Peripheral Beta-adrenergic Receptors Research Articles

LBMON137 Don't Be Fooled By Normotension Pheo Could Be The Potential

Abstract Introduction Sustained or proximal hypertension is the most common sign of pheochromocytoma, but approximately 5-15% of pts present with normal blood pressure. We report a case of a patient incidentally found to have a catecholamines secreting adrenal tumor, but was normotensive on admission. Case 30-year-old morbidly obese woman incidentally found to have a 4.8 cm left adrenal gland mass while being worked up for sepsis secondary to atypical pneumonia. Initially, the patient presented with dyspnea, chest pain, palpitation, nausea, and vomiting. Her past medical history is significant for preeclampsia, 200 lb wt loss in 1 year, NSTMI a few months prior to admission discharged on dual antiplatelet and metoprolol which she couldn't tolerate due to hypotensive episodes. On arrival to the ED the patient was afebrile, normotensive SBP 90-110 DBP 57-70 mmHg, HR 86 BPM, RR 20, saturating 98% on room air. Her laboratory workup was significant for leukocytosis, elevated D-dimer, hyperkalemia 5.9 mmol/L, mildly elevated liver enzymes, and mildly elevated troponin. MRI abdomen 4.8×4.4×5. 0 cm complex enhancing mass with eccentric necrosis and/or fibrosis arising from the left adrenal gland. Ur Normetanephrine 5867 mcg/24h, Ur Metanephrine 3017 Mcg/24hr, urine dopamine and norepinephrine were within normal limits. Serum Metanephrine 2.64 nmol/L normetanephrine 13.50 nmol/L, aldosterone, renin, and cortisol levels were normal. Discussion Sustained or proximal hypertension is the most common sign of pheochromocytoma, but approximately 5-15% of pts present with normal blood pressure. Other signs and symptoms that may occur include orthostatic hypotension, visual blurring, papilledema, weight loss, polyuria, polydipsia, constipation, increased ESR, insulin resistance, hyperglycemia, leukocytosis, psychiatric disorders, and, rarely, secondary erythrocytosis due to overproduction of erythropoietin. The beta-adrenergic blocker should never be started first because a blockade of vasodilatory peripheral beta-adrenergic receptors with unopposed alpha-adrenergic receptor stimulation can lead to a further elevation in blood pressure. Our patient was normotensive throughout the hospitalization, and before admission was on metoprolol for NSTMI, however, she was unable to tolerate it due to hypotensive episodes. Conclusion Most patients with pheochromocytoma present with hypertension, however, few cases could present with normotension or even hypotension. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

Protective effects of morphine in a rat model of post-traumatic stress disorder: Role of hypothalamic-pituitary-adrenal axis and beta- adrenergic system

Post-traumatic stress disorder (PTSD) arises after tremendous traumatic experiences. Recently, we have reported that morphine has time-dependent protective effects against behavioral and morphological deficits in the single prolonged stress (SPS) as an experimental model of PTSD in adult male rats. To find the mechanisms underlying the protective effects of morphine against SPS-induced PTSD-like symptoms, the present study investigated the interaction between morphine and hypothalamic-pituitary-adrenal (HPA) axis and beta - adrenergic system, which crucially involved in the stress response, on PTSD-like symptoms in male rats. The animals were exposed to the SPS procedure (restraint for 2 h, forced swimming for 20 min, and ether anesthesia) and morphine (10 mg/kg) or saline was injected 24 h following the SPS. The glucocorticoid receptor antagonist RU486 (20 mg/kg), the mineralocorticoid receptor antagonist spironolactone (50 mg/kg), and the corticosterone synthesis inhibitor metyrapone (50 mg/kg) were injected 90 min before morphine administration to block the HPA axis activity. The beta - adrenergic receptor blocker propranolol (10 mg/kg) and the peripheral beta-adrenergic receptor blocker nadolol (5 mg/kg) were administered 30 min before morphine injection to block the beta - adrenergic system. Anxiety-like behaviors were evaluated using the elevated plus maze (EPM) 11 days after the SPS. After that, animals were conditioned in a fear-conditioning task and extinction training was performed on days 1, 2, 3, 4 and 11 after fear conditioning. SPS increased anxiety-like behaviors and impaired fear extinction. Morphine injection 24 h after SPS significantly improved anxiety-like behaviors and enhanced fear extinction. The RU486, spironolactone and metyrapone prevented the protective effects of morphine on both SPS-induced anxiety-like behaviors and impaired fear extinction. The propranolol, and nadolol did not prevent the effect of morphine on anxiety-like behaviors, but the propranolol prevented morphine effects on fear extinction in SPS animals.These findings together suggest that the protective effects of morphine on PTSD-like symptoms in rats require a certain level of the HPA axis and central beta - adrenergic activity and any alteration in the function of these systems can impede the protective effects of morphine.

Spinal GABA-B receptor modulates neutrophil recruitment to the knee joint in zymosan-induced arthritis.

Recent studies have demonstrated that the central nervous system controls inflammatory responses by activating complex efferent neuroimmune pathways. The present study was designed to evaluate the role that central gamma-aminobutyric acid type B (GABA-B) receptor plays in neutrophil migration in a murine model of zymosan-induced arthritis by using different pharmacological tools. We observed that intrathecal administration of baclofen, a selective GABA-B agonist, exacerbated the inflammatory response in the knee after zymosan administration characterized by an increase in the neutrophil recruitment and knee joint edema, whereas saclofen, a GABA-B antagonist, exerted the opposite effect. Intrathecal pretreatment of the animals with SB203580 (an inhibitor of p38 mitogen-activated protein kinase) blocked the pro-inflammatory effect of baclofen. On the other hand, systemic administration of guanethidine, a sympatholytic drug that inhibits catecholamine release, and nadolol, a beta-adrenergic receptor antagonist, reversed the effect of saclofen. Moreover, saclofen suppressed the release of the pro-inflammatory cytokines into the knee joint (ELISA) and pain-related behaviors (open field test). Since the anti-inflammatory effect of saclofen depends on the sympathetic nervous system integrity, we observed that isoproterenol, a beta-adrenergic receptor agonist, mimics the central GABA-B blockade decreasing knee joint neutrophil recruitment. Together, these results demonstrate that the pharmacological manipulation of spinal GABAergic transmission aids control of neutrophil migration to the inflamed joint by modulating the activation of the knee joint-innervating sympathetic terminal fibers through a mechanism dependent on peripheral beta-adrenergic receptors and central components, such as p38 MAPK.

The in vitro pharmacology of the β-adrenergic receptor pet ligand ( s )-fluorocarazolol reveals high affinity for cloned β-adrenergic receptors and moderate affinity for the human 5-HT 1A receptor

s-Fluorocarazolol [(S)-FCZ] is the major positron emission tomography (PET) ligand currently used to visualize central beta-adrenergic receptors in vivo, although its pharmacology is incompletely known. Our objective was to comprehensively characterize the in vitro pharmacology of (S)- and (R)-FCZ to determine its suitability for study of central and peripheral beta-adrenergic receptors. We characterized the in vitro pharmacology of (S)-FCZ at 42 biogenic amine receptors and transporters in vitro using the resources of the National Institute of Mental Health Psychoactive Drug Screening Program. As expected (R)- and (S)-FCZ had high affinities for beta-adrenergic receptors (Ki values=0.08-0.45 nM) and negligible affinities (Ki values>100 nM) for nearly all other tested receptors and transporters with the exception of the h5-HT1A receptor for which (S)-FCZ had high affinity (Ki=34 nM). Interestingly, (R)-FCZ had low affinity for the h5-HT1A receptor (Ki=342 nM). The high affinity of (S)-FCZ for the h5-HT1A receptor is not likely to interfere with studies of peripheral beta-adrenergic receptors, since 5-HT1A receptors are expressed at very low levels outside the central nervous system. Indeed, computer simulations predict that even at low ligand concentrations, 5-HT1A binding in brain regions like hippocampus are likely to be substantial. Thus, (S)-FCZ may not be a suitable PET ligand for studies of central nervous system beta-adrenergic receptors unless the contribution by 5-HT1A sites can be shown to be negligible.

Treatment of essential tremor with arotinolol

We investigated the effect of arotinolol, a new peripherally acting beta-adrenergic blocker, in 15 patients with essential tremor. The patients received 30 mg per day of arotinolol for 8 weeks. Accelerometer readings showed a significant reduction in amplitude of postural tremor after treatment. Action tremor also improved to essentially the same degree as postural tremor. The present findings support the view that the therapeutic effect of beta-blockers in essential tremor is mediated by peripheral beta-adrenergic receptors.

Chronic Carbamazepine Treatment Increases Brain Adenosine Receptors

The effect of carbamazepine on adenosine receptors in vitro has been well documented, with findings from several groups showing that therapeutic doses of this drug are sufficient to inhibit binding to the major portion of adenosine receptors in brain. In this study, we describe the effects of chronic carbamazepine on central adenosine receptors from several areas of rat brain using [3H]diethylphenylxanthine [( 3H]DPX) and [3H]cyclohexyladenosine [( 3H]CHA) as ligands. Carbamazepine was administered to rats orally in the diet at doses of 2.25 g/kg of diet and 5.0 g/kg of diet for periods of 3 and 11 days, respectively. Carbamazepine-treated animals displayed higher levels of adenosine receptors in virtually all brain areas tested, most of which reached significance in the 11-day treatment group. Scatchard analysis revealed increases in the number of receptors. There was no change in peripheral and central type benzodiazepine receptors or beta-adrenergic receptors in the carbamazepine-treated animals. Therefore, carbamazepine treatment in vivo appears to upregulate adenosine receptors, suggesting that this drug may act as an adenosine antagonist.

Blockade of peripheral beta-adrenergic receptors fails to suppress the cerebral spread of an engram in mice

Using bitemporal injections of puromycin, we have reported observations interpreted to indicate that a systemic injection of (−)-propranolol (50 μg/kg) drastically suppressed the spread of an engram in mice from the hippocampalentorhinal area to widespread cerebral areas. The present experiments were made with a non-selective, irreversible beta-adrenergic receptor antagonist that fails to cross the blood-brain barrier in order to test the possibility that the propranolol-induced blockade of peripheral beta-receptors might contribute to its effect on engram spread. Prolonged blockade of peripheral receptors by the irreversible antagonist had no effect on engram spread, suggesting that propranolol's effect was centrally mediated.

Central and peripheral receptors in guinea-pigs exposed to simulated high altitude

Guinea-pigs, chronically exposed to simulated high altitude of 6000 m, showed alterations in some, but not all, neurotransmitter-receptor systems. Thus, peripheral (cardiac) beta-adrenergic receptors were decreased in numbers (Bmax) with an increased affinity although no alterations in endogenous cardiac norepinephrine content were found. In contrast, H1-histamine receptors in the guinea-pig ventricle and brain showed no changes in Bmax or affinity. Dopamine receptors of the caudate nucleus showed no differences between control and altitude-exposed guinea-pigs, although previous reports demonstrated a significant increase (19%) in the content of endogenous dopamine of the caudate. Thus, chronic exposure to simulated high altitude altered beta-adrenergic receptors so that they were more sensitive to small ligand concentrations and less sensitive to large ligand concentrations.

Neuropharmacological agents modifying endotoxin-induced changes in mice.

A variety of neuropharmacological agents were tested to elucidate how chlorpromazine influenced an endotoxin-induced reaction. The results obtained, particularly with beta-adrenergic blocking agents, reserpine and fusaric acid, suggested that the primary locus of chlorpromazine's action was mediated by peripheral beta-adrenergic receptor blockade. Such a locus is compatible with the low doses of propranolol which suppress the reaction, and with successful treatment of shock with dopamine.

Peripheral ß-Receptor Responsiveness in Patients With Essential Hypertension

Peripheral beta-adrenergic receptor sensitivity was characterized in 24 patients with essential hypertension and in 13 age-matched normotensive subjects using an isoproterenol hydrochloride bolus dose-response technique. Decreased beta-receptor responsiveness to this exogenously administered beta-agonist was observed in hypertensive patients; for an equivalent chronotropic effect, higher doses of isoproterenol were required in hypertensive subjects than in normal subjects. Among "normal-renin" hypertensive patients, beta-receptor responsiveness was directly related to furosemide-stimulated plasma renin activity (PRA), suggesting that independently stimulated PRA may provide an indirect estimate of endogenous beta-receptor sensitivity. Hypertensive patients whose mean arterial pressure fell at least 10 mm Hg after four weeks of treatment with hydrochlorothiazide had even further depression in beta-receptor responsiveness, whereas receptor sensitivity was unchanged in patients whose blood pressure was unaffected. Thus, it is unlikely that this decreased receptor responsiveness in patients with untreated essential hypertension is a direct consequence of elevated arterial pressure.

Beta-adrenergic mechanisms in action tremor.

To study the mechanisms by which propranolol suppresses essential tremor, accelerometric recordings were made from four normal subjects and eight patients with that tremor, and small amounts of isoproterenol and propranolol were infused intravenously or into one brachial artery. Intra-arterial isoproterenol increased tremor amplitude selectively in that arm in normal subjects and in patients with essential tremor (range, 1.85 to 3.50 with mean 2.74 times the base-line level). Intra-arterial or intravenous propranolol quickly blocked the enhanced action tremor in both groups. It did not simultaneously affect the underlying essential tremor, whereas long-term oral propranolol therapy did diminish the amplitude of the essential tremor in each patient. Peripheral beta-adrenergic tremorogenic receptors function normally even in patients with essential tremor; their function is not necessary for the production of essential tremor, and the efficacy of chronic propranolol therapy in the suppression of essential tremor is not mediated via its peripheral beta-adrenergic blocking action.

Autonomic Mechanisms in Hemodynamic Responses to Isometric Exercise

Selective autonomic blockade with intravenous propranolol, practolol, atropine, and combined atropine-propranolol was utilized to elucidate the role of the autonomic nervous system in the hemodynamic responses in young adult male volunteers to handgrip sustained at 30% of maximal voluntary contraction for 3 min. The initial 30 s of the tachycardia response was found to be mediated by withdrawal of vagal dominance, as evidenced by blockade of this response by prior atropinization. The mid and late portion of the heart rate response curve was demonstrated to be sympathetic in origin, since it was unaffected by atropine, but was suppressed by combined atropine-propranolol blockade. Sympathetic stimulation appears to be a secondary mechanism for increasing the heart rate, however, as it becomes operative only after the first mechanism of vagal withdrawal has been utilized. This was confirmed by the finding that beta adrenergic receptor blockade alone had little effect on the heart rate response curve. The pressor response to handgrip was accompanied by increased cardiac output and no change in calculated systemic vascular resistance. After propranolol, handgrip resulted in increased peripheral resistance and an equivalent rise in arterial pressure, but no increase in cardiac output. It was concluded that the increase in resistance was the result of sympathetically induced vasoconstriction. This response was shown to be independent of peripheral beta adrenergic receptor blockade by the use of practolol, a cardio-selective beta adrenergic receptor-blocking drug which caused identical hemodynamic responses to those observed after propranolol. Left ventricular ejection time (corrected for heart rate) was prolonged by handgrip. The increased afterload imposed on the left ventricle by sustained handgrip may explain the prolongation of ejection time index. Preejection period was prolonged by SHG after propranolol and shortened after atropine. In addition to confirming the previously defined role of the parasympathetic nervous system, this study delineates the role of the sympathetic nervous system in the heart rate and pressor responses to sustained handgrip.

Enhancement of peripheral alpha-receptor stimulation by blockade of "silent" beta receptors.

Evidence is presented for the existence of "silent" peripheral beta adrenergic receptors with which alpha-receptor stimulants might combine without producing measurable vasodilation. Addition of propranolol (1x10 -7 M) or MJ-1999 (5x10 -6 M) to Krebs solution perfusing canine isolated mesenteric arteries enhanced (1) the pressor responses to intra-arterially administered epinephrine, norepinephrine, and methoxamine and (2) the vasoconstrictor effects of perivascular sympathetic nerve stimulation. Enhancement of the pressor effects of epinephrine and norepinephrine was unaltered during cocaine or guanethidine potentiation. The doses of the beta-receptor blocking agents that enhanced pressor responses in isolated arteries were identical to those required to provide 80 to 100% blockade of the positive inotropic and chronotropic effects of epinephrine and norepinephrine in isolated rabbit hearts. Propranolol and MJ-1999 also enhanced the elevating effects of methoxamine on canine blood pressure. In higher concentrations, propranolol (1x10 -4 M) and MJ-1999 (1x10 -3 M) produced alpha-receptor blockade in the isolated arteries, and propranolol, but not MJ-1999, produced myocardial depression in isolated rabbit hearts. These data are interpreted as indicating that alpha-receptor stimulants usually combine with both peripheral alpha and beta adrenergic receptors, and blockade of the peripheral beta receptors makes more stimulant available for alpha-receptor stimulation.