Arterial Epinephrine Research Articles

A single, acute bout of yogic breathing reduces arterial catecholamines and cortisol

Yoga is thought to reduce stress; however, few studies have quantified plasma levels of stress hormones. Yoga includes physical postures, meditation, and pranayama (controlled breathing) therefore it is difficult to determine which dose and combination of these components is most beneficial. We hypothesized that a single 15 min bout of 6 breaths per minute would be sufficient to cause a reduction in stress hormones. Ten young healthy males (age 18–35, n=10) were instrumented with brachial arterial catheter for blood draws and respiration was monitored continuously using a double pneumobelt. Blood draws were taken after 15 min of supine rest with baseline ventilation and again after 15 min of slow paced breathing. Average baseline supine respiratory rate was 12.1 ± 0.5 breaths/min and during slow breathing it was 5.5 ± 0.4 breaths/min (p<0.05). After 15 min of slow breathing in the supine position there was a significant reduction in arterial norepinephrine (173.9 ± 15.5 vs 135.6 ± 42.9, p=0.002), cortisol (8.2 ± 0.7 vs 7.3 ± 0.59, p=0.002), and adrenocorticotrophic hormone (ACTH, 15.5 ± 2.4 vs 13.4 ± 2.2, p=0.009). As well, there was a trend for reduction in arterial epinephrine (82 ±28.2 vs 42.7 ± 9.7, p=0.15). These changes are consistent with a reduction in sympathetic nerve activity and a blunting of cortisol. In summary, acute yogic breathing significantly reduces stress hormones.

Activated plasma coagulation β-Factor XII-induced vasoconstriction in rats

By inducing BK (bradykinin)-stimulated adrenomedullary catecholamine release, bolus injection of the β-fragment of activated plasma coagulation Factor XII (β-FXIIa) transiently elevates BP (blood pressure) and HR (heart rate) of anaesthetized, vagotomized, ganglion-blocked, captopril-treated bioassay rats. We hypothesized that intravenous infusion of β-FXIIa into intact untreated rats would elicit a qualitatively similar vasoconstrictor response. BN (Brown Norway) rats received for 60 min either: (i) saline (control; n=10); (ii) β-FXIIa (85 ng/min per kg of body weight; n=9); or (iii) β-FXIIa after 2ADX (bilateral adrenalectomy; n=9). LV (left ventricular) volume and aortic BP were recorded before (30 min baseline), during (60 min) and after (30 min recovery) the infusion. TPR (total peripheral resistance) was derived from MAP (mean arterial pressure), SV (stroke volume) and HR. Saline had no haemodynamic effects. β-FXIIa infusion increased its plasma concentration 3-fold in both groups. In adrenally intact rats, β-FXIIa infusion increased MAP by 6% (5±2 mmHg) and TPR by 45% (0.50±0.12 mmHg/ml per min), despite falls in SV (−38±8 μl) and HR [−18±5 b.p.m. (beats/min)] (all P<0.05). In 2ADX rats, β-FXIIa had no HR effect, but decreased SV (−89±9 μl) and MAP (−4±1 mmHg), and increased TPR by 66% (0.59±0.15 mmHg/ml per min) (all P<0.05). After infusion, adrenally intact rats exhibited persistent vasoconstriction (MAP, 10±1 mmHg; TPR, 0.55±0.07 mmHg/ml per min; both P<0.05), whereas in 2ADX rats, MAP remained 5±1 mmHg below baseline (P<0.05) and TPR returned to baseline. End-study arterial adrenaline (epinephrine) concentrations in the three groups were 1.9±0.6, 9.8±4.1 and 0.6±0.2 nmol/l respectively. Thus, in neurally intact lightly anaesthetized untreated rats, β-FXIIa infusion induces both adrenal catecholamine-mediated and adrenally independent increases in peripheral resistance.

Influence of plaque volume on hemodynamic response and stress hormone release in patients undergoing carotid artery stenting.

Carotid artery stenting (CAS) may cause bradycardia and hypotension due to barostimulation. The impact of periprocedural hypotension on CAS outcome remains controversial. The role of carotid plaque volume and catecholamine hormone release during CAS on hemodynamic changes has not been investigated so far. The aim of this prospective study was to evaluate if carotid artery plaque characteristics are predictive for stress hormone release or for postprocedural hemodynamic instability. In 26 patients undergoing CAS, carotid plaque volume and morphology were assessed by two- and three-dimensional (3D)-Duplex sonography prior to the procedure. Arterial plasma adrenaline, noradrenaline and renin concentrations were measured at the time of sheath insertion and 5 minutes after stent placement. ECG, heart rate, and invasive blood pressure were monitored throughout the procedure. CAS caused no significant changes in hormone release, but increasing plaque volume was related to the degree of bradycardia following stent deployment (r=0.57; P=0.01). Plaque size was not associated with postprocedural hypotension. Plaque echogenicity (echolucent, heterogeneous or echogenic) did not correlate with changes in systolic blood pressure, heart rate or catecholamine hormone release. CAS caused bradycardia in relation to plaque size, but did not cause catecholamine release which may indicate that the endovascular procedure is not associated with a relevant stress reaction.

The effect of amino-acid infusion during off-pump coronary arterial bypass surgery on thermogenic and hormonal regulation

Amino-acid (AA) infusions promote thermogenesis and prevent perioperative hypothermia, but the mechanism of action is unknown. We sought to verify the hypothesis that AA infusions stimulate the release of metabolic hormones during surgery and increase energy expenditure, resulting in thermogenesis. Twenty-four patients were randomly assigned to receive AA (4 kJ x kg(-1) x h(-1)) or saline, which was infused for 2 h during off-pump coronary artery bypass surgery (OPCABS). Arterial adrenaline, thyroid hormone, insulin, and leptin levels were determined at five defined times during surgery. Oxygen consumption was measured 3 h after the start of infusion. AA infusion maintained the body core temperature during OPCABS. This effect was accompanied by an increase in oxygen consumption, which depended on increased heart rate. AA infusion prominently stimulated the secretion of insulin and leptin; the insulin level increased rapidly within 2 h after the start of infusion, whereas leptin levels increased gradually over a 6-h period after the start of infusion. AA infusion significantly increased body core temperature and oxygen consumption during surgery. Given the release of insulin and leptin in response to AA infusion, it is likely that these hormonal signaling pathways may, in part, have contributed to the thermogenic response that occurred during the surgery.

Selective Stimulation of Autonomic Nerves and Recording of Electroneurograms in a Canine Model

The article presents the results of modeling, design, and experimental testing of a multielectrode spiral cuff (CUFF) to determine to what extent a CUFF could be used for selective stimulation of different types of nerve fibers within particular compartments and for selective recording of electoneurograms (ENGs) from particular compartments of the peripheral autonomic nerve. The CUFF was implanted on the left cervical vagus nerve (LVN) of a dog. The relative positions of the particular nerve regions that innervated the cardiovascular (CV) and respiratory system (RS) were identified by delivering the stimuli to the particular group of three electrodes (GTE). The stimuli caused both selective stimulation of mainly B fibers within the particular compartments, and differential block of A fibers by membrane hyperpolarization. It was shown that when the stimuli were delivered to GTE9, the heart rate began to fall and when the stimuli were delivered to GTE4, the rate of breathing decreased. The defined and randomly chosen GTEs were used also as recording GTEs while CV or RS were stimulated by carotid artery massage, epinephrine injection, and noninvasive positive end-expiratory pressure ventilation (NIPEEPV). Results demonstrate that the function of a particular internal organ can be modulated via the selective stimulation of the innervating compartment of the peripheral nerve. Results also showed that stimulations elicited site-specific changes in ENG power spectra recorded from the particular compartments of the LVN.

Exercise intensity‐dependent contribution of β‐adrenergic receptor‐mediated vasodilatation in hypoxic humans

We previously reported that hypoxia-mediated reductions in alpha-adrenoceptor sensitivity do not explain the augmented vasodilatation during hypoxic exercise, suggesting an enhanced vasodilator signal. We hypothesized that beta-adrenoceptor activation contributes to augmented hypoxic exercise vasodilatation. Fourteen subjects (age: 29 +/- 2 years) breathed hypoxic gas to titrate arterial O(2) saturation (pulse oximetry) to 80%, while remaining normocapnic via a rebreath system. Brachial artery and antecubital vein catheters were placed in the exercising arm. Under normoxic and hypoxic conditions, baseline and incremental forearm exercise (10% and 20% of maximum) was performed during control (saline), alpha-adrenoceptor inhibition (phentolamine), and combined alpha- and beta-adrenoceptor inhibition (phentolomine/propranolol). Forearm blood flow (FBF), heart rate, blood pressure, minute ventilation, and end-tidal CO(2) were determined. Hypoxia increased heart rate (P < 0.05) and minute ventilation (P < 0.05) at rest and exercise under all drug infusions, whereas mean arterial pressure was unchanged. Arterial adrenaline (P < 0.05) and venous noradrenaline (P < 0.05) were higher with hypoxia during all drug infusions. The change (Delta) in FBF during 10% hypoxic exercise was greater with phentolamine (Delta306 +/- 43 ml min(-1)) vs. saline (Delta169 +/- 30 ml min(-1)) or combined phentolamine/propranolol (Delta213 +/- 25 ml min(-1); P < 0.05 for both). During 20% hypoxic exercise, DeltaFBF was greater with phentalomine (Delta466 +/- 57 ml min(-1); P < 0.05) vs. saline (Delta346 +/- 40 ml min(-1)) but was similar to combined phentolamine/propranolol (Delta450 +/- 43 ml min(-1)). Thus, in the absence of overlying vasoconstriction, the contribution of beta-adrenergic mechanisms to the augmented hypoxic vasodilatation is dependent on exercise intensity.

Do screening blood pressure and plasma catecholamines predict development of hypertension? Twenty‐year follow‐up of middle‐aged men

Objectives. The sympathetic nervous system is implicated in the development and maintenance of hypertension. However, the predictive impact of arterial plasma catecholamines has never been reported. We investigated arterial catecholamines and blood pressures (BPs) prospectively over 20 years in a group of well‐characterized middle‐aged men. Methods. Fifty‐six of original 79 men were available for the follow‐up. Multiple regression analysis was done with mean BP at follow‐up as a dependent variable, and arterial plasma catecholamines and BP at baseline as independent variables. Results. Half of the originally normotensive men developed hypertension during follow‐up. There were significant differences in the screening BP values measured at baseline between the new hypertensives and the sustained normotensives. Multiple regression analysis revealed arterial adrenaline at baseline as an independent predictor of mean BP at follow‐up in the new hypertensives (β = 0.646, R2 = 0.42, p = 0.007). Furthermore, arterial noradrenaline at baseline was a negative independent predictor of mean BP at follow‐up in the sustained normotensives (β = −0.578, R2 = 0.334, p = 0.020). Noradrenaline increased with age in the group as a whole (1318±373 vs 1534±505 pmol/l, p = 0.010) while adrenaline did not change. Conclusion. Our data suggest that arterial adrenaline is involved in the development of hypertension over 20 years in middle‐aged men. Men with sustained normotension may have an inherent protection against sympathetic overactivity. Furthermore, screening BP at baseline in normotensive men differentiated between those who developed hypertension and those who remained normotensive at follow‐up.

Epinephrine-infused CTHA for HCCs

Changes in the relative arterial flow to hepatocellular carcinomas and adjacent normal liver with hepatic arterial epinephrine infusion were studied with CT hepatic arteriography (CTHA). Data from 31 pathologically confirmed hepatocellular carcinomas were retrospectively analyzed in 16 patients who simultaneously underwent CT during arterial portography (CTAP) and CTHA for examination of liver tumors and then CTHA with hepatic arterial epinephrine infusion. Regarding visual analysis, tumor enhancement of hepatocellular carcinomas on CTHA after hepatic arterial epinephrine injection changed as follows: more clear in 83.9% (26/31), equal in 16.1% (5/31), and less clear in 0% (0/31). As for the quantitative analysis, CT attenuation value of hepatocellular carcinomas significantly increased after injection of epinephrine (mean increase from 225.8 to 333.9 HU; P < 0.0001, paired t test). The CT attenuation value of normal liver parenchyma around a tumor significantly decreased after injection of epinephrine (mean decrease from 101.1 to 84.6 HU; P < 0.0001, paired t test). The tumor-to-liver conspicuity significantly increased after injection of epinephrine (mean increase from 124.6 to 249.2 HU; P < 0.0001, paired t test). Hepatic arterial epinephrine infusion changes the relative arterial flow of hepatocellular carcinomas.

Head up tilt screening in healthy non‐fainters: relationships with other measures of autonomic function?

Head up tilt (HUT) is a meaningful diagnostic tool for baroreflex dysfunction or autonomic failure. We sought to determine if baroreflex sensitivity (BRS), the rise in plasma catecholamines, or 24-hr ambulatory HR variability (HRV) would correlate with HR and BP during HUT. We performed 60° HUT for 5 min followed by 2 modified Oxford trials in 46 young healthy males and females. Blood pressure (brachial artery) and HR (ECG) were recorded, while arterial epinephrine (Epi) and norepinephrine (NE) were assayed during the final 30 s of HUT. HUT increased HR (mean ± SD: 63 ± 9 to 79 ± 12), MAP (89 ± 7 to 93 ± 8), Epi (28 ± 13 to 61 ± 45), and NE (111 ± 57 to 242 ± 85) (p< 0.05 for all). Individuals with a high 24-hr HRV had a greater increase in HR during HUT (r= 0.41, P<0.05). Interestingly, a negative correlation was observed between BRS and the NE response to HUT (r= −0.36, p<0.05), such that individuals with low NE response to tilt also had a high BRS. The Epi response was not correlated with any of the measures. These findings suggest that subjects with high vagal activity (high BRS) require a lower sympathetic response (NE) to maintain BP during orthostatic stress. Supported by: K23 RR17520, HL 46493, K12 RR023263-03

Systemic and Myocardial Oxygen Transport Responses to Brain Death in Pigs

Background Brain death is associated with profound disturbances of systemic and myocardial oxygen transport, but little is known regarding the acute response of systemic oxygen consumption (VO 2). Methods Brain death was induced in 6 pigs (30.6 ± 3.0 kg) by balloon inflation into the cranial cavity. VO 2 was continuously measured by respiratory mass spectrometry. Blood pressures and gases were measured from the aorta, superior vena cava, and coronary sinus, with arterial epinephrine and norepinephrine, prior to brain death, at 1, 10, and 90 minutes after brain death. Cardiac output (CO), systemic vascular resistance (SVR), oxygen delivery (DO 2), oxygen extraction (EO 2), and myocardial oxygen (mEO 2) and lactate extractions (mE 1ac) were calculated. Left ventricular contractility was assessed by micromanometer tipped catheters. Results VO 2 increased from 4.8 ± 0.9 to 6.3 ± 0.9 mL/min/kg 1 minute after brain death ( P < .001), and subsequently decreased to below baseline at 90 minutes ( P < .001). Left ventricular contractility, CO, and DO 2 increased 1 minute after brain death ( P < .001), followed by a rapid decrease to baseline within 10 minutes ( P < .001). SVR and EO 2 decreased after brain death ( P < .01) and remained low. Lactate remained unchanged. mE 1ac decreased after brain death despite a decrease in mEO 2 ( P < .01), and returned to baseline at 90 minutes. Conclusions The initial surge in VO 2 after brain death is offset by the greater increase in DO 2, thus tissue perfusion remains adequate. The lower than baseline VO 2 and SVR at the end of the study period may indicate general metabolic and hemodynamic compromise. The information regarding the profound metabolic alterations imposed by brain death may have implications for management of brain death donors.

Multi-Scale Computational Model of Fuel Homeostasis During Exercise: Effect of Hormonal Control

A mathematical model of the whole-body metabolism is developed to predict fuel homeostasis during exercise by using hormonal control over cellular metabolic processes. The whole body model is composed of seven tissue compartments: brain, heart, liver, GI (gastrointestinal) tract, skeletal muscle, adipose tissue, and "other tissues". Each tissue compartment is described by dynamic mass balances and major cellular metabolic reactions. The glucagon-insulin controller is incorporated into the whole body model to predict hormonal changes during exercise. Moderate [150 W power output at 60% of peak oxygen consumption (VO(2max))] exercise for 60 min was implemented by increasing ATP utilization rates in heart and skeletal muscle. Arterial epinephrine level was given as an input function, which directly affects heart and skeletal muscle metabolism and indirectly other tissues via glucagon-insulin controller. Model simulations were validated with experimental data from human exercise studies. The exercise induced changes in hormonal signals modulated metabolic flux rates of different tissues in a coordinated way to achieve glucose homeostasis, demonstrating the efficacy of hormonal control over cellular metabolic processes. From experimental measurements of whole body glucose balance and arterial substrate concentrations, this model could predict the dynamic changes of hepatic glycogenolysis and gluconeogenesis, which are not easy to measure experimentally, suggesting the higher contribution of glycogenolysis ( approximately 75%). In addition, it could provide dynamic information on the relative contribution of carbohydrates and lipids for fuel oxidation in skeletal muscle. Model simulations indicate that external fuel supplies from other tissue/organ systems to skeletal muscle become important for prolonged exercise emphasizing the significance of interaction among tissues. In conclusion, this model can be used as a valuable complement to experimental studies due to its ability to predict what is difficult to measure directly, and usefulness to provide information about dynamic behaviors.

Systemic hypoxia and vasoconstrictor responsiveness in exercising human muscle

Exercise blunts sympathetic alpha-adrenergic vasoconstriction (functional sympatholysis). We hypothesized that sympatholysis would be augmented during hypoxic exercise compared with exercise alone. Fourteen subjects were monitored with ECG and pulse oximetry. Brachial artery and antecubital vein catheters were placed in the nondominant (exercising) arm. Subjects breathed hypoxic gas to titrate arterial O2 saturation to 80% while remaining normocapnic via a rebreath system. Baseline and two 8-min bouts of rhythmic forearm exercise (10 and 20% of maximum) were performed during normoxia and hypoxia. Forearm blood flow, blood pressure, heart rate, minute ventilation, and end-tidal CO2 were measured at rest and during exercise. Vasoconstrictor responsiveness was determined by responses to intra-arterial tyramine during the final 3 min of rest and each exercise bout. Heart rate was higher during hypoxia (P < 0.01), whereas blood pressure was similar (P = 0.84). Hypoxic exercise potentiated minute ventilation compared with normoxic exercise (P < 0.01). Forearm blood flow was higher during hypoxia compared with normoxia at rest (85 +/- 9 vs. 66 +/- 7 ml/min), at 10% exercise (276 +/- 33 vs. 217 +/- 27 ml/min), and at 20% exercise (464 +/- 32 vs. 386 +/- 28 ml/min; P < 0.01). Arterial epinephrine was higher during hypoxia (P < 0.01); however, venoarterial norepinephrine difference was similar between hypoxia and normoxia before (P = 0.47) and during tyramine administration (P = 0.14). Vasoconstriction to tyramine (%decrease from pretyramine values) was blunted in a dose-dependent manner with increasing exercise intensity (P < 0.01). Interestingly, vasoconstrictor responsiveness tended to be greater (P = 0.06) at rest (-37 +/- 6% vs. -33 +/- 6%), at 10% exercise (-27 +/- 5 vs. -22 +/- 4%), and at 20% exercise (-22 +/- 5 vs. -14 +/- 4%) between hypoxia and normoxia, respectively. Thus sympatholysis is not augmented by moderate hypoxia nor does it contribute to the increased blood flow during hypoxic exercise.

Adrenergic regulation of HSL serine phosphorylation and activity in human skeletal muscle during the onset of exercise

Skeletal muscle hormone-sensitive lipase (HSL) activity is increased by contractions and increases in blood epinephrine (EPI) concentrations and cyclic AMP activation of the adrenergic pathway during prolonged exercise. To determine the importance of hormonal stimulation of HSL activity during the onset of moderate- and high-intensity exercise, nine men [age 24.3 +/- 1.2 yr, 80.8 +/- 5.0 kg, peak oxygen consumption (VO2 peak) 43.9 +/- 3.6 ml x kg(-1) x min(-1)] cycled for 1 min at approximately 65% VO2 peak, rested for 60 min, and cycled at approximately 90% VO2 peak for 1 min. Skeletal muscle biopsies were taken pre- and postexercise, and arterial blood was sampled throughout exercise. Arterial EPI increased (P < 0.05) postexercise at 65% (0.45 +/- 0.10 to 0.78 +/- 0.27 nM) and 90% VO2 peak (0.57 +/- 0.34 to 1.09 +/- 0.50 nM). HSL activity increased (P < 0.05) following 1 min of exercise at 65% VO2 peak [1.05 +/- 0.39 to 1.78 +/- 0.54 mmol x min(-1) x kg dry muscle (dm)(-1)] and 90% VO2 peak (1.07 +/- 0.24 to 1.91 +/- 0.62 mmol x min(-1) x kg dm(-1)). Cyclic AMP content also increased (P < 0.05) at both exercise intensities (65%: 1.52 +/- 0.67 to 2.75 +/- 1.12, 90%: 1.85 +/- 0.65 to 2.64 +/- 0.93 micromol/kg dm). HSL Ser660 phosphorylation (approximately 55% increase) and ERK1/2 phosphorylation ( approximately 33% increase) were augmented following exercise at both intensities, whereas HSL Ser563 and Ser565 phosphorylation were not different from rest. The results indicate that increases in arterial EPI concentration during the onset of moderate- and high-intensity exercise increase cyclic AMP content, which results in the phosphorylation of HSL Ser660. This adrenergic stimulation contributes to the increase in HSL activity that occurs in human skeletal muscle in the first minute of exercise at 65% and 90% VO2 peak.

The effect of graded exercise on IL-6 release and glucose uptake in human skeletal muscle.

In this study, the hypothesis that the release of interleukin (IL)-6 from human muscle is linked to exercise intensity and muscle glucose uptake was investigated. In the overnight fasted state, seven healthy males performed knee extension exercise, kicking with both legs, each at 25 % of maximal power (W(max)) for 45 min (eliciting 23 +/- 1 % of pulmonary maximal oxygen uptake, V(O2,max)) and then simultaneously with one leg at 65 % and the other leg at 85 % W(max) for 35 min (40 +/- 1 % of pulmonary V(O2,max)). Blood was sampled from a femoral artery and both femoral veins, and blood flow was determined by thermodilution. Thigh plasma flow (0.15 +/- 0.01, 1.4 +/- 0.2, 2.0 +/- 0.1 and 2.3 +/- 0.2 l min(-1) thigh(-1) at rest and 25 %, 65 % and 85 % W(max), respectively) and thigh oxygen uptake (0.02 +/- 0.01, 0.27 +/- 0.03, 0.48 +/- 0.04 and 0.55 +/- 0.05 l min(-1) thigh(-1) at rest and 25 %, 65 % and 85 % W(max), respectively) increased with increasing exercise intensity (P < 0.05). Also, thigh IL-6 release (0.4 +/- 0.1, 1.3 +/- 0.5, 1.5 +/- 0.6 and 2.5 +/- 0.7 ng min(-1) thigh(-1) at rest and 25 %, 65 % and 85 % W(max), respectively) and thigh glucose uptake (0.05 +/- 0.01, 0.3 +/- 0.05, 0.75 +/- 0.16, 1.07 +/- 0.15 mmol min(-1) thigh(-1) at rest and 25 %, 65 % and 85 % W(max), respectively) increased with increasing exercise intensity (P < 0.05). During the last 35 min of exercise, arterial catecholamine concentrations were higher (P < 0.05) than at rest and during low-intensity exercise. During exercise, thigh IL-6 release was positively related to both thigh glucose uptake (P < 0.001) and thigh glucose delivery (P < 0.005), but not to thigh glucose extraction. Thigh IL-6 release was also positively related to arterial plasma adrenaline concentration. The pre-exercise muscle glycogen concentration tended to correlate with the arteriovenous IL-6 concentration difference at rest, and the postexercise glycogen concentration was inversely correlated with IL-6 release during the final 35 min of exercise. In conclusion, the study indicates that IL-6 release from human muscle is positively related to exercise intensity, arterial adrenaline concentration and muscle glucose uptake. This supports the hypothesis that IL-6 may be linked to the regulation of glucose homeostasis during exercise. The observation of a relationship between IL-6 release and muscle glycogen store both at rest and after exercise suggests that IL-6 may act as a carbohydrate sensor.

Epinephrine in the heart: uptake and release, but no facilitation of norepinephrine release.

Several studies have suggested that epinephrine augments the release of norepinephrine from sympathetic nerve terminals through stimulation of presynaptic receptors, but evidence pertaining to this mechanism in the heart is scarce and conflicting. Using the microdialysis technique in the porcine heart, we investigated whether epinephrine, taken up by and released from cardiac sympathetic nerves, can increase norepinephrine concentrations in myocardial interstitial fluid (NE(MIF)) under basal conditions and during sympathetic activation. During intracoronary epinephrine infusion of 10, 50, and 100 ng/kg per minute under basal conditions, large increments in interstitial (from 0.31+/-0.05 up to 140+/-30 nmol/L) and coronary venous (from 0.16+/-0.08 up to 228+/-39 nmol/L) epinephrine concentrations were found, but NE(MIF) did not change. Left stellate ganglion stimulation increased NE(MIF) from 3.4+/-0.5 to 8.2+/-1.5 nmol/L, but again, this increase was not enhanced by concomitant intracoronary epinephrine infusion. Intracoronary infusion of tyramine resulted in a negligible increase in epinephrine concentration in myocardial interstitial fluid (EPI(MIF)), whereas 30 minutes after infusion of epinephrine an increase of 9.5 nmol/L in EPI(MIF) was observed, indicating that epinephrine is taken up by and released from cardiac sympathetic neurons. Although 68% to 78% of infused epinephrine was extracted over the heart, the ratio of interstitial to arterial epinephrine concentrations was only approximately 20%, increasing to 29% with neuronal reuptake inhibition. Our findings demonstrate epinephrine release from cardiac sympathetic neurons, but they do not provide evidence that epinephrine augments cardiac sympathoneural norepinephrine release under basal conditions or during sympathetic activation.

Meal-induced insulin secretion in dogs is mediated by both branches of the autonomic nervous system.

We investigated the relationship between autonomic activity to the pancreas and insulin secretion in chronically catheterized dogs when food was shown, during eating, and during the early absorptive period. Pancreatic polypeptide (PP) output, pancreatic norepinephrine spillover (PNESO), and arterial epinephrine (Epi) were measured as indexes for parasympathetic and sympathetic nervous activity to the pancreas and for adrenal medullary activity, respectively. The relation between autonomic activity and insulin secretion was confirmed by autonomic blockade. Showing food to dogs initiated a transient increase in insulin secretion without changing PP output or PNESO. Epi did increase, suggesting beta(2)-adrenergic mediation, which was confirmed by beta-adrenoceptor blockade. Eating initiated a second transient insulin response, which was only totally abolished by combined muscarinic and beta-adrenoceptor blockade. During absorption, insulin increased to a plateau. PP output showed the same pattern, suggesting parasympathetic mediation. PNESO decreased by 50%, suggesting withdrawal of inhibitory sympathetic neural tone. We conclude that 1) the insulin response to showing food is mediated by the beta(2)-adrenergic effect of Epi, 2) the insulin response to eating is mediated both by parasympathetic muscarinic stimulation and by the beta(2)-adrenergic effect of Epi, and 3) the insulin response during early absorption is mediated by parasympathetic activation, with possible contribution of withdrawal of sympathetic neural tone.

Portal vein afferents are critical for the sympathoadrenal response to hypoglycemia.

We sought to elucidate the role of the portal vein afferents in the sympathetic response to hypoglycemia. Laparotomy was performed on 27 male Wistar rats. Portal veins were painted with either 90% phenol (denervation group [PDN]) or 0.9% saline solution (sham-operated group [SHAM]). Rats were chronically cannulated in the carotid artery (sampling), jugular vein (infusion), and portal vein (infusion). After a recovery period of 5 days, animals were exposed to a hyperinsulinemic-hypoglycemic clamp, with glucose infused either portally (POR) or peripherally (PER). In all animals, systemic hypoglycemia (2.48+/-0.09 mmol/l) was induced via jugular vein insulin infusion (50 mU x kg(-1) x min(-1)). Arterial plasma catecholamines were assessed at basal (-30 and 0 min) and during sustained hypoglycemia (60, 75, 90, and 105 min). By design, portal vein glucose concentrations were significantly elevated during POR versus PER (4.4+/-0.14 vs. 2.5+/-0.07 mmol/l; P<0.01, respectively) for both PDN and SHAM. There were no significant differences in arterial glucose or insulin concentration between the four experimental conditions at any point in time. When portal glycemia and systemic glycemia fell concomitantly (SHAM-PER), epinephrine increased 12-fold above basal (3.75+/-0.34 and 44.56+/-6.1 nmol/l; P<0.001). However, maintenance of portal normoglycemia (SHAM-POR) caused a 50% suppression of the epinephrine response, despite cerebral hypoglycemia (22.2+/-3.1 nmol/l, P<0.001). Portal denervation resulted in a significant blunting of the sympathoadrenal response to whole-body hypoglycemia (PDN-PER 27.6+/-3.8 nmol/l vs. SHAM-PER; P<0.002). In contrast to the sham experiments, there was no further suppression in arterial epinephrine concentrations observed during PDN-POR versus PDN-PER (P = 0.8). These findings indicate that portal vein afferent innervation is critical for hypoglycemic detection and normal sympathoadrenal counterregulation.

Norepinephrine spillover in forearm and subcutaneous adipose tissue before and after eating.

The sympathetic nervous system regulates lipolysis. There are regional differences in the sensitivity of lipolysis to adrenergic regulation. Little is known about regional sympathetic activity in response to eating in humans. We studied the effect of feeding on systemic and local sympathetic nervous system activity and lipolysis in lean healthy subjects (three women and five men; age, 27.0+/-2.0; body mass index, 23.4+/-1.2 kg/m(-2)) using isotope dilution methodology and arterio-venous sampling. Feeding increased arterial norepinephrine (NE) concentration (mean premeal, 0.96+/-0.12 nmol/L x L; mean postmeal, 1.28+/-0.14 nmol/L x L; P < 0.02) and total body NE spillover (mean premeal, 2.11+/-0.30 nmol/min x L; mean postmeal, 2.76+/-0.31 nmol/min x L; P < 0.02), whereas the arterial epinephrine concentration decreased (mean premeal, 289+/-61 pmol/L; mean postmeal, 170+/-5 pmol/L; P < 0.02). Palmitate concentration and total body systemic rate of appearance of palmitate declined postprandially (mean premeal, 117 +/- 15 micromol/min; mean postmeal, 38+/-4 micromol/min; P < 0.01). NE spillover increased by the same proportion in both forearm and adipose tissue [in forearm, mean premeal and postmeal, 1.02+/-0.11 and 2.41+/-0.44. nmol/100 mL x min, respectively (P < 0.02); in adipose tissue, mean premeal and postmeal, 0.41+/-0.12 and 0.73+/-0.17 nmol/100 g x min, respectively (P < 0.02)]. The results show that a meal caused differential changes in systemic sympatho-adrenal activity and an increase in sympathetic activity in adipose tissue postprandially, However, this increase in postprandial sympathetic activity was not enough to overcome the inhibition of lipolysis by insulin.

Insulin stimulates epinephrine release under euglycemic conditions in humans

In healthy subjects, acute physiological hyperinsulinemia induces activation of the sympathetic nervous system, but in the absence of hypoglycemia, plasma epinephrine levels have not been found to increase during insulin administration. However, the venous level of epinephrine reflects the net result of release, clearance, and uptake and therefore is not a good measure of adrenomedullary epinephrine secretion. The influence of 90 minutes of euglycemic physiological hyperinsulinemia (60 mU · m −2 · min −1; plasma insulin concentration, ⋍700 pmol · L −1) on epinephrine kinetics using the 3H-epinephrine tracer method was studied in 12 healthy normotensive, non-obese subjects. After bolus injection, [ 3H]-epinephrine was continuously infused with arterial and venous blood sampling at regular intervals, enabling calculation of total body (systemic) and forearm epinephrine release and clearance. Studies were performed in the basal state and during sympathetic stimulation by lower-body negative pressure (LBNP) of − 15 mm Hg for 15 minutes. Control experiments (“sham” clamps, but with LBNP) were performed in four of the 12 individuals. Euglycemic hyperinsulinemia (all arterial glucose samples ≥ 4.2 mmol · L −1) induced an increase of the arterial epinephrine concentration ( P = .03), and tended to increase total body epinephrine release ( P = .08). Total body epinephrine clearance did not change during hyperinsulinemia. The insulin-induced increase in forearm blood flow ([FBF] by plethysmography, from 3.0 ± 0.4 to 3.8 ± 0.6 mL · dL −1 · min −1, P = .01) was strongly correlated with the increase in arterial epinephrine ( r = .78, P < .01). Plasma epinephrine concentrations did not change during control experiments (sham clamp). Sympathetic stimulation alone as induced by LBNP did not stimulate epinephrine release. However, the combination of insulin and LBNP significantly increased epinephrine release (from 0.37 ± 0.06 to 0.56 ± 0.12 nmol · m −1 · min −1, P = .03). We conclude that acute physiological hyperinsulinemia under euglycemic conditions induces epinephrine release. This effect is enhanced when hyperinsulinemia is combined with sympathetic stimulation by LBNP. Due to increased forearm removal, venous epinephrine concentrations hardly change. Epinephrine release was strongly correlated with the hemodynamic effects of insulin.

Anesthetic regimen effects on a pediatric porcine model of asphyxial arrest

The effects of three anesthetic regimens on an established model of pediatric porcine hypoxic-hypercarbic arrest were examined. Twenty-four preadolescent miniature piglets were paralyzed, mechanically ventilated and anesthetized with one of three regimens: IM+IV pentobarbital ( n=8); IM+IV ketamine ( n=8); or IM ketamine+inhaled isoflurane ( n=8). Asphyxial cardiopulmonary arrest was induced and, after an 8 min cardiac arrest nonintervention interval, a standardized protocol of manual CPR with mechanical ventilation was performed. Outcome variables included incidence of ventricular fibrillation, time to cardiac arrest, endogenous plasma epinephrine levels and arteriovenous epinephrine gradients. IV Ketamine anesthesia produced the highest incidence of ventricular fibrillation ( P<0.01 vs. pentobarbital and isoflurane). Time to asphyxia induced cardiac arrest was greatest for the pentobarbital group ( P<0.05 vs. ketamine and isoflurane). During induction of asphyxial cardiac arrest (low cardiac flow), endogenous venous epinephrine accumulation was highest in the pentobarbital anesthetized group ( P<0.05). After 8 min of untreated cardiac arrest and 1 min of CPR (low flow), arterial epinephrine levels were highest in the ketamine group ( P<0.05). Endogenous epinephrine gradients were venous>arterial in all groups at the end of the 8 min cardiac arrest non-intervention interval (no flow). After 1 min of CPR, the gradients had either equalized or reversed to arterial>venous in all groups except for pentobarbital. As designed and expected, return of spontaneous circulation did not occur in any animal. We conclude that, in developing models of porcine asphyxial cardiopulmonary arrest and resuscitation to simulate pediatric human arrest, variations in anesthetic regimen produce significant differences in parameters that are important to consider: time to asphyxia induced cardiac arrest, fibrillation threshold, plasma epinephrine level and arteriovenous epinephrine gradient. Anesthetic effects need to be carefully considered and clearly explained to facilitate the interpretation of studies of interventions in cardiopulmonary arrest and resuscitation.