Chemistry, physiology, and pharmacology of ß-adrenergic mechanisms in the heart. Why are ß-blocker antiarrhythmics superior?

Stimulation of ß-adrenergic receptors in the heart is the most effective endogenous way to increase the mechanical performance of cardiac tissues to meet the requirements of a fight-or-flight situation or stress. On the other hand, sustained activation of cardiac ß-receptors initiates maladaptive remodeling of the myocardium leading to cardiomyopathies and heart failure. Since both acute and chronic stimulation of ß-adrenoceptors are arrhythmogenic, the application of ß-receptor blockers exerts effective antiarrhytmic actions at both short and long time scale. Compared to other classes of antiarrhythmic agents, ß-blockers are the class of antiarrhythmics that was shown to decrease mortality in postinfarct patients. Chemical, physiological, and pharmacological properties of the ß-adrenoceptor related signaling, the role of ß-1, ß-2, and ß-3 receptor subtypes, consequences of acute and long term ß-adrenergic stimulation and the underlying proarrhythmic mechanisms, including the changes in cardiac ion currents and Ca(2+) handling, are reviewed in this paper together with the clinical relevance of cardioprotective ß-blocking therapy.

The Janus face of adenosine: antiarrhythmic and proarrhythmic actions.

Adenosine is a ubiquitous, endogenous purine involved in a variety of physiological and pathophysiological regulatory mechanisms. Adenosine has been proposed as an endogenous antiarrhythmic substance to prevent hypoxia/ischemia-induced arrhythmias. Adenosine (and its precursor, ATP) has been used in the therapy of various cardiac arrhythmias over the past six decades. Its primary indication is treatment of paroxysmal supraventricular tachycardia, but it can be effective in other forms of supraventricular and ventricular arrhythmias, like sinus node reentry based tachycardia, triggered atrial tachycardia, atrioventricular nodal reentry tachycardia, or ventricular tachycardia based on a cAMP-mediated triggered activity. The main advantage is the rapid onset and the short half life (1- 10 sec). Adenosine exerts its antiarrhythmic actions by activation of A1 adenosine receptors located in the sinoatrial and atrioventricular nodes, as well as in activated ventricular myocardium. However, adenosine can also elicit A2A, A2B and A3 adenosine receptor-mediated global side reactions (flushing, dyspnea, chest discomfort), but it may display also proarrhythmic actions mediated by primarily A1 adenosine receptors (e.g. bradyarrhythmia or atrial fibrillation). To avoid the non-specific global adverse reactions, A1 adenosine receptor- selective full agonists (tecadenoson, selodenoson, trabodenoson) have been developed, which agents are currently under clinical trial. During long-term administration with orthosteric agonists, adenosine receptors can be internalized and desensitized. To avoid desensitization, proarrhythmic actions, or global adverse reactions, partial A1 adenosine receptor agonists, like CVT-2759, were developed. In addition, the pharmacologically "silent" site- and event specific adenosinergic drugs, such as adenosine regulating agents and allosteric modulators, might provide attractive opportunity to increase the effectiveness of beneficial actions of adenosine and avoid the adverse reactions.

Histamine and H1 -histamine receptors faster venous circulation.

The study has analysed the action of histamine in the rabbit venous system and evaluated its potential role in contraction during increased venous pressure. We have found that a great variety exists in histamine sensitivity and H(1) -histamine receptor expression in various types of rabbit veins. Veins of the extremities (saphenous vein, femoral vein, axillary vein) and abdomen (common iliac vein, inferior vena cava) responded to histamine by a prominent, concentration-dependent force generation, whereas great thoracic veins (subclavian vein, superior vena cavas, intrathoracic part of inferior vena cava) and a pelvic vein (external iliac vein) exhibited slight sensitivity to exogenous histamine. The lack of reactivity to histamine was not due to increased activity of nitric oxide synthase (NOS) or heme oxygenase-1. H(1) -histamine receptor expression of veins correlated well with the histamine-induced contractions. Voltage-dependent calcium channels mediated mainly the histamine-induced force generation of saphenous vein, whereas it did not act in the inferior vena cava. In contrast, the receptor-operated channels were not involved in this response in either vein. Tyrosine phosphorylation occurred markedly in response to histamine in the saphenous vein, but not in the inferior vena cava. Histamine induced a prominent ρ kinase activation in both vessels. Protein kinase C and mitogen-activated protein kinase (MAPK) were not implicated in the histamine-induced intracellular calcium sensitization. Importantly, transient clamping of the femoral vein in animals caused a short-term constriction, which was inhibited by H(1) -histamine receptor antagonist in vivo. Furthermore, a significantly greater histamine immunopositivity was detected in veins after stretching compared to the resting state. We conclude that histamine receptor density adapts to the actual requirements of the circulation, and histamine liberated by the venous wall during increased venous pressure contributes to the contraction of vessels, providing a force for the venous return.

Hypothermia translocates nitric oxide synthase from cytosol to membrane in snail neurons.

Neuronal nitric oxide (NO) levels are modulated through the control of catalytic activity of NO synthase (NOS). Although signals limiting excess NO synthesis are being extensively studied in the vertebrate nervous system, our knowledge is rather limited on the control of NOS in neurons of invertebrates. We have previously reported a transient inactivation of NOS in hibernating snails. In the present study, we aimed to understand the mechanism leading to blocked NO production during hypothermic periods of Helix pomatia. We have found that hypothermic challenge translocated NOS from the cytosol to the perinuclear endoplasmic reticulum, and that this cytosol to membrane trafficking was essential for inhibition of NO synthesis. Cold stress also downregulated NOS mRNA levels in snail neurons, although the amount of NOS protein remained unaffected in response to hypothermia. Our studies with cultured neurons and glia cells revealed that glia-neuron signaling may inhibit membrane binding and inactivation of NOS. We provide evidence that hypothermia keeps NO synthesis "hibernated" through subcellular redistribution of NOS.

Short-term adaptation of rat intestine to ileostomy: implication for pediatric practice.

BACKGROUND: Surgical neonates with complex intestinal conditions, such as enterocolitis, midgut volvulus with bowel loss and multiple atresias, often require temporary stomas. Little is known on the postsurgical response of the altered gut segments, although adaptation is an important consideration in neonatal postoperative care, particularly after stoma closure. MATERIALS AND METHODS: Rats underwent bowel resection at a point 15 cm proximal to the ileocecal valve, and a split ileostomy was performed. On the 6th postoperative day the mucosal thickness was calculated with Soft Imaging System Analysis Pro, the rate of proliferation was measured following Ki67 immunohistochemistry and the apoptotic index was determined on sections stained with ApopTag Plus. The intestinal motor activity was recorded on isolated gut segments. Neuronal nitric oxide synthase (nNOS) expression and distribution was examined with NADPH-diaphorase histochemistry and Western blot analysis. RESULTS: An increased wet weight of the mucosa and a pronounced mucosal thickening were observed in the proximal functional bowel segment. Enterocyte proliferation rate was increased significantly, while the apoptotic index remained unchanged in the epithelial layer. The dilation of the gut lumen resulted in a morphological change in the nitrergic myenteric network with an overexpression of nNOS. As a consequence of the surgical procedure, the functional proximal gut segment showed strong and frequent contraction waves, with an enhanced responsiveness to cholinergic stimuli. CONCLUSIONS: The dilated functional bowel segment was characterized by hyperplasic changes in the mucosa and stronger mechanical activity with overproduction of nNOS. Although early restoration of intestinal continuity is recommended, our observations on adaptive changes may partly explain intestinal motility disorders after early stoma closure, suggesting the need for a careful approach to a redo-laparotomy.

Acetylcholine inhibits nitric oxide (NO) synthesis in the gastropod nervous system.

Acetylcholine (ACh) is one of the main signals regulating nitric oxide synthase (NOS) expression and nitric oxide (NO) biosynthesis in mammals. However, few comparative studies have been performed on the role of ACh on NOS activity in non-mammalian animals. We have therefore studied the cholinergic control of NOS in the snail Helix pomatia and compared the effects of ACh on NO synthesis in the enteric nervous system of the snail and rat. Analyses by the NADPH-diaphorase reaction, immunocytochemistry, purification with ion-exchange chromatography, Western-blot, and quantitative polymerase chain reaction have revealed the expression of neuronal NOS in the rat intestine and of a 60-kDa subunit of NOS in the enteric nerve plexus of H. pomatia. In H. pomatia, quantification of the NO-derived nitrite ions has established that NO formation is confined to the NOS-containing midintestine. Nitrite production can be elevated by L-arginine but inhibited by N(omega)-nitro-L-arginine. In rats, ACh moderately elevates nitrite production, whereas ACh, the nicotinic receptor agonists (nicotine, acetyl thiocholine iodide, metacholine) and the cholinesterase inhibitor eserine reduce enteric nitrite formation in snails. The nicotinic receptor antagonist tubocurarine also provokes nitrite liberation, whereas the muscarinic receptor agonists or antagonists have no significant effect in snails. In the presence of EDTA or tetrodotoxin, ACh fails to inhibit nitrite production. In pharmacological studies, we have found that ACh contracts the midintestinal muscles and, in snails, simultaneously reduces the antagonistic muscle relaxant effect of L-arginine. Our experiments provide the first evidence for an inhibitory regulation of neuronal NO synthesis by ACh in an invertebrate species.

[Cardiovascular actions of a standardized polyphenol concentrate on patients undergoing coronary bypass grafting: a randomized, double-blind, placebo-controlled study]. / Standardizált polifenol-koncentrátum keringési hatásai koszorúérmutéten átesett betegeken: randomizált, kettos vak-, placebokontrollos vizsgálat.

In this study the authors analyzed the action of Flavon Max product on the cardiovascular system of patients with severe coronary disease. Two randomized, double-blind, placebo controlled trials were carried out using impedance-cardiography, arteriography, vascular Doppler and biochemical laboratory methods. The results demonstrate that Augmentation Index measured with arteriography and C reactive protein (CRP) levels were significantly ameliorated after 2 x 2 months Flavon Max therapy. In conclusion, this product is beneficial as adjuvant in the treatment of atherosclerotic coronary disease.

Characterization of nitric oxidergic neurons in the alimentary tract of the snail Helix pomatia L.: histochemical and physiological study.

By using NADPH-diaphorase (NADPH-d) histochemistry, nitric oxide synthase (NOS) immunohistochemistry, Western blotting, and NO pharmacology, we investigated the distribution and possible function of NOS-containing neurons in different units of the alimentary tract of the snail, Helix pomatia. Discrete populations of neurons in the buccal ganglia displayed NADPH-d reactivity. NADPH-d-reactive and NOS-immunoreactive (NOS-IR) neurons were present in the caecum, and labeled fibers were found to innervate the circular muscles of the proesophagus and caecum and to form axosomatic connections with neurons of the myenteric and submucosal plexi of the caecum. A 65-kDa protein was found to be nNOS-IR in the caecum protein extract. The majority of the NADPH-d-reactive neurons also displayed FMRFamide immunoreactivity, whereas a mutual innervation by NADPH-diaphorase-reactive and catch-relaxing peptide (CARP)-IR neurons was observed in the caecum. Application of NO-donors [glyceryl trinitrate, S-nitroso-N-acetyl-DL-penicillamine, sodium nitroprusside (SNP)] evoked a dose-dependent increase in tension, frequency, and amplitude of the spontaneous muscle contractions of the proesophagus and caecum. Contractions could be blocked by applying the NO scavenger 2-phenyl-4,4,5,5,-tetramethylimidazoline-1-oxyl-3-oxide. FMRFamide evoked a response of the caecum similar to that with NO, and its simultaneous application was additive. Preincubation with CARP blocked the increase of tension evoked by SNP, whereas Mytilus inhibitory peptide (MIP) decreased the rhythmic contractions induced by the NO donor. Our findings indicate that NO is an important signal molecule in the feeding system of Helix, involved, partially in cooperation with different molluscan neuropeptides, in the regulation of both neuronal and muscular activities.

Immunohistochemical studies using immunized Guinea pig sera with features of anti-human thyroid, eye and skeletal antibody and Graves' sera.

Type 2 5' deiodinase enzyme was observed in both thyroid and eye muscle tissues, highlighting its possible role as a common antigen in thyroid-associated ophthalmopathy. Sera of 105 Graves' patients and 40 controls, and immunized guinea pig sera against TCSS peptide, showing homology to the amino acid sequence from 132 to 152 of type 2 5' deiodinase, were investigated to demonstrate the binding effects to human thyroid, eye and skeletal muscle tissues. Twenty-two Graves' patients were positive for anti-TCSS peptide antibodies, of whom 18 cases had ophthalmopathy. The levels of anti-TCSS peptide antibodies were higher not only in Graves' patients with (P<0.0001) and without (P<0.036) eye symptoms compared to controls but also the difference was significant between patients with and without ophthalmopathy (P<0.049). In Western blot, immunized sera showed binding reactions to the supernatant fractions of human thyroid, eye and skeletal muscle tissues at the range of 29 kDa. Patient sera with Graves' ophthalmopathy resulted in positive reactions directed to membrane areas in thyroid follicular cells, and to fibers in eye and skeletal muscles using immunohistochemical method, while no positive staining was present after adding control sera. The binding features of immunized guinea pig sera exhibited similar staining in all human tissues but could be blocked with Graves' sera. Our results suggest that type 2 5' deiodinase enzyme protein could play a role as an antigen in Graves' disease. Immunized guinea pig sera against TCSS peptide exhibited similar binding reactions and stainings to human thyroid, eye and skeletal muscle tissues as patient sera with Graves' ophthalmopathy.

Phe-met-arg-phe (FMRF)-amide is a substrate source of NO synthase in the gastropod nervous system.

The possible involvement of the L-arginine-containing Phe-met-arg-phe (FMRF)-amide (FMRFa) in neuronal nitric oxide (NO) biosynthesis was studied in a gastropod species. We found NADPH-diaphorase-positive neurons and FMRFa-containing fibers in close proximity in the enteric nervous system. Administration of L-arginine and FMRFa induced quantitatively similar nitrite production in both intact intestinal tissues and tissue homogenates. These changes could be prevented by the presence of NOARG (an NO synthase inhibitor). Neither chemically modified FMRFa (D-arginine instead of L-arginine) nor amino acid constituents of FMRFa (methionine, phenylalanine) affected basal nitrite production. FMRFa-induced alterations were reduced in the presence of Na+ channel blockers (tetrodotoxin, amiloride, lidocaine), the Na+/K+ATPase inhibitor ouabain, or protease inhibitors (leupeptine, pepstatine-a). FMRFa and its amino acid constituents were analyzed by paper chromatography. When FMRFa was added to tissue homogenates, the peptide was eliminated within 1-2 min, whereas methionine, phenylalanine, arginine, and citrulline levels were elevated simultaneously. We tested the effects of FMRFa, L-arginine, and NOARG on intestinal contractile activity. FMRFa relaxed the intestine for 1-2 min and then induced contractions for 20-40 min. In the presence of NOARG, no relaxant effect of FMRFa was recorded. As administration of L-arginine strongly inhibits the mechanical activity of the intestinal muscle, NO production presumably plays a substantial role in the action of FMRFa, at least in the initial phase. Our biochemical data indicate a direct involvement of FMRFa in NO biosynthesis. FMRFa might be hydrolyzed by extracellular peptidases and then the locally released arginine might be transported into the cells and broken-down to produce NO. Depolarization-induced NO production attributable to the activation of amiloride-sensitive Na+ channels might also be involved.

Effect of rosiglitazone, an insulin sensitizer, on myelotoxicity caused by repeated doses of 5-fluorouracil.

Haematopoietic colony-stimulating factors are used frequently to moderate myelotoxicity, but administration of granulocyte-colony-stimulating factor (G-CSF) prior to chemotherapy actually may worsen the toxic effects on bone marrow. This is important in the design of clinical cancer treatment protocols. Previously, we found that rosiglitazone may protect granulocyte-macrophage progenitor cells (CFU-GM) against damage caused by a single dose of 5-fluorouracil (5-FU). Our new studies are designed to evaluate whether rosiglitazone has similar beneficial effects on bone marrow preservation when administered concurrently with repeated, daily doses of 5-FU while restricting regeneration time. Myelotoxicity characterized by the decrease in cellularity, frequency of granulocyte-macrophage progenitor cells and CFU-GM content of femoral bone marrow in mice. Five-day oral rosiglitazone pre-treatment decreased the susceptibility of granulocyte-macrophage progenitors to 5-FU damage. Significantly, more CFU-GM cells survived after the single intraperitoneal dose of 5-FU (100 mg kg(-1)). The increased frequency of CFU-GM cells with their intensive proliferation allowed faster restoration of the damaged CFU-GM compartment than was seen in the case of repeated daily administration of the cytostatic drug (25 or 50 mg kg(-1)) together with rosiglitazone for 7 consecutive days. The expansion of the CFU-GM compartment was 3 times and 50 times greater in the combined-treated mice than in their counterparts treated with repeated doses of 5-FU alone, although differences in absolute neutrophil counts were not significant. In conclusion, our results indicated that rosiglitazone has protective effects on bone marrow progenitor cells even after daily 5-FU treatment but further studies are warranted to evaluate the optimal treatment schedules.

Concentration estimation via curve fitting: quantification of negative inotropic agents by using a simple mathematical method in guinea pig atria.

We created a simple method based on curve fitting in order to assess the concentration of pharmacological agonists or antagonists in the microenvironment of the receptors. We tested our method in electrically driven guinea pig left atria by estimating the concentration of N6-cyclopentyladenosine (CPA; A1 adenosine receptor agonist), acetyl-beta-methylcholine (muscarinic receptor agonist) and verapamil (L-type Ca2+ channel inhibitor) added previously to the atria in known amounts. Our results validated the fitness of the model under specified conditions. In addition, our data suggest a relatively slow elimination of CPA in isolated, practically bloodless guinea pig atrial myocardium.

Nitric oxide synthesis is blocked in the enteral nervous system during dormant periods of the snail Helix lucorum.

During dormancy of terrestrial snails, the whole neuromodulation of the nervous system is deeply modified. In this work we studied the adaptation of a previously described, putatively nitric oxide (NO) forming enteral network to the long-term resting periods of the snail Helix lucorum. The standard NADPH diaphorase (NADPHd) technique, which is an accepted method for histochemical NO synthase (NOS) detection, labeled the same enteric neurons of the midintestine in active or hibernated snails. Quantification of the NO-derived nitrite by the Griess reaction established that the nitrite formation is confined to the NADPHd-reactive network containing the midintestinal segment. In active snails, the nitrite formation could be enhanced by the NOS substrate L-arginine (10 microM-1 mM), but decreased by the known NOS inhibitors 1 mM N(omega)-nitro-L-arginine (NOARG) and 10 mM aminoguanidine (AG). Application of 1 mM L-arginine and 1 mM NOARG decreased the amplitude of the midintestinal muscle contractile activity, but did not affect the rectal motility. In dormancy, the nitrite formation was reduced in the NADPHd-reactive midintestinal network. Application of l-arginine could not provoke nitrite production and did not influence the midintestinal motility. Our findings indicate that NO is involved in the neural transmission to intestinal muscles of gastropods, but enteric release of NO is blocked during dormancy. The decreased NO synthesis is possibly due to an as yet undefined mechanism, by which the L-arginine/NO conversion ability of NOS could temporarily be inhibited in the long-term resting period of H. lucorum.

Comparative pharmacological studies on the A2 adenosine receptor agonist 5'-n-ethyl-carboxamidoadenosine and its F19 isotope labelled derivative.

Adenosine receptors are expressed in various mammalian tissues where they mediate the effects of adenosine on cellular functions through a number of signalling mechanisms. 18F-NECA is the positron-emitting derivative of the A(2)-receptor agonist NECA (5'-n-ethyl-carboxamidoadenosine) and is a radioligand for PET imaging of adenosine receptors. Contractility and relaxation studies were performed on guinea pig atrial myocardium, pulmonary artery, and thoracic aorta to compare the pharmacological effects of NECA and F-NECA (a non-emitting derivative) on tissues. Furthermore, the effect of NECA and F-NECA on the potassium conductance was investigated in DDT1 MF-2 smooth muscle cells with the patch-clamp technique. Both NECA and F-NECA reduced the contractile force in atrial myocardium and evoked phasic contraction in pulmonary artery (A(1) adenosine-receptor-mediated actions) in a dose dependent manner; however, the apparent affinity was lower for F-NECA. No difference was found in relaxation induced by these compounds in 1 microM noradrenaline-precontracted aorta and pulmonary artery (in the presence of DPCPX, an A(1) adenosine receptor antagonist, tissue containing A(2B) adenosine receptors). NECA (5 microM) and F-NECA (5 microM) also decreased the peak current and accelerated activation and inactivation properties of the potassium channels, but F-NECA was less effective. These results suggest that while NECA and F-NECA are equivalent agonists of vascular A(2B) receptors, they mediate different changes of some parameters. When evaluating the data obtained by the use of radiolabelled ligands, one has to take into consideration the possible physiological effects of the ligands besides its binding properties to tissues.

Special sensitization pattern in adenosine-induced myocardial responses after thyroxine-treatment.

Chronic thyroxine treatment reduces the susceptibility of atrial myocardium to adenosine. While the possible role of membrane adenosine receptors in this action is supported by several studies, the involvement of intracellular adenosine mechanisms has not been defined. The present experiments were carried out in electrically driven euthyroid and hyperthyroid guinea pig atrial myocardium. The extracellular and intracellular actions of adenosine were analyzed pharmacologically by the use of specific blockers of membrane adenosine transport and intracellular adenosine deaminase (ADA). The involvement of phosphoprotein phosphatase, phospholamban, and sarcoplasmic reticulum Ca2+ ATPase (SERCA) in the adenosine-induced responses was also studied. The major findings were as follows: i) pD(2)- and E(max)-values for adenosine-induced decrease of mechanical activity were significantly reduced after an 8-day thyroxine treatment in atrial tissues; ii) in atria of thyroxine-treated animals, membrane purine transport inhibitors (dipyridamole, NBTI) induced similar leftward shifts in concentration-response curves for adenosine in both euthyroid and hyperthyroid atrial myocardium without altering the depressed E(max) values; iii) the leftward displacement evoked by inhibitors of intracellularly located ADA (coformycin, EHNA) was more striking in hyperthyroid than euthyroid myocardia. ADA inhibitors induced a complete reversal of the maximum adenosine actions; iv) inhibition by cantharidin of phosphoprotein phosphatases (after inhibition of ADA) reduced the adenosine-induced responses. This inhibition was stronger in hyperthyroid atria; v) pharmacological elimination of sarcoplasmic reticulum Ca2+ ATPase by cyclopiazonic acid did not alter the cardiac responses to adenosine and this was independent of thyroid status. It is suggested that distinct modulation of the extra- and intracellular adenosine actions is present in eu- and hyperthyroid hearts. In the latter, a predominance of intracellular adenosine mechanisms can be proposed.

A1 and A2 adenosine receptor activation inversely modulates potassium currents and membrane potential in DDT1 MF-2 smooth muscle cells.

Adenosine receptors are widely distributed in mammalian tissues and have been possibly involved through transmembrane potential changes in cell function regulation. The effect of A1 and A2A adenosine receptor ligands on transmembrane potential measured with flow cytometry and potassium conductance measured by the patch-clamp technique was investigated in DDT1 MF-2 smooth muscle cells. The A1 adenosine-receptor agonist CPA (50 nM) and the A2A adenosine-receptor agonist CGS 21680 (50 nM) elicited a rapid and maintained increase and decrease in the potassium conductance, respectively, and a concomitant hyperpolarization and depolarization of the membrane, respectively. These effects were eliminated by subtype-selective adenosine receptor antagonists (DPCPX, CSC, ZM 241385, all 1 microM). The ligand induced membrane potential changes were reversible. Based on these detected membrane potential changes along with the published voltage dependence of the adenylyl cyclase, the regulation of cAMP production by A1- and A2A-receptor activation is suggested to be mediated through the induced early hyperpolarization and depolarization. The interaction between the effects of these receptor subtypes allows for a complex regulation mechanism.

[In vivo investigation of the A2A adenosine receptor distribution using the [11C]-CSC radioligand]. / Az A2A-adenozin-receptor-eloszlás in vivo tanulmányozása [11C]-CSC-radioliganddal.

A 11C labeled selective adenosine A2A antagonist, (E)-8-(3-chlorostyryl)-1,3-dimethyl-7-[11C]-methylxanthine [(11C)-CSC] was prepared reacting (E)-8-(3-chlorostyryl)-1,3,-dimethylxanthine and [11C]-methyl iodide. A primary evaluation of [11C]-CSC as a potential tracer for mapping adenosine A2A receptors by positron emission tomography (PET) was also presented. Autoradiographic studies were carried out on Swiss mice. A high level accumulation of radioactivity was observed in the striatum and medulla oblongata in accordance with previous findings on the specific spatial distribution of A2A adenosine receptors. Dynamic PET studies on rabbits showed a fast brain uptake of CSC, reaching a maximum in less than 2 minutes. Competition experiments with the unlabeled ligand proved [11C]-CSC to bind specifically to the appropriate receptor.

[The [18F]-FNECA serves as a suitable radioligand for PET investigation of purinergic receptor expression]. / A [18F]-FNECA széleskörúen alkalmazható radioligand a purinerg receptorexpresszió PET-vizsgálatához.

The well known and widely used P1 adenosine agonist, 5'-N-ethyl-carboxamidoadenosine (NECA), was labelled with 18F isotope for the in vivo PET investigation of A1, A2 and A3 adenosine receptor expression. The precursor 2-[18F]fluoroethylamine was reacted with 2',3'-O-isopropylideneadenosine-5'-uronic acid. Specific activity of the [18F]-FNECA was (2.3 +/- 1.1) TBq/mmol (60 Ci/mmol). Dynamic PET measurements were carried out in rabbits to study the in vivo kinetics of the receptor saturation with the labelled ligand. The time dependent accumulation was followed up in the heart, lungs, liver, brain and testis. The radiotracer uptake was rapid and reached its maximum in less than two minutes in the heart and testes after v. injection of the radiopharmaceutical, while it took about 6 minutes in the brain, lungs and liver. High [18F]-FNECA accumulation was detected in the intestines, too. The specific binding of the [18F]-FNECA was tested in competition experiments in brain and heart sections using autoradiographic technique. The outlined synthesis provided sufficient amounts of [18F]-FNECA to map adenosine receptor expression under physiological conditions.