Hormonal and metabolic changes during exercise in cirrhotic patients

The metabolic response to exercise was compared in 10 cirrhotic patients (P) in a stable clinical condition and in 6 sedentary, age-matched, normal subjects (C) performing 32 minutes of treadmill exercise with the same constant workload corresponding to three to four times their resting oxygen uptake. Taking indirect calorimetry as reference, respiratory exchanges indicated that cirrhotic patients consumed carbohydrates almost exclusively, unlike the normal controls, who consumed lipids and glucids in about the same proportions (RQ: 0.98 +/- 0.04 v 0.87 +/- 0.04, P less than .0001). In the patients, this carbohydrate path of exercise metabolism lowered glycemia from the resting value of 5.23 +/- 0.16 mmol/L to 4.03 +/- 0.37 mmol/L (P less than .0001) and raised the plasma lactate concentration from 2.08 +/- 0.24 mmol/L at rest to 3.48 +/- 0.32 mmol/L at the eighth minute of exercise (P less than .001), thus suggesting defective liver glyconeogenesis. Fatty free acids and glycerol remained almost constant during exercise, whereas catecholamines increased. Insulin levels were high in patients at rest (67.1 +/- 14.5 U/mL v 15.1 +/- 3.5 U/mL); they declined sharply at the onset of exercise but nevertheless remained high compared to those observed in the controls (P less than .0001). Glucagon increased in exercising patients from 88.3 +/- 21.3 pg/mL to 127.4 +/- 30.6 pg/mL (NS). Esterified plasma carnitine declined in the patients from 13.0 +/- 2.2 mumol/L to 8.6 +/- 1.5 mumol/L (P less than .05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Hormonal effects of norepinephrine on acute glucose disposal in humans: a minimal model analysis

It is not known whether circulating norepinephrine (NE) has a direct hormonal influence on glucose disposal. This study examines whether moderate elevation of NE alters the disposal of an acute intravenous (IV) glucose load, as analysed by the minimal model of Bergman. Eight healthy normal subjects were infused with either 25 ng/kg/min NE (plasma NE 1,284 +/- 259 pg/mL) or normal saline (plasma NE 314 +/- 86 pg/mL), 30 minutes prior to and during an IV glucose tolerance test (GTT). There was a small but significant rise (P less than .05) in basal blood glucose levels during the initial 30-minute NE infusion which was accompanied by a 40% increase (0.39 +/- .02 to 0.59 +/- .07 nmol/L, P less than .01) in nonesterified fatty acid levels (NEFA). Insulin, C-peptide, and glucagon levels did not change. NE impaired the rate of acute glucose disposal (Kg 1.74 +/- 0.24 v 2.10 +/- 0.23 (min-1, P less than .05). Minimal model analysis revealed a corresponding 35% decrease in insulin sensitivity (SI 4.85 +/- 1.51 v 7.28 +/- 1.16 min-1 microU-1 mL-1 x 10(4), P less than .05) but no significant differences between glucose-mediated glucose disposal or pancreatic B-cell responsiveness. The glucose disposition index (si* phi2), a direct measure of an individual's overall insulin- mediated glucose disposal, was reduced by 70% in the NE-infussed subjects (si* phi2 69 +/-22 v 223 +/- 76 mg-1 ml-1 min-3 x 10(2), p< .05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Antioxidant enzyme activity during prolonged exercise in amenorrheic and eumenorrheic athletes

Exogenous 17 beta-estradiol (E2) has been shown to be associated with elevated levels of erythrocyte glutathione peroxidase (GPX) activity. The purpose of this study was to examine the influence of endogenous E2, as defined by menstrual status (amenorrhea v eumenorrhea), on activity of blood antioxidant enzymes at rest and during prolonged exercise. Six amenorrheic (AMc) and six eumenorrheic (EUc) athletes were subjected to a treadmill running test at 60% VO2max for 90 minutes. Serial blood samples were taken from a forearm vein at rest, 30, 60, and 90 minutes during exercise, and 15 minutes into recovery. Resting estrogen levels were significantly lower in AMc athletes at rest and during exercise as compared with EUc athletes, whereas plasma cortisol levels in AMc were significantly higher. GPX activity was significantly higher in AMc than EUc at rest (46.9 +/- 7.7 v 30.2 +/- 2.2 nmol/min x mg Hb, P less than .05, respectively) and throughout exercise. Glutathione reductase (GR) activity was similar between the two groups at rest and was significantly higher (P less than .01) in AMc than EUc during exercise. Plasma lipid peroxidation and catalase activity did not change significantly in response to exercise, nor were they different between AMc and EUc athletes. GPX activity was found to be negatively correlated with E2 (r = -.64, P less than .01) and positively correlated with cortisol (r = .69, P less than .01). It is tentatively concluded that the alteration of hormonal status in amenorrhea has an influence on the blood antioxidant enzyme system.     

Role of catecholamines and beta-receptors in ventilatory response during hypoxic exercise.

The ventilatory response to moderate exercise in hypoxia is potentiated in goats, decreasing PaCO2 more than in normoxic exercise. We investigated the hypothesis that this potentiation results from a ventilatory stimulus provided by increased levels of circulating catecholamines (norepinephrine and/or epinephrine), acting via beta-receptors. Plasma norepinephrine [NE] and epinephrine [E] concentrations, arterial blood gases and ventilation were measured in normoxia and hypoxia (PaO2 = 34-38 Torr) at rest and during moderate exercise (5.6 kph; 5% grade) in seven female goats. PaCO2 decreased from rest to exercise in normoxia (2.9 +/- 0.7 Torr; P less than 0.01), and decreased significantly more from rest during hypoxic exercise (6.4 +/- 0.6 Torr; P less than 0.01). [NE] increased in both normoxic (1.1 +/- 0.4 ng/ml; P less than 0.05) and hypoxic exercise (2.5 +/- 0.5 ng/ml; P less than 0.01); the [NE] increase in hypoxia was significantly greater (P less than 0.01). [E] increased in normoxic (0.3 +/- 0.1 ng/ml; P less than 0.05) but not hypoxic exercise (0.6 +/- 0.5 ng/ml; P greater than 0.2). Experiments were repeated following administration of the beta-adrenergic receptor blocker, propranolol (2 mg/kg, i.v.). After beta-blockade, PaCO2 decreases from rest to exercise in normoxia (3.2 +/- 0.7 Torr; P less than 0.01) and hypoxia (8.1 +/- 0.7 Torr; P less than 0.001) were not significantly different from control. The data indicate that beta-adrenergic receptor stimulation is not necessary for a greater decrease in PaCO2 during hypoxic versus normoxic exercise. The greater rise in [NE] suggests a possible role in ventilatory control during hypoxic exercise, perhaps via alpha-adrenergic receptors. However, recent evidence suggests that NE is inhibitory in goats, and that NE is unlikely to mediate extra ventilatory stimulation during hypoxic exercise.     

Impaired fibrinolytic response to exercise in type II diabetes: effects of exercise and physical training

We studied the effects of exercise and physical training on coagulation parameters and fibrinolytic activity in 16 sedentary non-insulin-dependent diabetics and nine control subjects matched for prior physical activity. Parameters were measured at rest and after 30 minutes of bicycle exercise at 70% to 75% of maximal oxygen uptake before and after 6 weeks of thrice-weekly physical training. In the untrained state, fibrinolytic activity was impaired in diabetics compared with controls (1.26 +/- 0.19 v 2.20 +/- 0.34 U; P less than .03), and resting levels of plasma fibrinogen (329 +/- 21 v 266 +/- 17 mg/dL; P less than .01) and the prothrombin time (PT) maximal velocity (Vmax) (4.9 +/- 0.5 v 2.9 +/- 0.5; P less than .05) were increased. The activated partial thromboplastin time (APTT) Vmax was also increased but this did not reach statistical significance (3.6 +/- 0.2 v 2.3 +/- 0.5; P less than 0.10). Activation of fibrinolysis occurred following exercise in both groups but the peak activity and increment were less in diabetics. Physical training for 6 weeks had no effect on plasma fibrinogen levels but significantly improved the resting and postexercise APTT Vmax and resting fibrinolytic activity in diabetics. The exercise-induced increment in fibrinolytic activity following training remained depressed compared with normal controls. The changes in APTT Vmax correlated with changes in the indices of blood glucose control. The relevance of these findings to possible antiatherogenic effects of exercise and the mechanism by which exercise produces these effects remain to be established.     

Interaction of gut and liver in nitrogen metabolism during exercise.

The role of the gut and liver in nitrogen metabolism was studied during rest, 150 minutes of moderate-intensity treadmill exercise, and 90 minutes of recovery in 18 hour-fasted dogs (n = 6). Dogs underwent surgery 16 days before an experiment for implantation of catheters in a carotid artery and in the portal and hepatic veins, and Doppler flow cuffs on the hepatic artery and portal vein. Arterial glutamine, alanine, and alpha-amino nitrogen (AAN) levels decreased gradually with exercise (P less than .05), while arterial glutamate, NH3, and urea were unchanged. Net gut glutamine uptake was 1.3 +/- 0.5 mumol/kg.min at rest, and increased transiently to 2.5 +/- 0.3 mumol/kg.min at 60 minutes of exercise (P less than .05) as gut extraction increased. Net hepatic glutamine uptake was 0.6 +/- 0.4 mumol/kg.min at rest, and increased to 3.4 +/- 0.6 and 2.6 +/- 0.5 mumol/kg.min after 60 and 150 minutes of exercise (P less than .05) as hepatic extraction increased. Net gut glutamate and NH3 output both increased transiently with exercise (P less than .05). These increases were matched by parallel increments in the net hepatic uptakes of these compounds. Alanine output by the gut and uptake by the liver were unchanged with exercise. Net gut AAN output was -2.1 +/- 1.8 mumol/kg.min at rest (uptake occurred), and increased transiently to 11.2 +/- 3.5 mumol/kg.min after 30 minutes of exercise (P less than .05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Interactions of galanin and arginine on growth hormone, prolactin, and insulin secretion in man.

Galanin (GAL), a 29 amino acid neuropeptide, is known to increase both basal and growth hormone-releasing hormone (GHRH)-induced growth hormone (GH) secretion while not significantly increasing prolactin (PRL) secretion in man. GAL is also endowed with an inhibiting effect on glucose-stimulated insulin release in animals, but not in man. We studied the effect of GAL (80 pmol/kg/min infused over 60 minutes) on the arginine- (ARG, 30 g infused over 30 minutes) stimulated GH, PRL, insulin, and C-peptide secretion in eight healthy volunteers (age, 20 to 30 years). GAL induced an increase of GH (GAL v saline, area under curve [AUC], mean +/- SEM: 316.5 +/- 73.9 v 93.2 +/- 20.9 micrograms/L/h, P less than .05), but failed to modify both PRL and insulin secretion. GAL enhanced the ARG-induced stimulation of both GH (1,634.1 +/- 293.1 v 566.9 +/- 144.0 micrograms/L/h, P less than .02) and PRL secretion (1,541.9 +/- 248.8 v 1,023.8 +/- 158.7 micrograms/L/h, P less than .02). On the contrary, GAL blunted the ARG-stimulated insulin (816.3 +/- 87.7 v 1,322.7 +/- 240.9 mU/L/h, P less than .05), as well as C-peptide secretion (105.1 +/- 9.8 v 132.8 +/- 17.3 micrograms/L/h, P less than .02). ARG administration induced a transient increase of glucose levels (P less than .01 v baseline) followed by a significant decrease (P less than .05 v baseline). This latter effect was prevented by the coadministration of GAL. In conclusion, these results show that in man GAL potentiates the GH response to ARG, suggesting that these drugs act at the hypothalamic level, at least in part, via different mechanisms.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of coronary artery bypass grafting on resting and exercise hemodynamics in patients with stable angina pectoris: a prospective, randomized study.

In this prospective randomized study, resting and exercise hemodynamics were determined in the nonmedicated state before ("entry") and 1 year after coronary bypass surgery in 38 patients, and at entry and 1 year in 40 patients treated medically. The surgical group showed a significant decrease in mean pulmonary arterial wedge pressure during exercise (entry 23.5 +/- 6.1 [standard error of the mean] mm Hg, 1 year 18.9 +/- 1.0, P less than 0.02); an increase in cardiac index during exercise (entry 4.3 +/- 0.1 liter/min per m2, 1 year 4.6 +/- 0.1, P less than 0.05); an increase in resting mean arterial pressure (entry 94.5 +/- 2.2 mm Hg, 1 year 100.2 +/- 2.2, P less than 0.02); and an increase in resting heart rate (entry 68.5 +/- 1.9 beats/min, 1 year: 76.0 +/- 2.0, P less than 0.01). Maximal treadmill exercise performance also improved significantly in the surgical group of patients (entry 285 +/- 24 seconds, 1 year 382 +/- 24, P less than 0.002). There were no significant changes in these variables in the medically treated "control" group. The improvement in pulmonary arterial wedge pressure during exercise and in maximal treadmill exercise time in the surgical group as a whole was due to striking improvement in these variables in a subgroup of 16 surgical patients who had a more than 10 mm Hg increase in pulmonary arterial wedge pressure during exercise in their entry study. In this subgoup, considered to contain those patients with marked "ischemicdysfunction," pulmonary arterial wedge pressure during exercise fell from 31.4 +/- 1.5 mm Hg (entry) to 19.l +/- 1.8 (1 year) (P less than 0.0001) and treadmill time increased from 217 +/- 24 seconds (entry) to 357 +/- 37 (1 year) (P less than 0.001). Thus, hemodynamic evidence of ischemic left ventricular dysfunction during stress may identify those patients who will show objective improvement in ventricular performance after bypass graft surgery.     

Changes in serum hypoxanthine levels by exercise in obese subjects

To study on effect of obesity on changes in serum hypoxanthine with exercise, exercise stress testing with treadmill was performed on 7 obese subjects (body mass index [BMI], 30.6 +/- 3.2 kg/m(2)) and 16 healthy volunteers (BMI, 21.5 +/- 2.10 kg/m(2)). Expiratory gas analysis during exercise showed that peak Vo(2) was significantly lower in the obese group than in the control group (28.1 +/- 4.0 v 37.1 +/- 4.7 mL/kg/min; P <.001). Furthermore, the obese group had lower anaerobic threshold (AT) values (P <.005), respiratory quotient at AT (P =.003), and exercise capacity reserve (P =.002) than the control group. Baseline serum hypoxanthine levels were significantly higher in the obese group than in the control group (3.46 +/- 3.70 v 1.23 +/- 1.16 micromol/L; P <.05). Exercise induced a pronounced increase in serum hypoxanthine level in the obese group compared with the control group (10.65 +/- 6.81 v 43.86 +/- 4.56 micromol/L; P <.01). Serum levels of uric acid before and after load were also higher in the obese group than in the control group (404 +/- 43 v 302 +/- 77 micromol/L; P <.005). A pronounced increase in hypoxanthine with exercise may result in organ damage caused by free radicals, and intermittent training from mild intensity may be less hazardous for exercise treatment of obesity.     

Hyperinsulinemia in the physiologic range is not superior to short-term fasting in suppressing insulin secretion in obese men

The negative-feedback control exerted by plasma insulin on beta-cell insulin release in normal-weight and obese subjects is still a matter of debate. Subjects submitted to a euglycemic insulin clamp undergo a suppression of insulin secretion that is due to both the infused insulin and the 2- to 3-hour fast during the procedure. We elected to elucidate the role of physiologic hyperinsulinemia per se in the insulin negative autofeedback in obese men. Ten men with massive uncomplicated obesity (age, 18 to 37 years; body mass index [BMI], 41 +/- 1.15 kg/m2) and 6 normal-weight healthy men (age, 22 to 30 years; BMI, 22 +/- 0.28 kg/m2) underwent 2 studies in random order: (1) a euglycemic-hyperinsulinemic glucose clamp with an insulin infusion rate of 1 mU/kg/min and (2) a control study with saline infusion. Serum C-peptide concentrations were significantly higher in obese versus control subjects at baseline (2.54 +/- 0.178 v 1.63 +/- 0.256 ng/mL, P < .05). Exogenous insulin infusion significantly suppressed serum C-peptide at steady state ([SS] last 30 minutes of insulin or saline infusion) in controls (mean of the last 4 measurements from 120 minutes to 150 minutes, 0.86 +/- 0.306 ng/mL, P < .05 vbaseline) but not in obese patients (2.03 +/- 0.26 ng/mL, nonsignificant [NS] v baseline). During the saline infusion studies, C-peptide levels slightly and similarly declined over time in both groups (2.71 +/- 0.350 at baseline v 2.31 +/- 0.300 ng/mL at SS in obese patients, NS, and 1.96 +/- 0.189 v 1.62 +/- 0.150 ng/mL in controls, NS). This study shows that in obese men hyperinsulinemia within the postprandial range is not superior to a 2.5-hour fast for the suppression of beta-cell activity, suggesting an impairment of the insulin negative autofeedback in this clinical condition.     

Increased lung water and ascites after massive cocaine overdosage in mice and improved survival related to beta-adrenergic blockage

STUDY OBJECTIVE: To determine the effect of massive cocaine intoxication on lung water and ascites accumulation and the effect of beta- and alpha-adrenergic blockade on survival in massive cocaine intoxication in the mouse. DESIGN: The effect of massive cocaine intoxication on lung water, ascitic fluid accumulation, and survival following LD 100 doses of intravenous cocaine with and without alpha- and beta-adrenergic blockade was determined. INTERVENTIONS: Cocaine hydrochloride (0.15 mg/g body weight) was administered intravenously with no other interventions; with propranolol hydrochloride intravenously (0.5 mg per mouse) before and after cocaine; and with phentolamine intravenously (10.5 micrograms per mouse) before cocaine. MEASUREMENTS AND MAIN RESULTS: Intravenous cocaine hydrochloride resulted in an increase in lung water (saline controls, 4.17 +/- 1.3 [standard deviation] mg water per g mouse; cocaine hydrochloride, 5.94 +/- 0.9 mg water per g mouse; P less than 0.002). Cocaine hydrochloride always resulted in the accumulation of transudative ascitic fluid (saline controls, no measurable ascitic fluid; cocaine administration, 20.2 +/- 12.9 micrograms per mouse; ascitic fluid protein concentration, 23.5 +/- 8.5 g/L). Propranolol hydrochloride administered before or after intravenous cocaine hydrochloride resulted in a striking reduction in mortality (84 of 84 mice without propranolol died [mortality = 100%]; 7 of 39 mice with propranolol died [mortality = 18%]; P less than 0.001). CONCLUSIONS: Massive cocaine intoxication is associated with increased lung water and transudative ascites. Fluid accumulation is not prevented by either alpha- or beta-adrenergic blockers. Propranolol, administered either before or after cocaine, sharply reduces mortality. The results should be extrapolated to treatment in humans with caution.     

Effects of moderate and high glycemic index meals on metabolism and exercise performance.

The purpose of this study was to determine whether pre-exercise ingestion of meals with moderate and high glycemic indexes (GI) affects glucose availability during exercise and exercise performance time. Six male volunteers (22 +/- 1 years; 80.4 +/- 3.7 kg; VO(2peak), 54.3 +/- 1.2 ml. kg(-1). min(-1)) ingested 75 g of carbohydrate in the form of 2 different breakfast cereals, rolled oats (moderate GI, approximately 61; MOD-GI) or puffed rice (high GI, approximately 82; HI-GI), combined with 300 mL of water; or water alone (control). The trials were randomized, and the meals were ingested 45 minutes before the subjects performed cycling exercise (60% VO(2peak)) to exhaustion. Venous blood samples were drawn to measure glucose, free fatty acids (FFAs), glycerol, insulin (INS), epinephrine (EPI) and norepinephrine (NE) concentrations. A muscle biopsy specimen was obtained from the vastus lateralis before the meal and immediately after exercise for glycogen determination. Before exercise, both test meals elicited significant (P <.05) hyperglycemia and hyperinsulinemia compared with control. The glycemic response was higher (P <.05) at the start of exercise after the HI-GI meal than after the control. During exercise, plasma glucose levels were higher (P <.05) at 60 (5.2 +/- 0.1, 4.2 +/- 0.2, and 4.6 +/- 0.1 mmol. L(-1)) and 90 (4.8 +/- 0.1, 4.1 +/- 0.1, and 4.3 +/- 0.1 mmol. L(-1)) minutes after the MOD-GI meal than after either the HI-GI or control. Total carbohydrate oxidation was greater (P <.05) during the MOD-GI trial than in control and was directly correlated with exercise performance time (r =.95, P <.0001). Pre-exercise plasma FFA levels were suppressed (P <.05) 30 and 45 minutes after ingestion of the HI-GI meal and 45 minutes after the MOD-GI meal compared with control. At 30, 60, and 120 minutes of exercise, FFAs remained suppressed (P <.05) for both test meals compared with control. At exhaustion, plasma glucose, INS, FFA, glycerol, EPI, and NE levels and muscle glycogen use were not different for all trials. Exercise time was prolonged (P <.05) after the MOD-GI meal compared with control, but the HI-GI trial was not different from control (MOD-GI, 165 +/- 11; HI-GI, 141 +/- 8; control, 134 +/- 13 minutes). Thus, in contrast to the HI-GI meal or control, the MOD-GI breakfast cereal ingested 45 minutes before exercise enhanced performance time, maintained euglycemia for a longer period during exercise, and resulted in greater total carbohydrate oxidation during the exercise bout. We conclude that a MOD-GI meal provides a significant performance and metabolic advantage when consumed 45 minutes before exercise.     

Value of the Bruce protocol to determine peak exercise oxygen consumption in patients evaluated for cardiac transplantation

BACKGROUND: Peak exercise oxygen consumption (peak VO2) is an important discriminator of survival in patients with systolic heart failure and is used to select ambulatory patients for transplantation. The major trials assessing the relationship between peak VO2 and survival have used a variety of low-level exercise protocols. It is unknown how peak VO2 measured in this patient population by the more vigorous Bruce treadmill protocol compares with that obtained on less intense protocols. METHODS: We studied 15 patients (50 +/- 12 years old) with severe heart failure (left ventricular ejection fraction 23.5% +/- 8.6%). Patients randomly performed 3 exercise tests with the Bruce treadmill, modified Naughton treadmill, and modified bicycle protocols within 14 days. To determine the ability of this patient population to perform the Bruce protocol, we also retrospectively analyzed the ability of 84 patients to perform this test on their initial evaluations at our center. RESULTS: All patients reached the anaerobic threshold (AT) on all 3 protocols. The Bruce and modified Naughton treadmill protocols resulted in similar peak VO2 percent predicted peak VO2, and VO2 at AT values (17.7 +/- 3.8 mL/kg/min, 57.2% +/- 21.1% and 15.4 +/- 4.1 mL/kg/min vs 18.0 +/- 4.7 mL/kg/min, 58.1% +/- 22.5% and 15.6 +/- 4.4 mL/kg/min, respectively). Peak VO2 and VO2 at AT on both treadmill protocols were higher than those obtained with bicycle testing (15.3 +/- 3.1 and 11.8 +/- 3.0 mL/kg/min, P <.05). Exercise duration was shorter with the Bruce and bicycle protocols (6.2 +/- 2.2 and 6.7 +/- 2.4 minutes, respectively) compared with the modified Naughton protocol (9.7 +/- 4.3 minutes, both P <.005). In addition, 79 of the 84 patients (94%) evaluated were able to complete the Bruce protocol and reach AT. CONCLUSIONS: The Bruce protocol was more time efficient than the modified Naughton protocol and yielded similar peak VO2, percent predicted peak VO2, and VO2 at AT values. Bicycle exercise may underestimate peak VO2 values. The form of exercise should be considered when assessing peak VO2 criteria for transplant listing.     

Serotoninergic receptor activation by dextrofenfluramine enhances the blunted pituitary-adrenal responsiveness to corticotropin-releasing hormone in obese subjects.

To explore the interrelationships between the serotoninergic system and the hypothalamic-pituitary-adrenal (HPA) axis in human obesity, we evaluated cortisol and adrenocorticotropic hormone (ACTH) response to synthetic human corticotropin-releasing hormone (hCRH, 1 microgram/kg intravenously [IV]) before and after stimulation of the serotoninergic system by dextrofenfluramine (d-FF, 30 mg/d for 3 months) in nine obese women. These responses were compared with a CRH test (1 microgram/kg) carried out in nine age-matched normal-weight women. Plasma cortisol of obese subjects did not significantly increase after CRH (peak value 127.1 +/- 11.2 ng/mL v 104.1 +/- 9.5 ng/mL). This response was lower (P less than .005) than in the controls, in whom the basal cortisol value of 120.6 +/- 11.8 ng/mL reached a peak value of 221.2 +/- 13.4 ng/mL. However, after administration of d-FF, CRH significantly increased (P less than .0001) plasma cortisol (peak value 170.6 +/- 18.0 ng/mL v 111.5 +/- 10.8 ng/mL) and the response was enhanced (P less than .05) as compared with that obtained before d-FF. The ACTH levels of our patients showed a small increment after CRH injection (peak value 13.5 +/- 1.7 pg/mL v 9.6 +/- 1.1 pg/mL), but the hormonal response was lower (P less than .005) than in controls (peak value 38.1 +/- 5.5 pg/mL v 13.8 +/- 0.8 pg/mL). However, after d-FF, CRH induced a significant increment (P less than .05) in plasma ACTH at 30 minutes (20.4 +/- 3.7 pg/mL v 10.9 +/- 0.9 pg/mL) and 45 minutes (18.0 +/- 2.6 pg/mL), even though this response was not significantly different from that observed before d-FF administration.(ABSTRACT TRUNCATED AT 250 WORDS)     

Exaggerated cardiovascular effects of cocaine in conscious dogs with pacing-induced dilated cardiomyopathy

BACKGROUND: The aim of this study was to explore the characteristics and mechanisms of the cardiovascular effects of cocaine in dilated cardiomyopathy. METHODS AND RESULTS: We studied the cardiovascular responses to acute intravenous cocaine (1 mg/kg) in 8 conscious, chronically instrumented dogs before and after the development of dilated cardiomyopathy induced by rapid ventricular pacing. To help elucidate the role of altered baroreflex function in mediating the cardiovascular effects of cocaine, we also studied responses in 3 conscious, chronically instrumented dogs that had undergone surgical sinoaortic baroreceptor denervation. Cocaine produced greater increases in heart rate (+57 +/- 8% from 112 +/- 5 beats/min versus +28 +/- 3% from 100 +/- 4 beats/min; P <.01), first derivative of left ventricular pressure (+30 +/- 5% from 1,714 +/- 147 mm Hg/sec versus +15 +/- 3% from 3,032 +/- 199 mm Hg/sec; P <.01), coronary vascular resistance (+28 +/- 5% from 2.3 +/- 0.3 mm Hg/mL/min versus +11 +/- 5% from 2.2 +/- 0.3 mm Hg/mL/min; P <.05) and plasma norepinephrine concentration (+130 +/- 31% from 462 +/- 102 pg/mL versus +86 +/- 32% from 286 +/- 77 pg/mL; P <.05) in dogs with dilated cardiomyopathy as compared to controls. In addition, responses were much more rapid in onset following the development of dilated cardiomyopathy. Chronotropic and inotropic responses to cocaine were similarly rapid and exaggerated in dogs after baroreceptor denervation. CONCLUSIONS: Cocaine produces rapid and exaggerated chronotropic, inotropic, and coronary vasoconstrictor responses in conscious dogs with pacing-induced dilated cardiomyopathy. Alterations in arterial baroreflex function may play a role in these observations, which in turn may underlie the clinically observed association between cocaine and heart failure.     

Alcohol and postexercise metabolic responses in type 2 diabetes.

The objective was to investigate the impact of the combination of exercise and alcohol on the metabolic response in nonfasting and fasting type 2 diabetic subjects. In part 1, 12 untrained middle-aged type 2 diabetic subjects participated on 3 test days. On each day, they ingested a light meal (1,824 kJ) containing 48 energy percent (E%) carbohydrate, 38 E% fat, and 14 E% protein. The meal was followed by either (A) rest or (B) 30 minutes of exercise (40% of maximum O2 consumption [VO2max]) or (C) taken with alcohol (0.4 g/kg body weight) followed by 30 minutes of exercise (40% of VO2max). In part 2, 11 untrained middle-aged type 2 diabetic subjects participated on 4 test days without a meal. The subjects were either (A) resting, (B) drinking alcohol (0.4 g/kg body weight), (C) exercising 30 minutes (40% of VO2max), or (D) drinking alcohol (0.4 g/kg body weight) and exercising 30 minutes (40% of VO2max). On each test day, regular blood samples were drawn for 4 hours for analysis of glucose, insulin, lactate, triglycerides, nonesterified fatty acid (NEFA), and ethanol. Comparing exercise and rest following a light meal (part 1, no change (7%) occurred in the plasma glucose response area (642 +/- 119 v 724 +/- 109 mmol x L(-1) x 240 min, NS). However, it was significantly reduced (by 27%) in response to exercise and alcohol (509 +/- 98 v 724 +/- 109 mmol x L(-1) x 240 min; P = .03). Similar serum insulin response areas were obtained. After exercise and alcohol, plasma lactate increased compared with the resting state (2.2 +/- 0.2 v 1.6 +/- 0.1 mmol x L(-1), P = .004) and with exercise alone (2.2 +/- 0.2 v 1.8 +/- 0.2 mmol x L(-1), P = .04). Serum NEFAs were significantly reduced by exercise and alcohol compared with the resting state (0.50 +/- 0.04 v 0.65 +/- 0.06 mmol x L(-1), P = .008) and with exercise alone (0.50 +/- 0.04 v 0.61 +/- 0.05 mmol x L(-1), P = .02). Similar serum triglycerides were found. During the fasting state (part 2), similar plasma glucose response areas were obtained in the four situations. The insulin response area to exercise and alcohol increased significantly compared with the resting state (3,325 +/- 744 v 882 +/- 295 pmol x L(-1) x 240 min, P = .02) and with exercise alone (3,325 +/- 744 v 1,328 +/- 422 pmol x L(-1) x 240 min, P = .007). No difference was found compared with alcohol alone. Plasma lactate was higher after alcohol intake versus the resting state (1.9 +/- 0.1 v 1.3 +/- 0.1 mmol x L(-1), P = .003), as well as after exercise and alcohol (1.9 +/- 0.1 v 1.3 +/- 0.1 mmol x L(-1), P = .01). After exercise and alcohol serum NEFAs were significantly reduced compared with the resting state (0.43 +/- 0.02 v 0.64 +/- 0.02 mmol x L(-1), P < .001), alcohol alone (0.43 +/- 0.02 v 0.51 +/- 0.02 mmol x L(-1), P < .001), and exercise alone (0.43 +/- 0.02 v 0.64 +/- 0.02 mmol x L(-1), P < .001). Serum triglycerides were similar in the four situations. We conclude that moderate exercise with or without moderate alcohol intake does not cause acute hypoglycemia either after a light meal or in the fasting state in untrained overweight type 2 diabetic subjects.     

Effect of beta-adrenergic blockade on circulating catecholamines and dopamine-beta-hydroxylase activity during exercise in normal subjects

We investigated the effects of beta-adrenergic blockade with propranolol (P) on circulating catecholamines at rest and during isometric and dynamic exercise. By means of a radioenzymatic assay, we measured plasma norepinephrine (NE) and epinephrine (E) concentrations in nine normal, sedentary men, aged 22 to 34 years. Measurements were made during resting conditions, at 3 minutes of 30% maximal isometric handgrip exercise (IHE), and during submaximal and maximal dynamic treadmill exercise. Measurements were repeated one week later after the subjects received P in doses ranging from 40 to 80 mg four times a day (plasma P levels at the time of exercise ranged from 96 to 303 ng/ml with a mean of 178 ng/ml). We also measured serum dopamine-beta-hydroxylase (DBH) activity to detect changes in chronic sympathetic tone. Changes in NE from rest to exercise were significant (p less than 0.01) at all exercise loads with or without P. Changes in E from rest to exercise were significant (p less than 0.01) at all exercise loads with or without P except for submaximal dynamic exercise during the control study (p greater than 0.05). For NE, there were no significant differences between the control and P values either at rest or during any form of exercise. For E, there were no significant changes between the control and p values at rest or at maximal dynamic exercise, although there were mild increases (p less than 0.05) with IHE and submaximal dynamic exercise. DBH activity increased significantly (p less than 0.01) from rest to exercise for all exercise points with and without P, but there were no significant differences between the control and p values either at rest or during any form of exercise. In conclusion, we have demonstrated that competitive blockade of beta-adrenergic receptors at the tissue level does not alter neural release of NE or DBH and has little effect on adrenal release of E.     

Effects of dietary composition and exercise timing on substrate utilization and sympathoadrenal function in healthy young women

The effects of dietary composition (high-fat [FAT] or high-carbohydrate [CHO]) and exercise timing (preprandial exercise [Ex-] or postprandial exercise [-Ex]) on postprandial substrate utilization and sympathoadrenal function were studied in seven women aged 20 to 21 years. The experimental protocol included four different sessions (Ex-FAT, FAT-Ex, Ex-CHO, and CHO-Ex). The FAT and CHO diets provided 48% and 5% fat, respectively. On the experimental days, subjects ate a meal containing the same caloric energy at lunchtime, and they exercised for 30 minutes on a bicycle ergometer at an intensity of 60% maximal oxygen consumption (VO2max) before and after the meal, followed by rest for 3 hours. The resting respiratory quotient (RQ) was significantly lower (P < .05) with the FAT diet or postprandial exercise. The mean RQ during the experimental period was 0.78, 0.75, 0.81, and 0.77 in Ex-FAT, FAT-Ex, Ex-CHO, and CHO-Ex groups, respectively. The total area under the curve of serum norepinephrine (NE) as an index of NE secretion was significantly higher (P < .05) with the FAT diet or postprandial exercise (130.2, 175.8, 33.0, and 136.9 ng x mL(-1) x min, respectively). A negative correlation was observed between the RQ and the total area of NE (r = .49, P < .05). The serum thyroid hormone level was not influenced by dietary composition and exercise timing. These results suggest that postprandial exercise, especially after intake of a FAT diet, increases fat utilization via a slightly larger decrease in the RQ. This might be related to the sympathoadrenal system at rest and during exercise.     

Hepatic and gut clearance of catecholamines in the conscious dog

Our aim was to assess hepatic and gut catecholamine clearance under normal and simulated stress conditions. Following a 90-minute saline infusion period, epinephrine ([EPI] 180 ng/kg x min) and norepinephrine ([NE] 500 ng/kg x min) were infused peripherally for 90 minutes into five 18-hour fasted, conscious dogs undergoing a pancreatic clamp (somatostatin plus basal insulin and glucagon). Arterial plasma levels of EPI and NE increased from 44 +/- 9 to 2,961 +/- 445 and 96 +/- 6 to 6,467 +/- 571 pg/mL, respectively (both P < .05). Portal vein plasma levels of EPI and NE increased from 23 +/- 8 to 1,311 +/- 173 and 79 +/- 10 to 3,477 +/- 380 pg/mL, respectively (both P < .05). Hepatic vein plasma levels of EPI and NE increased from 5 +/- 2 to 117 +/- 33 and 48 +/- 10 to 448 +/- 59 pg/mL, respectively (both P < .05). Net hepatic and gut EPI uptake increased from 0.5 +/- 0.1 to 30.0 +/- 3.0 and 0.4 +/- 0.1 to 26.3 +/- 4.0 ng/kg x min, respectively (both P < .05). Net hepatic and gut NE uptake increased from 1.5 +/- 0.4 to 74.7 +/- 8.4 and 0.8 +/- 0.2 to 57.9 +/- 7.6 ng/kg x min, respectively (both P < .05). Neither the net hepatic (0.86 +/- 0.05 to 0.93 +/- 0.02) nor gut (0.45 +/- 0.10 to 0.55 +/- 0.04) fractional extraction of EPI changed significantly during the simulated stress condition. Net hepatic and gut spillover of NE increased from 0.8 +/- 0.2 to 3.5 +/- 1.3 and 0.6 +/- 0.2 to 8.8 +/- 2.0 ng/kg x min, respectively, during catecholamine infusion (both P < .05). These results indicate that (1) approximately 30% of circulating catecholamines are cleared by the splanchnic bed (16% and 14% by the liver and gut, respectively); (2) the liver and gut remove a large proportion (approximately 86% to 93% and 45% to 55%, respectively) of the catecholamines delivered to them on first pass; and (3) high levels of plasma catecholamines increase NE spillover from both the liver and gut, suggesting that the percentage of NE released from the presynaptic neuron that escapes the synaptic cleft is increased in the presence of high circulating catecholamine levels.     

Effects of aerobic training on exercise tolerance and echocardiographic dimensions in untrained postmenopausal women

The cardiovascular effects of physical training were evaluated in a controlled trial involving 32 healthy, untrained, postmenopausal women. The subjects were randomly assigned to an aerobic exercise training program or a control group. The exercise group participated in at least three 40-minute supervised sessions per week for 8 months. Twenty-five subjects completed the study: eight in the control group and 17 in the training group. The training group had a significant increase over the training period in maximal oxygen consumption (27.3 +/- 4.6 ml/kg/min vs 30.8 +/- 5.4 ml/kg/min, p less than 0.05) and maximal treadmill exercise duration (9.8 +/- 2.6 minutes vs 11.3 +/- 2.2 minutes; p less than 0.05). The control group had no significant change in maximal treadmill exercise duration (9.0 +/- 1.2 minutes vs 9.2 +/- 1.4 minutes) but had a slight increase in maximal oxygen consumption (23.7 +/- 3.4 ml/kg/min vs 24.4 +/- 4.1 ml/kg/min, p less than 0.05). The training group had significant increases in M-mode echocardiographic left ventricular end-diastolic dimension (4.6 +/- 0.6 cm vs 4.8 +/- 0.4 cm, p less than 0.05) and calculated left ventricular ejection fraction (0.66 +/- 0.14 vs 0.74 +/- 0.12, p less than 0.05). M-mode echocardiograms demonstrated no significant change in left ventricular dimensions or wall thickness in the control group. In this group of untrained postmenopausal women, a training effect was associated with enhanced resting left ventricular ejection fraction and increased resting left ventricular end-diastolic dimension.