Role of cardiac β1-adrenergic and A1-adenosine receptors in severe arrhythmias related to Parkinson's disease

Abstract Aims Although reduced life expectancy in Parkinson's Disease (PD) patients has been related to severe cardiac arrhythmias due to autonomic dysfunctions, its molecular mechanisms remain unclear. To investigate the role of cardiac β1-Adrenergic (β1AR) and A1-Adenosine (A1R) receptors in these dysfunctions, the pharmacological effects of stimulation of cardiac β1AR (isoproterenol, ISO), in the absence and presence of cardiac β1AR (atenolol, AT) or A1R (1,3-dipropyl-8-cyclopentyl xanthine, DPCPX) blockade, on the arrhythmias induced by Ischemia/Reperfusion (CIR) in an animal PD model were studied. Methods PD was produced by dopaminergic lesions (confirmed by immunohistochemistry analysis) caused by the injection of 6-hydroxydopamine (6-OHDA, 6 μg) in rat striatum. CIR was produced by a surgical interruption for 10 min followed by reestablishment of blood circulation in the descendent left coronary artery. On the incidence of CIR-Induced Ventricular Arrhythmias (VA), Atrioventricular Block (AVB), and Lethality (LET), evaluated by Electrocardiogram (ECG) analysis, the effects of intravenous treatment with ISO, AT and DPCPX (before CIR) were studied. Results VA, AVB and LET incidences were significantly higher in 6-OHDA (83%, 92%, 100%, respectively) than in control rats (58%, 67% and 67%, respectively). ISO treatment significantly reduced these incidences in 6-OHDA (33%, 33% and 42%, respectively) and control rats (25%, 25%, 33%, respectively), indicating that stimulation of cardiac β1AR induced cardioprotection. This response was prevented by pretreatment with AT and DPCPX, confirming the involvement of cardiac β1AR and A1R. Conclusion Pharmacological modulation of cardiac β1AR and A1R could be a potential therapeutic strategy to reduce severe arrhythmias and increase life expectancy in PD patients.

Participation of hepatic α/β-adrenoceptors and AT1 receptors in glucose release and portal hypertensive response induced by adrenaline or angiotensin II

It has been previously demonstrated that the hemodynamic effect induced by angiotensin II (AII) in the liver was completely abolished by losartan while glucose release was partially affected by losartan. Angiotensin II type 1 (AT1) and adrenergic (∝1- and β-) receptors (AR) belong to the G-proteins superfamily, which signaling promote glycogen breakdown and glucose release. Interactive relationship between AR and AT1-R was shown after blockade of these receptors with specific antagonists. The isolated perfused rat liver was used to study hemodynamic and metabolic responses induced by AII and adrenaline (Adr) in the presence of AT1 (losartan) and ∝1-AR and β-AR antagonists (prazosin and propranolol). All antagonists diminished the hemodynamic response induced by Adr. Losartan abolished hemodynamic response induced by AII, and AR antagonists had no effect when used alone. When combined, the antagonists caused a decrease in the hemodynamic response. The metabolic response induced by Adr was mainly mediated by ∝1-AR. A significant decrease in the hemodynamic response induced by Adr caused by losartan confirmed the participation of AT1-R. The metabolic response induced by AII was impaired by propranolol, indicating the participation of β-AR. When both ARs were blocked, the hemodynamic and metabolic responses were impaired in a cumulative effect. These results suggested that both ARs might be responsible for AII effects. This possible cross-talk between β-AR and AT1-R signaling in the hepatocytes has yet to be investigated and should be considered in the design of specific drugs.

Maprotiline treatment differentially influences cardiac β -adrenoreceptors expression under normal and stress conditions

Alterations in cardiac function were observed in antidepressants treated patients and published in several clinical reports. These detected changes could be either a consequence of the treatment or of depression itself, which has already been proved to be a risk factor in heart diseases. In order to determine a possible influence of chronic treatment with norepinephrinergic reuptake inhibitor, maprotiline, on the heart, we investigated gene expression of cardiac β-adrenoceptors both in controls and in animals with signs of depression. The rats were divided into two groups, unstressed controls and those exposed to chronic unpredictable mild stress (CUMS). The groups were further divided into two subgroups, one receiving daily intraperitoneal injections of vehicle (sterile water) and another one maprotiline (10 mg/kg) for four weeks. Tissue samples were collected after the last application. Gene expression of cardiac β1- and β2-adrenoceptor was determined using Real-time RT-PCR analysis. Our results show that in control animals expression of both adrenoreceptors was decreased in the right atria after 4 weeks of maprotiline application. Contrary, the same treatment led to a significant increase in expression of cardiac β1-adrenoceptor in the stressed rats, with no change in the characteristics of β2-adrenoceptor. Our findings might reflect the that molecular mechanisms are underlying factors involved in the development of cardiovascular diseases linked with antidepressant treatment.

Vários relatórios clínicos observaram alterações de funcionamento cardíaco de pacientes depressivos que foram tratados com os antidepressivos. As alterações detectadas podem ser consequência do tratamento ou, por outro lado, da depressão que, como se tem provado, é um fator de risco no caso de doenças cardíacas. De modo a determinar a possível influência de tratamento crônico com o inibidor da recaptação de norepinefrina, maprotilina, no coração, foi investigada a expressão do gene aos receptores β-adrenérgicos cardíacos dos animais em grupos de controle e em grupos com sinais de depressão. Os ratos foram divididos em grupos de controle não estressados e os grupos de ratos submetidos ao estresse crônico moderado imprevisível (CUMS). Os grupos foram, ainda, divididos em dois subgrupos, que, durante quatro semanas, diariamente receberam injeções intraperitoneais de placebo (água estéril) ou de maprotilina (10 mg/kg). As amostras de tecido foram coletadas após a última aplicação. A expressão do gene aos receptores adrenérgicos β1 e β2 foi determinada utilizando a análise PCR quantitativa em tempo real (RT-PCR). Os nossos resultados demonstram a diminuição de expressão dos ambos os receptores adrenérgicos no átrio direito dos animais do grupo de controle depois de quatro semanas de aplicação de maprotilina. Em contraste, o mesmo tratamento conduziu ao aumento significativo na expressão do receptor β1-adrenérgico no coração dos ratos estressados, sem qualquer alteração nas características do receptor β2-adrenérgico. Estes resultados podem refletir os mecanismos moleculares envolvidos no desenvolvimento de doenças cardiovasculares associadas ao tratamento com os antidepressivos.

Tratamiento farmacológico en la hiperplasia prostática benigna / Pharmacological treatment of the benign prostatic hyperplasia

La hiperplasia prostática benigna, enfermedad común en hombres a partir de los 50 años de edad, consiste en el crecimiento benigno e incontrolado de la glándula prostática y produce diversos síntomas del tracto bajo urinario. Su agente causal multifactorial involucra fundamentalmente el incremento de la conversión de testosterona en dihidrotestosterona por acción de la 5 a-reductasa prostática, lo cual desencadena eventos que propician el incremento en el tamaño de la próstata (componente estático) y el aumento del tono del músculo liso de vejiga y próstata (componente dinámico) regulado por los adrenoreceptores (ADR)-a1. El tratamiento farmacológico de la hiperplasia prostática benigna incluye los inhibidores de la 5a-reductasa, antagonistas de ADR-a1, su terapia combinada y la fitoterapia. El objetivo del presente trabajo fue presentar los aspectos más relevantes de la farmacología de los fármacos utilizados en el tratamiento de la hiperplasia prostática benigna y brindar elementos de su eficacia, seguridad y tolerabilidad. Para ello, se realizó una reseña de los diferentes fármacos utilizados en el tratamiento de esta afección, los que fueron clasificados de acuerdo con su mecanismo de acción. Se incluyeron productos de origen natural como los extractos lipídicos del Serenoa repens y Pygeum africanum, así como el D-004, extracto lipídico de los frutos de la Roystonea regia, que ejerce efectos beneficiosos sobre los principales factores causales de la hiperplasia prostática benigna, ya que es un inhibidor de la 5 a-reductasa prostática, un antagonista de los ADR-a1, un inhibidor de la 5-lipooxigenasa y tiene acción antioxidante, lo que evidencia un mecanismo multifactorial. Los resultados hasta el presente indican que el D-004 es seguro y bien tolerado

Benign prostatic hyperplasia is a common disease in over 50 years-old men consisting in uncontrolled and benign growth of prostatic gland that leads to lower urinary tract symptoms. The etiology of benign prostatic hyperplasia is multifactoral involving the increased conversion of testosterone in dihydrotestosterone by the prostatic 5a-reductase action, which brought about events that encourage the prostate growth (static component) and the increase of the bladder and prostate smooth muscle tone (dynamic component) regulated by the a1 -adrenoceptors (ADR). The pharmacological treatment of the benign prostatic hyperplasia includes the prostatic 5a-reductase inhibitors, the a1-adrenoreceptor blockers, their combined therapy and the phytotherapy. This paper was aimed at presenting the most relevant aspects of the pharmacology of drugs used for treating the benign prostatic hyperplasia, and providing elements to analyze their efficacy, safety and tolerability. To this end, a review was made of the different drugs for the treatment of this pathology and they were grouped according to their mechanism of action. Natural products were included as lipid extracts from Serenoa repens and Pygeum africanum as well as D-004, a lipid extract from Roystonea regia fruits, with proved beneficial effects on the main etiological factors of benign prostatic hyperplasia. D-004 is a prostatic 5a-reductase inhibitor, an a1-adrenoceptor antagonist, a 5-lipooxygenase inhibitor and has antioxidant action, all of which reveals a multifactoral mechanism. The results achieved till now indicate that D-004 is a safe and well-tolerated product

C-Jun NH2-Terminal Kinase Contributes to Dexmedetomidine-Induced Contraction in Isolated Rat Aortic Smooth Muscle

PURPOSE: Dexmedetomidine, a full agonist of alpha2B-adrenoceptors, is used for analgesia and sedation in the intensive care units. Dexmedetomidine produces an initial transient hypertension due to the activation of post-junctional alpha2B-adrenoceptors on vascular smooth muscle cells (SMCs). The aims of this in vitro study were to identify mitogen-activated protein kinase (MAPK) isoforms that are primarily involved in full, alpha2B-adrenoceptor agonist, dexmedetomidine-induced contraction of isolated rat aortic SMCs. MATERIALS AND METHODS: Rat thoracic aortic rings without endothelium were isolated and suspended for isometric tension recording. Cumulative dexmedetomidine (10(-9) to 10(-6) M) dose-response curves were generated in the presence or absence of extracellular signal-regulated kinase (ERK) inhibitor PD 98059, p38 MAPK inhibitor SB 203580, c-Jun NH2-terminal kinase (JNK) inhibitor SP 600125, L-type calcium channel blocker (verapamil and nifedipine), and alpha2-adrenoceptor inhibitor atipamezole. Dexmedetomidine-induced phosphorylation of ERK, JNK, and p38 MAPK in rat aortic SMCs was detected using Western blotting. RESULTS: SP 600125 (10(-6) to 10(-5) M) attenuated dexmedetomidine-evoked contraction in a concentration-dependent manner, whereas PD 98059 had no effect on dexmedetomidine-induced contraction. SB 203580 (10(-5) M) attenuated dexmedetomidine-induced contraction. Dexmedetomidine-evoked contractions were both abolished by atipamezole and attenuated by verapamil and nifedipine. Dexmedetomidine induced phosphorylation of JNK and p38 MAPK in rat aortic SMCs, but did not induce phosphorylation of ERK. CONCLUSION: Dexmedetomidine-induced contraction involves a JNK- and p38 MAPK-mediated pathway downstream of alpha2-adrenoceptor stimulation in rat aortic SMCs. In addition, dexmedetomidine-induced contractions are primarily dependent on calcium influx via L-type calcium channels.

Lack of evidence for regulation of cardiac P-type ATPases and MAP kinases in transgenic mice with cardiac-specific overexpression of constitutively active á1B-adrenoceptors

The regulatory function of á1B-adrenoceptors in mammalian heart homeostasis is controversial. The objective of the present study was to characterize the expression/activity of key proteins implicated in cardiac calcium handling (Na+/K+-ATPase and Ca2+-ATPases) and growth (ERK1/2, JNK1/2 and p38) in mice with cardiac-selective overexpression of constitutively active mutant á1B-adrenoceptor (CAMá1B-AR), which present a mild cardiac hypertrophy phenotype. Immunoblot assays showed that myocardial plasma membrane Ca2+-ATPase (PMCA) expression was increased by 30 percent in CAMá1B-AR mice (N = 6, P < 0.05), although there was no change in sarco/endoplasmic reticulum Ca2+-ATPase (SERCA2) expression. Moreover, total Ca2+-ATPase activity was not modified, but a significant increase in the activity of the thapsigargin-resistant (PMCA) to thapsigargin-sensitive (SERCA) ratio was detected. Neither Na+/K+-ATPase activity nor the expression of á1 and á2 subunit isoforms was changed in CAMá1B-AR mouse hearts. Moreover, immunoblot assays did not provide evidence for an enhanced activation of the three mitogen-activated protein kinases studied in this stage of hypertrophy. Therefore, these findings indicate that chronic cardiac á1B-AR activation in vivo led to mild hypertrophy devoid of significant signs of adaptive modifications concerning primary intracellular calcium control and growth-related proteins, suggesting a minor pathophysiological role of this adrenergic receptor in mouse heart at this stage of development.

Glucocorticoids, master modulators of the thymic catecholaminergic system?

There is evidence that the major mediators of stress, i.e., catecholamines and glucocorticoids, play an important role in modulating thymopoiesis and consequently immune responses. Furthermore, there are data suggesting that glucocorticoids influence catecholamine action. Therefore, to assess the putative relevance of glucocorticoid-catecholamine interplay in the modulation of thymopoiesis we analyzed thymocyte differentiation/maturation in non-adrenalectomized and andrenalectomized rats subjected to treatment with propranolol (0.4 mg·100 g body weight-1·day-1) for 4 days. The effects of β-adrenoceptor blockade on thymopoiesis in non-adrenalectomized rats differed not only quantitatively but also qualitatively from those in adrenalectomized rats. In adrenalectomized rats, besides a more efficient thymopoiesis [judged by a more pronounced increase in the relative proportion of the most mature single-positive TCRαβhigh thymocytes as revealed by two-way ANOVA; for CD4+CD8- F (1,20) = 10.92, P < 0.01; for CD4-CD8+ F (1,20) = 7.47, P < 0.05], a skewed thymocyte maturation towards the CD4-CD8+ phenotype, and consequently a diminished CD4+CD8-/CD4-CD8+ mature TCRαβhigh thymocyte ratio (3.41 ± 0.21 in non-adrenalectomized rats vs 2.90 ± 0.31 in adrenalectomized rats, P < 0.05) were found. Therefore, we assumed that catecholaminergic modulation of thymopoiesis exhibits a substantial degree of glucocorticoid-dependent plasticity. Given that glucocorticoids, apart from catecholamine synthesis, influence adrenoceptor expression, we also hypothesized that the lack of adrenal glucocorticoids affected not only β-adrenoceptor- but also α-adrenoceptor-mediated modulation of thymopoiesis.

Expression and function of G-protein-coupled receptorsin the male reproductive tract

This review focuses on the expression and function of muscarinic acetylcholine receptors (mAChRs), α1-adrenoceptors and relaxin receptors in the male reproductive tract. The localization and differential expression of mAChR and α1-adrenoceptor subtypes in specific compartments of the efferent ductules, epididymis, vas deferens, seminal vesicle and prostate of various species indicate a role for these receptors in the modulation of luminal fluid composition and smooth muscle contraction, including effects on male fertility. Furthermore, the activation of mAChRs induces transactivation of the epidermal growth factor receptor (EGFR) and the Sertoli cell proliferation. The relaxin receptors are present in the testis, RXFP1 in elongated spermatids and Sertoli cells from rat, and RXFP2 in Leydig and germ cells from rat and human, suggesting a role for these receptors in the spermatogenic process. The localization of both receptors in the apical portion of epithelial cells and smooth muscle layers of the vas deferens suggests an involvement of these receptors in the contraction and regulation of secretion.

Esta revisão enfatiza a expressão e a função dos receptores muscarínicos, adrenoceptores α1 e receptores para relaxina no sistema reprodutor masculino. A expressão dos receptores muscarínicos e adrenoceptores α1 em compartimentos específicos de dúctulos eferentes, epidídimo, ductos deferentes, vesícula seminal e próstata de várias espécies indica o envolvimento destes receptores na modulação da composição do fluido luminal e na contração do músculo liso, incluindo efeitos na fertilidade masculina. Além disso, a ativação dos receptores muscarínicos leva à transativação do receptor para o fator crescimento epidermal e proliferação das células de Sertoli. Os receptores para relaxina estão presentes no testículo, RXFP1 nas espermátides alongadas e células de Sertoli de rato e RXFP2 nas células de Leydig e germinativas de ratos e humano, sugerindo o envolvimento destes receptores no processo espermatogênico. A localização de ambos os receptores na porção apical das células epiteliais e no músculo liso dos ductos deferentes de rato sugere um papel na contração e na regulação da secreção.

Efeitos dos receptores adrenérgicos no reparo tecidual cutâneo / Effects of adrenergic receptors in cutaneous tissue repair

Os receptores adrenérgicos regulam diversas funções do sistema tegumentar; entretanto, o papel destes receptores no processo de reparo tecidual cutâneo ainda não é completamente compreendido. O objetivo deste trabalho foi investigar o papel dos receptores alfa- e beta-adrenérgicos no reparo tecidual cutâneo em ratos. Inicialmente observamos que o bloqueio dos receptores beta1- e beta2-adrenérgicos (através da administração de propranolol) reduz a contração, a re-epitelização e a deposição de colágeno em lesões excisionais cutâneas, mas aumenta o infiltrado inflamatório, a proliferação celular, a densidade miofibroblástica e de vasos sanguíneos. Em seguida avaliamos se ambos receptores beta1- e beta2-adrenérgicos participam das alterações causadas pela administração de propranolol no reparo de lesões excisionais cutâneas e se os receptores alfa1- e alfa2-adrenérgicos participam do reparo destas lesões. O bloqueio de ambos receptores beta1- e beta1-adrenérgicos retarda a resposta inflamatória, o desenvolvimento do tecido de granulação e o remodelamento do tecido. Entretanto, o bloqueio do receptor beta1-adrenérgico não altera a re-epitelização. Além disso, o bloqueio dos receptores alfa1- e alfa2-adrenérgicos não compromete o reparo de lesões excisionais cutâneas. Posteriormente investigamos se o retardo induzido pela administração de propranolol no reparo tecidual cutâneo ocorre através da ativação dos receptores alfa-adrenérgicos. O bloqueio simultâneo dos receptores beta1-, beta2-, alfa1- e alfa2-adrenérgicos prejudica o fechamento, a re-epitelização, a mobilização de mastócitos e a proliferação celular de lesões excisionais cutâneas sem um efeito sinérgico ou a ativação dos receptores a-adrenérgicos. Além disso, estudamos os efeitos dos receptores alfa- e beta-adrenérgicos na formação do tecido de granulação em implantes de esponjas de poliuretano. O bloqueio dos receptores beta1- e beta2-adrenérgicos, mas não o bloqueio dos receptores alfa1 e alfa2...

Adrenoceptors regulate several functions of the skin; however, the role of adrenoceptors on cutaneous wound healing is not completely understood yet. The aim of this study was to investigate the role of the alfa- and beta-adrenoceptors on cutaneous wound healing in rats. Firstly, we observe that the blockage of beta1- and beta2-adrenoceptors (through propranolol administration) reduces wound contraction, re-epithelialization, and collagen deposition, but increases inflammatory infiltrate, cellular proliferation, density of myofibroblasts and blood vessels. Subsequently, we evaluate if both beta1- and beta2-adrenoceptors play a role in the propranolol-induced alterations on cutaneous wound healing and if alfa1- and alfa2-adrenoceptors participate in cutaneous wound healing. The blockade of both beta1- e beta2-adrenoceptors delays inflammatory response, granulation tissue formation and tissue remodeling. However, the blockade of beta1-adrenoceptors does not alter re-epithelialization. Moreover, the blockage of the alfa1- and alfa2-adrenoceptors does not compromise tissue repair of the cutaneous excisional lesions. Furthermore, we evaluate if propranolol-induced alterations on cutaneous wound healing occur through alfa1- and alfa2-adrenoceptors activation. The simultaneous blockade of beta1-, beta2-, alfa1- and alfa2-adrenoceptors impairs wound contraction, re-epithelialization, mast cells mobilization, and cellular proliferation of the cutaneous excisional lesions without a synergic effect or alfa-adrenoceptors activation. In addition, we study the effects of alfa- and beta-adrenoceptors blockade on granulation tissue formation in polyurethane sponges implants. The blockade of beta1- and beta2-adrenoceptors, but not alfa1- and alfa2-adrenoceptors, delays inflammatory cells migration, myofibroblastic differentiation, angiogenesis, and collagen fibers organization. Moreover, we also evaluate the effects of administration of a low dose of propranolol ...

Correlation of expressions of center and peripheral adrenoceptors with blood pressure regulation after acute intracerebral hemorrhage in spontaneously hypertensive rats / 国际脑血管病杂志

Objective To observe the changes of the blood pressure after intracerebral hemorrhage (ICH) in spontaneously hypertensive rats (SHRs) as well as the expressions of α2A-adrenergic receptor (AR) in center (brain tissue) and peripheral (renal tissue) α1A-AR and to investigate the correlation between α1A-AR/α2A-AR and blood pressure regulation in acute hypertensive ICH. Methads A total of 30 six-month-old male SHRs were randomly divided into a sham-operation group and ICH (day 1,3, 7 and 14) groups (n =6 in each group). Blood pressure was measured by the tail-cuff method. Collagenase Ⅳ was injected into caudate-puta-men nucleus to induce a model of ICH. The expressions of α1A-AR and α2A-AR were detected by using immunohistochemistry and reverse-transcription polymerase chain reaction. Results One day after ICH, the blood pressure was 195.4 ± 8.39 mm Hg, and it was significantly higher than 177.8 ± 8.69 mm Hg (P = 0. 000) before ICH and 184. 1 ± 3.76 mm Hg in the sham-operation group (P=0. 002). At day 3 it was 185.3 ±9.22 mm Hg, and it was lower than that at day 1. It was 177.7 ±5.62 mm Hg and 176.7 ±6. 06 mm Hg at day7 and 14 respectively, which almost returned to the normal level before ICH. The α1A-AR mRNA and protein in renal tissue at day 1 after ICH were 0. 91 ±0. 013 and 0. 944 ±0. 142%, respectively, They were higher than 0. 89 ±0. 018 and0. 779 ±0. 103% in the sham-operation group, and they reached the peak (0. 93 ±0.015, P =0.008; 1.526 ± 0.296%, P =0.010) at day 3. The α2A-AR mRNA and protein in brain tissue were 0. 93 ±0. 020 and 2.64 ±0. 293% at day 3 after ICH, and they were significantly higher than 0. 86 ±0. 019 (P =0. 001) and 1. 070 ±0. 155% (P = 0. 020), and0.87 ±0. 029 (P =0. 000) at day 1 after ICH and 1. 629 ±0. 488% (P =0. 023) in the sham-operation group. The changes of blood pressure in the ICH day 1 to day 7 grottos in SHRs and correlation coefficient of α2A-AR mRNA absorbance in brain tissue r was - 0. 509 (P = 0.031), and the correlation coefficient of α2A-AR protein-expression volume fraction in brain tissue r was - 0. 473 (P = 0. 047). Conelusions Regulation of blood pressure during acute ICH may have certain correlation with the up-expressions of α2A-AR in brain tissue and α1A-AR in renal tissue.

Effect of Electroacupuncture on Reperfusion Ventricular Arrhythmia in Rat / 华中科技大学学报（医学）（英德文版）

Protective effect and mechanism of electroacupuncture (EA) on acute reperfusion ventricular arrhthmia was investigated. Ventricular arrhythmia was induced by occlusion of the proximal left anterior descend (LAD) branch of coronary artery for 5 min and followed with 15 min reperfusion . EA on acupoint "Neiguan", "Jianshi" was performed at 30 min before ligation and continued another 5 min during ischemia. Isoprenaline (20, 30 and 50 μg/kg) or atropine (1 mg/kg) was intravenously injected at 5min before ischemia. The results showed that EA significantly decreased the incidence of ischemia/reperfusion (I/R) induced ventricular tachycardia (VT), ventricular fibrillation (VF) and mortality as compared to I/R group. Atropine partially suppressed the EA's effect of antiarrhythmia; Isoprenaline increased the incidence and severity of reperfusion arrhythmia, which was inhibited by EA, but this inhibition of EA was blocked with increasing dose of isoprenaline. The results indicated that EA treatment could prevent the occurrence of reperfusion ventricular arrhythmia in rats with myocardial ischemia, and its mechanism might be related to the regulation of EA on the β-adrenoceptors and M-cholinergic receptor activation in myocardium.

An Insertion/Deletion Polymorphism in the alpha(2B)-Adrenoceptor Gene is not a Genetic Risk Factor for Coronary Artery Disease in the Korean Population

BACKGROUND AND OBJECTIVES: Cardiovascular disease (CVD) is a complex multigenic disorder, with significant inheritable elements having important roles relating to environmental factors. Recently, the alpha 2 adrenoceptor (alpha(2)-AR) gene has been reported to be involved in the development of coronary artery disease (CAD). The aim of this study was to investigate the relationships between an insertion/deletion (I/D) in alpha(2B)-AR and CAD in Korean subjects. SUBJECTS AND METHODS: The alpha(2B)-AR I/D polymorphism, which was located in the third intracellular loop of the receptor polypeptide, was examined in 292 patients (M:F=219:73) with CAD and 151 healthy control subjects (M:F=70:81) who visited the Cardiovascular Genome Center in Yonsei Cardiovascular Hospital. RESULTS: In the patient group, 77 men (35.1%) and 26 women (35.6%) had the I/I genotype; 105 men (47.9%) and 39 women (53.4%) a heterozygous genotype and 37 (17.0%) and 8 (11.0%) the D/D genotype. In the controls, 23 men (32.8%) and 29 women (35.8%) had the I/I genotype; 38 (54.3%) and 39 (48.1%) the I/D genotype and 9 (12.9%) and 13 (16.1%) the D/D genotype. There were no differences in the genotype frequencies between the patient and control groups, either in men or women. From a logistical regression analysis, the alpha(2B)-AR genotype was not significantly associated with CAD in our study group. CONCLUSION: The alpha(2B)-AR I/D polymorphism is not a risk factor for CAD in the Korean population.

Experimental study on relationship between ?_3-adrenoceptors and detrusor instability secondary to bladder outflow obstruction / 中华泌尿外科杂志

Objective To investigate the effect of ? 3-adrenoceptors(? 3-AR) on rat detrusor instability(DI) secondary to bladder outflow obstruction(BOO). Methods Animal models of DI were made in 15 female Wister rats.The filling cystometry was conducted after 6 weeks,and the rats were divided into DI group and detrusor stabitily (DS) group based on the detrusor function. The effects of ? 3-AR agonist BRL37344A on the frequency of contraction and relaxation response to isolated detrusor were examined by means of the in vitro detrusor strip study.And the expression of ? 3-AR subtypes mRNA was investigated in rat detrusor muscle by RT-PCR. Results The occurrence rate of DI was 67%(10/15).BRL37344A could inhibit the contraction frequence and amplitude of the isolated detrusor which was concentration-dependent.The intensity did differ significantly between normal controls or DS group and DI group.The relative contents of ? 3-adrenoceptor mRNA in DI group,controls and DS group were 10.27?3.54,19.84?2.62 and 18.38?1.95.There was a significant decrease in the concentration of ? 3-adrenoceptors in DI group compared with controls and DS group( P

Alpha-2 Adrenoceptor Binding Profile of Natural Products Used to Treat Psychotic illnesses / 대한정신약물학회지

Natural products have long been major sources of pharmaceutical products in medicine. We have undertaken a series of studies designed to characterize the pharmacologic profiles of natural products used to treat psychotic illnesses in Korean traditional medicine. In our previous screening assays, we found that three of plant extracts (Coptidis j, Citrus u, and Phellodendron a) contain active components which show relatively potent binding to alpha-2 adrenoceptors. The present study is to explore pharmacologic activities of extracts as agonism or antagonism by G-protein modulations in radioligand receptor binding study. We have found that two extracts(Coptidis j and Phellodendron a) contain active ingredients which have antagonistic properties to alpha-2 adrenoceptors, whereas one plant extract (Citrus u) has agonistic properties. The demonstration of three plant extracts used to treat psychotic illnesses in Korea may help in the elucidation or their pharmacologic characteristics and provide insights for the development of new psychotropic drugs.

Pressor Effect of Intracerebroventricular 4-Aminopyridine on the Systemic Arterial Pressure in the Rabbit

A K+-channel blocker, 4-aminopyridine(4-AP) increases neurotransmitter release from motor nerve terminals and has been shown to restore neuromuscular transmission in the myasthenic syndrome. It has been reported that the intravenous injection of 4-AP in the myasthenic patients caused many central adverse effects including anxiety and restlessness, but did not affect the blood pressure. The aim of this study was to observe the effect of intracerebroventricularly administered 4-AP on the blood pressure and to elucidate the mechanism of the action in urethane-anesthetized rabbits. Intracerebroventricular(icv) 4-AP produced pressor effects in a dose-dependent fashion, but intravenous(iv) 4-AP of the same dose did not altered the blood pressure. Tetraethylammonium, a K+-channel blocker which differs from 4-AP structurally, had little effect on the blood pressure, but 3,4-diaminopyridine, another derivative of the aminopyridine, produced pressor effect similar to 4-AP. The pressor effect of icv 4-AP was not affected by the treatment with iv phenoxybenzamine and chlorisondamine, and in bilateral adrenalectomized rabbits. These results suggest that the 4-AP pressor effect is not related to the periphral sympathetic nerve nor adrenal gland. The pretreatment with icv phentolamine and prazosin did not altered the 4-AP pressor. However, the icv 4-AP pressor effect was significantly attenuated by the treatment with icv yohimbine, and significantly potentiated by the treatment with icv clonidine. The treatment with icv diltiazem markedly inhibited the icv 4-AP pressor effect. It is concluded that 4-AP-sensitive K+-channels in rabbit brain might play a role in the regulation of blood pressure and that the 4-AP pressor effect is closely related to the central alpha2-adrenoceptors and L-type calcium channels.

Characterization of lnhibition by Nifedipine and Nitroprusside of the Pressor Respones to alpha1-Adrenoceptor Agonists Cirazoline and Sgd 101/75 in Pithed Rats

In this study the effects of two unrelated vasodilators, nifedipine and nitroprusside, on the pressor responsiveness to the 1-adrenoceptor full agonist cirazoline and partial agonist Sgd 101/75 in pithed rats were examined. The experiments were performed on the vasoconstriction which was mediated by newly synthetized 1-adrenoceptors after removal of existing 1-adrenoceptors by phenoxybenzamine treatment(5mg/kg, i. p.). The t1/2 for recovery of the maximum response and ED50 of cirazoline were 23.1 +/- 5.5 and 26.9 +/- 7.4 hours, respectively, while that for recovery of the maximum response of Sgd 101/75 was 59.2 +/- 18.9 hours. The relationship between the pressor response and the fractional receptor occupancy for cirazoline showed a rectangular hyperbola. This occupancy-response curve markedly shifted to the right one day after phenoxybenzamine and subsequently returned to the control, indicative of a large receptor reserve. However, for Sgd 101/75 the occupancy-response curve exerted less of a hyperbola and shifited little after phenoxybenzamine. While the maximum response to cirazoline in the control rats was resistant to inhibition by the calcium entry blocker nifedipine, this resistance was significantly reduced one and 3 days after phenoxybenzamine, just as the maximum response to Sgd 101/75 was sensitive to nifedipine in the control rats. Likewise, when nitroprusside was used instead, the results were similar for the cirazoline and Sgd 101/75 effects. In summary, it seems unlikely that the resistance to the calcium entry blocker of the full agonist effect can be wholly ascribed either to the receptor reserves or to the differential calcium utilization itself. Alternatively, it is suggested that the differential resistance to calcium antagonists can result from the magnitude of the variables involved in the activation of 1-adrenoceptor coupling processes depending on the full or partial agonist.

Protective effect of dl-tetrahydropalmatine on cardiac arrhythmias induced by reperfusion of ischemic myocardium / 中国药理学通报

Dl-tetrahydropalmatine (THP) 5 ~ 15 mg ? kg-1 iv markedly reduced the incidences of cardiac arrhythmias and myocardial lipidperoxide content after reperfusion of the is-chemic myocardium in rats. In isolated rat ventricular muscles, THP 1,3 and 10 ?mol?L-1 shifted the concentration-effect curves for phenylephrine to the right unparally, together with decreasing their maximal responses,exhibiting a non-competed antagonistic action. It was also found that THP 10 ?mol?L-1was able to reduce the amplitude of delayed afterdepolar-izations and to stop triggered activity and/or ab-normal automatic activity induced by reoxygena-tion of hypoxic myocardium in isolated ventricular muscles of guinea pig. These results suggest that the protective effects of THP might be attributed, at least in part, to the depression of delayed afterdepolarizations and the prevention of oxygen free radical injury without the involvement of the cardiac ?1-adrenoceptors.

Effects of SRBC immunization on beta-adrenoceptors in lymphocytes isolated from the spleens of rats / 中国免疫学杂志

The Bmax and Kd of beta-adrenoceptors in splenie lymphocytes of rats were determined by direct binding of radioligand, ~3H-dihydroalpranolol. Bmax of beta-adrenoceptors was significantly increased on day+1, was peak on day+2 and gradually reduced to control values on day+ 6 after the intraperitoneal injection of 5?10~9SRBC. A positive correlation (r=0. 86) was found between the Bmax of beta-adrtenoceptors on day+1 to+3 and the amount of Ig M in s(?)rum after 72 hours. Both the Bmax of beta-adrenoceptors on day+2 and the amount of Ig M in serum on day+5 were reduced by the intraperitoneal injection of propranolol. In study on antibody response to SRBC.in vitro, Ig M Synthesis in mouse spleen cells was enhanced by norepinephrine (10?mol/L), and blocked by propranolol (1?mol/L). These results indicated that: (1) the immune response to SRBC in vivo up-regulates the density of beta-adrenoceptors in splenic lymphocytes; (2) the up-regulation of Bmax of beta-adrenceptors in splenic lymphocytes may increase its Ig M synthesis;(3) the enhancement of the Ig M antibody response to SRBC in vitro by norepinephrine was mediated by the beta-adrenoceptors.

The Studies on the Contractile Response of Serotinin in Rat Aorta

The mechanism of serotonin(5-HT) induced contraction and Ca++ mobilization was investigated in right cut from rat aorta. Since it is known that 5-HT can interact with alpha-adrenoceptors in addition to a specific action on 5-HT receptors, the effects alpha-adrenoceptors antagonists on these contractile responses to 5-HT were investigated. The results are as follows : 1) 5-HT produced a strong transient contraction and a concentration dependent contraction. 2) The contractile tension to 5-HT increased with extracellular Ca++ concentration (0.1-5mM). 3) The response produced by rings exposed to Ca++-free PSS was significantly weaker than that produced by rings exposed to calcium containing PSS. When rings of aorta that had been stimulated with 5-HT once for 30 min in Ca++-free TBT were washed 4 times for at least; 20 min in zero Ca++PSS to remove 5-HT, than reexposed to 5-HT in Ca++-free TBT, a phasic contraction was not seen during the second stimulation with 5-HT. 4) The contractile response of 5-HT was inhibited by alpha-adrenergic receptor blocker, phenoxybenzamine and phentolamine. Phentolamine(10(-8)M) antagonized response to high concentrations of 5-HT but responses to low concentrations of 5-HT were not antagonized. 5) The contraction induced by 5-HT in Ca++-free PSS was investigated with phentolamin, methysergide. It was blocked by methysergide but not blocked by phentolamine. 6) These results suggest that 5-HT -induced contraction is the effect of both transmembrane Ca++ influx and the mobilization of intracellular Ca++. Low concentration of 5-HT act on specific 5-HT receptors but high concentration of 5-HT also act on alpha-adreno-receptors.

Study on the molecular mechanism of beta3- adrenoceptor subtypes mediating rat detrusor relaxation / 解放军医学杂志

Objective To investigate the molecular mechanisms of beta3 adrenoceptor subtypes mediating rat detrusor relaxation. Methods Cyclic adenosine monophosphate(cAMP) was detected by radioimmunoassay, the effects of the cyclic AMP inhibitor SQ 22,536 and the cyclic AMP dependent protein kinase inhibitor H 89 on the relaxation elicited by ISO and BRL37344A in the rat ditrusor were investigated based on pharmacological evaluations. Results After the stimulating of ? AR by ISO, the levels of intracellular cAMP was increased, and the relaxation mediated via ISO could be partly inhibited by SQ 22,536 or H 89 The concentrations of intracellular cAMP had no changes in the presence of SQ 22,536 or H 89, and the relaxant responses to BRL37344A was not affected by SQ 22,536 or H 89. Conclusion The effects of ISO via? AR on relaxant responses to detrusor was mediated mainly by the cyclic AMP independent pathway and in part by the cyclic AMP dependent pathway, but cAMP PKA pathway were not involved in the beta3 adrenoceptor signaling pathway