs control). IGFBP-1 and IGFBP-2 concentrations were about sevenfold lower in amniotic fluid than in fetal plasma, but amniotic and plasma concentrations were closely correlated (r=0.75, P<0.0001 and r=0.55 P<0.0001 respectively). Embolisation transiently decreased fetal blood oxygen content (40%, P<0.002), and increased blood lactate concentrations (213%, P<0.04). Both returned to pre-embolisation levels after embolisation stopped, but blood glucose concentrations declined steadily in IUGR+vehicle fetuses. GH treatment maintained fetal blood glucose concentrations at control levels. Our study shows that GH infusion to the IUGR fetal sheep restores fetal IGF-I levels but does not improve fetal growth, and further reduces the fetal kidney and intestine weights. Thus, fetal GH therapy does not seem a promising treatment stratagem for the IUGR fetus.

Régulation de l’absorption intestinale du calcium chez le chamelon (&lt;em&gt;Camelus dromedarius&lt;/em&gt;)

L’hypercalcémie et l’hyperphosphatémie postprandiales, ainsi que l’absorption intestinale du calcium (Ca), ont été mesurées chez 12 chamelons. Les animaux ont été divisés en quatre groupes de trois individus. Les groupes 1 et 2 ont reçu une perfusion intraveineuse (IV) respectivement du fragment synthétique du peptide apparenté à l’hormone parathyroïdienne (PTHrP) et du solvant. Au début de la perfusion, les groupes 1 et 2 ont reçu par voie orale du lait artificiel. Les groupes 3 et 4 ont reçu des injections IV respectivement de 1α,25-dihydroxyvitamine D3 (1α,25(OH)2D3) et du solvant. A la dernière injection, les groupes 3 et 4 ont reçu par voie orale une solution de SrCl2. Le PTHrP a induit une élévation significative de l’hypercalcémie et de l’hyperphosphatémie postprandiales. Ce peptide n’a influencé ni le volume urinaire, ni l’excrétion rénale du Ca, alors qu’il a provoqué une augmentation de l’excrétion rénale du phosphore (P). La 1α,25(OH)2D3 a engendré une augmentation significative des taux plasmatiques du strontium (Sr), du Ca et du P. La 1α,25(OH)2D3 n’a induit d’effet significatif ni sur le volume urinaire, ni sur l’excrétion rénale du Ca, du P et du Sr. Au vu de ces résultats, le PTHrP et la 1α,25(OH)2D3 semblent jouer un rôle prépondérant dans la croissance osseuse chez le chamelon.

Preliminary observations on the effects of acute infusion of growth hormone on coronary vasculature and on myocardial function and energetics of an isolated and blood-perfused heart.

Recent studies have shown that growth hormone (GH) deficiency may deteriorate post-ischemic myocardial reperfusion damage. Furthermore, GH has been reported to be a promising therapeutic option in the treatment of chronic myocardial dysfunction. However, the exact mechanisms of action of GH on the cardiovascular system, particularly in the acute setting, are still unclear. The aim of our study consisted of monitoring the acute effects of GH infusion on isolated blood-perfused rabbit heart according to dose-response pattern and during ischemic conditions to test its anti-ischemic property. Seven blood-donors perfused isolated hearts were used as experimental model. The mechanical and metabolic data of the isolated organs were continuously monitored. Under aerobic conditions, dose-response curves were initially tested after intracoronary infusion of GH at increasing dosages (1, 2, 3 mg/l). After a stabilization period, the effects of GH infusion (5 mg/kg) administered 30 minutes prior to acute global myocardial ischemia (30 minutes) were also investigated. At the doses tested, GH did not induce any changes either in the developed or in the diastolic pressures of the isolated organ. However, transient reduction of the coronary perfusion pressure was observed at the dosage of 3 mg/l. During the ischemia/reperfusion study, at the dosages used in this study, GH did not modify either the degree of stunning in the early reperfusion or the recovery of the developed pressure at the end of reperfusion. In addition, GH did not prevent either the increase of diastolic pressure during ischemia or the release of lactate and CPK during reperfusion. Tissue content of high-energy phosphates was also not changed by GH infusion. In our experimental model, acute GH infusion did not reduce the ischemic/reperfusion damage of the myocardium. However, GH transiently induced coronary vasodilation without modifying the myocardial contractility. Acute effects of GH appear, therefore, to predominantly relate to vascular dilation suggesting that the effects on myocardial contractility may require long-lasting intake being likely linked to enhancement of specific protein synthesis or gene expression of cardiac myocytes.

Effects of thyroid hormones on pulmonary and renal angiotensin-converting enzyme concentrations in fetal sheep near term

In the sheep fetus, pulmonary and renal concentrations of angiotensin-converting enzyme (ACE) increase towards term in parallel with the prepartum surges in plasma cortisol and tri-iodothyronine (T(3)). The ontogenic change in pulmonary ACE has been shown to be induced, at least in part, by cortisol but the role of the thyroid hormones is unknown. Therefore, this study investigated the effects of thyroid hormones on tissue ACE concentration in fetal sheep during late gestation. Pulmonary and renal ACE concentrations were measured in sheep fetuses after experimental manipulation of thyroid hormone status by fetal thyroidectomy and exogenous hormone infusion. In intact fetuses, pulmonary and renal ACE concentrations increased between 127-132 and 142-145 days of gestation (term 145 +/- 2 days), coincident with the prepartum rises in plasma cortisol and T(3). The ontogenic increment in pulmonary ACE concentration was abolished when the prepartum surge in T(3), but not cortisol, was prevented by fetal thyroidectomy. At 143-145 days, ACE concentration in the lungs and kidneys of the thyroidectomised fetuses were both lower than those in the intact fetuses. In intact fetuses at 127-132 days, pulmonary ACE was upregulated by intravenous infusions of either cortisol (2-3 mg/kg per day) or T(3) (8-12 microg/kg per day) for 5 days. Renal ACE was unaffected by cortisol or T(3) infusion. Therefore, thyroid hormones have an important role in the developmental control of pulmonary and renal ACE concentration in the sheep fetus towards term. In addition, the prepartum rise in plasma T(3) appears to mediate, in part, the maturational effect of cortisol on pulmonary ACE concentration.

Thyroid hormones and the mRNA of the GH receptor and IGFs in skeletal muscle of fetal sheep.

Thyroid hormones are required for the normal development of skeletal muscle in utero, although their mechanism of action is poorly understood. The present study examined the effects of the thyroid hormones on the gene expression of the growth hormone receptor (GHR) and the insulin-like growth factors (IGFs) IGF-I and IGF-II, in skeletal muscle of fetal sheep during late gestation (term 145 +/- 2 days) and after manipulation of plasma thyroid hormone concentration. Thyroidectomy at 105-110 days of gestation suppressed muscle GHR and IGF-I gene expression in fetuses studied at 127-130 and 142-145 days. Muscle GHR mRNA abundance remained unchanged with increasing gestational age in intact and thyroidectomized fetuses. In the intact fetuses, a decrease in muscle IGF-I gene expression was observed between 127-130 and 142-145 days, which coincided with the normal prepartum surges in plasma cortisol and triiodothyronine (T3). At 127-130 days, downregulation of muscle IGF-I mRNA abundance was induced prematurely in intact fetuses by an infusion of cortisol for 5 days (2-3 mg x kg(-1) x day(-1) iv), which increased plasma cortisol and T3 concentrations to values seen near term. However, increasing plasma T3 alone by an infusion of T3 for 5 days (8-12 microg x kg(-1) x day(-1) iv) in intact fetuses at this age had no effect on GHR or IGF-I gene expression in skeletal muscle. In the thyroidectomized fetuses, no additional change in the low level of muscle IGF-I mRNA abundance was seen with increasing gestational age, but at 127-130 days, IGF-I gene expression was reduced further when plasma cortisol and T3 concentrations were increased by exogenous cortisol infusion. Muscle IGF-II mRNA abundance was not affected by thyroidectomy, gestational age, or exogenous hormone infusion. These findings show, in the sheep fetus, that thyroid hormones may influence the growth and development of skeletal muscle via changes in the local activity of the somatotrophic axis.

Effects of intravenous insulin-like growth factor-I and insulin administration on insulin-like growth factor-binding proteins in the ovine fetus.

The insulin-like growth factors (IGF) are important anabolic hormones in the mammalian fetus; their anabolic actions are potentially modulated by alterations in the IGF-binding proteins (IGFBP). We have previously shown that the nutritional state of the fetus affects both IGF-I and the IGFBP concentrations. The present study was designed to determine the effect of alterations in insulin and IGF-I circulating concentrations on the IGFBPs. Because both insulin and IGF-I elicit decreases in glucose and amino acid concentrations, the concentrations of these substrates were clamped during the hormone infusions. Sixteen ovine fetuses were chronically catheterized at approximately 115 days of gestation, and experimental procedures performed at approximately 130 days of gestation. Insulin, IGF-I or both were infused for an 8-h period. Baseline concentrations of hormones and binding proteins were obtained, and concentrations were also obtained at the end of the infusion. Hepatic IGFBP-1 mRNA expression was also determined. Intravenous infusion of IGF-I significantly increased IGF-I concentrations in plasma in the ovine fetus. Intravenous infusion of insulin inhibited hepatic IGFBP-1 gene expression when amino acids and glucose were clamped. In contrast, intravenous infusion of recombinant human IGF-I (rhIGF-I) enhanced hepatic IGFBP-1 gene expression. Neither insulin nor rhIGF-I treatment had an effect on hepatic IGFBP-3 gene expression. Insulin did not alter plasma IGFBP-1 significantly, but it increased IGFBP-3 in plasma. rhIGF-I increased both IGFBP-1 and IGFBP-3 protein levels in plasma. The responses of IGFBP-1 and IGFBP-3 to increased plasma IGF-I and insulin may serve to protect the fetus from exaggerated anabolic effects and to blunt the hypoglycemic potential of circulating IGFs and insulin.

The effects of vasopressin on systemic hemodynamics in catecholamine-resistant septic and postcardiotomy shock: a retrospective analysis.

We retrospectively investigated the effects of continuous arginine vasopressin (AVP) infusion on systemic hemodynamics, acid/base status, and laboratory variables in patients (mean age [mean +/- SD]= 66.3 +/- 10.1 yr) with catecholamine-resistant septic (n = 35) or postcardiotomy shock (n = 25). Hemodynamic and acid/base data were obtained before; 30 min after; and 1, 4, 12, 24, 48, and 72 h after the start of AVP infusion. Laboratory examinations were recorded before and 24, 48, and 72 h after the start of AVP infusion. For statistical analysis, a mixed-effects model was used. The overall intensive care unit mortality was 66.7%. AVP administration caused a significant increase in mean arterial pressure (+29%) and systemic vascular resistance (+56%), accompanied by a significant decrease in heart rate (-24%) and mean pulmonary arterial pressure (-11%) without any change in stroke volume index. Norepinephrine requirements could be reduced by 72% within 72 h. During AVP infusion, a significant increase in liver enzymes and total bilirubin concentration and a significant decrease in platelet count occurred. Arginine vasopressin was effective in reversing systemic hypotension. However, adverse effects on gastrointestinal perfusion and coagulation cannot be excluded. In this retrospective analysis, the influence of a continuous infusion of an endogenous hormone (arginine vasopressin) on systemic hemodynamics and laboratory variables was assessed in patients with vasodilatory shock unresponsive to conventional therapy. Arginine vasopressin was effective in reversing systemic hypotension. However, adverse effects on gastrointestinal perfusion and coagulation cannot be excluded.

Type I diabetes mellitus does not alter initial splanchnic glucose extraction or hepatic UDP-glucose flux during enteral glucose administration.

Our aim was to determine whether an alteration in splanchnic glucose metabolism could contribute to postprandial hyperglycaemia in people with Type I (insulin-dependent) diabetes mellitus. Splanchnic glucose extraction, hepatic glycogen synthesis and endogenous glucose production were compared in 8 Type I diabetic patients and in 11 control subjects. Endogenous hormone secretion was inhibited with somatostatin while insulin (approximately 550 pmol/l) and glucagon (approximately 130 ng/l) concentrations were matched with exogenous hormone infusions. Glucose containing [3-3H] glucose was infused into the duodenum at a rate of 20 micromol.kg(-1).min(-1). Plasma glucose concentrations were maintained at about 8.5 mmol/l in both groups by means of a separate variable intravenous glucose infusion. Initial splanchnic glucose uptake, calculated by subtracting the systemic rate of appearance of [3-3H] glucose from the rate of infusion of [3-3H] glucose into the duodenum, did not differ in the diabetic and non-diabetic patients (4.1 +/- 0.8 vs 3.0 +/- 1.0 micromol/kg/min). In addition, hepatic glycogen synthesis, measured using the acetaminophen glucuronide method did not differ (10.7 +/- 2.4 vs 10.1 +/- 2.7 micromol.kg(-1).min(-1)). On the other hand, suppression of endogenous glucose production, measured by an intravenous infusion of [6,6-2H2] glucose, was greater (p < 0.05) in the diabetic than in the non-diabetic subjects (1.7 +/- 1.6 vs 5.8 +/- 1.9 micromol.kg(-1).min(-1)). When glucose, insulin and glucagon concentrations are matched in individuals with relatively good chronic glycaemic control, Type I diabetes does not alter initial splanchnic glucose uptake of enterally delivered glucose or hepatic glycogen synthesis. Alterations in splanchnic glucose metabolism are not likely to contribute to postprandial hyperglycaemia in people with well controlled Type I diabetes.