Role Of Adrenergic Receptors Research Articles

The ATP-gated P2X1 Receptor Plays a Pivotal Role in Activation of Aspirin-treated Platelets by Thrombin and Epinephrine

Human platelets express protease-activated receptor 1 (PAR1) and PAR4 but limited data indicate for differences in signal transduction. We studied the involvement of PAR1 and PAR4 in the cross-talk between thrombin and epinephrine. The results show that epinephrine acted via alpha(2A)-adrenergic receptors to provoke aggregation, secretion, and Ca(2+) mobilization in aspirin-treated platelets pre-stimulated with subthreshold concentrations of thrombin. Incubating platelets with antibodies against PAR4 or the PAR4-specific inhibitor pepducin P4pal-i1 abolished the aggregation. Furthermore, platelets pre-exposed to the PAR4-activating peptide AYPGKF, but not to the PAR1-activating peptide SFLLRN, were aggregated by epinephrine, whereas both AYPGKF and SFLLRN synergized with epinephrine in the absence of aspirin. The roles of released ATP and ADP were elucidated by using antagonists of the purinergic receptors P2X(1), P2Y(1), and P2Y(12) (i.e. NF449, MRS2159, MRS2179, and cangrelor). Intriguingly, ATP, but not ADP, was required for the epinephrine/thrombin-induced aggregation. In Western blot analysis, a low concentration of AYPGKF, but not SFLLRN, stimulated phosphorylation of Akt on serine 473. Moreover, the phosphatidyl inositide 3-kinase inhibitor LY294002 antagonized the effect of epinephrine combined with thrombin or AYPGKF. Thus, in aspirin-treated platelets, PAR4, but not PAR1, interacts synergistically with alpha(2A)-adrenergic receptors, and the PI3-kinase/Akt pathway is involved in this cross-talk. Furthermore, in PAR4-pretreated platelets, epinephrine caused dense granule secretion, and subsequent signaling from the ATP-gated P2X(1)-receptor and the alpha(2A)-adrenergic receptor induced aggregation. These results suggest a new mechanism that has ATP as a key element and circumvents the action of aspirin on epinephrine-facilitated PAR4-mediated platelet activation.

The role of adrenergic receptors and pain: The good, the bad, and the unknown

Adrenergic receptors appear to play an important role in the modulation of pain. There is now abundant evidence that activation of adrenergic receptors can, in certain circumstances, generate impressive analgesic effects. However, under other circumstances, adrenergic receptors can contribute to chronic neuropathic pain and hyperalgesia. This review will focus on the beneficial effects of adrenergic pain modulation, and the circumstances when this modulation appears to magnify pain. This review will also address controversies surrounding how these two opposing processes occur via the same mediators.

Neurohumoral activation in heart failure: the role of adrenergic receptors

Heart failure (HF) is a common endpoint for many forms of cardiovascular disease and a significant cause of morbidity and mortality. The development of end-stage HF often involves an initial insult to the myocardium that reduces cardiac output and leads to a compensatory increase in sympathetic nervous system activity. Acutely, the sympathetic hyperactivity through the activation of beta-adrenergic receptors increases heart rate and cardiac contractility, which compensate for decreased cardiac output. However, chronic exposure of the heart to elevated levels of catecholamines released from sympathetic nerve terminals and the adrenal gland may lead to further pathologic changes in the heart, resulting in continued elevation of sympathetic tone and a progressive deterioration in cardiac function. On a molecular level, altered beta-adrenergic receptor signaling plays a pivotal role in the genesis and progression of HF. beta-adrenergic receptor number and function are decreased, and downstream mechanisms are altered. In this review we will present an overview of the normal beta-adrenergic receptor pathway in the heart and the consequences of sustained adrenergic activation in HF. The myopathic potential of individual components of the adrenergic signaling will be discussed through the results of research performed in genetic modified animals. Finally, we will discuss the potential clinical impact of beta-adrenergic receptor gene polymorphisms for better understanding the progression of HF.

The role of adrenergic receptors on the antinociception of intrathecal zaprinast in the formalin test of rats

The role of adrenergic receptors on the antinociception of intrathecal zaprinast in the formalin test of rats

Role of adrenergic receptors in the reflex diuresis in rabbits during pulmonary lymphatic obstruction

The role of adrenergic receptors in the reflex diuresis in response to pulmonary lymphatic drainage was examined in anaesthetized, artificially ventilated New Zealand White rabbits. Pulmonary lymphatic drainage was obstructed by raising the pressure in a pouch created from the right external jugular vein. This pulmonary lymphatic obstruction results in a reflex increase in urine flow and sodium excretion. This reflex is abolished by renal denervation and by administration of L-NAME, a non-selective inhibitor of nitric oxide synthase. Also, infusion of the relatively selective neuronal nitric oxide synthase blocker, 7-nitroindazole sodium salt, into the renal medulla abolished the reflex diuresis. In this study the effects of adrenergic receptor antagonists on the reflex increase in urine were observed. Both ureters were cannulated in order to determine urine flow from both kidneys separately. Prazosin, an alpha1 adrenergic receptor antagonist, was infused into the renal medulla of the right kidney, while the left kidney acted as control. Administration of prazosin in this manner did not block the reflex diuresis in response to pulmonary lymphatic obstruction in either kidney. However, rauwolscine, an alpha2 adrenergic receptor antagonist, abolished the reflex increase in urine and sodium excretion in the ipsilateral kidney while preserving it in the contralateral kidney. These findings suggest that the increase in urine flow in rabbits caused by pulmonary lymphatic obstruction is dependent upon activation of alpha2 adrenergic receptors within the renal medulla.

Network integration of the adrenergic system in cardiac hypertrophy

Adrenergic receptors play a pivotal role in regulating cardiac function in response to a constantly changing environment. Altered alpha and beta adrenergic receptor signaling in vivo is associated with cardiac hypertrophy and failure. This review focuses on the different roles of adrenergic receptors in regulating cardiac function under normal and pathological conditions. Understanding the signaling mechanisms of these receptors in the context of the heart is likely to provide a better therapeutic approach towards treatment of heart failure.

ROLE OF THE SYMPATHETIC NERVOUS SYSTEM IN CARDIAC REMODELING IN HYPERTENSION

The role of the sympathetic nervous system in the settings of cardiac hypertrophy is postulated on the basis of experimental and clinical evidence. Only recently, the intimate mechanisms underlying hypertrophic responses of cardiac cell have been explored. Recent evidence spots the role of adrenergic receptors in the activation of several intracellular pathways of signaling that lead to nuclear responses of myocardiocyte.The molecular structures involved in these pathways may represent novel targets of future therapeutic interventions for cardiac hypertrophy and vascular remodeling in hypertension.

Role of adrenergic receptors in veratridine-stimulated amylase secretion from rabbit pancreatic lobules.

Sympathetic inhibition of pancreatic enzyme secretion has been attributed to vasoconstriction and direct inhibition of acinar cells. We observed both adrenergic inhibition and facilitation of cholinergic transmission in rabbit pancreatic ganglia, which innervate acini. Here we used pancreatic lobules to determine whether adrenergic receptors also regulate synaptic transmission between pancreatic nerves and acini. Stimulation of pancreatic nerve terminals with veratridine (Ver), an activator of voltage-dependent Na+ channels, resulted in a 102% increase in amylase secretion, which was unaffected by alpha and beta receptor antagonists but inhibited 65% by atropine. At a concentration of 10 microM, norepinephrine inhibited (38%) and epinephrine potentiated (40%) Ver-stimulated secretion. At the same concentration, the alpha2 agonist clonidine (Clon) inhibited (39%), whereas the nonselective beta agonist isoproterenol (Iso) and the selective beta3 agonist BRL 37344 potentiated (71 and 67%, respectively) nerve-stimulated secretion. The effects of Clon and Iso and BRL 37344 were antagonized by yohimbine and propranolol, respectively. Phenylephrine, dobutamine, and terbutaline had no effect. Neither basal, bethanechol-stimulated, nor noncholinergic nerve-stimulated secretion was significantly altered by Clon or Iso. Thus, cholinergic nerve terminals innervating pancreatic acini exhibit both inhibitory alpha2 and atypical facilitatory beta adrenergic receptors. The apparent lack of adrenergic innervation suggests that adrenergic receptors on the nerve terminals of cholinergic pancreatic neurons are under hormonal control by circulating catecholamines. These results provide further evidence that intrinsic pancreatic neurons, which supply most, if not all, of the cholinergic innervation of acini, are important sites of sympathetic regulation of pancreatic exocrine secretion.

α1-Adrenergic Hypothesis for Pulmonary Hypertension

Pulmonary hypertension (PH) is a chronic and disabling condition that affects the pulmonary vasculature. Once PH is diagnosed, the prognosis is generally poor with a rapid downhill course. PH management is largely empirical because the underlying pathophysiologic mechanisms that are responsible for the excessive vasoconstrictor and vascular smooth muscle proliferative responses are poorly understood. Based on new information concerning the role of adrenergic receptors in regulating various cellular functions, a new perspective on the genesis of PH has emerged, along with a unifying hypothesis for the role of alpha1-adrenergic receptors present in the pulmonary vasculature as the major contributor to the pathophysiologic changes associated with PH. Adrenergic receptors that are present on vascular smooth muscle cells regulate vascular tone and growth. The alpha1-adrenergic receptors that are present on the small- and medium-sized pulmonary arteries have a unique and greatly enhanced affinity and activity to alpha1-adrenergic agonists. Under physiologic conditions, this helps in regulating vascular tone and maintains an adequate ventilation/perfusion matching. However, the excessive stimulation of alpha1-adrenergic receptors produces not only smooth muscle contraction but also proliferation and growth. The conditions that produce an increase in alpha1-adrenoreceptor gene synthesis, density, and activity (such as hypoxia or changes in vessel wall pressure) or increase the levels of its agonists (such as norepinephrine, appetite suppressants, or cocaine) greatly enhance pulmonary vascular smooth muscle contractile and proliferative responses and lead to the development of PH. An understanding of the role played by these receptors in the pathophysiology of PH would not only help to avoid the use of alpha1-agonists for appetite suppression and other disease states, but also would help in developing new drugs to block these receptors. A further understanding of the alpha1-adrenoreceptor subtypes present in the pulmonary vasculature, the factors that regulate their expression, and their intracellular signaling pathways would help researchers to devise newer therapeutic strategies and, hopefully, to find a cure for this crippling condition.

Effects of topical application of adrenergic agents on refraction and accommodation

In an attempt to clarify the functional role of adrenergic receptors on accommodation, effects of various adrenergic agents on the state of accommodation were studied. Fifty-two emmetropic normal subjects (age: 19-28 y) participated in this study. We examined the effect of the alpha agonist phenylephrine hydrochloride (5%), the alpha 1 antagonist adrenergic bunazosin hydrochloride (0.1%), the beta antagonist timolol maleate (0.5%), the beta 2 antagonist betaxolal hydrochloride (0.5%), and the beta agonist isoproterenol hydrochloride (3%). Using an infrared optometer, the refraction, far point and near point of accommodation, resting point of accommodation (empty-field accommodation and dark focus of accommodation), and accommodative adaptation were measured before and after topical application of various adrenergic agents. Application of bunazosin slightly but significantly decreased the near point of accommodation. Isoproterenol evoked a hyperopic shift on the far point of accommodation. None of the agents had any effect on the resting point of accommodation. Accommodative adaptation was increased by timolol and betaxolol, and decreased by isoproterenol. We surmised that beta adrenergic agents exerted an indirect influence on the parasympathetic nervous system. The activation of beta receptors produced a hyperopic shift on the far point of accommodation and decreased accommodative adaptation, which suggests that activation of adrenergic receptors may reduce parasympathetic activity, hence affecting the state of accommodation.

The role of adrenergic receptors in mediating sickness behavior

The role of adrenergic receptors in mediating sickness behavior

Effect of adrenergic receptor activation on post-herpetic neuralgia pain and sensory disturbances

Patients with acute herpes zoster, and to a lesser extent post-herpetic neuralgia (PHN), have been reported to respond to local anesthetic blockade of the sympathetic nervous system. In animal models of nerve injury, local injection of adrenergic agonists after nerve injury, but not before, excites nociceptors. In some patients with chronic neuropathic pain, local application of norepinephrine evokes pain. In 15 subjects with PHN, the role of adrenergic receptors in PHN pain was assessed in a two-session double blind study comparing the response to cutaneous infiltration of epinephrine or phenylephrine (30 μg in 3 ml) with the response to normal saline in both the painfully affected skin and mirror-image normal skin. Two adjacent sites were studied on each side of the body, one site for injection and the other for measuring sensory effects of the injection. In the morning part of each session, mirror-image normal skin was injected. In the afternoon portion of each session, skin in the most painful area affected by PHN was injected. Injection of saline or the adrenergic agonist in normal skin produced mild and transient pain without development of allodynia and without affecting overall PHN pain intensity. In PHN skin, injection of saline and the adrenergic agonist produced an equivalent degree of transient pain that was slightly greater than injection into mirror-image normal skin. After injection of the adrenergic agonist into PHN skin, both overall PHN pain and allodynia severity were significantly greater than after saline injection, peaking at 10–15 min post-injection. Even when PHN has been present for years, adrenergic receptor stimulation in PHN skin increases pain, most likely through direct activation of C-nociceptors in the painful skin. Increased allodynia is most likely mediated centrally and driven by the increase in C-nociceptor input.

Aging and cardiovascular disease: a summary of the Eighth Münster International Arteriosclerosis Symposium.

This unique symposium focused on the remarkable increase in the older population that is occurring in many countries of the world. The international experts spoke on the effects of aging on cardiovascular disease, which is by far the most prominent cause of morbidity and mortality in the elderly. The program highlighted some of the most prominent changes that occur in the elderly and influence the toll that cardiovascular disease takes. The program was divided into four sessions: (1) the effects of aging on some of the cardiovascular risk factors; (2) the effects of aging on the heart muscle; (3) reports on recent studies of the effects of aging on morphology and function of the conduction system; and (4) a session featuring outstanding authorities on aging and the elastin, collagen, and calcium of the vessel wall, all of which are frequently added to the artery wall during aging. The speakers were carefully selected from top scholars in England, Germany, Finland, France, Italy, Japan, and the United States. Professor W.H. Hauss, who pioneered the development of the Institute for Arteriosclerosis Research at the University of Munster, Germany, and is now in his 80s, opened the symposium and introduced four prominent officials in health, education, and other German government posts, who added their words of welcome. The first session was chaired by Professor G. Assmann, who is the current director of the Arteriosclerosis Research Institute in Munster, Germany. He gave the opening presentation on genetic determinants of life expectancy, a subject on which he is a world authority. He began his presentation with a brief description of the very large PROCAM study of more than 35 000 individuals, two thirds of whom are male, being carried out at the University of Munster Arteriosclerosis Institute in Westphalia. This long-term study of the natural history …

β- and α-adrenergic mechanisms are involved in regulating type II thyroxine 5′-deiodinase in rat thymus

The role of adrenergic receptors in regulation of rat thymus type II thyroxine 5′-deiodinase (5′-D) activity was investigated. Our results show that norepinephrine, an α- and β-adrenergic agonist elicited an increase in thymus 5′-D activity. Isoproterenol, a β-adrenergic agonist, also increased the enzyme activity, being less effective than norepinephrine. Moreover, α-adrenergic agonists, i.e., methoxamine, an α 1-agonist, and clonidine, an α 2-agonist, did not increase 5′-D activity. The effect of isoproterenol was potentiated by methoxamine, but the potentiating effect was observed only at doses of isoproterenol which induce submaximal activation of the enzyme. Administration of propranolol, a β-adrenergic blocker, and prazosin, an α 1-adrenergic blocker, inhibited significantly the activation of the enzyme induced by norepinephrine. However, yohimbine, an α 2-adrenergic blocker, had small effect These results show, in hypothyroid rats, a clear regulation by adrenergic mechanisms of 5′-D activity in the thymus, where α- and β-adrenergic receptors might be involved.

Blockade of Vasospastic Attacks by α 2 -Adrenergic but Not α 1 -Adrenergic Antagonists in Idiopathic Raynaud’s Disease

Idiopathic Raynaud's disease is characterized by cold-induced digital vasospasms, but its origin has not been established. Previous research has shown that peripheral vascular alpha 2-adrenergic receptors are hypersensitive to local cooling in these patients, but the role of alpha 1-adrenergic receptors is not clear. Moreover, the role of adrenergic receptors in the production of actual vasospastic symptoms has not been investigated. We studied 23 patients with idiopathic Raynaud's disease who were screened using conservative criteria. They were randomly assigned to receive brachial artery infusions of an alpha 1-antagonist, an alpha 2-antagonist, or both while vasospastic attacks were induced by cooling in the laboratory. Each patient's hands were photographed, and the number of attacks in the infused hand was compared with the number in the contralateral hand. The number of fingers (mean +/- SEM) with attacks in infused hands was yohimbine 0.3 +/- 0.3, prazosin 2.3 +/- 0.3, and both drugs 0.6 +/- 0.2. The difference between prazosin and the other two drug groups was significant (P < .001). These findings demonstrate that activation of alpha 2-adrenergic receptors but not alpha 1-adrenergic receptors is necessary for the production of vasospastic attacks in idiopathic Raynaud's disease.

Role of adrenergic receptors in experimental cardiac hypertrophy

Role of adrenergic receptors in experimental cardiac hypertrophy

Effects of delta-aminolaevulinic acid on contractile activity in the isolated small intestine of the rabbit: Role of adrenergic receptors

The porphyrin precursor, delta-aminolaevulinic acid (ALA) at concentrations of 0.23–7.6 mM caused dose-dependent inhibition of spontaneous contractions in isolated preparations of rabbit small intestine, suspended in Ringer-Locke solution. Contractions which returned after inhibition from 3.8 and 7.6 mM ALA showed increased amplitude and from 7.6 mM ALA a reduction in rate. Pretreatment with prazosin (10 −7 M) significantly reduced the duration of inhibition exerted by 3.8 and 7.6 mM ALA and also the amplitude of contractions returning after this inhibition. Pretreatment with yohimbine (10 −6M) and propranolol (7 × 10 −6M) had no significant effects. Blocking of the release of noradrenaline in preparations by incubation with 6-hydroxydopamine (10 −3M) or guanethidine (1.5 × 10 −5M) did not prevent the inhibitory effects of ALA. The alpha, agonist, cirazoline (10 −5 M), inhibited contractile activity. This effect was blocked by prazosin (10 −7M). The alpha 2 agonist, guanoxabenz (10 −5M) had no detectable effect, in the presence of prazosin, to block any residual alpha 1 actions. It is concluded that alpha 1 receptors mediate inhibitory effects in this preparation and that ALA appears to have direct effects upon these receptors.

Role of adrenergic receptors in the mechanism of the influence of catecholamines and dopa on proliferation

Role of adrenergic receptors in the mechanism of the influence of catecholamines and dopa on proliferation

The role of adrenergic receptors and Ca 2+ in the action of endotoxin on human fat cells

Incubation of isolated human adipocytes with Escherichia coli endotoxin increases basal lipolysis without influencing basal cAMP levels. Hormonally stimulated fatty acid release (norepinephrine, 1.2 μM; isoproterenol, 0.95 μM) is depressed by endotoxin, while norepinephrine-stimulated cAMP concentrations remain unchanged. The β blocker, propranolol (10 -2 m M), depresses norepinephrine-stimulated lipolysis, and endotoxin does not alter its actions. Phentolamine (the α blocker, 10 -2 mM) enhances norepinephrine-stimulated lipolysis and also cAMP levels. Endotoxin alters the cellular response to this α blocker such that its stimulatory influence on norepinephrine-induced glycerol release and cAMP levels is depressed. The divalent cation ionophore A23187 stimulates basal and norepinephrine-induced glycerol release with no influence on the release of fatty acids. These actions do not appear to be mediated via a cAMP mechanism since ionophore has no influence on basal and depresses norepinephrine-stimulated cAMP levels. Pre-incubation of cells with endotoxin does not alter A23187 action on glycerol release. However, endotoxin does obviate the depressant action of the ionophore on norepinephrine-stimulated cAMP concentrations. The results indicate that under our experimental conditions endotoxin may be altering the activity of the β receptor, while not interfering with the β receptor. Similarities between endotoxin and ionophore actions are compatible with the hypothesis that endotoxin may be exerting its influence on the cellular level, at least in part, by acting as an ionophore.

Dynamics of acute retention in prostatic patient and role of adrenergic receptors

The dynamic changes in the lower urinary tract associated with acute retention in the prostatic patient were investigated by pressure studies. These revealed that the site of maximal urethral pressure was in the prostatic segment, the bladder neck was not tightly closed, and the normal tone of the external sphincter was inhibited. Bladder decompression altered these findings, and alpha-adrenergic blockade produced a reduction in all pressure parameters in the posterior urethra. The significance of the findings is discussed in relation to present-day knowledge of lower tract urodynamics. It is concluded that certain cases of acute retention in the prostatic patient may be initiated by stimulation of the prostatic alpha-adrenergic receptors, and may then be perpetuated by a secondary fall in intravesical pressure together with a supplementary “feed-back” stimulation of these receptors due to the bladder overdistention itself. Decompression and/or alpha-adrenergic block may sometimes reverse this process.