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Adrenergic
Terms modified by Adrenergic Selected AbstractsNeural Circuits Regulating Pulsatile Luteinizing Hormone Release in the Female Guinea-Pig: Opioid, Adrenergic and Serotonergic InteractionsJOURNAL OF NEUROENDOCRINOLOGY, Issue 3 2001A. C. Gore Abstract We studied three neurotransmitters involved in the regulation of pulsatile luteinizing hormone (LH) release: opioid peptides, serotonin and norepinephrine, using the ovariectomized guinea-pig. This is an attractive animal model due to the regularity of its LH pulses, enabling any disruptions to be clearly ascertained. In all experiments, a specific agonist or antagonist was administered, either alone or serially to enable detection of interactions, and effects on mean LH concentrations, pulse amplitude and interpulse interval were determined by PULSAR analysis. In the ovariectomized guinea-pig, catecholamines are stimulatory (acting through the ,1 and ,2 but not , receptors, unlike other species), opioids inhibitory and serotonin permissively stimulatory to pulsatile LH release. Stimulatory effects of the opiate antagonist were not blocked by pretreatment with an ,1 - or ,2 -adrenergic antagonist. Similarly, pretreatment with the opiate antagonist did not prevent the suppression of LH release by ,1 and ,2 antagonists. This suggests that, in the guinea-pig, effects of opiates and catecholamines on LH release are exerted by independent pathways to luteinizing hormone releasing hormone (LHRH) neurones. For the opiate,serotonin interactions, pretreatment with the serotonergic antagonist did not block the stimulatory effect of the opiate antagonist on LH release. However, pretreatment with the opiate agonist could not be overcome by the serotonergic agonist. This suggests that the effects of the serotonin system on LHRH release may be indirectly mediated by opioid neurones. Taken together, these studies demonstrate that the three neurotransmitter systems studied are critically involved in normal pulsatile LH release in the female guinea-pig, and demonstrate novel functional relationships between the opioid and the adrenergic and serotonergic systems. [source] Differential expression of catecholamine biosynthetic enzymes in the rat ventrolateral medullaTHE JOURNAL OF COMPARATIVE NEUROLOGY, Issue 1 2001Jacqueline K. Phillips Abstract Adrenergic (C1) neurons located in the rostral ventrolateral medulla are considered a key component in the control of arterial blood pressure. Classically, C1 cells have been identified by their immunoreactivity for the catecholamine biosynthetic enzymes tyrosine hydroxylase (TH) and/or phenylethanolamine N-methyltransferase (PNMT). However, no studies have simultaneously demonstrated the expression of aromatic L-amino acid decarboxylase (AADC) and dopamine ,-hydroxylase (DBH) in these neurons. We examined the expression and colocalization of all four enzymes in the rat ventrolateral medulla using immunohistochemistry and reverse transcription-polymerase chain reaction (RT-PCR) analysis. Retrograde tracer injected into thoracic spinal segments T2,T4 was used to identify bulbospinal neurons. Using fluorescence and confocal microscopy, most cells of the C1 group were shown to be double or triple labeled with TH, DBH, and PNMT, whereas only 65,78% were immunoreactive for AADC. Cells that lacked detectable immunoreactivity for AADC were located in the rostral C1 region, and approximately 50% were spinally projecting. Some cells in this area lacked DBH immunoreactivity (6.5,8.3%) but were positive for TH and/or PNMT. Small numbers of cells were immunoreactive for only one of the four enzymes. Numerous fibres that were immunoreactive for DBH but not for TH or PNMT were noted in the rostral C1 region. Single-cell RT-PCR analysis conducted on spinally projecting C1 neurons indicated that only 76.5% of cells that contained mRNA for TH, DBH, and PNMT contained detectable message for AADC. These experiments suggest that a proportion of C1 cells may not express all of the enzymes necessary for adrenaline synthesis. J. Comp. Neurol. 432:20,34, 2001. © 2001 Wiley-Liss, Inc. [source] ,-Adrenergic and neuropeptide Y Y1 receptor control of collateral circuit conductance: influence of exercise trainingTHE JOURNAL OF PHYSIOLOGY, Issue 24 2008Jessica C. Taylor This study evaluated the role of ,-adrenergic receptor- and neuropeptide Y (NPY) Y1 receptor-mediated vasoconstriction in the collateral circuit of the hind limb. Animals were evaluated either the same day (Acute) or 3 weeks following occlusion of the femoral artery; the 3-week animals were in turn limited to cage activity (Sed) or given daily exercise (Trained). Collateral-dependent blood flows (BFs) were measured during exercise with microspheres before and after ,-receptor inhibition (phentolamine) and then NPY Y1 receptor inhibition (BIBP 3226) at the same running speed. Blood pressures (BPs) were measured above (caudal artery) and below (distal femoral artery) the collateral circuit. Arterial BPs were reduced by ,-inhibition (50,60 mmHg) to ,75 mmHg, but not further by NPY Y1 receptor inhibition. Effective experimental sympatholysis was verified by 50,100% increases (P < 0.001) in conductance of active muscles not affected by femoral occlusion with receptor inhibition. In the absence of receptor inhibition, vascular conductance of the collateral circuit was minimal in the Acute group (0.13 ± 0.02), increased over time in the Sed group (0.41 ± 0.03; P < 0.001), and increased further in the Trained group (0.53 ± 0.03; P < 0.02). Combined receptor inhibition increased collateral circuit conductances (P < 0.005), most in the Acute group (116 ± 37%; P < 0.02), as compared to the Sed (41 ± 6.6%; P < 0.001) and Trained (31 ± 5.6%; P < 0.001) groups. Thus, while the sympathetic influence of the collateral circuit remained in the Sed and Trained animals, it became less influential with time post-occlusion. Collateral conductances were collectively greater (P < 0.01) in the Trained as compared to Sed group, irrespective of the presence or absence of receptor inhibition. Conductances of the active ischaemic calf muscle, with combined receptor inhibition, were suboptimal in the Acute group, but increased in Sed and Trained animals to exceptionally high values (e.g. red fibre section of the gastrocnemius: ,7 ml min,1 (100 g),1 mmHg,1). Thus, occlusion of the femoral artery promulgated vascular adaptations, even in vessels that are not part of the collateral circuit. The presence of active sympathetic control of the collateral circuit, even with exercise training, raises the potential for reductions in collateral BF below that possible by the structure of the collateral circuit. However, even with release of this sympathetic vasoconstriction, conductance of the collateral circuit was significantly greater with exercise training, probably due to the network of structurally larger collateral vessels. [source] Adrenergic and Cholinergic Innervation of the Mammary Gland in the PigANATOMIA, HISTOLOGIA, EMBRYOLOGIA, Issue 1 2002A. FRANKE-RADOWIECKA Adrenergic and acetylcholinesterase-positive (AChE-positive) innervation of the mammary gland in the sexually immature and mature pigs was studied using histochemical methods. Upon examining the adrenergic and cholinergic innervation, the adrenergic innervation was found to be much more developed. The majority of both sub-populations of the nerve fibres studied was localized in the subcutaneous tissue of the mammary gland. Adrenergic and AChE-positive nerve fibres also supplied structures of the nipple (subcutaneous tissue, blood vessels, smooth muscles fibres) and glandular tissue (blood vessels, lactiferous ducts). The glandular tissue contained the smallest number of adrenergic and AChE-positive nerve fibres. No distinct differences were observed in the adrenergic and AChE-positive innervation of the porcine mammary gland between the juvenile and non-pregnant adult animals. [source] Molecular characterization of regenerated cardiomyocytes derived from adult mesenchymal stem cellsCONGENITAL ANOMALIES, Issue 1 2002Keiichi Fukuda ABSTRACT, We recently isolated a cardiomyogenic (CMG) cell line from murine bone marrow stroma, and in this paper characterize regenerated cardiomyocytes derived from adult mesenchymal stem cells at the molecular level. Stromal cells were immortalized, exposed to 5-azacytidine, and repeatedly screened for spontaneously beating cells. CMG cells began to beat spontaneously after 2 weeks, and beat synchronously after 3 weeks. They exhibited sinus-node-like or ventricular-cell-like action potentials. Analysis of the isoforms of contractile protein genes, such as of myosin and ,-actin, indicated that their phenotype was similar to that of fetal ventricular cardiomyocytes. The cells expressed Nkx2.5, GATA4, TEF-1, and MEF2-C mRNA before 5-azacytidine exposure, and MEF2-A and MEF2-D after exposure. CMG cells expressed ,1A, ,1B, and ,1D -adrenergic receptor mRNA prior to differentiation, and ,1, ,2 -adrenergic and M1, M2 -muscarinic receptors after acquiring the cardiomyocyte phenotype. Phenylephrine induced phosphorylation of ERK1/ 2, and the phosphorylation was inhibited by prazosin. Isoproterenol increased the cAMP level 38-fold and beating rate, cell motion, % shortening, and contractile velocity by 48%, 38%, 27%, and 51%, respectively, and the increases were blocked by CGP20712A (,1 -selective blocker). Car-bachol increased IP3 32-fold, and the increase was inhibited by AFDX116 (M2 -selective blocker). These findings demonstrated that the regenerated cardiomyocytes were capable of responding to adrenergic and muscarinic stimulation. This new cell line provides a model for the study of cardiomyocyte transplantation. [source] The role of the ,-adrenergic receptor in the leg vasoconstrictor response to orthostatic stressACTA PHYSIOLOGICA, Issue 3 2009M. Kooijman Abstract Aim:, The prompt increase in peripheral vascular resistance, mediated by sympathetic ,-adrenergic stimulation, is believed to be the key event in blood pressure control during postural stress. However, despite the absence of central sympathetic control of the leg vasculature, postural leg vasoconstriction is preserved in spinal cord-injured individuals (SCI). This study aimed at assessing the contribution of both central and local sympathetically induced ,-adrenergic leg vasoconstriction to head-up tilt (HUT) by including healthy individuals and SCI, who lack central sympathetic baroreflex control over the leg vascular bed. Methods:, In 10 controls and nine SCI the femoral artery was cannulated for drug infusion. Upper leg blood flow (LBF) was measured bilaterally using venous occlusion strain gauge plethysmography before and during 30° HUT throughout intra-arterial infusion of saline or the non-selective ,-adrenergic receptor antagonist phentolamine respectively. Additionally, in six controls the leg vascular response to the cold pressor test was assessed during continued infusion of phentolamine, in order to confirm complete ,-adrenergic blockade by phentolamine. Results:, During infusion of phentolamine HUT still caused vasoconstriction in both groups: leg vascular resistance (mean arterial pressure/LBF) increased by 10 ± 2 AU (compared with 12 ± 2 AU during saline infusion), and 13 ± 3 AU (compared with 7 ± 3 AU during saline infusion) in controls and SCI respectively. Conclusion:, Effective ,-adrenergic blockade did not reduce HUT-induced vasoconstriction, regardless of intact baroreflex control of the leg vasculature. Apparently, redundant mechanisms compensate for the absence of sympathetic ,-adrenoceptor leg vasoconstriction in response to postural stress. [source] Influence of sympathetic and AT1 -receptor blockade on angiotensin II and adrenergic agonist-induced renal vasoconstrictions in spontaneously hypertensive ratsACTA PHYSIOLOGICA, Issue 3 2009M. H. Abdulla Abstract Aim:, This study investigated the influence of angiotensin II (Ang II) receptor and adrenergic blockade on the renal vasoconstrictions caused by Ang II and adrenergic agonists in spontaneously hypertensive rats (SHR). Methods:, Forty-eight SHR were subjected to 7 days of losartan (10 mg kg,1 day,1 p.o.), carvedilol (5 mg kg,1 day,1 p.o.) or losartan + carvedilol (10 mg kg,1 day,1 + 5 mg kg,1 day,1 p.o.). On day 8, the rats were anaesthetized and renal vasoconstrictor experiments performed. One group of rats underwent acute unilateral renal denervation. Results:, There were significant (P < 0.05) reductions in the renal vasoconstrictor responses to noradrenaline, phenylephrine, methoxamine and Ang II after losartan and carvedilol treatments compared with that in untreated rats (all P < 0.05). However, in renally denervated SHR treated with carvedilol, the vasoconstrictor responses to all the vasoactive agents were enhanced compared with those in SHR with intact renal nerves treated with carvedilol. Intact SHR given both losartan and carvedilol showed greater renal vasoconstrictor responses to the vasoactive agents than when given either losartan or carvedilol alone (all P < 0.05). Conclusion:, Carvedilol reduced the vasoconstrictor response to Ang II and all the adrenergic agonists in the presence of the renal nerves, but, following the removal of renal sympathetic activity, carvedilol enhanced the sensitivity of both renal ,1 -adrenoceptors and AT1 receptors to the vasoactive agents. Co-treatment with losartan and carvedilol reduced the renal vasoconstrictor responses to exogenously administered vasoactive agents but to a lesser extent than losartan or carvedilol alone. The results obtained demonstrate an interaction between Ang II receptors and adrenergic neurotransmission in the SHR. [source] Severe neuroglycopaenia secondary to severe hypoglycaemia from serendipitous overdose of gliclazide without adrenergic or autonomic responseDIABETIC MEDICINE, Issue 11 2009G. R. Ling No abstract is available for this article. [source] Mechanistic studies of blood pressure in rats treated with a series of cholesteryl ester transfer protein inhibitors,DRUG DEVELOPMENT RESEARCH, Issue 1 2009Michael DePasquale Abstract ILLUMINATE, the Phase 3 clinical trial of morbidity and mortality (M&M) with the cholesteryl ester transfer protein inhibitor (CETPi), torcetrapib (CP-529,414), was terminated in December 2006 due to an imbalance in all cause mortality. The underlying cause of the M&M remains undetermined. While torcetrapib produced dose-related increases in blood pressure in clinical trials, the mechanism of the increase in blood pressure is also undetermined. The pressor effects of torcetrapib and structurally related compounds were studied in several pathways involved in blood pressure control. Studies were conducted in rats treated with a series of structurally related molecules (CP-529,414, CP-532,623, PF-868,348, CP-746,281, CP-792,485, PF-868,343, and CE-308,958). CP-529,414, CP-532,623, CP-868,343, and CP-792,485 are potent CETP inhibitors; PF-868,348 is weakly potent and CP-746,281 and CE-308,958 are CETP-inactive. Changes in blood pressure were determined in conscious animals in conjunction with pharmacologic blockade of numerous pressor agents/pathways. Torcetrapib and CP-532,623 increased blood pressure following both chronic PO and acute IV administration. The CETP-inactive enantiomer of CP-532,623, CP-746,281 failed to raise blood pressure. PF-868,348, a structural analogue with ,50-fold lower CETPi activity also displayed pressor activity. Blockade of adrenergic, cholinergic, angiotensin, endothelin, NOS, Rho kinase, and thromboxane pathways failed to attenuate the pressor response. These data demonstrate that the blood pressure activity seen with torcetrapib can be dissociated from CETP inhibitor pharmacology and numerous pharmacology pathways can be discounted in the attempt to understand the molecular basis of the pressor pharmacology. Drug Dev Res 70:2009 © 2009 Wiley-Liss, Inc. [source] A tethered ascorbate-norepinephrine compound, 4-UT, displays long-acting adrenergic activity on rabbit aortic smooth muscleDRUG DEVELOPMENT RESEARCH, Issue 5 2008Robert Root-Bernstein Abstract We previously demonstrated that adrenergic and histaminergic receptors have an ascorbic acid (vitamin C) binding site on the first extracellular loop, immediately adjacent to the aminergic binding site. Binding of ascorbate to this site strongly potentiates any sub-maximal dose of an adrenergic or histaminergic compound, significantly increasing its duration of activity. We report here the successful synthesis of a tethered compound that mimics the combined effects of a mixture of ascorbate with norepinephrine. The tethered compound uses a four-unit polyethylene linker to tether ascorbate to norepinephrine. The tethered compound is about tenfold less effective than norepinephrine in stimulating rabbit aortic smooth muscle, but has a very significantly enhanced duration of activity compared with norepinephrine alone and comparable to a mixture of norepinephrine and ascorbate. Additional ascorbate does not enhance the tethered compound's effects and we demonstrate that the compound binds to a synthetic peptide spanning the ascorbate binding site of the receptor. These experiments strongly suggest that the compound binds to both the adrenergic binding site and the ascorbate binding site simultaneously. Tethered compounds with linkers of other lengths did not have these properties. We believe that the synthesis of enhanced adrenergic and histaminergic drugs by tethering them to potentiators such as ascorbate will permit a new class of potential drugs to be created with high specificity and long duration of activity. Drug Dev Res 69:242,250, 2008. © 2008 Wiley-Liss, Inc. [source] Mirtazapine enhances frontocortical dopaminergic and corticolimbic adrenergic, but not serotonergic, transmission by blockade of ,2 -adrenergic and serotonin2C receptors: a comparison with citalopramEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 3 2000M. J. Millan Abstract Mirtazapine displayed marked affinity for cloned, human ,2A -adrenergic (AR) receptors at which it blocked noradrenaline (NA)-induced stimulation of guanosine-5,-O-(3-[35S]thio)-triphosphate ([35S]-GTP,S) binding. Similarly, mirtazapine showed high affinity for cloned, human serotonin (5-HT)2C receptors at which it abolished 5-HT-induced phosphoinositide generation. Alpha2 -AR antagonist properties were revealed in vivo by blockade of UK-14,304-induced antinociception, while antagonist actions at 5-HT2C receptors were demonstrated by blockade of Ro 60 0175-induced penile erections and discriminative stimulus properties. Mirtazapine showed negligible affinity for 5-HT reuptake sites, in contrast to the selective 5-HT reuptake inhibitor, citalopram. In freely moving rats, in the dorsal hippocampus, frontal cortex (FCX), nucleus accumbens and striatum, citalopram increased dialysate levels of 5-HT, but not dopamine (DA) and NA. On the contrary, mirtazapine markedly elevated dialysate levels of NA and, in FCX, DA, whereas 5-HT was not affected. Citalopram inhibited the firing rate of serotonergic neurons in dorsal raphe nucleus, but not of dopaminergic neurons in the ventral tegmental area, nor adrenergic neurons in the locus coeruleus. Mirtazapine, in contrast, enhanced the firing rate of dopaminergic and adrenergic, but not serotonergic, neurons. Following 2 weeks administration, the facilitatory influence of mirtazapine upon dialysate levels of DA and NA versus 5-HT in FCX was maintained, and the influence of citalopram upon FCX levels of 5-HT versus DA and NA was also unchanged. Moreover, citalopram still inhibited, and mirtazapine still failed to influence, dorsal raphe serotonergic neurons. In conclusion, in contrast to citalopram, mirtazapine reinforces frontocortical dopaminergic and corticolimbic adrenergic, but not serotonergic, transmission. These actions reflect antagonist properties at ,2A -AR and 5-HT2C receptors. [source] Effects of amphetamine on salivary secretionEUROPEAN JOURNAL OF ORAL SCIENCES, Issue 3 2009Bengt Götrick Amphetamine induces xerogenic effects, but its mechanism of action and xerogenic potency are unknown. In the current in vivo study on the rat parotid gland, the effects of amphetamine on reflex-evoked and acetylcholine-evoked salivation were examined in the absence and presence of adrenergic and dopaminergic antagonists. Under anaesthesia, amphetamine increased the secretion of salivary fluid and the amount of protein therein in response to acetylcholine. Phentolamine abolished the increase in salivary flow and had no effect on the salivary protein concentration, whereas propranolol only reduced the salivary protein concentration. Reflex activation of the secretion evoked a well-maintained level of secretion that was reduced by amphetamine [50% inhibitory dose (ID50) 1.9 ± 0.1 mg kg,1 intravenously); the salivary protein concentration was increased in the presence of amphetamine. Phentolamine and haloperidol reduced the amphetamine-inhibitory effect on the reflex-evoked fluid response, whereas propranolol had no effect on the fluid response. The xerogenic effect of amphetamine is mainly exerted by central mechanisms involving ,-adrenoceptors, while, indirectly, amphetamine causes secretion of protein by inducing the release of noradrenaline from glandular nerve terminals. [source] Potential clinical relevance of the ,little brain' on the mammalian heartEXPERIMENTAL PHYSIOLOGY, Issue 2 2008J. A. Armour It is hypothetized that the heart possesses a nervous system intrinsic to it that represents the final relay station for the co-ordination of regional cardiac indices. This ,little brain' on the heart is comprised of spatially distributed sensory (afferent), interconnecting (local circuit) and motor (adrenergic and cholinergic efferent) neurones that communicate with others in intrathoracic extracardiac ganglia, all under the tonic influence of central neuronal command and circulating catecholamines. Neurones residing from the level of the heart to the insular cortex form temporally dependent reflexes that control overlapping, spatially determined cardiac indices. The emergent properties that most of its components display depend primarily on sensory transduction of the cardiovascular milieu. It is further hypothesized that the stochastic nature of such neuronal interactions represents a stabilizing feature that matches cardiac output to normal corporal blood flow demands. Thus, with regard to cardiac disease states, one must consider not only cardiac myocyte dysfunction but also the fact that components within this neuroaxis may interact abnormally to alter myocyte function. This review emphasizes the stochastic behaviour displayed by most peripheral cardiac neurones, which appears to be a consequence of their predominant cardiac chemosensory inputs, as well as their complex functional interconnectivity. Despite our limited understanding of the whole, current data indicate that the emergent properties displayed by most neurones comprising the cardiac neuroaxis will have to be taken into consideration when contemplating the targeting of its individual components if predictable, long-term therapeutic benefits are to accrue. [source] Downregulation of protease-activated receptor-1 in human lung fibroblasts is specifically mediated by the prostaglandin E2 receptor EP2 through cAMP elevation and protein kinase AFEBS JOURNAL, Issue 14 2008Elena Sokolova Many cellular functions of lung fibroblasts are controlled by protease-activated receptors (PARs). In fibrotic diseases, PAR-1 plays a major role in controlling fibroproliferative and inflammatory responses. Therefore, in these diseases, regulation of PAR-1 expression plays an important role. Using the selective prostaglandin EP2 receptor agonist butaprost and cAMP-elevating agents, we show here that prostaglandin (PG)E2, via the prostanoid receptor EP2 and subsequent cAMP elevation, downregulates mRNA and protein levels of PAR-1 in human lung fibroblasts. Under these conditions, the functional response of PAR-1 in fibroblasts is reduced. These effects are specific for PGE2. Activation of other receptors coupled to cAMP elevation, such as ,-adrenergic and adenosine receptors, does not reproduce the effects of PGE2. PGE2 -mediated downregulation of PAR-1 depends mainly on protein kinase A activity, but does not depend on another cAMP effector, the exchange protein activated by cAMP. PGE2 -induced reduction of PAR-1 level is not due to a decrease of PAR-1 mRNA stability, but rather to transcriptional regulation. The present results provide further insights into the therapeutic potential of PGE2 to specifically control fibroblast function in fibrotic diseases. [source] Evidence against ,2 -adrenoceptors mediating relaxation in rat thoracic aortae: ,2 -agonists relaxation depends on interaction with ,1 -adrenoceptorsFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 4 2006Enrique F. Castillo Abstract In rat aorta, the presence of functional ,2 -adrenoceptors (,2 -AR) was investigated in ring preparations preconstricted with ,1 -adrenergic and non- ,1 -adrenergic agonists. Particularly, the hypothetical interference of ,2 -AR agonists with ,1 -AR-mediated vasoconstriction was evaluated. Relaxant and contractile responses to ,2 -AR agonists were obtained. In endothelium-intact and endothelium-denuded aortic rings preconstricted with phenylephrine (1 × 10,6 m), the imidazoline derivatives, clonidine and UK14304, induced relaxations with similar order of potencies (,log EC50) and maxima relaxant effects respectively. Pretreatment with the NO synthase inhibitor, NG -nitro- l -arginine methyl ester (l -NAME) had no effect on the relaxant responses to clonidine and UK14304. In phenylephrine-constricted rings with endothelium, relaxations to clonidine and UK 14304 were not antagonized by the selective ,2 -AR antagonist, rauwolscine (,1 × 10,6 m). Clonidine and UK 14304 induced only contractions on endothelium-intact and endothelium-denuded aortic rings contracted with prostaglandin F2, (3 × 10,7 m). Moreover, clonidine and UK 14304-induced relaxation of endothelium-denuded arteries precontracted with methoxamine but not with serotonin. Finally, the concentration,contraction curves to clonidine and UK 14304 in endothelium-denuded aortic rings were significantly shifted to the right by the ,1D -AR selective antagonist, BMY 7378, and rauwolscine. The pA2 and pKB values for BMY 7378 and rauwolscine, respectively, against endothelium-independent actions of clonidine and UK 14304 were characteristic of an effect on the ,1D -AR. The other selective ,2 -AR agonist tested BHT 933 (an azepine derivative), lacks considerable relaxant and contractile effects in rat aorta. The results provide no evidence for the presence of functional ,2 -AR in rat aorta. Respectively, the relaxant and contractile effects of the imidazoline derivatives, clonidine and UK 14304, may be due to an adjustable (in relation to the agonist-dependent active state of the ,1 -AR), inhibitory and excitatory, interaction with ,1 -ARs. [source] An abnormal gene expression of the ,-adrenergic system contributes to the pathogenesis of cardiomyopathy in cirrhotic rats,HEPATOLOGY, Issue 6 2008Giulio Ceolotto Decreased cardiac contractility and ,-adrenergic responsiveness have been observed in cirrhotic cardiomyopathy, but their molecular mechanisms remain unclear. To study ,-adrenergic,stimulated contractility and ,-adrenergic gene expression patterns, 20 Wistar Kyoto rats were treated with carbon tetrachloride to induce cirrhosis and 20 rats were used as controls. Left ventricular contractility was recorded in electrically driven isolated hearts perfused at constant flow with isoproterenol (10,10 to 10,6 M). A cardiac gene expression profile was obtained using a microarray for the myocyte adrenergic pathway. The cardiac contractility maximal response to isoproterenol was significantly reduced in cirrhotic rats in comparison to control rats, whereas the half-maximal effective concentration was not different. In cirrhotic rats, cardiac gene expression analysis showed a significant overexpression of G protein alpha,inhibiting subunit 2 (G,i2), cyclic nucleotide phosphodiesterase (PDE2a), regulator of G-protein signaling 2 (RGS2), and down-expression of adenylate cyclase (Adcy3). These results indicate that overexpression of G,i2, PDE2a, and RGS2 down-regulates the ,-adrenergic signaling pathway, thus contributing to the pathogenesis of cirrhotic cardiomyopathy. (HEPATOLOGY 2008;48:1913-1923.) [source] Effect of dietary clenbuterol and cimaterol on muscle composition, ,-adrenergic and androgen receptor concentrations in broiler chickensJOURNAL OF ANIMAL PHYSIOLOGY AND NUTRITION, Issue 3-4 2004A. Schiavone Summary Illegal dietary supplementation with ,2 -agonists has been shown to increase protein deposition and decrease fat accretion in domestic animals. In poultry the metabolic and endocrine responses to ,2 -agonists are not fully elucidated. In this trial the effects of dietary clenbuterol (1 p.p.m.) and cimaterol (1 p.p.m.) on muscle composition and endocrine response of male broiler chickens were studied. Dietary clenbuterol induced a slight, but in general not significant, improvement of zootechnical performances and carcass yields. Chemical composition of muscle was not influenced by dietary treatments, even if a slight improvement of protein content was observed in treated groups. No effects on fatty acid composition of meat were detected. Both clenbuterol and cimaterol treatments caused a downregulation in testicular androgen receptors and in pulmonary, cardiac and central nervous system , -adrenergic receptors. [source] Ischemic Preconditioning: Fact or Fantasy?JOURNAL OF CARDIAC SURGERY, Issue 6 2002Christopher D. Raeburn M.D. In the ensuing years, surgeons have learned to discriminate a biochemical/metabolic/functional spectrum of cardiac states ranging from healthy myocardium to "stunned" or "hibernating" heart to the modes of "apoptotic" or "necrotic" cardiomyocyte death. It is now clear that "protective cardiac preconditioning" influences all of these cardiac states. The cellular mechanisms of preconditioning (PC) are now sufficiently understood to permit clinical application. Ligation of adrenergic, adenosine, bradykinin or opioid receptors involves signaling via both tyrosine and calcium-dependent protein kinases (PKC), which activate mitochondrial ATP-dependent potassium channels. Subsequently, the release of oxygen radicals induces nuclear translocation of transcriptional regulators, which transform the cardiomyocyte into a more resilient cell. Although preconditioning was initially recognized as protecting only against infarction, PC also limits postischemic dysrhythmias and enhances contractile function. Phase I (safety) and phase II (efficacy) clinical trials now persuasively support pharmacological preconditioning as a safe mode of preventing postcardiac surgical complications. Indeed, preconditioning is currently being proposed as adjunctive to hypothermic perfusates in protecting against the obligate organ ischemia during transplantation. [source] Vagal Paroxysmal Atrial Fibrillation: Prevalence and Ablation Outcome in Patients Without Structural Heart DiseaseJOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, Issue 5 2010RAPHAEL ROSSO M.D. Prevalence of Vagal Paroxysmal Atrial Fibrillation.,Introduction: The prevalence of vagal and adrenergic atrial fibrillation (AF) and the success rate of pulmonary vein isolation (PVI) are not well defined. We investigated the prevalence of vagal and adrenergic AF and the ablation success rate of antral pulmonary vein isolation (APVI) in patients with these triggers compared with patients with random AF. Methods and Results: Two hundred and nine consecutive patients underwent APVI due to symptomatic drug refractory paroxysmal AF. Patients were diagnosed as vagal or adrenergic AF if >90% of AF episodes were related to vagal or adrenergic triggers; otherwise, a diagnosis of random AF was made. Clinical, electrocardiogram (ECG), and Holter follow-up was every 3 months in the first year and every 6 months afterward and for symptoms. Of 209 patients, 57 (27%) had vagal AF, 14 (7%) adrenergic AF, and 138 (66%) random AF. Vagal triggers were sleep (96.4%), postprandial (96.4%), late post-exercise (51%), cold stimulus (20%), coughing (7%), and swallowing (2%). At APVI, 94.3% of patients had isolation of all veins. Twenty-five (12%) patients had a second APVI. At a follow-up of 21 ± 15 months, the percentage of patients free of AF was 75% in the vagal group, 86% in the adrenergic group, and 82% for random AF (P = 0.51). Conclusion: In patients with PAF and no structural heart disease referred for APVI, vagal AF is present in approximately one quarter. APVI is equally effective in patients with vagal AF as in adrenergic and random AF. (J Cardiovasc Electrophysiol, Vol. 21, pp. 489-493, May 2010) [source] Adrenergic-Cholinergic Interaction that Modulates Repolarization in the Atrium is Altered with AgingJOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, Issue 4 2002EUGENE A. SOSUNOV Ph.D. Autonomic Modulation of Atrial Repolarization.Introduction: Aging is associated with involution of both limbs of the autonomic nervous system, and the prejunctional and postjunctional effects of adrenergic and cholinergic stimulation are altered with senescence. Hence, postjunctional age-related changes in adrenergic-cholinergic interaction are a likely occurrence and may contribute to an altered substrate for arrhythmias. Methods and Results: Microelectrode techniques were used to record action potentials from epicardial slices of Bachmann's bundles of dogs aged 3 to 5 years (adult) and 8 to 12 years (old) in the absence or presence of acetylcholine and isoproterenol (separately and in combination). In control, action potential duration to 90% repolarization (APD) was longer in old atria. Acetylcholine (10,8 to 10,5 mol/L) in a concentration-dependent manner hyperpolarized and shortened APD in both tissues, with more prominent effects in the old. The effects of isoproterenol (10,9 to 10,6 mol/L) to elevate the plateau and shorten APD were about the same in both adult and old tissues. In adults, low concentrations of isoproterenol (10,9 and 10,8 mol/L) significantly prolonged APD, which had been first shortened by acetylcholine. This effect of isoproterenol was decreased in old atrial tissue, resulting in shorter APD in old than adult atria in the combined presence of beta-adrenergic and muscarinic agonists. Conclusion: In adult Bachmann's bundle, beta-adrenergic stimulation effectively operates as a "brake" to decrease the extent of cholinergic-induced APD shortening. The action of beta-adrenergic stimulation to antagonize acetylcholine-induced acceleration of repolarization declines with age, which may contribute to an altered arrhythmogenic substrate. [source] G-protein coupled receptors: SAR analyses of neurotransmitters and antagonistsJOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 3 2004C. L. Kuo MS Summary Background:, From the deductive point of view, neurotransmitter receptors can be divided into categories such as cholinergic (muscarinic, nicotinic), adrenergic (, - and , -), dopaminergic, serotoninergic (5-HT1,5-HT5), and histaminergic (H1 and H2). Selective agonists and antagonists of each receptor subtype can have specific useful therapeutic applications. For understanding the molecular mechanisms of action, an inductive method of analysis is useful. Objective:, The aim of the present study is to examine the structure,activity relationships of agents acting on G-protein coupled receptors. Method:, Representative sets of G-PCR agonists and antagonists were identified from the literature and Medline [P.M. Walsh (2003) Physicians' desk reference; M.J. O'Neil (2001) The Merck index]. The molecular weight (MW), calculated logarithm of octanol/water partition coefficient (C log P) and molar refraction (CMR), dipole moment (DM), Elumo (the energy of the lowest unoccupied molecular orbital, a measure of the electron affinity of a molecule and its reactivity as an electrophile), Ehomo (the energy of the highest occupied molecular orbital, related to the ionization potential of a molecule, and its reactivity as a nucleophile), and the total number of hydrogen bonds (Hb) (donors and receptors), were chosen as molecular descriptors for SAR analyses. Results:, The data suggest that not only do neurotransmitters share common structural features but their receptors belong to the same ensemble of G-protein coupled receptor with seven to eight transmembrane domains with their resultant dipoles in an antiparallel configuration. Moreover, the analysis indicates that the receptor exists in a dynamic equilibrium between the closed state and the open state. The energy needed to open the closed state is provided by the hydrolysis of GTP. A composite 3-D parameter frame setting of all the neurotransmitter agonists and antagonists are presented using MW, Hb and , as independent variables. Conclusion:, It appears that all neurotransmitters examined in this study operate by a similar mechanism with the G-protein coupled receptors. [source] Cholinergic and adrenergic influences on the heart of the African lungfish Protopterus annectensJOURNAL OF FISH BIOLOGY, Issue 4 2010E. Sandblom Cardiac cholinergic and adrenergic tones were determined in minimally instrumented African lungfish Protopterus annectens. Mean ±S.E. routine heart rate (fH) was 31·6 ± 1·4 beats min,1, cholinergic tone was 34·6 ± 5·2% and adrenergic tone was 9·4 ± 2·3%, while the intrinsic fH after blockade of both adrenergic and cholinergic control systems was 39·1 ± 1·3 beats min,1. It is demonstrated that routine cholinergic tone has probably been underestimated in previous studies on lungfishes, suggesting that withdrawal of vagal tone may provide an important mechanism to increase fH in this group of fishes during, for example, air breathing. [source] Acute Stent Thrombosis in the Setting of Cocaine Abuse Following Percutaneous Coronary InterventionJOURNAL OF INTERVENTIONAL CARDIOLOGY, Issue 1 2009JOHN N. MAKARYUS M.D. The treatment of acute coronary syndrome (ACS) in patients with documented cocaine abuse has always presented significant challenges. Issues related to medication compliance, the potential risks of beta adrenergic blockade, and possible continued cocaine abuse postmyocardial infarction necessitate a unique, individualized approach to these patients. Recent data in the era of extensive percutaneous coronary interventions (PCI) and intracoronary stent (ICS) implantation have raised questions regarding the safety of ICS in patients who may revert to cocaine abuse postacute coronary syndrome as a result of the potentially higher risk of stent thrombosis in these patients. While the precise reason as to why cocaine use may increase the risk of stent thrombosis is not fully understood, it is likely the result of a confluence of factors, including coronary vessel vasoconstriction, impaired vascular compliance, as well as the platelet-activating effect of cocaine. We present the case a 46-year-old male with a history of cocaine abuse who presented with an acute stent thrombosis 2 days post-PCI likely as a result of cocaine abuse on the day of discharge following initial stent implantation for a non-ST-elevation myocardial infarction (NSTEMI). We also review the literature regarding the safety of PCI in cocaine abusers. [source] Adenovirus-Mediated Leptin Expression Normalises Hypertension Associated with Diet-Induced ObesityJOURNAL OF NEUROENDOCRINOLOGY, Issue 3 2010W. Zhang In our previous study, moderate increases in plasma leptin levels achieved via administration of recombinant adenovirus containing the rat leptin cDNA were shown to correct the abnormal metabolic profile in rats with diet-induced obesity, suggesting that these animals had developed resistance to the metabolic effects of leptin, which could be reversed by leptin gene over-expression. However, the effect of this therapeutic strategy on blood pressure was not investigated. The present study aimed to determine whether a moderate increase of endogenous plasma leptin levels affected arterial blood pressure in rats with diet-induced obesity and hypertension. The major finding from the present study was that the natural rise in plasma leptin with weight-gain is insufficient to counterbalance high blood pressure associated with obesity, additional increases of circulating leptin levels with adenoviral leptin gene therapy led to normalisation of blood pressure in high-fat diet-induced obese and hypertensive rats. Mechanistically, the reduction of blood pressure by leptin in obese rats was likely independent of ,-adrenergic and acetylcholinergic receptor mediation. This is the first study to demonstrate that further increases in circulating leptin levels by leptin gene transfer during obesity could reduce blood pressure. [source] Serotonergic and Catecholaminergic Interactions with Co-Localised Dopamine-Melatonin Neurones in the Hypothalamus of the Female TurkeyJOURNAL OF NEUROENDOCRINOLOGY, Issue 1 2009S. W. Kang Serotonin and catecholamines (dopamine, norepinephrine, epinephrine) have important roles as neurotransmitters in avian reproduction, but their anatomical relationship to the neuroendocrine circuitry that regulates reproduction is poorly understood. Our previous studies have shown that co-localised dopamine-melatonin (DA-MEL) neurones in the avian premammillary nucleus (PMM) are active during periods of photoresponsiveness and, therefore, are potentially photosensitive neurones. Because serotonergic and catecholaminergic neurotransmitters are important regulators of reproductive function in the female turkey, we hypothesised that the serotonergic/catecholaminergic neurones within the brainstem might interact with PMM DA-MEL neurones and constitute an important circuit for reproductive function. To examine this possible interaction, the retrograde fluorescent tract tracer, 1,1,dioctadecyl-3,3,3,3,-tetramethyleindocarbocyanine perchlorate (DiI) was injected into the PMM, and combined with serotonin, tyrosine hydroxylase (TH), dopamine ,-hydroxylase (DBH) and phenyl N -methyltransferse (PNMT) immunocytochemistry to reveal neuroanatomical connections. Changes in the activities of serotonergic, dopaminergic, adrenergic and noradrenergic neuronal systems projecting to the PMM were measured at different reproductive states with in situ hybridisation (ISH) techniques, using tryptophan hydroxylase 2 (TPH2) and TH mRNA expression, respectively. Cells labelled with DiI were found in anatomically discrete areas in or near the hypothalamus and the brainstem. Double immunocytochemistry confirmed that there were serotonin, DBH and PNMT fibres in close apposition to DA-MEL neurones. TPH2 mRNA expression in serotonin neurones was found in several nuclei, and its most abundant mRNA expression was seen in the nucleus Locus ceruleus of laying and incubating hens. TH mRNA expression levels in the six catecholaminegic areas labelled with DiI was measured across the different reproductive states. In the nucleus tractus solitarius (adrenergic), the highest level of TH mRNA expression was found in photorefractory hens and the lowest level in incubating hens. These observed patterns of serotonin/catecholamine neuronal distribution and their variable interactions with PMM DA-MEL neurones during different reproductive states may offer a significant neuroanatomical basis for understanding the control of avian reproductive seasonality. [source] Neural Circuits Regulating Pulsatile Luteinizing Hormone Release in the Female Guinea-Pig: Opioid, Adrenergic and Serotonergic InteractionsJOURNAL OF NEUROENDOCRINOLOGY, Issue 3 2001A. C. Gore Abstract We studied three neurotransmitters involved in the regulation of pulsatile luteinizing hormone (LH) release: opioid peptides, serotonin and norepinephrine, using the ovariectomized guinea-pig. This is an attractive animal model due to the regularity of its LH pulses, enabling any disruptions to be clearly ascertained. In all experiments, a specific agonist or antagonist was administered, either alone or serially to enable detection of interactions, and effects on mean LH concentrations, pulse amplitude and interpulse interval were determined by PULSAR analysis. In the ovariectomized guinea-pig, catecholamines are stimulatory (acting through the ,1 and ,2 but not , receptors, unlike other species), opioids inhibitory and serotonin permissively stimulatory to pulsatile LH release. Stimulatory effects of the opiate antagonist were not blocked by pretreatment with an ,1 - or ,2 -adrenergic antagonist. Similarly, pretreatment with the opiate antagonist did not prevent the suppression of LH release by ,1 and ,2 antagonists. This suggests that, in the guinea-pig, effects of opiates and catecholamines on LH release are exerted by independent pathways to luteinizing hormone releasing hormone (LHRH) neurones. For the opiate,serotonin interactions, pretreatment with the serotonergic antagonist did not block the stimulatory effect of the opiate antagonist on LH release. However, pretreatment with the opiate agonist could not be overcome by the serotonergic agonist. This suggests that the effects of the serotonin system on LHRH release may be indirectly mediated by opioid neurones. Taken together, these studies demonstrate that the three neurotransmitter systems studied are critically involved in normal pulsatile LH release in the female guinea-pig, and demonstrate novel functional relationships between the opioid and the adrenergic and serotonergic systems. [source] Effects of Chronic Oestrogen Replacement on Stress-Induced Activation of Hypothalamic-Pituitary-Adrenal Axis Control PathwaysJOURNAL OF NEUROENDOCRINOLOGY, Issue 8 2000C. V. Dayas Abstract Oestrogen replacement therapy reportedly suppresses hypothalamic-pituitary-adrenal (HPA) axis responses to an emotional stressor in postmenopausal women. However, most studies in the rat suggest a facilitatory role for oestrogen in the control of HPA axis function. One explanation for this difference may be the regimen of oestrogen replacement: during oestrogen replacement therapy, oestrogen levels are low and constant whereas most animal studies examined the HPA axis response when oestrogen levels are rising. In the present study, we assessed HPA axis stress responses in mature ovariectomized rats after plasma oestrogen levels had been maintained at physiological levels for a prolonged period (25 or 100 pg/ml for 7 days). In the case of both an emotional stressor (noise) and a physical stressor (immune challenge by systemic interleukin-1, administration), oestrogen replacement suppressed stress-related Fos-like immunolabelling, in hypothalamic neuroendocrine cells and plasma adrenocorticotropin hormone responses. From the present data, and past reports, it appears unlikely that these effects of oestrogen are due to a direct action on corticotropin-releasing factor or oxytocin cells. Therefore, to obtain some indication of oestrogen's possible site(s) of action, Fos-like immunolabelling was mapped in the amygdala and in brainstem catecholamine groups, which are neuronal populations demonstrating substantial evidence of involvement in the generation of HPA axis stress responses. In the amygdala, oestrogen replacement suppressed central nucleus responses to immune challenge, but not to noise. Amongst catecholamine cells, oestrogen replacement was more effective against responses to noise than immune challenge, suppressing A1 and A2 (noradrenergic) and C2 (adrenergic) responses to noise, but only A1 responses to immune challenge. These data suggest that, as in postmenopausal women on oestrogen replacement therapy, chronic low-level oestrogen replacement can suppress HPA axis stress responses in the rat. Moreover, oestrogen appears to exert effects at multiple sites within putative HPA axis control pathways, even though most of the relevant neuronal populations do not contain genomic receptors for this gonadal steroid and the pattern of oestrogen action differs for an emotional vs a physical stressor. [source] Mechanisms involved in the relaxant action of the ethanolic extract of propolis in the guinea-pig trachea in-vitroJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 6 2002Niraldo Paulino This study examines the mechanisms by which the standardised ethanolic extract of propolis induces relaxation of the guinea-pig trachea in-vitro. In guinea-pig trachea with or without epithelium and contracted by histamine, the propolis extract caused reproducible and graded relaxation, with a mean EC50 value of 3.8 or 10.5 ,g mL,1 and Emax of 100%, respectively. The propolis extract-induced relaxation was markedly reduced (26 ± 9 and 96 ± 3%) when guinea-pig tracheas were exposed to Krebs solution containing elevated K+ in the medium (40 or 80 mM). Pre-incubation of guinea-pig tracheas with tetraethylamonium (100 mM) or with 4-aminopyridine (10 mM) reduced the propolis extract-induced relaxation by 31±10% and 28 ± 2%. Likewise, apamin (0.1 ,M), charybdotoxin (0.1 ,M) or iberiotoxin (0.1 ,M) caused marked inhibition of propolis extract-mediated relaxation in guinea-pig trachea (percentage of inhibition: 65 ± 3%, 60 ± 5% and 65 ± 9%, respectively). Also, glibenclamide (1 ,M) inhibited the relaxant response caused by the propolis extract by 57 ± 4%. ,-Conotoxin GIVA (0.1 ,M) or capsaicin (1 ,M) produced small but significant inhibition (30 ± 5% or 47 ± 7%, respectively) of the propolis extract-induced relaxation. The vasoactive intestinal peptide (VIP) antagonist D- P -CI-Phe6, Leu17[VIP] porcine (0.1 ,M) inhibited relaxation by 55 ± 5%, while propranolol (1 ,M) induced a parallel rightward displacement (about 20 fold) of the propolis extract concentration-response curve. Finally, the propolis extract-induced relaxation was inhibited by the nitric oxide synthase inhibitor L-NG -nitroarginine (L-NOArg, 100 ,M) (48 ± 6%), and by the soluble guanylate cyclase inhibitor methylene blue (10 ,M) (37 ± 6%), while the more selective soluble guanylate cyclase inhibitor 1H -[1,2,4]oxadiazolol[4,3-a]quinoxalin-1-one (ODQ, 1 ,M) produced only a parallel (about 3 fold) rightward displacement of the propolis extract concentration-response curve. Collectively, these results support the notion that the propolis extract-mediated relaxation in the guinea-pig trachea involves the release of nitric oxide, probably from sensory neurons, besides the activation of soluble guanylate cyclase and activation of Ca2+ - and ATP-sensitive K+channels. Furthermore, the stimulation of ,2 -adrenergic and VIP receptors also seems to account for its relaxant action. [source] Effect of Repeated Doses of Ethanol on Hepatic Mg2+ Homeostasis and MobilizationALCOHOLISM, Issue 7 2007Andrew Young The acute administration of a first dose of ethanol (EtOH) to rat liver cells reduces the amount of Mg2+ extruded by a second dose of EtOH or the subsequent addition of adrenergic agonists. In contrast, the Mg2+ extrusion normally elicited by the ,1 -adrenergic or , -adrenergic agonist does not impair the Mg2+ mobilization induced by the subsequent addition of EtOH. Inhibition of EtOH metabolism by 4-methylpyrazole abolishes almost completely the Mg2+ extrusion induced by the first dose of EtOH, and partially enlarges that elicited by the second dose of alcohol or the subsequent adrenergic stimulation. Ethanol-treated liver cells stimulated by the adrenergic agonist show a reduced level of membrane-bound G,s as well as a reduced cellular cAMP content. Analysis of cellular Mg2+ distribution indicates that EtOH administration decreases the Mg2+ content of the cytoplasm, mitochondria, and endoplasmic reticulum to a comparable extent. These data indicate that acute EtOH administration directly impairs cellular Mg2+ homeostasis and also prevents a further Mg2+ mobilization by additional doses of alcohol or ,1 -adrenoceptor and , -adrenoceptor agonist by decreasing cytosolic and intraorganelle Mg2+ content and by affecting G-protein membrane distribution/signaling. [source] ,2 -agonist treatment enhances uterine oxytocin receptor mRNA expression in pregnant ratsMOLECULAR REPRODUCTION & DEVELOPMENT, Issue 1 2004Anna Klukovits Abstract The objective of this study was to disclose an interaction between ,2 -adrenergic (,2 -ARs) and oxytocin (OT) receptors (OTRs) in the late-pregnant rat uterus. We investigated the level of uterine OTR mRNA expression after the administration of ,2 -AR agonists fenoterol and hexoprenaline to rats from day 18 to 22 of pregnancy, and also tested the effect of fenoterol on uterine explants. Hexoprenaline induced a maximum 24% increase of OTR mRNA. Fenoterol in vivo elicited a maximum 125% increase of OTR mRNA, in vitro produced a maximum fourfold increase in OTR mRNA. In fenoterol-treated rats the maximal contractility increasing effect of OT on isolated uterine rings was significantly higher than in intact term pregnant rats, but the EC50 values were not statistically different. It was concluded that the enhanced expression of OTR mRNA induced by ,2 -agonists in the late-pregnant rat uterus may be a possible drawback to effective therapy of preterm uterine contractions with ,2 -agonists. Mol. Reprod. Dev. 69: 60,65, 2004. © 2004 Wiley-Liss, Inc. [source] | ||||||||||||||||||||||||||||||||||