Direct Effects Of Catecholamines Research Articles

Abstract # 1856 Breast cancer patients undergoing surgery and subjected to perioperative inhibition of COX-2 and β-adrenoceptor blockade: Effects on number and cytotoxicity of circulating NK cells and their relations to cytokine levels

Preclinical research has implicated the release of catecholamines, glucocorticoids, and prostaglandins in mediating the effects of stress and surgery on NK cell cytotoxicity (NKCC) and distribution. Whereas ex-vivo findings regarding cell distribution are valid, we recently reported that the direct effects of catecholamines and prostaglandins on NKCC are transient and not reflected ex-vivo. Here, in a double-blind placebo-controlled randomized clinical trial in 36 breast cancer patients, we tested a combined perioperative β-adrenoceptor and COX-2 blockade, using propranolol and etodolac, respectively. An 11-day oral drug treatment was initiated five days prior to surgery. Blood samples were taken before treatment (T1), on the mornings before and after surgery (T2& T3), and after treatment cessation (T4). Cortisol levels were unaffected by treatment, increasing from T1 to T2, and progressively decreased at T3 and T4. Circulating NK cell numbers increased in placebo-treated patients preparing for surgery (T1–T2), while drug treatment significantly inversed this pattern, presumably through β -adrenergic blockade. Postoperatively (T3), a significant decrease in NK cell numbers, NKCC/ml, and NKCC/NK cell were evident in both groups, without correlation to serum cortisol levels. Interestingly, IL-6 and IL-10 serum levels were inversely related to NKCC/ml and NKCC/NK cell, but not to NK cell numbers, suggesting a minor role for NK cell numbers in perturbed T3 NKCC. These findings further demonstrate the complexity of ex-vivo assessment of NK cell parameters.

Stress cardiomyopathy: a syndrome of catecholamine-mediated myocardial stunning?

During the past few years, a novel syndrome of heart failure and transient left ventricular systolic dysfunction precipitated by acute emotional or physical stress has been described. While patients with "stress cardiomyopathy"(SCM) typically present with signs and symptoms that resemble an acute coronary syndrome, it has become clear that this syndrome has unique clinical features that can readily be distinguished from acute infarction.In particular, in contrast to the irreversible myocardial injury seen with infarction, the myocardial dysfunction of SCM is completely reversible and occurs in the absence of plaque rupture and coronary thrombosis. There is increasing evidence that exaggerated sympathetic stimulation may play a pathogenic role in the development of SCM. Plasma catecholamine levels have been found to be markedly elevated in some patients with SCM, and the syndrome has been observed in other clinical states of catecholamine excess such as central neurologic injury and pheochromocytoma.Further, intravenous catecholamines can precipitate SCM in humans and can reproduce the syndrome in animal models. The precise mechanism in which excessive sympathetic stimulation may result in transient left ventricular dysfunction remains controversial. Abnormal myocardial blood flow due to sympathetically mediated microvascular dysfunction has been suggested and is supported by decreased coronary flow reserve during the acute phase of this syndrome. An alternative explanation is the direct effect of catecholamines on cardiac myocytes, possibly through cyclic AMP-mediated calcium overload. This manuscript will review the clinical and diagnostic features of SCM and will summarize the evidence supporting a sympathetically mediated pathogenesis. Clinical risk factors that appear to increase susceptibility to SCM, possibly by modulating myocyte and microvascular sensitivity to catecholamines, will also be highlighted.

Adrenergic regulation of cardiac myocyte apoptosis.

The direct effects of catecholamines on cardiac myocytes may contribute to both normal physiologic adaptation and pathologic remodeling, and may be associated with cellular hypertrophy, apoptosis, and alterations in contractile function. Norepinephrine (NE) signals via alpha- and beta-adrenergic receptors (AR) that are coupled to G-proteins. Pharmacologic studies of cardiac myocytes in vitro demonstrate that stimulation of beta1-AR induces apoptosis which is cAMP-dependent and involves the voltage-dependent calcium influx channel. In contrast, stimulation of beta2-AR exerts an anti-apoptotic effect which appears to be mediated by a pertussis toxin-sensitive G protein. Stimulation of alpha1-AR causes myocyte hypertrophy and may exert an anti-apoptotic action. In transgenic mice, myocardial overexpression of either beta1-AR or G(alpha)s is associated with myocyte apoptosis and the development of dilated cardiomyopathy. Myocardial overexpression of beta2-AR at low levels results in improved cardiac function, whereas expression at high levels leads to dilated cardiomyopathy. Overexpression of wildtype alpha1B-AR does not result in apoptosis, whereas overexpression of G(alpha)q results in myocyte hypertrophy and/or apoptosis depending on the level of expression. Differential activation of the members of the mitogen-activated protein kinase (MAPK) superfamily and production of reactive oxygen species appear to play a key role in mediating the actions of adrenergic pathways on myocyte apoptosis and hypertrophy. This review summarizes current knowledge about the molecular and cellular mechanisms involved in the regulation of cardiac myocyte apoptosis via stimulation of adrenergic receptors and their coupled effector pathways.

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

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

IP1 Direct effects of catecholamines on T and B cell lines of the channel catfish, ictalurus punctatus

IP1 Direct effects of catecholamines on T and B cell lines of the channel catfish, ictalurus punctatus

Direct effects of catecholamines on hepatic glucose production in conscious dog are due to glycogenolysis.

The effects of catecholamines (CATS) infused into the hepatic portal vein were studied in ten 18-h-fasted conscious dogs. Glucose production (GP) and gluconeogenesis (GNG) were assessed using tracer ([3H]glucose, [14C]alanine) and arteriovenous difference techniques. Each experiment consisted of a 100-min equilibration, a 40-min basal, and two 90-min test periods. A pancreatic clamp (somatostatin + basal portal insulin and glucagon) was used to fix insulin and glucagon at basal levels. Propranolol (1 microgram.kg-1.min-1) and phentolamine (2 micrograms.kg-1.min-1) were infused intraportally during both test periods of the blockade group while a carrier solution was infused in the control group. Norepinephrine (NE; 100 ng.kg-1.min-1) and epinephrine (Epi; 40 ng.kg-1.min-1) were infused intraportally during the second test period of both protocols. Portal NE (70 +/- 46 to 8,404 +/- 674 and 162 +/- 57 to 6,530 +/- 624 pg/ml, respectively) and portal Epi (21 +/- 11 to 3,587 +/- 309 and 29 +/- 6 to 2,989 +/- 406 pg/ml, respectively) rose in the control and adrenergic blockade groups, respectively. The increases in arterial NE and Epi were modest in both groups. Intraportal infusion of CATS increased GP from 2.1 +/- 0.2 to 6.2 +/- 1.0 mg.kg-1.min-1 in the control group but did not change it (2.7 +/- 0.4 to 2.7 +/- 0.3 mg.kg-1.min-1) in the blockade group. Portal CATS had no effect on GNG in the presence or absence of adrenergic blockade (GNG rose from 0.7 +/- 0.2 to 0.9 +/- 0.2 and 0.8 +/- 0.2 to 1.0 +/- 0.2 mg.kg-1.min-1 in the control and blockade groups, respectively). In conclusion, portal infusion of catecholamines significantly augmented GP by selectively stimulating glycogenolysis. The increase in hepatic GP could be completely inhibited by intraportal adrenergic blockade.

Catecholamine inhibition of luteinizing hormone secretion in isolated pig pituitary cells.

This study investigated the direct effect of catecholamines, epinephrine (EPI), and norepinephrine (NE) on basal and gonadotropin-releasing hormone (GnRH)-stimulated secretion of luteinizing hormone (LH) from dispersed pig pituitary cells in vitro. Pig pituitaries were dispersed into cells with collagenase and DNAase and then cultured in McCoy's 5a medium containing horse serum (10%) and fetal calf serum (2.5%) pretreated with dextran-coated charcoal for 3 days. EPI and NE did not affect basal LH secretion after 4 h of incubation. When pituitary cells were incubated with EPI or NE (1 microgram/ml) for longer than 30 min, GnRH-stimulated LH secretion was reduced. The degree of this reduction was dependent on EPI and NE, and a concentration of EPI and NE higher than 1 ng/ml and 100 ng/ml, respectively, was needed. L-isoproterenol, a nonselective beta-agonist, also inhibited the LH response to GnRH. Propranolol, a beta-antagonist, blocked the inhibitory effect of EPI, whereas phentolamine, an alpha-antagonist, had no effect. These results suggest that catecholamines, acting by a beta 2-adrenergic receptor, may play a role in the control of the porcine pituitary gonadotrope's response to GnRH.

Direct effects of catecholamines, thyrotropin-releasing hormone, and somatostatin on growth hormone and prolactin secretion from adenomatous and nonadenomatous human pituitary cells in culture.

To determine the mechanism and the site of action of catecholamines as well as hormones including thyrotropin-releasing hormone (TRH)1 and somatostatin on pituitary hormone release in patients with acromegaly and in normal subjects, the effects of these substances on growth hormone (GH) and prolactin (PRL) secretion from adenomatous and nonadenomatous human pituitary cells in culture were examined. When dopamine (0.01-0.1 microM) or bromocriptine (0.01-0.1 microM) was added to the culture media, a significant inhibition of GH and PRL secretion from adenoma cells from acromegalic patients was observed. This inhibition was blocked by D2 receptor blockade with metoclopramide or sulpiride, but not by D1 receptor blockade. Similarly, dopamine suppressed GH and PRL release by nonadenomatous pituitary cells in a dose-dependent manner, which was again blocked by D2 receptor blockade. The minimum effective concentration of dopamine required for a significant inhibition of PRL secretion (0.01 microM) was lower than that for GH release (0.1 microM). Norepinephrine, likewise, caused a suppression of PRL secretion from adenomatous and nonadenomatous pituitary cells. This effect was blocked by sulpiride, phentolamine, however, was ineffective. When TRH was added to the media, both GH and PRL secretion were enhanced in adenoma cells, while only the stimulation of PRL release was observed in nonadenomatous pituitary cells. Coincubation of TRH and dopamine resulted in variable effects on GH and PRL secretion. Somatostatin consistently lowered GH and PRL secretion in both adenomatous and nonadenomatous pituitary cells and completely blocked the TRH-induced stimulation of GH and PRL secretion from adenoma cells. Opioid peptides (1 microM) failed to affect hormone release. These results suggest that no qualitative difference in GH and PRL responses to dopaminergic agonists or to somatostatin exists between adenoma cells of acromegalic patients and normal pituitary cells, and that the direct effect of catecholamines on GH and PRL secretion from human pituitary cells is mediated mainly through dopamine receptor activation.

Direct effects of catecholamines and tyramine on sinoatrial conduction in isolated and blood-perfused dog atria.

We have investigated the effects of catecholamines (dopamine, norepinephrine, epinephrine and isoproterenol) and tyramine on sinoatrial conduction time (SACT), sinus cycle length (SCL) and developed tension (DT) in isolated atrial muscle, using an isolated and blood-perfused dog atrial preparation, perfused with heparinized blood from the carotid artery of the anesthetized donor dog. Each substance was continuously administered intraarterially into the cannulated sinus node artery. They had dose-dependent positive chronotropic and inotropic effects. Each produced not only a shortening but a prolongation of SACT. In experiments in which only a shortening occurred, the order of the potency for inducing the shortening of the SACT was isoproterenol greater than norepinephrine = epinephrine greater than dopamine greater than tyramine. The ratio of doses required to produce roughly a 15-25% shortening of the SACT was 1: 10: 10: 100: 300, respectively. The isoproterenol-induced shortening of the SACT was inhibited by treatment with propranolol. Tyramine-induced shortening was inhibited by imipramine. From these results, it is suggested that sympathomimetic amines induce a shortening of SACT through adrenergic beta-receptors and also readily induce a pacemaker shift in the SA nodal area.

A pace-maker-like current in the sheep atrium and its modulation by catecholamines.

A modified single-sucrose-gap system was used to study sheep atrial trabeculae under voltage-clamp conditions. A time- and voltage-dependent current system is described, which resembles the current if in Purkinje fibres. This current was activated at membrane potentials of between -60 and -70 mV in many fibres. The addition of Ba2+ reduced the instantaneous current (the 'jump') and thus facilitated the study of the current if. Current tails were more prominent in the presence of TTX and Mn2+. Most experiments were done in the presence of Ba2+, Mn2+ and TTX. Standard envelope tests and conductance measurements indicated that this current is an inward current, activated on hyperpolarization. We have also labelled the atrial current if. The instantaneous fully activated current-voltage relationship, i(E) was found to be linear in the activation range. Increasing the level of K+, which increased the current magnitude, also increased the slope of the i(E) curve. The current magnitude was also dependent on the level of Na+ in the medium. The current magnitude was increased by adrenaline or isoprenaline. Only a small part of the increase could be attributed to a shift in the voltage dependence of the gating kinetics. The shifts in activation curves were much smaller (3-4 mV in the depolarizing direction) than those in Purkinje fibres. Large shifts in activation curves were obtained with theophylline, indicating that the presence of Ba2+ or Mn2+ did not occlude any shifts by adrenaline. The magnitude of if was increased by theophylline, with a further increase by adrenaline. There is therefore no mutual occlusion of the two effects on if. The slope of the i(E) curve was increased by isoprenaline, indicating that there was an increase in conductance. The presence of propranolol did not prevent the increase in current amplitude by isoprenaline. A direct effect of catecholamines on the channel is suggested.

Circulating catecholamines and sympathetic activity after head injury.

Plasma norepinephrine (NE) and dopamine beta-hydroxylase (DBH) levels were measured during the first 7 days after head injury in 48 patients. Blood pressure, pulse, temperature, and Glasgow coma score (GCS) were recorded at the time of sampling for each patient, and the relationships of these to NE and DBH were examined. In patients with multiple trauma, NE levels were usually elevated, regardless of the GCS. In patients with head injury alone, however, NE was proportional to GCS. Alert patients after a brief loss of consciousness (GCS, 14) had normal NE levels. Those in coma had levels as high as 7 times normal. Blood pressure, pulse, and temperature were found to be elevated proportionally to elevations in plasma NE in patients with head injury. The finding of elevated plasma NE in patients with severe head injury raises the possibility of adverse effects of sympathetic hyperactivity in patients with severe head injury, including hypermetabolism, cardiovascular abnormalities, and direct effects of catecholamines on the damaged central nervous system.