Β-adrenergic Mechanisms Research Articles

Cerebral lactate uptake during exercise is driven by the increased arterial lactate concentration.

Exercise facilitates cerebral lactate uptake, likely by increasing arterial lactate concentration and hence the diffusion gradient across the blood-brain barrier. However, nonspecific β-adrenergic blockade by propranolol has previously reduced the arterio-jugular venous lactate difference (AVLac) during exercise, suggesting β-adrenergic control of cerebral lactate uptake. Alternatively, we hypothesized that propranolol reduces cerebral lactate uptake by decreasing arterial lactate concentration. To test that hypothesis, we evaluated cerebral lactate uptake taking changes in arterial concentration into account. Nine healthy males performed incremental cycling exercises to exhaustion with and without intravenous propranolol (18.7 ± 1.9 mg). Lactate concentration was determined in arterial and internal jugular venous blood at the end of each workload. To take changes in arterial lactate into account, we calculated the fractional extraction (FELac) defined as AVLac divided by the arterial lactate concentration. Arterial lactate concentration was reduced by propranolol at any workload (P < 0.05), reaching 14 ± 3 and 11 ± 3 mmol·l-1 during maximal exercise without and with propranolol, respectively. Although AVLac and FELac increased during exercise (both P < 0.05), they were both unaffected by propranolol at any workload (P = 0.68 and P = 0.26) or for any given arterial lactate concentration (P = 0.78 and P = 0.22). These findings support that while propranolol may reduce cerebral lactate uptake, this effect reflects the propranolol-induced reduction in arterial lactate concentration and not inhibition of a β-adrenergic mechanism within the brain. We hence conclude that cerebral lactate uptake during exercise is directly driven by the increasing arterial concentration with work rate.NEW & NOTEWORTHY During exercise the brain consumes lactate as a substitute for glucose. Propranolol has previously attenuated this cerebral lactate uptake, suggesting a β-adrenergic transport mechanism. However, in the present study, we demonstrate that the fractional extraction of arterial lactate by the brain is unaffected by propranolol throughout incremental exercise to exhaustion. We conclude that cerebral lactate uptake during exercise is passively driven by the increasing arterial concentration, rather than by a β-adrenergic mechanism within the brain.

Макро- и микрогемодинамика легких при экспериментальной тромбоэмболии легочной артерии в условиях блокады альфа- и бета-адренорецепторов

The pulmonary microhemodynamics changes in the experimental pulmonary thromboembolism model were studied in acute experiments on anesthetized rabbits with isolated dual channels lungs perfusion in control and after the blockade of α-adrenoceptors with phentolamine and β-adrenoceptors with propranolol. In control animals, pulmonary embolism caused the increasing of the pulmonary artery pressure, pulmonary vascular resistance, and precapillary resistance as well as elevating of the capillary filtration coefficient and postcapillary resistance. Phentolamine caused the decrease of the pulmonary artery pressure, pulmonary vascular resistance, and precapillary resistance. After the propranolol injection, the changes in most of the investigated parameters were opposite comparing with their shifts after the blockade of α-adrenoceptors. In the last case, pulmonary thromboembolism caused less increasing of the pulmonary microcirculatory parameters. However, the capillary filtration coefficient was elevated more, then in the control animals. In case of pulmonary thromboembolism after the blockade of the β-adrenoceptors, the most of the hemodynamic parameters increased more, than after the blockade of α-adrenoceptors; in both cases the capillary filtration coefficient increased to the same level. The value of its changes is determined of the reciprocal interaction of the α- and β-adrenergic mechanisms of the regulation of the permeability of the endothelium of the pulmonary vessels.

Role of Noradrenergic Brain Nuclei in the Regulation of Carotid Artery Blood Flow: Pharmacological Evidence from Anesthetized Pigs with Alpha-2 Adrenergic Receptor Modulator Drugs.

Cerebral hypoperfusion and degeneration of the noradrenergic locus coeruleus (LC) occur early in Alzheimer's disease (AD). Cerebral blood vessels are densely innervated by noradrenergic projections from the LC suggesting a functional role for the regulation of cerebral blood flow (CBF). Experimental LC stimulation, however, has provided no clarity as decreases or increases in CBF were reported from different experimental settings and investigators. To find out with pharmacological methods whether endogenously released norepinephrine (NE) increases or decreases carotid artery blood flow (CABF) in anesthetized pigs by investigating the effect of centrally acting alpha-2 adrenergic drugs, which increase (atipamezole) or decrease (xylazine) NE in the brain. CABF was measured by a Doppler-flow probe placed around the left carotid artery in pentobarbital anesthetized young pigs. Neither current antihypertensive drugs nor pharmacological stimulation of dopamine, histamine, serotonin or acetylcholine receptors changed CABF. The alpha-2 adrenergic-receptor agonist xylazine decreased, while the antagonist atipamezole raised CABF. This rise was abolished by a combined treatment with endothelial NO-synthase inhibitor Nω-Nitro-L-arginine methyl ester (L-NAME) and the non-selective β-receptor antagonist propranolol. Propranolol alone did not decrease CABF in contrast to L-NAME but decreased CABF after L-NAME, surprisingly. Pharmacological evidence suggests that NE released in the brain of anesthetized pigs raises CABF involving β-adrenergic mechanisms and nitric oxide. If in awake humans NE released from the LC had vasodilator effects early LC degeneration could be involved in early cerebral hypoperfusion of AD. Moreover, a cerebral adrenergic vascular innervation deficit, possibly resulting from LC degeneration, and systemic endothelial dysfunction together may act synergistically to reduce CBF.

An in vitro study on noradrenergic modulation of final oocyte maturation in the catfish Heteropneustes fossilis

This study was aimed to elucidate in vitro the effects of endogenous catecholamines: dopamine (DA), noradrenaline (NA) and adrenaline (A), and the β-adrenergic blocker propranolol on induction of final oocyte maturation (FOM) in the catfish Heteropneustes fossilis. With this aim, post vitellogenic follicles from sexually mature gravid female catfish were incubated with each of DA, NA and A in a concentration range of 5–250 μM, and propranolol in a concentration range of 1–200 μg/mL at time points varying from 0 to 30 h). Translucent follicles without germinal vesicle (GV) and opaque follicles with GV were scored separately for the calculation of percentage germinal vesicle breakdown (GVBD), an index of FOM. Data were analyzed by one-way ANOVA and were considered statistically significant when P values were less than 0.05. The analysis of the data showed that the incubation with NA only stimulated GVBD in a concentration - and time-dependent manner. Though the incubation with propranolol decreased total follicular cAMP level significantly at and above 10 μg/mL concentrations, a significant effect of the GVBD increase was noticed at 50 μg/mL or higher. However, the 10 μg/mL concentration of propranolol was effective to inhibit the NA-induced GVBD significantly albeit at a low level (39%). The present study suggests that final oocyte maturation is modulated by NA through a β-adrenergic mechanism, implicating a neural control of oocyte maturation and ovulation in teleosts.

Evidence for β-adrenergic modulation of sweating during incremental exercise in habitually trained males.

The aim of the present study was to determine the β-adrenergic contribution to sweating during incremental exercise in habitually trained males. Nine habitually trained and 11 untrained males performed incremental cycling until exhaustion (20 W/min). Bilateral forearm sweat rates (ventilated capsule) were measured at two skin sites that were transdermally administered via iontophoresis with either 1% propranolol (Propranolol, a nonselective β-adrenergic receptor antagonist) or saline (Control). The sweat rate was evaluated as a function of both relative (percentage of maximum workload) and absolute exercise intensities. The sweat rate at the Propranolol site was lower than the control during exercise at 80 (0.57 ± 0.21 and 0.45 ± 0.19 mg·cm-2·min-1 for Control and Propranolol, respectively) and 90% (0.74 ± 0.22 and 0.65 ± 0.17 mg·cm-2·min-1, respectively) of maximum workload in trained males (all P < 0.05). By contrast, no between-site differences in sweat rates were observed in untrained counterparts (all P > 0.05). At the same absolute intensity, higher sweat rates on the control site were observed in trained males relative to the untrained during exercise at 160 (0.23 ± 0.20 and 0.04 ± 0.05 mg·cm-2·min-1 for trained and untrained, respectively) and 180 W (0.40 ± 0.20 and 0.13 ± 0.13 mg·cm-2·min-1, respectively) (all P < 0.05), whereas this between-group difference was not observed at the Propranolol site (all P > 0.05). We show that the β-adrenergic mechanism does modulate sweating during exercise at a submaximal high relative intensity in habitually trained males. The β-adrenergic mechanism may in part contribute to the greater sweat production in habitually trained males than in untrained counterparts during exercise.NEW & NOTEWORTHY We demonstrated for the first time that the β-adrenergic mechanism does modulate sweating (i.e., β-adrenergic sweating) during exercise using a localized β-adrenoceptor blockade in humans in vivo. β-Adrenergic sweating was evident in habitually trained individuals during exercise at a submaximal high relative intensity (80-90% maximal work). This observation advances our understanding of human thermoregulation during exercise and of the mechanism that underlies sweat gland adaptation to habitual exercise training.

Cardiac Consequences of Autonomic Dysreflexia in Spinal Cord Injury.

Autonomic dysreflexia (AD), which describes episodic hypertension, is highly prevalent in people with spinal cord injury (SCI). In non-SCI, primary hypertension depresses cardiac contractile reserve via β-adrenergic mechanisms. In this study, we investigated whether AD contributes to the impairment in cardiac contractile function that accompanies SCI. We induced SCI in rodents and stratified them into sham, SCI, or SCI plus repetitive induction of AD. At 6-week post-SCI, we assessed cardiac function using in vivo (speckle-tracking echocardiography), ex vivo (working heart), and molecular approaches (Western blot). We also provide unique translational insight by comparing the relationship between the number of daily AD events and cardiac function in 14 individuals with cervical SCI. We found SCI and SCI plus repetitive induction of AD exhibited a reduction in left ventricular dimensions at 6-week post-SCI versus preinjury (P<0.049). Compared with sham, SCI exhibited a reduction in peak radial strain along with a down and rightward shift in the Starling curve (P<0.037), both of which were further depressed in SCI plus repetitive induction of AD (P<0.042). In response to β-adrenergic stimulation, SCI plus repetitive induction of AD exhibited an attenuated increase in contractile indices (P<0.001), despite no differences in β-receptor expression within the left ventricle. Our clinical data confirm our experimental findings by demonstrating significant associations between the number of daily AD events and markers of systolic and diastolic function along with left ventricular mechanics. Here, we provide the first evidence from a translational perspective that AD exerts insidious effects on cardiac function in rodents and humans with SCI.

Sympathetic β-adrenergic mechanism in pudendal inhibition of nociceptive and non-nociceptive reflex bladder activity.

This study investigated the role of the hypogastric nerve and β-adrenergic mechanisms in the inhibition of nociceptive and non-nociceptive reflex bladder activity induced by pudendal nerve stimulation (PNS). In α-chloralose-anesthetized cats, non-nociceptive reflex bladder activity was induced by slowly infusing saline into the bladder, whereas nociceptive reflex bladder activity was induced by replacing saline with 0.25% acetic acid (AA) to irritate the bladder. PNS was applied at multiple threshold (T) intensities for inducing anal sphincter twitching. During saline infusion, PNS at 2T and 4T significantly (P < 0.01) increased bladder capacity to 184.7 ± 12.6% and 214.5 ± 10.4% of the control capacity. Propranolol (3 mg/kg iv) had no effect on PNS inhibition, but 3-[(2-methyl-4-thiazolyl)ethynyl]pyridine (MTEP; 1-3 mg/kg iv) significantly (P < 0.05) reduced the inhibition. During AA irritation, the control bladder capacity was significantly (P < 0.05) reduced to ∼22% of the saline control capacity. PNS at 2T and 4T significantly (P < 0.01) increased bladder capacity to 406.8 ± 47% and 415.8 ± 46% of the AA control capacity. Propranolol significantly (P < 0.05) reduced the bladder capacity to 276.3% ± 53.2% (at 2T PNS) and 266.5 ± 72.4% (at 4T PNS) of the AA control capacity, whereas MTEP (a metabotropic glutamate 5 receptor antagonist) removed the residual PNS inhibition. Bilateral transection of the hypogastric nerves produced an effect similar to that produced by propranolol. This study indicates that hypogastric nerves and a β-adrenergic mechanism in the detrusor play an important role in PNS inhibition of nociceptive but not non-nociceptive reflex bladder activity. In addition to this peripheral mechanism, a central nervous system mechanism involving metabotropic glutamate 5 receptors also has a role in PNS inhibition.

Pudendal but not tibial nerve stimulation inhibits bladder contractions induced by stimulation of pontine micturition center in cats.

This study examined the possibility that pudendal nerve stimulation (PNS) or tibial nerve stimulation (TNS) inhibits the excitatory pathway from the pontine micturition center (PMC) to the urinary bladder. In decerebrate cats under α-chloralose anesthesia, electrical stimulation of the PMC (40 Hz frequency, 0.2-ms pulse width, 10-25 s duration) using a microelectrode induced bladder contractions >20 cmH2O amplitude when the bladder was filled to 60-70% capacity. PNS or TNS (5 Hz, 0.2 ms) at two and four times the threshold (2T and 4T) to induce anal or toe twitch was applied to inhibit the PMC stimulation-induced bladder contractions. Propranolol, a nonselective β-adrenergic receptor antagonist, was administered intravenously (1 mg/kg i.v.) to determine the role of sympathetic pathways in PNS/TNS inhibition. PNS at both 2T and 4T significantly (P < 0.05) reduced the amplitude and area under the curve of the bladder contractions induced by PMC stimulation, while TNS at 4T facilitated the bladder contractions. Propranolol completely eliminated PNS inhibition and TNS facilitation. This study indicates that PNS, but not TNS, inhibits PMC stimulation-induced bladder contractions via a β-adrenergic mechanism that may occur in the detrusor muscle as a result of reflex activity in lumbar sympathetic nerves. Neither PNS nor TNS activated a central inhibitory pathway with synaptic connections to the sacral parasympathetic neurons that innervate the bladder. Understanding the site of action involved in bladder neuromodulation is important for developing new therapies for bladder disorders.

Effect of autonomic blocking agents on the respiratory-related oscillations of ventricular action potential duration in humans.

Ventricular action potential duration (APD) is an important component of many physiological functions including arrhythmogenesis. APD oscillations have recently been reported in humans at the respiratory frequency. This study investigates the contribution of the autonomic nervous system to these oscillations. In 10 patients undergoing treatment for supraventricular arrhythmias, activation recovery intervals (ARI; a conventional surrogate for APD) were measured from multiple left and right ventricular (RV) endocardial sites, together with femoral artery pressure. Respiration was voluntarily regulated and heart rate clamped by RV pacing. Sympathetic and parasympathetic blockade was achieved using intravenous metoprolol and atropine, respectively. Metroprolol reduced the rate of pressure development (maximal change in pressure over time): 1,271 (± 646) vs. 930 (± 433) mmHg/s; P < 0.01. Systolic blood pressure (SBP) showed a trend to decrease after metoprolol, 133 (± 21) vs. 128 (± 25) mmHg; P = 0.06, and atropine infusion, 122 (± 26) mmHg; P < 0.05. ARI and SBP exhibited significant cyclical variations (P < 0.05) with respiration in all subjects with peak-to-peak amplitudes ranging between 0.7 and 17.0 mmHg and 1 and 16 ms, respectively. Infusion of metoprolol reduced the mean peak-to-peak amplitude [ARI, 6.2 (± 1.4) vs. 4.4 (± 1.0) ms, P = 0.008; SBP, 8.4 (± 1.6) vs. 6.2 (± 2.0) mmHg, P = 0.002]. The addition of atropine had no significant effect. ARI, SBP, and respiration showed significant coupling (P < 0.05) at the breathing frequency in all subjects. Directed coherence from respiration to ARI was high and reduced after metoprolol infusion [0.70 (± 0.17) vs. 0.50 (± 0.23); P < 0.05]. These results suggest a role of respiration in modulating the electrophysiology of ventricular myocardium in humans, which is partly, but not totally, mediated by β-adrenergic mechanisms.

Differential contribution of ACh-muscarinic and β-adrenergic receptors to vasodilatation in noncontracting muscle during voluntary one-legged exercise.

We have demonstrated the centrally induced cholinergic vasodilatation in skeletal muscle at the early period of voluntary one‐legged exercise and during motor imagery in humans. The purpose of this study was to examine whether central command may also cause β‐adrenergic vasodilatation during the exercise and motor imagery. Relative changes in oxygenated hemoglobin concentration (Oxy‐Hb) of bilateral vastus lateralis (VL) muscles, as index of tissue blood flow, and femoral blood flow to nonexercising limb were measured during one‐legged cycling and mental imagery of the exercise for 1 min before and after propranolol (0.1 mg/kg iv). The Oxy‐Hb of noncontracting muscle increased (P <0.05) at the early period of exercise and the increase was sustained throughout exercise, whereas the Oxy‐Hb of contracting muscle increased at the early period but thereafter decreased. We subtracted the Oxy‐Hb response with propranolol from the control response in individual subjects to identify the propranolol‐sensitive component of the Oxy‐Hb response during exercise. In both noncontracting and contracting VL muscles, the increase in Oxy‐Hb at the early period of one‐legged exercise did not involve a significant propranolol‐sensitive component. However, as the exercise proceeded, the propranolol‐sensitive component of the Oxy‐Hb response was developed during the later period of exercise. Propranolol also failed to affect the initial increases in femoral blood flow and vascular conductance of nonexercising leg but significantly attenuated (P <0.05) their later increases during exercise. Subsequent atropine (10–15 μg/kg iv) abolished the initial increases in Oxy‐Hb of both VL muscles. Mental imagery of the one‐legged exercise caused the bilateral increases in Oxy‐Hb, which were not altered by propranolol but abolished by subsequent atropine. It is likely that the rapid cholinergic and delayed β‐adrenergic vasodilator mechanisms cooperate to increase muscle blood flow during exercise.

Role of &amp;#945;- and &amp;#946;-adrenergic Mechanisms in the Pathogenesis of Pulmonary Injuries Characterized by Edema, Inflammation and Fibrosis

Adrenergic mechanisms are involved in the formation of several types of pulmonary edema (PE) such as neurogenic pulmonary edema (NPE) or PE in patients with pheochromocytoma, but also in the development of pulmonary fibrosis and pulmonary hypertension. In severe cases of PE such as in the adult respiratory distress syndrome (ARDS), PE is typically accompanied by inflammation and followed by pulmonary vascular hypertrophy and pulmonary fibrosis. Norepinephrine and other adrenoceptor agonists are known to provoke activation of proinflammatory cytokines such as interleukin (IL)-1 and IL-6. These cytokines are involved both in the pathogenesis of PE and of pulmonary fibrosis. We therefore assume that adrenergic mechanisms may have an important role in the pathogenesis of pulmonary injuries characterized by edema, inflammation and fibrosis. The contribution of adrenoceptor stimulation, particularly the distinct role of α- and β-adrenergic mechanisms, to the development of PE and pulmonary fibrosis is reviewed in this paper.

Pilot study of the effect of lipophilic vs. hydrophilic beta-adrenergic blockers being taken at time of intracardiac defibrillator discharge on subsequent PTSD symptoms

A pathophysiological model of posttraumatic stress disorder (PTSD) posits that an overly strong stress response at the time of the traumatic event leads to overconsolidation of the event’s memory in part through a central β-adrenergic mechanism. We hypothesized that the presence of a β-blocker in the patient’s brain at the time of the traumatic event would reduce the PTSD outcome by blocking this effect. The unpredictable, uncontrollable discharge of an implantable intracardiac defibrillator (ICD) is experienced by most patients as highly stressful, and it has previously been shown to be capable of causing PTSD symptoms. The present pilot study evaluated a convenience sample of 18 male cardiac patients who had been taking either a lipophilic β-blocker (which penetrates the blood-brain barrier) or a hydrophilic β-blocker (which does not) at the time of a discharge of their ICD. The self- report PTSD Checklist-Specific Version quantified 17 PTSD symptoms pertaining to the ICD discharge during the month preceding the evaluation. There was a statistical trend for patients who had been taking a lipophilic β-blocker at the time of the ICD discharge to have (35%) less severe PTSD symptoms than patients who had been taking a hydrophilic β-blocker (one-tailed p=0.07, g=0.64). Further, prospective, randomized, controlled studies are suggested.

Neuroendocrine mediators regulate production of B cell activating factor of the tumor necrosis factor family (BAFF) in human synovial fibroblasts

B cell activating factor of the tumor necrosis factor family (abbreviated BAFF) is a cytokine important for the stimulation and survival of autoreactive B cells and, therefore, might play a role in several autoimmune disease, e.g. autoimmune arthritis. In psoriasis arthritis (PsA), BAFF correlates with disease activity and testosterone, but only in male patients, suggesting a role for sex hormones in the regulation of BAFF. Thus, we wanted to determine whether BAFF production is regulated by neuroendocrine mediators in rheumatoid arthritis (RA) and osteoarthritis (OA) synovial fibroblasts. First, fibroblasts isolated from synovial tissue of RA (n = 10) and OA (n = 10) patients were cultured in the presence or absence of interferon (IFN)-γ, IL-1, lipopolysaccharide (LPS), tumor necrosis factor (TNF) and cortisol in different combinations for 24, 48, and 72 h to determine the optimal stimulation strategy for induction of BAFF production (measured by ELISA in supernatants). IFN-γ in a concentration-dependent manner induced BAFF in RA and OA fibroblasts. Interestingly, we were able to induce significantly more BAFF in synovial fibroblasts from OA patients as compared to RA patients. Additionally, IFN-γ induced BAFF production in fibroblasts (OA n = 10, RA n = 10) was decreased by α-adrenergic and increased by β-adrenergic mechanisms. Furthermore, estradiol inhibited and dihydrotestosterone increased IFN-γ production. Taken together, BAFF production in synovial fibroblasts is modulated by sex hormones and adrenergic stimuli. Therefore, the known influence of neuroendocrine mechanisms in the context of arthritis might be in part mediated by regulating BAFF production from synovial fibroblasts via regulation of IFN-γ.

Regulatory role of leptin in glucose and lipid metabolism in skeletal muscle

Leptin is a hormone secreted by adipocytes that plays a pivotal role in regulation of food intake, energy expenditure, and neuroendocrine function. Several lines of evidences indicate that independent of the anorexic effect, leptin regulates glucose and lipid metabolism in peripheral tissues in rodents and humans. It has been shown that leptin improves the diabetes phenotype in lipodystrophic patients and rodents. Moreover, leptin suppresses the development of severe, progressive impairment of glucose metabolism in insulin-deficient diabetes in rodents. We found that leptin increases glucose uptake and fatty acid oxidation in skeletal muscle in rats and mice in vivo. Leptin increases glucose uptake in skeletal muscle via the hypothalamic–sympathetic nervous system axis and β-adrenergic mechanism, while leptin stimulates fatty acid oxidation in muscle via AMP-activated protein kinase (AMPK). Leptin-induced fatty acid oxidation results in the decrease of lipid accumulation in muscle, which can lead to functional impairments called as “lipotoxicity.” Activation of AMPK occurs by direct action of leptin on muscle and through the medial hypothalamus–sympathetic nervous system and α-adrenergic mechanism. Thus, leptin plays an important role in the regulation of glucose and fatty acid metabolism in skeletal muscle.

Catecholamines Can Induce Pulmonary Remodeling in Rats

Background/Aims: Previously, we found that catecholamine (CA) infusion in rats induced pulmonary injury with edema and inflammation resembling acute lung injury in humans. Here, we examined effects of norepinephrine (NE) and of selective α- and β-adrenergic agonists on the remodeling of pulmonary extracellular matrix. Methods: Eighty rats were infused over 8-72 h with NE, phenylephrine (PE), isoproterenol (ISO) or NaCl solution. We investigated mRNA expression of collagen, matrix metalloproteinase (MMP)-2, its tissue inhibitor (TIMP-2) and transforming growth factor (TGF)-β isoforms in lung tissue. Additionally, lung histology, hemodynamic function and cardiac hypertrophy were evaluated. Results: After 72 h of infusion, lung histology showed beginning fibrosis and vascular hypertrophy. Collagen type I, MMP-2 and TIMP-2 mRNA expression were significantly elevated. All these effects were most pronounced with NE while PE and ISO induced weaker responses. TGF-β mRNA expression was also elevated after 72 h, predominantly after PE infusion. Cardiac hypertrophy was most pronounced after ISO infusion. Conclusion: CA infusion over 72 h may induce pulmonary remodeling. Mainly α-adrenergic but also β-adrenergic mechanisms contribute to these processes. In contrast, cardiac hypertrophy is predominantly mediated by β-adrenergic stimulation and hence, is considered to be a direct adrenergic effect rather than a consequence of pulmonary fibrosis.

Ageing uncompensated: exercise, nitric oxide and hypoxia

Ageing uncompensated: exercise, nitric oxide and hypoxia

Psychological stress regulates antimicrobial peptide expression by both glucocorticoid and β-adrenergic mechanisms

Psychological stress (PS) exerts well-known negative consequences for permeability barrier function in humans and mice, and deterioration of barrier function appears to be attributable largely to excess production of endogenous glucocorticoids (GC). More recently, PS has been shown to compromise antimicrobial defense, also by GC-dependent mechanisms. We assessed here changes in a third antimicrobial peptide (AMP); i.e., the neuropeptide, catestatin (Cst), which also is expressed in the outer epidermis, and previously shown to be regulated by changes in permeability barrier status. In these studies, PS again provoked a decline in both mouse cathelicidin (CAMP) and mouse β-defensin 3 (mBD3) expression, in a GC-dependent fashion. In contrast, Cst immunostaining instead increased after short-term PS, but then began to decline with more sustained PS. In cultured keratinocytes, we showed further that GC downregulate Cst expression, but β-adrenergic blockade increased immunostaining for Cst in the face of long-term PS. Furthermore, β-adrenergic blockade also upregulated CAMP and mBD3 expression. Together, these results suggest that both endogenous GC and β-adrenergic signaling regulate AMP expression.

Repeated treatment with amitriptyline reduces immobility in the behavioural 'despair' test in rats by activating dopaminergic and beta-adrenergic mechanisms.

Seven days of treatment with amitriptyline 10 mg kg-1 day-1, reduced the immobility time in the behavioural 'despair' test in rats. 0.5, but not 0.25 mg kg-1 haloperidol significantly counteracted the reduction of immobility caused by amitriptyline. Its anti-immobility effect was reduced by 50 and 100 mg kg-1 sulpiride, another blocker of dopamine receptors, and 5 mg kg-1 (+/-)-propranolol, a beta-adrenolytic drug. Prazosin, 3 mg kg-1, an antagonist of post-synaptic alpha-adrenoceptors, had no effect. It is suggested that dopaminergic and beta-adrenoceptors mediate the anti-immobility effect of repeated amitriptyline treatment in rats.

β-Adrenoceptor Profile of Ractopamine HCl in Isolated Smooth and Cardiac Muscle Tissues of Rat and Guinea-pig

The investigational sympathomimetic amine, ractopamine hydrochloride, has been profiled for adrenergic activity in selected smooth and cardiac muscle preparations. There was no significant interaction of ractopamine with alpha-adrenergic receptors in the rat vas deferens at concentrations up to 10(-5) M. However, ractopamine produced a concentration-dependent increase in the force and rate of contractions of atria isolated from normal and reserpinized guinea-pigs (EC50 = 1 x 10(-7) M). These increases were submaximal compared with isoprenaline (70-85%), suggesting partial agonist activity at the beta 1-receptor site. Ractopamine completely relaxed the KCl-contracted guinea-pig trachea and rat costo-uterine smooth muscle to their resting tensions (EC50 = 3 x 10(-7) and 5.5 x 10(-8) M, respectively), indicative of full beta 2-agonist properties. Propranolol blocked the response of ractopamine in isolated tracheal and atrial tissues (pA2 = 7.70), demonstrating a beta-adrenergic mechanism of activity. Ractopamine also exhibited antagonism of the response of the guinea-pig trachea to the beta-agonist, isoprenaline. Relative to other beta-agonists, ractopamine was 100-fold more potent than the phenethanolamines, salbutamol and ritodrine, at the beta 1-adrenoceptor, and approximately 7- to 11-fold more potent than ritodrine, but only one-sixth to one-tenth as potent as salbutamol at the beta 2-adrenoceptor. Thus, ractopamine possesses significant beta 1- and beta 2-agonist properties. The submaximal stimulation of the force and rate of atrial contractions is indicative of a partial beta 1-agonist, while the maximal relaxation of the tracheal and costo-uterine smooth muscle is characteristic of a full beta 2-agonist.

Nitric oxide-mediated vasodilation becomes independent of β-adrenergic receptor activation with increased intensity of hypoxic exercise

Hypoxic vasodilation in skeletal muscle at rest is known to include β-adrenergic receptor-stimulated nitric oxide (NO) release. We previously reported that the augmented skeletal muscle vasodilation during mild hypoxic forearm exercise includes β-adrenergic mechanisms. However, it is unclear whether a β-adrenergic receptor-stimulated NO component exists during hypoxic exercise. We hypothesized that NO-mediated vasodilation becomes independent of β-adrenergic receptor activation with increased exercise intensity during hypoxic exercise. Ten subjects (7 men, 3 women; 23 ± 1 yr) breathed hypoxic gas to titrate arterial O(2) saturation to 80% while remaining normocapnic. Subjects performed two consecutive bouts of incremental rhythmic forearm exercise (10% and 20% of maximum) with local administration (via a brachial artery catheter) of propranolol (β-adrenergic receptor inhibition) alone and with the combination of propranolol and nitric oxide synthase inhibition [N(G)-monomethyl-l-arginine (l-NMMA)] under normoxic and hypoxic conditions. Forearm blood flow (FBF, ml/min; Doppler ultrasound) and blood pressure [mean arterial pressure (MAP), mmHg; brachial artery catheter] were assessed, and forearm vascular conductance (FVC, ml·min(-1)·100 mmHg(-1)) was calculated (FBF/MAP). During propranolol alone, the rise in FVC (Δ from normoxic baseline) due to hypoxic exercise was 217 ± 29 and 415 ± 41 ml·min(-1)·100 mmHg(-1) (10% and 20% of maximum, respectively). Combined propranolol-l-NMMA infusion during hypoxic exercise attenuated ΔFVC at 20% (352 ± 44 ml·min(-1)·100 mmHg(-1); P < 0.001) but not at 10% (202 ± 28 ml·min(-1)·100 mmHg(-1); P = 0.08) of maximum compared with propranolol alone. These data, when integrated with earlier findings, demonstrate that NO contributes to the compensatory vasodilation during mild and moderate hypoxic exercise; a β-adrenergic receptor-stimulated NO component exists during low-intensity hypoxic exercise. However, the source of the NO becomes less dependent on β-adrenergic mechanisms as exercise intensity increases.