Effect of histamine and cimetidine on retinal and choroidal blood flow in humans

Intravenous administration of histamine causes an increase in choroidal blood flow and retinal vessel diameter in healthy subjects. The mechanism underlying this effect remains to be elucidated. In the present study, we hypothesized that H2 receptor blockade alters hemodynamic effects of histamine in the choroid and retina. Eighteen healthy male nonsmoking volunteers were included in this randomized, double-masked, placebo-controlled two-way crossover study. Histamine (0.32 microg.kg(-1).min(-1) over 30 min) was infused intravenously in the absence (NaCl as placebo) or presence of the H2 blocker cimetidine (2.3 mg/min over 50 min). Ocular hemodynamic parameters, blood pressure, and intraocular pressure were measured before drug administration, after infusion of cimetidine or placebo, and after coinfusion of histamine. Subfoveal choroidal blood flow and fundus pulsation amplitude were measured with laser-Doppler flowmetry and laser interferometry, respectively. Retinal arterial and venous diameters were measured with a retinal vessel analyzer. Retinal blood velocity was assessed with bidirectional laser-Doppler velocimetry. Histamine increased subfoveal choroidal blood flow (+14 +/- 15%, P < 0.001), fundus pulsation amplitude (+11 +/- 5%, P < 0.001), retinal venous diameter (+3.0 +/- 3.6%, P = 0.002), and retinal arterial diameter (+2.8 +/- 4.2%, P < 0.01) but did not change retinal blood velocity. The H2 antagonist cimetidine had no significant effect on ocular hemodynamic parameters. In addition, cimetidine did not modify effects of histamine on choroidal blood flow, fundus pulsation amplitude, retinal venous diameter, and retinal arterial diameter compared with placebo. The present data confirm that histamine increases choroidal blood flow and retinal vessel diameters in healthy subjects. This ocular vasodilator effect of histamine is, however, not altered by administration of an H2 blocker. Whether the increase in blood flow is mediated via H1 receptors or other hitherto unidentified mechanisms remains to be elucidated.     

Whole body and abdominal lipolytic sensitivity to epinephrine is suppressed in upper body obese women

We measured whole body and regional lipolytic and adipose tissue blood flow (ATBF) sensitivity to epinephrine in 8 lean [body mass index (BMI): 21 +/- 1 kg/m(2)] and 10 upper body obese (UBO) women (BMI: 38 +/- 1 kg/m(2); waist circumference >100 cm). All subjects underwent a four-stage epinephrine infusion (0.00125, 0.005, 0.0125, and 0.025 microgram. kg fat-free mass(-1). min(-1)) plus pancreatic hormonal clamp. Whole body free fatty acid (FFA) and glycerol rates of appearance (R(a)) in plasma were determined by stable isotope tracer methodology. Abdominal and femoral subcutaneous adipose tissue lipolytic activity was determined by microdialysis and (133)Xe clearance methods. Basal whole body FFA R(a) and glycerol R(a) were both greater (P < 0.05) in obese (449 +/- 31 and 220 +/- 12 micromol/min, respectively) compared with lean subjects (323 +/- 44 and 167 +/- 21 micromol/min, respectively). Epinephrine infusion significantly increased FFA R(a) and glycerol R(a) in lean (71 +/- 21 and 122 +/- 52%, respectively; P < 0.05) but not obese subjects (7 +/- 6 and 39 +/- 10%, respectively; P = not significant). In addition, lipolytic and ATBF sensitivity to epinephrine was blunted in abdominal but not femoral subcutaneous adipose tissue of obese compared with lean subjects. We conclude that whole body lipolytic sensitivity to epinephrine is blunted in women with UBO because of decreased sensitivity in upper body but not lower body subcutaneous adipose tissue.     

Free fatty acids do not acutely increase asymmetrical dimethylarginine concentrations.

Concentrations of asymmetrical dimethylarginine (ADMA) and free fatty acids (FFAs) are elevated in insulin resistance which is associated with impaired vascular function. We hypothesized that FFAs could alter vascular tone by affecting ADMA concentrations. Plasma FFA levels were increased in seventeen healthy male volunteers by Intralipid/heparin infusion; hemodynamic and biochemical parameters were measured after 90 minutes. Plasma collected before and during Intralipid/heparin or equivalent synthetic FFAs was incubated with human umbilical vein endothelial cells (HUVECs) in vitro. Intralipid/heparin infusion resulted in an approximately seven-fold increase in plasma FFA levels to 1861 +/- 139 micromol/l, which was paralleled by increased systemic blood pressure and forearm blood flow. Intralipid/heparin did not affect ADMA (baseline mean 0.59 [95 % confidence interval [CI]: 0.54; 0.64] and 0.56 [CI: 0.51; 0.59] after 90 minutes), but slightly decreased SDMA (from 0.76, [CI: 0.70; 0.83] to 0.71 [CI: 0.64; 0.74], p < 0.05), and had no effect on ADMA/SDMA ratio. There was no correlation between ADMA and FFA concentrations or forearm blood flow. Incubation of HUVECs with FFA-rich plasma or synthetic FFAs induced an ADMA release after 24 hours, but not after 90 minutes. Acutely increased FFA levels caused hemodynamic effects but did not affect ADMA. Prolonged elevation of FFA levels might influence vascular function by increasing ADMA levels.     

FFA cause hepatic insulin resistance by inhibiting insulin suppression of glycogenolysis

Free fatty acids (FFA) have been shown to inhibit insulin suppression of endogenous glucose production (EGP). To determine whether this is the result of stimulation by FFA of gluconeogenesis (GNG) or glycogenolysis (GL) or a combination of both, we have determined rates of GNG and GL (with (2)H(2)O) and EGP in 16 healthy nondiabetic volunteers (11 males, 5 females) during euglycemic-hyperinsulinemic (~450 pM) clamping performed either with or without simultaneous intravenous infusion of lipid plus heparin. During insulin infusion, FFA decreased from 571 to 30 micromol/l (P < 0.001), EGP from 15.7 to 2.0 micromol x kg(-1) x min(-1) (P < 0.01), GNG from 8.2 to 3.7 micromol x kg(-1). min(-1) (P < 0.05), and GL from 7.4 to -1.7 micromol x kg(-1). min(-1) (P < 0.02). During insulin plus lipid/heparin infusion, FFA increased from 499 to 1,247 micromol/l (P < 0.001). EGP decreased 64% less than during insulin alone (-5.1 +/- 0.7 vs. -13.7 +/- 3.4 micromol x kg(-1). min(-1)). The decrease in GNG was not significantly different from the decrease of GNG during insulin alone (-2.6 vs. -4.5 micromol x kg(-1). min(-1), not significant). In contrast, GL decreased 66% less than during insulin alone (-3.1 vs. -9.2 micromol x kg(-1). min(-1), P < 0.05). We conclude that insulin suppressed EGP by inhibiting GL more than GNG and that elevated plasma FFA levels attenuated the suppression of EGP by interfering with insulin suppression of GL.     

Effect of training on insulin sensitivity of glucose uptake and lipolysis in human adipose tissue

Training increases insulin sensitivity of both whole body and muscle in humans. To investigate whether training also increases insulin sensitivity of adipose tissue, we performed a three-step hyperinsulinemic, euglycemic clamp in eight endurance-trained (T) and eight sedentary (S) young men [insulin infusion rates: 10,000 (step I), 20,000 (step II), and 150,000 (step III) microU x min(-1) x m(-2)]. Glucose and glycerol concentrations were measured in arterial blood and also by microdialysis in interstitial fluid in periumbilical, subcutaneous adipose tissue and in quadriceps femoris muscle (glucose only). Adipose tissue blood flow was measured by (133)Xe washout. In the basal state, adipose tissue blood flow tended to be higher in T compared with S subjects, and in both groups blood flow was constant during the clamp. The change from basal in arterial-interstitial glucose concentration difference was increased in T during the clamp but not in S subjects in both adipose tissue and muscle [adipose tissue: step I (n = 8), 0.48 +/- 0.18 mM (T), 0.23 +/- 0.11 mM (S); step II (n = 8), 0.19 +/- 0.09 (T), -0.09 +/- 0.24 (S); step III (n = 5), 0.47 +/- 0.24 (T), 0.06 +/- 0.28 (S); (T: P < 0.001, S: P > 0.05); muscle: step I (n = 4), 1. 40 +/- 0.46 (T), 0.31 +/- 0.21 (S); step II (n = 4), 1.14 +/- 0.54 (T), -0.08 +/- 0.14 (S); step III (n = 4), 1.23 +/- 0.34 (T), 0.24 +/- 0.09 (S); (T: P < 0.01, S: P > 0.05)]. Interstitial glycerol concentration decreased faster in T than in S subjects [half-time: T, 44 +/- 9 min (n = 7); S, 102 +/- 23 min (n = 5); P < 0.05]. In conclusion, training enhances insulin sensitivity of glucose uptake in subcutaneous adipose tissue and in skeletal muscle. Furthermore, interstitial glycerol data suggest that training also increases insulin sensitivity of lipolysis in subcutaneous adipose tissue. Insulin per se does not influence subcutaneous adipose tissue blood flow.     

Pulsatile flow during cardiopulmonary bypass preserves postoperative microcirculatory perfusion irrespective of systemic hemodynamics

The onset of nonpulsatile cardiopulmonary bypass is known to deteriorate microcirculatory perfusion, but it has never been investigated whether this may be prevented by restoration of pulsatility during extracorporeal circulation. We therefore investigated the distinct effects of nonpulsatile and pulsatile flow on microcirculatory perfusion during on-pump cardiac surgery. Patients undergoing coronary artery bypass graft surgery were randomized into a nonpulsatile (n = 17) or pulsatile (n = 16) cardiopulmonary bypass group. Sublingual mucosal microvascular perfusion was measured at distinct perioperative time intervals using sidestream dark field imaging, and quantified as the level of perfused small vessel density and microvascular flow index (vessel diameter < 20 μm). Microcirculation measurements were paralleled by hemodynamic and free hemoglobin analyses. The pulse wave during pulsatile bypass estimated 58 ± 17% of the baseline blood pressure waveform. The observed reduction in perfused vessel density during aorta cross-clamping was only restored in the pulsatile flow group and increased from 15.5 ± 2.4 to 20.3 ± 3.7 mm/mm(2) upon intensive care admission (P < 0.01). The median postoperative microvascular flow index was higher in the pulsatile group [2.6 (2.5-2.9)] than in the nonpulsatile group [2.1 (1.7-2.5); P = 0.001]. Pulsatile flow was not associated with augmentation of free hemoglobin production and was paralleled by improved oxygen consumption from 70 ± 14 to 82 ± 16 ml·min(-1)·m(-2) (P = 0.01) at the end of aortic cross-clamping. In conclusion, pulsatile cardiopulmonary bypass preserves microcirculatory perfusion throughout the early postoperative period, irrespective of systemic hemodynamics. This observation is paralleled by an increase in oxygen consumption during pulsatile flow, which may hint toward decreased microcirculatory heterogeneity during extracorporeal circulation and preservation of microcirculatory perfusion throughout the perioperative period.     

Hypercapnia-induced cerebral and ocular vasodilation is not altered by glibenclamide in humans

Carbon dioxide is an important regulator of vascular tone. Glibenclamide, an inhibitor of ATP-sensitive potassium channel (K(ATP)) activation, significantly blunts vasodilation in response to hypercapnic acidosis in animals. We investigated whether glibenclamide also alters the cerebral and ocular vasodilator response to hypercapnia in humans. Ten healthy male subjects were studied in a controlled, randomized, double-blind two-way crossover study under normoxic and hypercapnic conditions. Glibenclamide (5 mg po) or insulin (0.3 mU. kg(-1). min(-1) iv) were administered with glucose to achieve comparable plasma insulin levels. In control experiments, five healthy volunteers received glibenclamide (5 mg) or nicorandil (40 mg) or glibenclamide and nicorandil in a randomized, three-way crossover study. Mean blood flow velocity and resistive index in the middle cerebral artery (MCA) and in the ophthalmic artery (OA) were measured with Doppler sonography. Pulsatile choroidal blood flow was assessed with laser interferometric measurement of fundus pulsation. Forearm blood flow was measured with venous occlusion plethysmography. Hypercapnia increased ocular fundus pulsation amplitude by +18.2-22.3% (P < 0. 001) and mean flow velocity in the MCA by +27.4-33.3% (P < 0.001), but not in the OA (2.1-6.5%, P = 0.2). Forearm blood flow increased by 78.2% vs. baseline (P = 0.041) after nicorandil administration. Glibenclamide did not alter hypercapnia-induced changes in cerebral or ocular hemodynamics and did not affect systemic hemodynamics or forearm blood flow but significantly increased glucose utilization and blunted the nicorandil-induced vasodilation in the forearm. This suggests that hypercapnia-induced changes in the vascular beds under study are not mediated by activation of K(ATP) channels in humans.     

Substrate utilization in leg muscle of men after heat acclimation

Eight men were heat acclimated (39.6 degrees C and 29.2% rh) for 8 days to examine changes in substrate utilization. A heat exercise test (HET), (cycling for 60 min; 50% maximal O2 consumption) was performed before (UN-HET) and after (ACC-HET) the acclimation period. Muscle glycogen utilization (67.0 vs. 37.6 mmol/kg wet wt), respiratory exchange ratio (0.85 +/- 0.002 vs. 0.83 +/- 0.001), and calculated rate of carbohydrate oxidation (75.15 +/- 1.38 vs. 64.80 +/- 1.52 g/h) were significantly reduced (P less than 0.05) during the ACC-HET. Significantly lower (P less than 0.05) femoral venous glucose (15, 30, and 45 min) and lactate (15 min) levels were observed during the ACC-HET. No differences were observed in plasma free fatty acid (FFA) and glycerol concentrations or glucose, lactate and glycerol arteriovenous uptake/release between tests. A small but significant increase (P less than 0.05) above resting levels in FFA uptake was observed during the ACC-HET. Leg blood flow was slightly greater (P greater than 0.05) during the ACC-HET (4.64 +/- 0.13 vs. 4.80 +/- 0.13 l/min). These findings indicate a reduced use of muscle glycogen following heat acclimation. However, the decrease is not completely explained by a shift toward greater lipid oxidation or increased blood flow.     

Fasting for 72 h increases intramyocellular lipid content in nondiabetic,physically fit men

The purpose of this study was to determine changes in intramyocellular lipid (IMCL) content in the vastus lateralis of nondiabetic, physically fit males over 72 h of fasting. Six men, mean age 35 yr (range 23-55 yr), body mass index 23.7 kg/m2 (21.2-27.4 kg/m2), undertook a water-only fast for 84 h. Vastus lateralis IMCL content was determined using proton magnetic resonance spectroscopy after 12 and 84 h of fasting. Venous blood was sampled at 12-h intervals throughout the fast. IMCL-(CH2)n/water and IMCL-(CH2)n/total creatine ratios increased from 0.00623 +/- 0.00065 to 0.0142 +/- 0.0015 (P = 0.002) and 6.82 +/- 0.87 to 14.96 +/- 1.73 (P = 0.001), respectively. Plasma free fatty acid (FFA), serum triglyceride, and whole blood 3-hydroxybutyrate concentrations increased (P < 0.001, <0.05, <0.03, respectively), whereas plasma glucose and serum insulin concentrations decreased (both P < 0.001) during fasting. In conclusion, 72-h water-only fasting produces a large increase in plasma FFA concentration, a drop in serum insulin concentration, and accumulation of IMCL in the vastus lateralis muscle of nondiabetic, physically fit men.     

Oral antioxidant therapy improves endothelial function in Type 1 but not Type 2 diabetes mellitus

Oxidative stress decreases the bioavailability of endothelium-derived nitric oxide in diabetic patients. We investigated whether impaired endothelium-dependent vasodilation (EDV) in diabetes can be improved by long-term administration of oral antioxidants. Forty-nine diabetic subjects [26 Type 1 (T1) and 23 Type 2 (T2)] and 45 matched healthy control subjects were randomized to receive oral vitamin C (1,000 mg) and vitamin E (800 IU) daily or matching placebo for 6 mo. Vascular ultrasonography was used to determine brachial artery EDV and endothelium-independent vasodilation (EIV). EDV was decreased in both T1 (4.9 +/- 0.9%, P = 0.015) and T2 (4.1 +/- 1.0%, P < 0.01) subjects compared with control subjects (7.7 +/- 0.7%). EIV was decreased in T2 (15.0 +/- 1.2%, P < 0.01) but not T1 subjects (18.5 +/- 2.3%, P = 0.3) compared with controls (21.8 +/- 1.8%). Administration of antioxidant vitamins increased EDV in T1 (by 3.4 +/- 1.4%, P = 0.023) but not T2 subjects (by 0.5. +/- 0.4%, P = 0.3). Antioxidant therapy had no significant affect on EIV. Oral antioxidant therapy improves EDV in T1 but not T2 diabetes. These results are consistent with the lack of clinical benefit in studies that have included primarily T2 diabetic patients.     

Intramyocellular lipid content is increased after exercise in nonexercising human skeletal muscle.

Intramyocellular lipid (IMCL) content has been reported to decrease after prolonged submaximal exercise in active muscle and, therefore, seems to form an important local substrate source. Because exercise leads to a substantial increase in plasma free fatty acid (FFA) availability with a concomitant increase in FFA uptake by muscle tissue, we aimed to investigate potential differences in the net changes in IMCL content between contracting and noncontracting skeletal muscle after prolonged endurance exercise. IMCL content was quantified by magnetic resonance spectroscopy in eight trained cyclists before and after a 3-h cycling protocol (55% maximal energy output) in the exercising vastus lateralis and the nonexercising biceps brachii muscle. Blood samples were taken before and after exercise to determine plasma FFA, glycerol, and triglyceride concentrations, and substrate oxidation was measured with indirect calorimetry. Prolonged endurance exercise resulted in a 20.4 +/- 2.8% (P < 0.001) decrease in IMCL content in the vastus lateralis muscle. In contrast, we observed a substantial (37.9 +/- 9.7%; P < 0.01) increase in IMCL content in the less active biceps brachii muscle. Plasma FFA and glycerol concentrations were substantially increased after exercise (from 85 +/- 6 to 1450 +/- 55 and 57 +/- 11 to 474 +/- 54 microM, respectively; P < 0.001), whereas plasma triglyceride concentrations were decreased (from 1498 +/- 39 to 703 +/- 7 microM; P < 0.001). IMCL is an important substrate source during prolonged moderate-intensity exercise and is substantially decreased in the active vastus lateralis muscle. However, prolonged endurance exercise with its concomitant increase in plasma FFA concentration results in a net increase in IMCL content in less active muscle.     

Effects of spaceflight on human calf hemodynamics.

Chronic microgravity may modify adaptations of the leg circulation to gravitational pressures. We measured resting calf compliance and blood flow with venous occlusion plethysmography, and arterial blood pressure with sphygmomanometry, in seven subjects before, during, and after spaceflight. Calf vascular resistance equaled mean arterial pressure divided by calf flow. Compliance equaled the slope of the calf volume change and venous occlusion pressure relationship for thigh cuff pressures of 20, 40, 60, and 80 mmHg held for 1, 2, 3, and 4 min, respectively, with 1-min breaks between occlusions. Calf blood flow decreased 41% in microgravity (to 1.15 +/- 0.16 ml x 100 ml(-1) x min(-1)) relative to 1-G supine conditions (1.94 +/- 0.19 ml x 100 ml(-1) x min(-1), P = 0.01), and arterial pressure tended to increase (P = 0.05), such that calf vascular resistance doubled in microgravity (preflight: 43 +/- 4 units; in-flight: 83 +/- 13 units; P < 0.001) yet returned to preflight levels after flight. Calf compliance remained unchanged in microgravity but tended to increase during the first week postflight (P > 0.2). Calf vasoconstriction in microgravity qualitatively agrees with the "upright set-point" hypothesis: the circulation seeks conditions approximating upright posture on Earth. No calf hemodynamic result exhibited obvious mechanistic implications for postflight orthostatic intolerance.     

Imaging hemoglobin oxygen saturation in sickle cell disease patients using noninvasive visible reflectance hyperspectral techniques: effects of nitric oxide

Sickle cell disease is characterized by microvascular occlusion and hemolytic anemia, factors that impair tissue oxygen delivery. We use visible reflectance hyperspectral imaging to quantitate skin tissue hemoglobin oxygen saturation (HbO2) and to determine whether changes in blood flow during nitric oxide (NO) stimulation or gas administration (therapies proposed for this disease) improve skin tissue oxygen saturation in five patients with sickle cell disease. Compared with six healthy African-American subjects, sickle cell patients exhibited higher forearm blood flows (7.4 +/- 1.8 vs. 3.2 +/- 0.4 ml.min-1.100 ml tissue-1, P = 0.037) but significantly reduced percentages of skin HbO2 (61.0 +/- 0.2 vs. 77.5 +/- 0.2%, P < 0.001). Administration of acetylcholine to patients increased blood flow by 15.1 +/- 3.8 ml.min-1.100 ml tissue-1 and the percentage of skin HbO2 by 4.1 +/- 0.3% (P = 0.02, P < 0.001, respectively, from baseline values). Sodium nitroprusside, a direct NO donor, increased blood flow by 3.9 +/- 1.1 ml/min and the percentage of skin HbO2 by 2.9 +/- 0.3% (P = 0.02, P < 0.001, respectively). NO inhalation had no effect on forearm blood flow, yet increased the percentage of skin HbO2 by 2.3 +/- 0.3% (P < 0.001). Percentages of skin HbO2 were exponentially related to blood flow (R = 0.97, P < 0.001), indicating a limit to skin tissue oxygen saturation at high blood flows. Thus, for acetylcholine infusion leading to blood flows sevenfold greater than those of healthy resting African-American subjects, patients still exhibited lower percentages of skin HbO2 (65.2 +/- 0.2 vs. 77.5 +/- 0.2%, P < 0.001). Visible reflectance hyperspectral imaging demonstrates that either the stimulation or the administration of NO pharmacologically or by gas inhalation improves, but does not normalize, skin tissue oxygen saturation in patients with sickle cell disease.     

Blunted muscle vasodilatation during chemoreceptor stimulation in patients with heart failure

Chemoreflex control of sympathetic nerve activity is exaggerated in heart failure (HF) patients. However, the vascular implications of the augmented sympathetic activity during chemoreceptor activation in patients with HF are unknown. We tested the hypothesis that the muscle blood flow responses during peripheral and central chemoreflex stimulation would be blunted in patients with HF. Sixteen patients with HF (49 +/- 3 years old, Functional Class II-III, New York Heart Association) and 11 age-paired normal controls were studied. The peripheral chemoreflex control was evaluated by inhalation of 10% O(2) and 90% N(2) for 3 min. The central chemoreflex control was evaluated by inhalation of 7% CO(2) and 93% O(2) for 3 min. Muscle sympathetic nerve activity (MSNA) was directly evaluated by microneurography. Forearm blood flow was evaluated by venous occlusion plethysmography. Baseline MSNA were significantly greater in HF patients (33 +/- 3 vs. 20 +/- 2 bursts/min, P = 0.001). Forearm vascular conductance (FVC) was not different between the groups. During hypoxia, the increase in MSNA was significantly greater in HF patients than in normal controls (9.0 +/- 1.6 vs. 0.8 +/- 2.0 bursts/min, P = 0.001). The increase in FVC was significantly lower in HF patients (0.00 +/- 0.10 vs. 0.76 +/- 0.25 units, P = 0.001). During hypercapnia, MSNA responses were significantly greater in HF patients than in normal controls (13.9 +/- 3.2 vs. 2.1 +/- 1.9 bursts/min, P = 0.001). FVC responses were significantly lower in HF patients (-0.29 +/- 0.10 vs. 0.37 +/- 0.18 units, P = 0.001). In conclusion, muscle vasodilatation during peripheral and central chemoreceptor stimulation is blunted in HF patients. This vascular response seems to be explained, at least in part, by the exaggerated MSNA responses during hypoxia and hypercapnia.     

Effect of insulin on exocrine pancreatic secretion in healthy and diabetic anaesthetised rats

This investigation characterised the effects of exogenous insulin on exocrine pancreatic secretion in anaesthetised healthy and diabetic rats. Animals were rendered diabetic by a single injection of streptozotocin (STZ, 60 mg kg(-1) I.P.). Age-matched controls were injected citrate buffer. Rats were tested for hyperglycaemia 4 days after STZ injection and 7-8 weeks later when they were used for the experiments. Following anaesthesia (1 g kg(-1) urethane I.P.), laparotomy was performed and the pancreatic duct cannulated for collection of pure pancreatic juice. Basal pancreatic juice flow rate in diabetic rats was significantly (p < 0.001) increased whereas protein and amylase outputs were significantly (p < 0.001) decreased compared to control rats. Insulin (1 IU, I.P.) produced in healthy rats significant increases in pancreatic flow rate, amylase secretion and protein output compared to basal (p < 0.05). Insulin action also included a reduction in blood glucose (152.7 +/- 16.9 mg dl(-1), n = 6, prior to insulin and 42.0 +/- 8.4 mg dl(-1), n = 4, 100 min later). In fact, flow rate and glycaemia showed a strong negative correlation (p < 0.01, Pearson). Pretreatment with atropine (0.2 mg kg(-1), I.V.) abolished the effects of insulin on secretory parameters despite a similar reduction in glycaemia; in this series of experiments the correlation between flow rate and blood glucose was lost. In diabetic rats, insulin (4 IU, I.P.) did not modify exocrine pancreatic secretion. There was a fall in blood glucose (467.6 +/- 14.0 mg dl(-1), n = 10, prior to insulin and 386.6 +/- 43.6 mg dl(-1), n = 7, 120 min later). Rats, however, did not become hypoglycaemic. Similar results were observed in diabetic atropinized rats. The results of this study indicate that the effects of insulin on exocrine pancreatic secretion in anaesthetised healthy rats are mediated by hypoglycaemia-evoked vagal cholinergic activation.     

Effect of elevated FFA on carbohydrate and lipid oxidation during prolonged exercise in humans

Increased availability of circulating free fatty acids (FFA) inhibits the rate of glycolysis in heart and resting skeletal muscle (Randle effect). Whether elevated FFA may play a role in decreasing carbohydrate oxidation during prolonged exercise in humans is more controversial. Using respiratory exchange measurements, we measured substrate utilization during 2.5 h of exercise at approximately 44 +/- 1% maximal O2 uptake (VO2 max) in the presence or absence of elevated FFA levels. After 30 min of base-line determinations, 1,000 U heparin was given intravenously and a 3-h constant infusion of Intralipid 10% (150 g/h) and heparin (500 U/h) was started. After an additional 30 min of rest, subjects exercised for 2.5 h (study 1, n = 6). In another five subjects (study 2) 100 g glucose was ingested after 30 min of exercise. The same protocols (studies 1 and 2) were also performed during a 0.9%-saline infusion. During exercise, without glucose ingestion, higher FFA concentrations prevailed during the Intralipid infusion (1,122 +/- 40 vs. 782 +/- 65 mumol/l), but the relative contributions of carbohydrate (49 +/- 4 vs. 50 +/- 4%) or lipid (49 +/- 4 vs. 47 +/- 6%) oxidation to the total energy expenditure were different only during the first 30 min of exercise. Similarly, higher FFA levels (1,032 +/- 62 vs. 568 +/- 46 mumol/l) did not alter the relative contributions of carbohydrate (62 +/- 4 vs. 69 +/- 2%) or lipid (36 +/- 4 vs. 29 +/- 2%) oxidation to the total energy expenditure after glucose feeding.(ABSTRACT TRUNCATED AT 250 WORDS)     

Arginine vasopressin reduces intestinal oxygen supply and mucosal tissue oxygen tension

We investigated intestinal oxygen supply and mucosal tissue PO2 during administration of increasing dosages of continuously infused arginine vasopressin (AVP) in an autoperfused, innervated jejunal segments in anesthetized pigs. Mucosal tissue PO2 was measured by employing two Clark-type surface oxygen electrodes. Oxygen saturation of jejunal microvascular hemoglobin was determined by tissue reflectance spectrophotometry. Microvascular blood flow was assessed by laser-Doppler velocimetry. Systemic hemodynamic variables, mesenteric venous and systemic acid-base and blood gas variables, and lactate measurements were recorded. Measurements were performed at baseline and at 20-min intervals during incremental AVP infusion (n = 8; 0.007, 0.014, 0.029, 0.057, 0.114, and 0.229 IU.kg(-1).h(-1), respectively) or infusion of saline (n=8). AVP infusion led to a significant (P < .05), dose-dependent decrease in cardiac index (from 121 +/- 31 to 77 +/- 27 ml.kg(-1).min(-1) at 0.229 IU.kg(-1).h(-1)) and systemic oxygen delivery (from 14 +/- 3 to 9 +/- 3 ml.kg(-1).min(-1) at 0.229 IU.kg(-1).h(-1)) concomitant with an increase in systemic oxygen extraction ratio (from 31 +/- 4 to 48 +/- 10%). AVP decreased microvascular blood flow (from 133 +/- 47 to 82 +/- 35 perfusion units at 0.114 IU.kg(-1).h(-1)), mucosal tissue PO2 (from 26 +/- 7 to 7 +/- 2 mmHg at 0.229 IU.kg(-1).h(-1)), and microvascular hemoglobin oxygen saturation (from 51 +/- 9 to 26 +/- 12% at 0.229 IU.kg(-1).h(-1)) without a significant increase in mesenteric venous lactate concentration (2.3 +/- 0.8 vs. 3.4 +/- 0.7 mmol/l). We conclude that continuously infused AVP decreases intestinal oxygen supply and mucosal tissue PO2 due to a reduction in microvascular blood flow and due to the special vascular supply in the jejunal mucosa in a dose-dependent manner in pigs.     

Interaction of free fatty acids and epinephrine in regulating hepatic glucose production in conscious dogs

To determine the effects of an increase in lipolysis on the glycogenolytic effect of epinephrine (EPI), the catecholamine was infused portally into 18-h-fasted conscious dogs maintained on a pancreatic clamp in the presence [portal (Po)-EPI+FFA, n = 6] and absence (Po-EPI+SAL, n = 6) of peripheral Intralipid infusion. Control groups with high glucose (70% increase) and free fatty acid (FFA; 200% increase; HG+FFA, n = 6) and high glucose alone (HG+SAL, n = 6) were also included. Hepatic sinusoidal EPI levels were elevated (Delta 568 +/- 77 and Delta 527 +/- 37 pg/ml, respectively) in Po-EPI+SAL and EPI+FFA but remained basal in HG+FFA and HG+SAL. Arterial plasma FFA increased from 613 +/- 73 to 1,633 +/- 101 and 746 +/- 112 to 1,898 +/- 237 micromol/l in Po-EPI+FFA and HG+FFA but did not change in EPI+SAL or HG+SAL. Net hepatic glycogenolysis increased from 1.5 +/- 0.3 to 3.1 +/- 0.4 mg x kg(-1) x min(-1) (P < 0.05) by 30 min in response to portal EPI but did not rise (1.8 +/- 0.2 to 2.1 +/- 0.3 mg x kg(-1) x min(-1)) in response to Po-EPI+FFA. Net hepatic glycogenolysis decreased from 1.7 +/- 0.2 to 0.9 +/- 0.2 and 1.6 +/- 0.2 to 0.7 +/- 0.2 mg x kg(-1) x min(-1) by 30 min in HG+FFA and HG+SAL. Hepatic gluconeogenic flux to glucose 6-phosphate increased from 0.6 +/- 0.1 to 1.2 +/- 0.1 mg x kg(-1) x min(-1) (P < 0.05; by 3 h) and 0.7 +/- 0.1 to 1.6 +/- 0.1 mg x kg(-1) x min(-1) (P < 0.05; at 90 min) in HG+FFA and Po-EPI+FFA. The gluconeogenic parameters remained unchanged in the Po-EPI+SAL and HG+SAL groups. In conclusion, increased FFA markedly changed the mechanism by which EPI stimulated hepatic glucose production, suggesting that its overall lipolytic effect may be important in determining its effect on the liver.     

Leg free fatty acid kinetics during exercise in men and women

We previously reported that epinephrine stimulates leg free fatty acid (FFA) release in men but not in women. The present studies were conducted to determine whether the same is true during exercise. Six men and six women bicycled for 90 min at 45% of peak O(2) consumption, during which time systemic and leg FFA kinetics ([9, 10-(3)H]palmitate) were measured. The catecholamine and hormonal responses to exercise were not different in men and women. The baseline systemic and leg palmitate release was 94 +/- 15 vs. 114 +/- 5 micromol/min and 16 +/- 2 and 20 +/- 3 micromol/min, respectively, in men and women [P = nonsignificant (NS)]. Systemic and leg palmitate release increased (both P < 0.001) to 251 +/- 18 vs. 212 +/- 16 micromol/min and 73 +/- 19 vs. 80 +/- 12 micromol/min in men and women, respectively, during the last 30 min of exercise (P = NS, men vs. women). We conclude that the systemic and leg adipose tissue lipolytic response to exercise is not different in nonobese men and women.     

Coronary nitric oxide production controls cardiac substrate metabolism during pregnancy in the dog

The aim of this study was to examine the role of nitric oxide (NO) in the control of cardiac metabolism at 60 days of pregnancy (P60) in the dog. There was a basal increase in diastolic coronary blood flow during pregnancy and a statistically significant increase in cardiac output (55 +/- 4%) and in cardiac NOx production (44 +/- 4 to 59 +/- 3 nmol/min, P < 0.05). Immunohistochemistry of the left ventricle showed an increase in endothelial nitric oxide synthase staining in the endothelial cells at P60. NO-dependent coronary vasodilation (Bezold-Jarisch reflex) was increased by 20% and blocked by N(G)-nitro-l-arginine methyl ester (l-NAME). Isotopically labeled substrates were infused to measure oleate, glucose uptake, and oxidation. Glucose oxidation was not significantly different in P60 hearts (5.4 +/- 0.5 vs. 6.2 +/- 0.4 micromol/min) but greatly increased in response to l-NAME injection (to 19.9 +/- 0.9 micromol/min, P < 0.05). Free fatty acid (FFA) oxidation was increased in P60 (from 5.3 +/- 0.6 to 10.4 +/- 0.5 micromol/min, P < 0.05) and decreased in response to l-NAME (to 4.5 +/- 0.5 micromol/min, P < 0.05). There was an increased oxidation of FFA for ATP production but no change in the respiratory quotient during pregnancy. Genes associated with glucose and glycogen metabolism were downregulated, whereas genes involved in FFA oxidation were elevated. The acute inhibition of NO shifts the heart away from FFA and toward glucose metabolism despite the downregulation of the carbohydrate oxidative pathway. The increase in endothelium-derived NO during pregnancy results in a tonic inhibition of glucose oxidation and reliance on FFA uptake and oxidation to support ATP synthesis in conjunction with upregulation of FFA metabolic enzymes.