Norepinephrine kinetics in freely moving rats

Norepinephrine (NE) kinetics were investigated in freely moving (FM) and minimally stressed (MS) rats with the isotope dilution technique. 1) The mean NE spillover rate (NE-SOR) was 79 +/- 6 ng. kg(-1). min(-1), and the mean NE metabolic clearance rate (NE-MCR) 179 +/- 9 ml. kg(-1). min(-1) (n = 31). Thus the NE kinetics in FM and MS rats are much faster than in human beings, probably related to a higher sympathetic drive. 2) Whether the magnitude of NE-MCR is related to the level of plasma NE concentration was investigated. No significant correlation was calculated between plasma NE concentration and NE-MCR in 31 control rats. When plasma NE concentration was varied during either acute or chronic infusion of exogenous NE, NE-MCR remained unchanged as long as animal hemodynamics were not altered. When plasma NE concentration was high enough to increase mean arterial pressure (MAP), NE-MCR was decreased. However, when MAP was increased within comparable magnitude, NE-MCR was decreased during NE and increased during epinephrine (Epi) infusion. Thus the existence of an alpha-/beta-adrenergic mechanism involved in the regulation of NE-MCR independent of known hemodynamic mechanisms is suggested. 3) The "epinephrine hypothesis" was revisited in FM and MS rats. At variance with humans, very high plasma Epi concentrations have to be induced to increase NE-SOR in resting rats. Furthermore, NE-MCR was also increased, accounting for the nonsignificant increase of plasma NE concentration. Within the range of Epi concentrations with no effect on NE-SOR, an increase of NE release was revealed when the presynaptic alpha(2)-adrenoreceptors were partially inhibited by yohimbine. This suggests the existence of a second epinephrine hypothesis.     

Osmotic regulation of prolactin secretion in the fetal sheep

The functions of prolactin in the fetus remain speculative. No obvious physiological role has been found for the prolactin present in the fetal or maternal plasma and amniotic fluid compartments. The aim of the present study was to investigate changes in fetal plasma prolactin following intracerebroventricular (i.c.r.) administration to the fetus of artificial cerebrospinal fluid of different tonicities. A lateral ventricle catheter was placed in 11 fetuses at 107-128 days of gestation. Either isotonic artificial cerebrospinal fluid (300 mOsm.1(-1);n = 9), 15% polyethylene glycol (340 mOsm.1(-1);n = 5), or 7% distilled water in isotonic artificial cerebrospinal fluid (270 mOsm.1(-1);n = 9) was infused i.c.v. at 35 mu1.min-1 for 240 min. At 180 min thyrotropin releasing hormone (TRH) was administered through a fetal a fetal jugular catheter. Fetal carotid arterial blood gases, plasma osmolality and concentrations of prolactin, vasopressin (AVP), and norepinephrine (NE) were measured. Administration of hypotonic artificial cerebrospinal fluid produced an increase in fetal plasma prolactin from 46.6 +/- 36 ng.ml-1 at 0 min to 83.3 +/- 49 ng.ml-1 at 180 min (mean +/- SEM; P less than 0.05). No changes in either AVP or NE were observed. Administration of hypertonic artificial cerebrospinal fluid produced a decrease in plasma prolactin from 85 +/- 57 at time 0 to 49 +/- 35 at 180 min (P less than 0.05). No changes in either AVP or NE were observed. Fetal plasma prolactin, AVP, and NE did not change during control infusion of isotonic artificial cerebrospinal fluid.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of prolonged glucose infusion into fetal sheep on body growth, fat deposition and gestation length

Eleven Merino sheep fetuses were supplemented with glucose by direct continuous intravenous infusion of 50% dextrose into the fetus from day 115 of gestation until spontaneous delivery. Infusion rates of 15 or 25 g/day per kg were used and equivalent volumes of saline were infused into 11 control fetuses. Infusion periods approximated 27 days in both groups. Fetal plasma glucose concentrations were significantly (P less than 0.001) elevated throughout glucose infusion and resulted in variable but consistently higher plasma insulin concentrations in the glucose than in the saline-infused fetuses. Glucose-infused fetuses were significantly heavier than controls (mean +/- SEM; 3.86 +/- 0.16 vs 3.28 +/- 0.24 kg, P less than 0.05) and body fat depots (in g/kg body wt.) were larger in glucose-infused than control fetuses (9.91 +/- 0.65 vs 6.73 +/- 0.37, P less than 0.005, for internal brown fat depots; 1.25 +/- 0.44 vs 0.27 + 0.13, P less than 0.05, for subcutaneous white adipose tissue). The results indicate that growth and lipid deposition in the sheep fetus are responsive to increased glucose supply, an effect which may be mediated through the actions of insulin. Mean gestation length was 146.60 +/- 1.45 days for controls and 144.18 +/- 1.23 days for glucose-infused animals (normal term 150 days).     

Differing physiological effects of epinephrine in type 1 diabetes and nondiabetic humans

Acute increases of the key counterregulatory hormone epinephrine can be modified by a number of physiological and pathological conditions in type 1 diabetic patients (T1DM). However, it is undecided whether the physiological effects of epinephrine are also reduced in T1DM. Therefore, the aim of this study was to determine whether target organ (liver, muscle, adipose tissue, pancreas, cardiovascular) responses to epinephrine differ between healthy subjects and T1DM patients. Thirty-four age- and weight-matched T1DM (n = 17) and healthy subjects (n = 17) underwent two randomized, single-blind, 2-h hyperinsulinemic euglycemic clamp studies with (Epi) and without epinephrine infusion. Muscle biopsy was performed at the end of each study. Epinephrine levels during Epi were similar in all groups (4,039 +/- 384 pmol/l). Glucose (5.3 +/- 0.06 mmol/l) and insulin levels (462 +/- 18 pmol/l) were also similar in all groups during the glucose clamps. Glucagon responses to Epi were absent in T1DM and significantly reduced compared with healthy subjects. Endogenous glucose production during the final 30 min was significantly greater during Epi in healthy subjects compared with T1DM (8.4 +/- 1.3 vs. 4.4 +/- 0.6 micromol.kg(-1).min(-1), P = 0.041). Glucose uptake showed almost a twofold greater decrease with Epi in healthy subjects vs. T1DM (Delta31 +/- 2 vs. Delta17 +/- 2 nmol.kg(-1).min(-1), respectively, P = 0.026). Glycerol, beta-hydroxybutyrate, and nonesterified fatty acid (NEFA) all increased significantly more in T1DM compared with healthy subjects. Increases in systolic blood pressure were greater in healthy subjects, but reductions of diastolic blood pressure were greater in T1DM patients with Epi. Reduction of glycogen synthase was significantly greater during epinephrine infusion in T1DM vs. healthy subjects. In summary, despite equivalent epinephrine, insulin, and glucose levels, changes in glucose flux, glucagon, and cardiovascular responses were greater in healthy subjects compared with T1DM. However, T1DM patients had greater lipolytic responses (glycerol and NEFA) during Epi. Thus we conclude that there is a spectrum of significant in vivo physiological differences of epinephrine action at the liver, muscle, adipose tissue, pancreas, and cardiovascular system between T1DM and healthy subjects.     

Catecholamine response is attenuated during moderate-intensity exercise in response to the "lactate clamp"

Catecholamine release is known to be regulated by feedforward and feedback mechanisms. Norepinephrine (NE) and epinephrine (Epi) concentrations rise in response to stresses, such as exercise, that challenge blood glucose homeostasis. The purpose of this study was to assess the hypothesis that the lactate anion is involved in feedback control of catecholamine concentration. Six healthy active men (26 +/- 2 yr, 82 +/- 2 kg, 50.7 +/- 2.1 ml.kg(-1).min(-1)) were studied on five occasions after an overnight fast. Plasma concentrations of NE and Epi were determined during 90 min of rest and 90 min of exercise at 55% of peak O2 consumption (VO2 peak) two times with exogenous lactate infusion (lactate clamp, LC) and two times without LC (CON). The blood lactate profile ( approximately 4 mM) of a preliminary trial at 65% VO2 peak (65%) was matched during the subsequent LC trials. In resting men, plasma NE concentration was not different between trials, but during exercise all conditions were different with 65% > CON > LC (65%: 2,115 +/- 166 pg/ml, CON: 1,573 +/- 153 pg/ml, LC: 930 +/- 174 pg/ml, P < 0.05). Plasma Epi concentrations at rest were different between conditions, with LC less than 65% and CON (65%: 68 +/- 9 pg/ml, CON: 59 +/- 7 pg/ml, LC: 38 +/- 10 pg/ml, P < 0.05). During exercise, Epi concentration showed the same trend (65%: 262 +/- 37 pg/ml, CON: 190 +/- 34 pg/ml, LC: 113.2 +/- 23 pg/ml, P < 0.05). In conclusion, lactate attenuates the catecholamine response during moderate-intensity exercise, likely by feedback inhibition.     

Increase in epinephrine-induced responsiveness during microgravity simulated by head-down bed rest in humans.

The epinephrine (Epi)-induced effects on the sympathetic nervous system (SNS) and metabolic functions were studied in men before and during a decrease in SNS activity achieved through simulated microgravity. Epi was infused at 3 graded rates (0.01, 0.02, and 0. 03 microg. kg(-1). min(-1) for 40 min each) before and on the fifth day of head-down bed rest (HDBR). The effects of Epi on the SNS (assessed by plasma norepinephrine levels and spectral analysis of systolic blood pressure and heart rate variability), on plasma levels of glycerol, nonesterified fatty acids (NEFA), glucose and insulin, and on energy expenditure were evaluated. HDBR decreased urinary norepinephrine excretion (28.1 +/- 4.2 vs. 51.5 +/- 9.1 microg/24 h) and spectral variability of systolic blood pressure in the midfrequency range (16.3 +/- 1.9 vs. 24.5 +/- 0.9 normalized units). Epi increased norepinephrine plasma levels (P < 0.01) and spectral variability of systolic blood pressure (P < 0.009) during, but not before, HDBR. No modification of Epi-induced changes in heart rate and systolic and diastolic blood pressures were observed during HDBR. Epi increased plasma glucose, insulin, and NEFA levels before and during HDBR. During HDBR, the Epi-induced increase in plasma glycerol and lactate levels was more pronounced than before HDBR (P < 0.005 and P < 0.001, respectively). Epi-induced energy expenditure was higher during HDBR (P < 0.02). Our data suggest that the increased effects of Epi during simulated microgravity could be related to both the increased SNS response to Epi infusion and/or to the beta-adrenergic receptor sensitization of end organs, particularly in adipose tissue and skeletal muscle.     

Cerebrovascular effects of intravenous dopamine infusions in fetal sheep.

Preterm infants are often treated with intravenous dopamine to increase mean arterial blood pressure (MAP). However, there are few data regarding cerebrovascular responses of developing animals to dopamine infusions. We studied eight near-term and eight preterm chronically catheterized unanesthetized fetal sheep. We measured cerebral blood flow and calculated cerebral vascular resistance (CVR) at baseline and during dopamine infusion at 2.5, 7.5, 25, and 75 microg x kg(-1) x min(-1). In preterm fetuses, MAP increased only at 75 microg x kg(-1) x min(-1) (25 +/- 5%), whereas in near-term fetuses MAP increased at 25 microg x kg(-1) x min(-1) (28 +/- 4%) and further at 75 microg x kg(-1) x min(-1) (51 +/- 3%). Dopamine infusion was associated with cerebral vasoconstriction in both groups. At 25 microg x kg(-1) x min(-1), CVR increased 77 +/- 51% in preterm fetuses and 41 +/- 11% in near-term fetuses, and at 75 microg x kg(-1) x min(-1), CVR increased 80 +/- 33% in preterm fetuses and 83 +/- 21% in near-term fetuses. We tested these responses to dopamine in 11 additional near-term fetuses under alpha-adrenergic blockade (phenoxybenzamine, n = 5) and under dopaminergic D(1)-receptor blockade (SCH-23390, n = 6). Phenoxybenzamine completely blocked dopamine's pressor and cerebral vasoconstrictive effects, while D(1)-receptor blockade had no effect. Therefore, in unanesthetized developing fetuses, dopamine infusion is associated with cerebral vasoconstriction, which is likely an autoregulatory, alpha-adrenergic response to an increase in blood pressure.     

Regulation of glucose production in rainbow trout: role of epinephrine in vivo and in isolated hepatocytes

The rate of hepatic glucose production (R(a) glucose) of rainbow trout (Oncorhynchus mykiss) was measured in vivo by continuous infusion of [6-(3)H]glucose and in vitro on isolated hepatocytes to examine the role of epinephrine (Epi) in its regulation. By elevating Epi concentration and/or blocking beta-adrenoreceptors with propranolol (Prop), our goals were to investigate the mechanism for Epi-induced hyperglycemia to determine the possible role played by basal Epi concentration in maintaining resting R(a) glucose and to assess indirect effects of Epi in the intact animal. In vivo infusion of Epi caused hyperglycemia (3.75 +/- 0.16 to 8.75 +/- 0.54 mM) and a twofold increase in R(a) glucose (6.57 +/- 0.79 to 13.30 +/- 1.78 micromol. kg(-1). min(-1), n = 7), whereas Prop infusion decreased R(a) from 7.65 +/- 0.92 to 4.10 +/- 0.56 micromol. kg(-1). min(-1) (n = 10). Isolated hepatocytes increased glucose production when treated with Epi, and this response was abolished in the presence of Prop. We conclude that Epi-induced trout hyperglycemia is entirely caused by an increase in R(a) glucose, because the decrease in the rate of glucose disappearance normally seen in mammals does not occur in trout. Basal circulating levels of Epi are involved in maintaining resting R(a) glucose. Epi stimulates in vitro glucose production in a dose-dependent manner, and its effects are mainly mediated by beta-adrenoreceptors. Isolated trout hepatocytes produce glucose at one-half the basal rate measured in vivo, even when diet, temperature, and body size are standardized, and basal circulating Epi is responsible for part of this discrepancy. The relative increase in R(a) glucose after Epi stimulation is similar in vivo and in vitro, suggesting that indirect in vivo effects of Epi, such as changes in hepatic blood flow or in other circulating hormones, do not play an important role in the regulation of glucose production in trout.     

Effect of epinephrine on net lactate uptake by contracting skeletal muscle.

The purpose of this study was to determine the effect of epinephrine on net lactate (La(-)) uptake at constant elevated blood La(-) concentration and steady level metabolic rate (O(2) uptake) in the canine gastrocnemius-plantaris muscle in situ. Infusion of La(-)/lactic acid (pH 3.5) established a mean arterial blood La(-) concentration of ~10 mM while normal blood-gas and pH status were maintained as the gastrocnemius-plantaris was stimulated with tetanic trains at a rate of one contraction every 4 s. After steady-state control measures, epinephrine was infused for 35 min at rates that produced a high physiological concentration with (Pro; n = 6) and without (Epi; n = 6) beta-adrenergic-receptor blockade via propranolol. Net La(-) uptake values during the control conditions were not significantly different between trials (Epi: 0.756 +/- 0.043; Pro: 0.703 +/- 0.061 mmol. kg(-1). min(-1)). Steady level O(2) uptake averaged approximately 69.5 ml. kg(-1). min(-1) for both control conditions and did not significantly change over the course of the experiments in either set of trials. Epi experiments resulted in a significantly reduced net La(-) uptake (0.346 +/- 0.088 mmol. kg(-1). min(-1) after 5 min of infusion) compared with control value at all sample times measured. However, net La(-) uptake was not significantly different from control at any time during Pro (0.609 +/- 0.052 mmol. kg(-1). min(-1) after 5 min of infusion). When the change from the respective control values for net La(-) uptake was compared across time for both series of experiments, Epi resulted in a significantly greater change from control than did Pro. This study suggests that epinephrine can have a profound effect on net La(-) uptake by contracting muscle and that these effects are elicited through beta-adrenergic-receptor stimulation.     

Prostaglandin E2 inhibition of fetal breathing movements is not sustained during prolonged reduced uterine blood flow in sheep

Fetal breathing movements (FBM) are inhibited by both exogenous prostaglandin E2 (PGE2) and ethanol in sheep. Maternal ethanol exposure in late-gestation sheep also increases fetal [PGE2]. However, during prolonged reduced uterine blood flow (RUBF) when [PGE2] in fetal plasma is already elevated, FBM are not inhibited by ethanol. These experiments were designed, therefore, to test the hypothesis that the FBM response to PGE2 is also diminished during RUBF. PGE2 (594+/-19 ng.min(-1).kg(-1) fetal body weight) was infused for 6 h into the jugular vein of RUBF (PO2 = 14+/-1 mmHg (1 mmHg = 133.3 Pa); n = 7) and control (PO2 = 22+/-1 mmHg (p < 0.01); n = 7) ovine fetuses, and the effect on FBM, electrocortical (ECoG), and electroocular activities was determined. The infusion of PGE2 increased plasma [PGE2] from 881+/-162 to 1189+/-114 pg.mL(-1) in RUBF fetuses and from 334+/-72 to 616+/-118 pg.mL(-1) (p < 0.05) in control fetuses. FBM were initially inhibited by PGE2 from 22.5+/-9.4 and 17.9+/-6.5% of the time to 6.9+/-2.4 and 0.5+/-0.4% (p < 0.01) in RUBF and control fetuses, respectively. FBM remained inhibited in control fetuses throughout the infusion but returned to baseline incidence in RUBF fetuses in the last 2 h of the infusion. These results are consistent with the hypothesis that one component of the adaptative mechanisms of the fetus to prolonged RUBF is an altered response of FBM to exogenous PGE2. We speculate that the lack of a sustained inhibition in FBM during RUBF with infusion of PGE2 may be a result of an alteration in brainstem receptor function or number or local PGE2 removal.     

Epinephrine infusion during moderate intensity exercise increases glucose production and uptake

The glucoregulatory response to intense exercise [IE, >80% maximum O(2) uptake (VO(2 max))] comprises a marked increment in glucose production (R(a)) and a lesser increment in glucose uptake (R(d)), resulting in hyperglycemia. The R(a) correlates with plasma catecholamines but not with the glucagon-to-insulin (IRG/IRI) ratio. If epinephrine (Epi) infusion during moderate exercise were able to markedly stimulate R(a), this would support an important role for the catecholamines' response in IE. Seven fit male subjects (26 +/- 2 yr, body mass index 23 +/- 0.5 kg/m(2), VO(2 max) 65 +/- 5 ml x kg(-1) x min(-1)) underwent 40 min of postabsorptive cycle ergometer exercise (145 +/- 14 W) once without [control (CON)] and once with Epi infusion [EPI (0.1 microg x kg(-1) x min(-1))] from 30 to 40 min. Epi levels reached 9.4 +/- 0.8 nM (20x rest, 10x CON). R(a) increased approximately 70% to 3.75 +/- 0.53 in CON but to 8.57 +/- 0.58 mg x kg(-1) x min(-1) in EPI (P < 0.001). Increments in R(a) and Epi correlated (r(2) = 0.923, P 相似文献   

Hormone-independent activation of EGP during hypoglycemia is absent in type 1 diabetes mellitus

It has been suggested that insulin-induced suppression of endogenous glucose production (EGP) may be counteracted independently of increased epinephrine (Epi) or glucagon during moderate hypoglycemia. We examined EGP in nondiabetic (n = 12) and type 1 diabetic (DM1, n = 8) subjects while lowering plasma glucose (PG) from clamped euglycemia (5.6 mmol/l) to values just above the threshold for Epi and glucagon secretion (3.9 mmol/l). Individualized doses of insulin were infused to maintain euglycemia during pancreatic clamps by use of somatostatin (250 microg/h), glucagon (1.0 ng. kg(-1). min(-1)), and growth hormone (GH) (3.0 ng. kg(-1). min(-1)) infusions without need for exogenous glucose. Then, to achieve physiological hyperinsulinemia (HIns), insulin infusions were fixed at 20% above the rate previously determined for each subject. In nondiabetic subjects, PG was reduced from 5.4 +/- 0.1 mmol/l to 3.9 +/- 0.1 mmol/l in the experimental protocol, whereas it was held constant (5. 3 +/- 0.2 mmol/l and 5.5 mmol/l) in control studies. In the latter, EGP (estimated by [3-(3)H]glucose) fell to values 40% of basal (P < 0.01). In contrast, in the experimental protocol, at comparable HIns but with PG at 3.9 +/- 0.1 mmol/l, EGP was activated to values about twofold higher than in the euglycemic control (P < 0.01). In DM1 subjects, EGP failed to increase in the face of HIns and PG = 3.9 +/- 0.1 mmol/l. The decrease from basal EGP in DM1 subjects (4.4 +/- 1.0 micromol. kg(-1). min(-1)) was nearly twofold that in nondiabetics (2.5 +/- 0.8 micromol. kg(-1). min(-1), P < 0.02). When PG was lowered further to frank hypoglycemia ( approximately 3.1 mmol/l), the failure of EGP activation in DM1 subjects was even more profound but associated with a 50% lower plasma Epi response (P < 0. 02) compared with nondiabetics. We conclude that glucagon- or epinephrine-independent activation of EGP may accompany other counterregulatory mechanisms during mild hypoglycemia in humans and is impaired or absent in DM1.     

Epinephrine effects on insulin-glucose dynamics: the labeled IVGTT two-compartment minimal model approach

The hyperglycemic effects of epinephrine (Epi) are established; however, the modulation of Epi-stimulated endogenous glucose production (EGP) by glucose and insulin in vivo in humans is less clear. Our aim was to determine the effect of exogenously increased plasma Epi concentrations on insulin and glucose dynamics. In six normal control subjects, we used the labeled intravenous glucose tolerance test (IVGTT) interpreted with the two-compartment minimal model, which provides not only glucose effectiveness (S(G)(2*)), insulin sensitivity (S(I)(2*)), and plasma clearance rate (PCR) at basal state, but also the time course of EGP. Subjects were randomly studied during either saline or Epi infusion (1.5 microg/min). Exogenous Epi infusion increased plasma Epi concentration to a mean value of 2,034 +/- 138 pmol/l. During the stable-label IVGTT, plasma glucose, tracer glucose, and insulin concentrations were significantly higher in the Epi study. The hormone caused a significant (P < 0.05) reduction in PCR in the Epi state when compared with the basal state. The administration of Epi has a striking effect on EGP profiles: the nadir of the EGP profiles occurs at 21 +/- 7 min in the basal state and at 55 +/- 13 min in the Epi state (P < 0.05). In conclusion, we have shown by use of a two-compartment minimal model of glucose kinetics that elevated plasma Epi concentrations have profound effects at both hepatic and tissue levels. In particular, at the liver site, this hormone deeply affects, in a time-dependent fashion, the inhibitory effect of insulin on glucose release. Our findings may explain how even a normal subject may have the propensity to develop glucose intolerance under the influence of small increments of Epi during physiological stress.     

Effects of atrial natriuretic factor on urinary concentration of catecholamines and renin secretion in dogs

This study evaluated the effects of synthetic atrial natriuretic factor (ANF) on renal hemodynamics, urinary excretion of electrolytes, norepinephrine (NE), and dopamine (DA); and renal production of renin in anesthetized dogs. Following a bolus (1 micrograms/kg body weight) and infusion (0.1 microgram/kg/min) for 30 min, there was significant increase in urine flow (220 +/- 41%), glomerular filtration rate (72 +/- 14%), and urinary sodium excretion (170 +/- 34%). There was a decrease in renin secretory rate and the concentration ratio of urine NE to DA following ANF was decreased (p less than 0.05). These data suggest that ANF decreases renal production of NE and renin.     

Chronic cardiovascular and renal actions of leptin during hyperinsulinemia

Hyperinsulinemia and hyperleptinemia occur concurrently in obese subjects, and both have been suggested to mediate increased blood pressure associated with excess weight gain. The goal of this study was to determine whether chronic hyperleptinemia exacerbates the effects of insulin on arterial pressure and renal function. Group I and II rats were infused with insulin (1.5 mU. kg(-1). min(-1)) for 21 days while maintaining euglycemia. After 7 days of insulin infusion, group II rats received leptin (1.0 microg. kg(-1). min(-1)) for 7 days, concomitant with insulin. Insulin plus glucose infusion reduced food intake to 55 +/- 7% of control, while leptin + insulin lowered food intake further to 22 +/- 4% of the initial control. Insulin initially raised mean arterial pressure (MAP) by 12 +/- 1 mmHg; then MAP declined to 5-8 mmHg above control during continued hyperinsulinemia. Leptin + insulin infusion increased MAP by 7 +/- 2 mmHg above the level observed in rats infused with insulin alone. Insulin raised heart rate (HR) by 17 +/- 5 beats/min, whereas leptin + insulin increased HR by 34 +/- 5 beats/min. Thus leptin appears to increase the effects of insulin to suppress appetite and to raise arterial pressure and HR.     

Hepatic alpha- and beta-adrenergic receptors are not essential for the increase in R(a) during exercise in diabetes

The purpose of this study was to determine the role of direct hepatic adrenergic stimulation in the control of endogenous glucose production (R(a)) during moderate exercise in poorly controlled alloxan-diabetic dogs. Chronically catheterized and instrumented (flow probes on hepatic artery and portal vein) dogs were made diabetic by administration of alloxan. Each study consisted of a 120-min equilibration, 30-min basal, 150-min moderate exercise, 30-min recovery, and 30-min blockade test period. Either vehicle (control; n = 6) or alpha (phentolamine)- and beta (propranolol)-adrenergic blockers (HAB; n = 6) were infused in the portal vein. In both groups, epinephrine (Epi) and norepinephrine (NE) were infused in the portal vein during the blockade test period to create suprapharmacological levels at the liver. Isotopic ([3-(3)H]glucose, [U-(14)C]alanine) and arteriovenous difference methods were used to assess hepatic function. Arterial plasma glucose was similar in controls (345 +/- 24 mg/dl) and HAB (336 +/- 23 mg/dl) and was unchanged by exercise. Basal arterial insulin was 5 +/- 1 mU/ml in controls and 4 +/- 1 mU/ml in HAB and fell by approximately 50% during exercise in both groups. Basal arterial glucagon was similar in controls (56 +/- 10 pg/ml) and HAB (55 +/- 7 pg/ml) and rose similarly, by approximately 1.4-fold, with exercise in both groups. Despite greater arterial Epi and NE levels in HAB compared with controls during the basal and exercise periods, exercise-induced increases in catecholamines from basal were similar in both groups. Gluconeogenic conversion from alanine and lactate and the intrahepatic efficiency of this process were increased by twofold during exercise in both groups. R(a) rose similarly by 2.9 +/- 0.7 and 2.7 +/- 1.0 mg. kg(-1). min(-1) at time = 150 min during exercise in controls and HAB. During the blockade test period, arterial plasma glucose and R(a) rose to 454 +/- 43 mg/dl and 11.3 mg. kg(-1). min(-1) in controls, respectively, but were essentially unchanged in HAB. The attenuated response to the blockade test in HAB substantiates the effectiveness of the hepatic adrenergic blockade. In conclusion, these results demonstrate that direct hepatic adrenergic stimulation does not play a role in the stimulation of R(a) during exercise in poorly controlled diabetes.     

Evidence against a role for insulin-signaling proteins PI 3-kinase and Akt in insulin resistance in human skeletal muscle induced by short-term GH infusion

Prolonged growth hormone (GH) excess is known to be associated with insulin resistance, but the underlying mechanisms remain unknown. The aim of this study was to assess the impact of GH on insulin-stimulated glucose metabolism and insulin signaling in human skeletal muscle. In a cross-over design, eight healthy male subjects (age 26.0 +/- 0.8 yr and body mass index 24.1 +/- 0.5 kg/m2) were infused for 360 min with either GH (Norditropin, 45 ng.kg(-1).min(-1)) or saline. During the final 180 min of the infusion, a hyperinsulinemic euglycemic clamp was performed (insulin infusion rate: 1.2 mU.kg(-1).min(-1)). Muscle biopsies from vastus lateralis were taken before GH/saline administration and after 60 min of hyperinsulinemia. GLUT4 content and insulin signaling, as assessed by insulin receptor substrate (IRS)-1-associated phosphatidylinositol 3-kinase and Akt activity were determined. GH levels increased to a mean (+/-SE) level of 20.0 +/- 2.3 vs. 0.5 +/- 0.2 microg/l after saline infusion (P < 0.01). During GH infusion, the glucose infusion rate during hyperinsulinemia was reduced by 38% (P < 0.01). In both conditions, free fatty acids were markedly suppressed during hyperinsulinemia. Despite skeletal muscle insulin resistance, insulin still induced a similar approximately 3-fold rise in IRS-1-associated PI 3-kinase activity (269 +/- 105 and 311 +/- 71% compared with baseline, GH vs. saline). GH infusion did not change Akt protein expression, and insulin caused an approximately 13-fold increase in Akt activity (1,309 +/- 327 and 1,287 +/- 173%) after both GH and saline infusion. No difference in total GLUT4 content was noted (114.7 +/- 7.4 and 107.6 +/- 16.7 arbitrary units, GH vs. saline, compared with baseline). In conclusion, insulin resistance in skeletal muscle induced by short-term GH administration is not associated with detectable changes in the upstream insulin-signaling cascade or reduction in total GLUT4. Yet unknown mechanisms in insulin signaling downstream of Akt may be responsible.     

Effects of gestational age on myocardial blood flow and coronary flow reserve in pressure-loaded ovine fetal hearts

To test the hypothesis that coronary flow and coronary flow reserve are developmentally regulated, we used fluorescent microspheres to investigate the effects of acute (6 h) pulmonary artery banding (PAB) on baseline and adenosine-enhanced right (RV) and left ventricular (LV) blood flow in two groups of twin ovine fetuses (100 and 128 days of gestation, term 145 days, n = 6 fetuses/group). Within each group, one fetus underwent PAB to constrict the main pulmonary artery diameter by 50%, and the other twin served as a nonbanded control. Physiological measurements were made 6 h after the surgery was completed; tissues were then harvested for analysis of selected genes that may be involved in the early phase of coronary vascular remodeling. Within each age group, arterial blood gas values, heart rate, and mean arterial blood pressure were similar between control and PAB fetuses. Baseline endocardial blood flow in both ventricles was greater in 100 than 128-day fetuses (RV: 341 +/- 20 vs. 230 +/- 17 ml*min(-1)*100 g(-1); LV: 258 +/- 18 vs. 172 +/- 23 ml*min(-1)*100 g(-1), both P < 0.05). In both age groups, RV and LV endocardial blood flows increased significantly in control animals during adenosine infusion and were greater in PAB compared with control fetuses. After PAB, adenosine further increased RV blood flow in 128-day fetuses (from 416 +/- 30 to 598 +/- 33 ml*min(-1)*g(-1), P < 0.05) but did not enhance blood flow in 100-day animals (490 +/- 59 to 545 +/- 42 ml*min(-1)*100 g(-1), P > 0.2). RV vascular endothelial growth factor and Flk-1 mRNA levels were increased relative to controls (P < 0.05) in 128 but not 100-day PAB fetuses. We conclude that in the ovine fetus, developmentally related differences exist in 1) baseline myocardial blood flows, 2) the adaptive response of myocardial blood flow to acute systolic pressure load, and 3) the responses of selected genes involved in vasculogenesis to increased load in the fetal myocardium.     

The direct effects of catecholamines on hepatic glucose production occur via alpha(1)- and beta(2)-receptors in the dog

The role of alpha- and beta-adrenergic receptor subtypes in mediating the actions of catecholamines on hepatic glucose production (HGP) was determined in sixteen 18-h-fasted conscious dogs maintained on a pancreatic clamp with basal insulin and glucagon. The experiment consisted of a 100-min equilibration, a 40-min basal, and two 90-min test periods in groups 1 and 2, plus a 60-min third test period in groups 3 and 4. In group 1 [alpha-blockade with norepinephrine (alpha-blo+NE)], phentolamine (2 microg x kg(-1) x min(-1)) was infused portally during both test periods, and NE (50 ng x kg(-1) x min(-1)) was infused portally at the start of test period 2. In group 2, beta-blockade with epinephrine (beta-blo+EPI), propranolol (1 microg x kg(-1) x min(-1)) was infused portally during both test periods, and EPI (8 ng x kg(-1) x min(-1)) was infused portally during test period 2. In group 3 (alpha(1)-blo+NE), prazosin (4 microg x kg(-1) x min(-1)) was infused portally during all test periods, and NE (50 and 100 ng x kg(-1) x min(-1)) was infused portally during test periods 2 and 3, respectively. In group 4 (beta(2)-blo+EPI), butoxamine (40 microg x kg(-1) x min(-1)) was infused portally during all test periods, and EPI (8 and 40 ng x kg(-1) x min(-1)) was infused portally during test periods 2 and 3, respectively. In the presence of alpha- or alpha(1)-adrenergic blockade, a selective rise in hepatic sinusoidal NE failed to increase net hepatic glucose output (NHGO). In a previous study, the same rate of portal NE infusion had increased NHGO by 1.6 +/- 0.3 mg x kg(-1) x min(-1). In the presence of beta- or beta(2)-adrenergic blockade, the selective rise in hepatic sinusoidal EPI caused by EPI infusion at 8 ng x kg(-1) x min(-1) also failed to increase NHGO. In a previous study, the same rate of EPI infusion had increased NHGO by 1.6 +/- 0.4 mg x kg(-1) x min(-1). In conclusion, in the conscious dog, the direct effects of NE and EPI on HGP are predominantly mediated through alpha(1)- and beta(2)-adrenergic receptors, respectively.     

High plasma norepinephrine attenuates the dynamic heart rate response to vagal stimulation

To better understand the pathophysiological significance of high plasma norepinephrine (NE) concentration in regulating heart rate (HR), we examined the interactions between high plasma NE and dynamic vagal control of HR. In anesthetized rabbits with sinoaortic denervation and vagotomy, using a binary white noise sequence (0-10 Hz) for 10 min, we stimulated the right vagus and estimated the transfer function from vagal stimulation to HR response. The transfer function approximated a first-order low-pass filter with pure delay. Infusion of NE (100 microg. kg(-1) x h(-1) iv) attenuated the dynamic gain from 6.2 +/- 0.8 to 3.9 +/- 1.2 beats x min(-1) x Hz(-1) (n = 7, P < 0.05) without affecting the corner frequency or pure delay. Simultaneous intravenous administration of phentolamine (1 mg x kg(-1) x h(-1)) and NE (100 microg x kg(-1) x h(-1)) abolished the inhibitory effect of NE on the dynamic gain (6.3 +/- 0.8 vs. 6.4 +/- 1.3 beats x min(-1) x Hz(-1), not significant, n = 7). The inhibitory effect of NE at infusion rates of 10, 50, and 100 microg x kg(-1) x h(-1) on dynamic vagal control of HR was dose-dependent (n = 5). In conclusion, high plasma NE attenuated the dynamic HR response to vagal stimulation, probably via activation of alpha-adrenergic receptors on the preganglionic and/or postganglionic cardiac vagal nerve terminals.