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Adrenoceptor Stimulation (adrenoceptor + stimulation)
Selected AbstractsRole of Ca2+ -Activated Cl, Current in Ventricular Action Potentials of Sheep During Adrenoceptor StimulationEXPERIMENTAL PHYSIOLOGY, Issue 2 2001Arie O. Verkerk Adrenoceptor stimulation enhances repolarising and depolarising membrane currents to different extents in cardiac myocytes. We investigated the opposing effects of the repolarising Ca2+ -activated Cl, current (ICl(Ca)) and depolarising L-type Ca2+ current (ICa,L) on the action potential configuration of sheep ventricular myocytes stimulated with noradrenaline. Whole-cell current-clamp recordings revealed that noradrenaline accelerated and prolonged phase-1 repolarisation. We define the minimal potential at the end of phase-1 repolarisation as ,notch level'. Noradrenaline (1 ,M) caused the notch level to fall from 14 ± 2.6 to 7.8 ± 2.8 mV (n= 24), but left action potential duration, resting membrane potential or action potential amplitude unaffected. Whole-cell voltage-clamp recordings showed that 1 ,M noradrenaline increased both ICa,L and ICl(Ca), but it had no significant effect on the principal K+ currents. Blockage of ICl(Ca) by 0.5 mM 4,4,-diisothiocyanatostilbene-2,2,-disulphonic acid (DIDS) in both the absence and the presence of noradrenaline abolished phase-1 repolarisation. In the presence of noradrenaline, DIDS caused elevation of the plateau phase amplitude and an increase in the action potential duration. In conclusion, elevation of the plateau phase amplitude and action potential prolongation associated with an increased ICa,L upon adrenoceptor stimulation is prevented by an increased ICl(Ca) in sheep ventricular myocytes. [source] Activation of Arylalkylamine N -Acetyltransferase by Phorbol Esters in Bovine Pinealocytes Suggests a Novel Regulatory Pathway in Melatonin SynthesisJOURNAL OF NEUROENDOCRINOLOGY, Issue 9 2004C. Schomerus Abstract In all mammalian species investigated, noradrenaline activates a ,-adrenoceptor/cAMP/protein kinase A-dependent mechanism to switch on arylalkylamine N -acetyltransferase and melatonin biosynthesis in the pineal gland. Other compounds which are known to influence the melatonin-generating system are phorbol esters. The effect of phorbol esters on regulation of melatonin synthesis has been mainly investigated in rat pinealocytes. In these cells, phorbol esters do not increase cAMP levels and arylalkylamine N -acetyltransferase on their own; however, phorbol esters potentiate the effects on cAMP and AANAT activity induced upon ,-adrenoceptor stimulation. In the present study, we investigated the effect of phorbol esters on the regulation of melatonin synthesis in bovine pinealocytes. We show that, in these cells, the phorbol esters 4,-phorbol 12-myristate 13-acetate (PMA) or phorbol 12,13-dibutyrate have a direct stimulatory effect and induced 4,10-fold increases in AANAT protein levels, AANAT activity and melatonin production. The extent of these effects was similar to those induced by noradrenaline. Notably, responses to PMA were not accompanied by increases in cAMP levels. Northern blot analysis showed that Aanat mRNA levels did not change upon PMA treatment indicating that phorbol esters control AANAT at a post-transcriptional level. The effects on AANAT and melatonin production were reduced by use of protein kinase C inhibitors, but not by blockade of the cyclic AMP/protein kinase A pathway. Our results point towards a novel mechanism in the regulation of melatonin production that is cAMP-independent and involves protein kinase C. The study is of particular interest because regulation of melatonin biosynthesis in bovines may resemble that in primates more closely than that in rodents. [source] Pre-junctional ,2 -adrenoceptors modulation of the nitrergic transmission in the pig urinary bladder neck,NEUROUROLOGY AND URODYNAMICS, Issue 4 2007Medardo Hernández Abstract Aims To investigate the nitric oxide (NO)-mediated nerve relaxation and its possible modulation by pre-junctional ,2 -adrenoceptors in the pig urinary bladder neck. Methods Urothelium-denuded bladder neck strips were dissected, and mounted in isolated organ baths containing a physiological saline solution (PSS) at 37°C and continuously gassed with 5% CO2 and 95% O2, for isometric force recording. The relaxations to transmural nerve stimulation (electrical field stimulation [EFS]) or exogenously applied NO were carried out on strips pre-contracted with 1 µM phenylephrine (PhE) and treated with guanethidine (10 µM) and atropine (0.1 µM), to block noradrenergic neurotransmission and muscarinic receptors, respectively. Results EFS (0.2,1 Hz, 1 msec duration, 20 sec trains, current output adjusted to 75 mA) evoked frequency-dependent relaxations which were abolished by the neuronal voltage-activated Na+ channel blocker tetrodotoxin (TTX, 1 µM). These responses were potently reduced by the nitric oxide synthase (NOS) inhibitor NG -nitro- L -arginine (L-NOARG, 30 µM) and further reversed by the NO synthesis substrate L -arginine (L-ARG, 3 mM). The ,2 -adrenoceptor agonist BHT-920 (2 µM) reduced the electrically evoked relaxations, its effectiveness being higher on the responses induced by low frequency stimulation. BHT-920-elicited reductions were fully reversed by the ,2 -adrenoceptor antagonist rauwolscine (RAW, 1 µM). Exogenous NO (1 µM,1 mM) induced concentration-dependent relaxations which were not modified by BHT-920, thus eliminating a possible post-junctional modulation. Conclusions These results indicate that NO is involved in the non-adrenergic non-cholinergic (NANC) inhibitory neurotransmission in the pig urinary bladder neck, the release of NO from intramural nerves being modulated by pre-junctional ,2 -adrenoceptor stimulation. Neurourol. Urodynam. 26:578,583, 2007. © 2007 Wiley-Liss, Inc. [source] The peripheral sympathetic nervous system in human obesityOBESITY REVIEWS, Issue 1 2001M. A. van Baak Summary The peripheral sympathetic nervous system is a key factor in the regulation of energy balance in humans. Differences in sympathetic nervous system activity may contribute to variations in 24 h energy expenditure between individuals. ,-Adrenoceptors play a more important role than ,-adrenoceptors in this regulation. The involvement of both ,1-and ,2-adrenoceptor subtypes has been demonstrated, the role of the ,3-adrenoceptor subtype is not yet clear. Normal or increased levels of sympathetic nervous system activity and reduced reactivity appear to be present in established obesity. Furthermore, the sensitivity for ,-adrenoceptor stimulation is impaired in obesity. The blunted reactivity and sensitivity may contribute to the maintenance of the obese state. There are data to suggest that they may also play a role in the aetiology of obesity, because the impairments often remain after weight reduction. Furthermore, a negative correlation between baseline sympathetic nervous system activity and weight gain during follow-up has been found in Pima Indians. Recently, genetic evidence about the involvement of adrenoceptors in obesity has become available. Although the results of association and linkage studies on polymorphisms in the ,2-, ,3- and ,2-adrenoceptor genes are inconsistent, the functional correlates of some of these polymorphisms (changes in agonist-promoted down-regulation, protein expression levels, lipolytic sensitivity, basal metabolic rate, sympathetic nervous system activity) suggest that they may be important in the aetiology of obesity. [source] Stimulation of cardiac ,-adrenoceptors targets connexin 43BRITISH JOURNAL OF PHARMACOLOGY, Issue 1 2009Kerstin Boengler Connexin 43 (Cx43) is the major protein of cardiac ventricular gap junctions and is crucial to cell,cell communication and cardiac function. The protein level of Cx43 is reduced in patients with heart failure or dilated cardiomyopathy (DCM), pathophysiological conditions often associated with arrhythmias. As catecholamines are often increased in cardiac diseases, Salameh et al., in this issue of the BJP, investigated the effect of ,-adrenoceptor stimulation of neonatal cardiomyocytes on Cx43 expression and found increased Cx43 mRNA and protein levels following 24 h stimulation. Up-regulation of Cx43 was associated with phosphorylation of mitogen-activated protein kinases and translocation of transcription factors into the nucleus. In patients with DCM, a situation often associated with desensitization of the ,-adrenoceptor system, Cx43 expression was reduced. The characterization of the signal transduction pathways involved in Cx43 expression and intracellular localization in human myocardium in vivo is a promising target for the development of new anti-arrhythmic strategies. [source] The signal transduction cascade regulating the expression of the gap junction protein connexin43 by ,-adrenoceptorsBRITISH JOURNAL OF PHARMACOLOGY, Issue 1 2009A Salameh Background and purpose:, In mammalian heart, connexin43 (Cx43) represents the predominant connexin in the working myocardium. As the ,-adrenoceptor is involved in many cardiac diseases, we wanted to clarify the pathway by which ,-adrenoceptor stimulation may control Cx43 expression. Experimental approach:, Cultured neonatal rat cardiomyocytes were stimulated with isoprenaline. Cx43 expression as well as activation of p38 mitogen-activated protein kinase (MAPK), p42/44 MAPK, JUN NH2 -terminal kinase (JNK) and nuclear translocation of the transcription factors activator protein 1 (AP1) and CRE-binding protein (CREB) were investigated. Additionally, we assessed Cx43 expression and distribution in left ventricular biopsies from patients without any significant heart disease, and from patients with either congestive heart failure [dilated cardiomyopathy (DCM)] or hypertrophic cardiomyopathy (HCM). Key results:, Isoprenaline exposure caused about twofold up-regulation of Cx43 protein with a pEC50 of 7.92 ± 0.11, which was inhibited by propranolol, SB203580 (4-(4-fluorophenyl)-2-(4-methylsulphinylphenyl)-5-(4-pyridyl)-1H-imidazole) (p38 inhibitor), PD98059 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one) (MAPK 1 kinase inhibitor) (Alexis Biochemicals, San Diego, CA, USA) or cyclosporin A. Similar findings were obtained for Cx43 mRNA. Furthermore, Cx43 up-regulation was accompanied by phosphorylation of p38, p42/44 and JNK, and by translocation of AP1 and CREB to the nucleus. Analysis of Cx43 protein and mRNA in ventricular biopsies revealed that in patients with DCM, Cx43 content was significantly lower, and in patients with HCM, Cx43 content was significantly higher, relative to patients without any cardiomyopathy. More importantly, Cx43 distribution also changed with more Cx43 being localized at the lateral border of the cardiomyocytes. Conclusion and implication:, ,-adrenoceptor stimulation up-regulated cardiac Cx43 expression via a protein kinase A and MAPK-regulated pathway, possibly involving AP1 and CREB. Cardiomyopathy altered Cx43 expression and distribution. [source] Testosterone protects rat hearts against ischaemic insults by enhancing the effects of ,1 -adrenoceptor stimulationBRITISH JOURNAL OF PHARMACOLOGY, Issue 4 2008S Tsang Background and purpose: Testosterone alleviates symptoms in patients with ischaemic heart disease. Androgen receptors are present in the heart, and testosterone upregulates gene expression of cardiac ,1 -adrenoceptors. We hypothesize that testosterone may confer cardioprotection by interacting with adrenoceptors. Experimental approach: In isolated perfused hearts and ventricular myocytes from orchidectomized rats without or with testosterone (200 ,g/100 g) replacement, we first determined the effect of ischaemia/reperfusion in the presence of noradrenaline (10,7 M). Then we determined the contribution of interactions between testosterone and ,1 - or ,1 -adrenoceptors in cardiac injury/protection (infarct size, release of lactate dehydrogenase, viability of myocytes, recovery of contractile function and incidence of arrhythmias) upon ischaemia/reperfusion by pharmacological manipulation using selective adrenoceptor agonists (,1 -adrenoceptor agonist: phenylephrine 10,6 M; non-selective ,-adrenoceptor agonist: isoprenaline 10,7 M) and antagonists (,1: prazosin or benoxathian 10,6 M; ,1: CGP 20712A 5 × 10,7 M). We also determined the expression of ,1 and ,1 -adrenoceptor in the hearts from rats with and without testosterone. Key results: Testosterone reduced injury induced by ischaemia/reperfusion and noradrenaline. This was achieved by enhancing the beneficial effect of ,1 -adrenoceptor stimulation, which was greater than the deleterious effect of ,1 -adrenoceptor stimulation (also enhanced by testosterone). The effects of testosterone were abolished or attenuated by blockade of androgen receptors. Testosterone also enhanced the expression of ,1A and ,1 -adrenoceptor. Conclusions and implications: Testosterone conferred cardioprotection by upregulating the cardiac ,1 -adrenoceptor and enhancing the effects of stimulation of this adrenoceptor. The effect of testosterone was at least partly mediated by androgen receptors. British Journal of Pharmacology (2008) 153, 693,709; doi:10.1038/sj.bjp.0707624; published online 24 December 2007 [source] ,1 -Adrenoceptor effects mediated by protein kinase C , in human cultured prostatic stromal cellsBRITISH JOURNAL OF PHARMACOLOGY, Issue 1 2003A Preston We have investigated the effects of ,1 -adrenoceptor stimulation upon contractility, Ca2+ influx, inositol phosphate production, and protein kinase C (PKC) translocation in human cultured prostatic stromal cells (HCPSC). The ,1 -adrenoceptor selective agonist phenylephrine elicited contractile responses of HCPSC, i.e. a maximal cell shortening of 45±6% of initial cell length, with an EC50 of 1.6±0.1 ,M. The ,1 -adrenoceptor selective antagonists prazosin (1 ,M) and terazosin (1 ,M) both blocked contractions to phenylephrine (10 ,M). The L-type calcium channel blocker nifedipine (10 ,M), and the PKC inhibitors Gö 6976 (1 ,M) and bisindolylmaleimide (1 ,M) also inhibited phenylephrine-induced contractions. Phenylephrine caused a concentration dependent increase in inositol phosphate production (EC50 119±67 nM). This response was blocked by terazosin (1 ,M). Phenylephrine caused the translocation of the PKC , isoform, but not the ,, ,, ,, , or , isoforms, from the cytosolic to the particulate fraction of HCPSC, with an EC50 of 5.7±0.5 ,M. In FURA-2AM (5 ,M) loaded cells, phenylephrine elicited concentration dependent increases in [Ca2+]i, with an EC50 of 3.9±0.4 ,M. The response to phenylephrine (10 ,M) was blocked by prazosin (1 ,M), bisindolymaleimide (1 ,M), and nifedipine (10 ,M). In conclusion, this study has shown that HCPSC express functional ,1 -adrenoceptors, and that the intracellular pathways responsible for contractility may be largely dependent upon protein kinase C activation and subsequent opening of L-type calcium channels. British Journal of Pharmacology (2003) 138, 218,224. doi:10.1038/sj.bjp.0705021 [source] Activation Of ,1 -Adrenoceptors Is Not Essential For The Mediation Of Ischaemic Preconditioning In Rat HeartCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 1-2 2002E Vasara SUMMARY 1. The aim of the present study was to clarify the role of ,1 -adrenoceptors in the mechanism of ischaemic preconditioning (IP). 2. Rat isolated perfused hearts were either non- preconditioned, preconditioned with 5 min ischaemia or treated for 5 min with ,1 -adrenoceptor agonists (50 ,mol/L phenylephrine; 0.1, 0.5 and 1 ,mol/L methoxamine) before being subjected to 45 min of sustained ischaemia followed by 60 min reperfusion. 3. Within each of the above protocols, hearts were divided into groups to which ,1 -adrenoceptor antagonists (prazosin, 5,-methyl urapidil and chloroethylclonidine (CEC)) were administered. Functional recovery and infarct size were used as indices of the effects of ischaemia. Ischaemic contracture characteristics and maximal diastolic pressure during reflow were also assessed. 4. Blockade of ,1 -adrenoceptors with prazosin or the subtype-selective antagonists 5,-methyl urapidil and CEC did not abolish the protective effect of IP with respect to both functional recovery and infarct size reduction. 5. Protection afforded by phenylephrine was attenuated in hearts treated with prazosin or the ,1B -adrenoceptor- selective antagonist CEC, but not in those treated with the ,1A -adrenoceptor-selective antagonist 5,-methyl urapidil. 6. Treatment with low concentrations of methoxamine, considered to be ,1A -adrenoceptor selective, did not confer any protection to the ischaemic myocardium. 7. A close relationship between accelerated ischaemic contracture and enhanced cardioprotection was observed. 8. The results suggest that ,1 -adrenoceptor stimulation mimics IP, but it is not an essential component in the mechanism behind the protective effect of IP in rat heart. In addition, the present study demonstrates that stimulation of the ,1B - but not the ,1A -adrenoceptor subtype is responsible for the catecholamine-induced protection of ischaemic myocardium in rat. [source] | ||||||||||