Simultaneous Guillain-Barrè syndrome and active human herpesvirus 6 infection in the central nervous system.
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Central Nervous System Diseases↗
Biomedical subjects
M Galvan
Publications and source records attributed to M Galvan.
Macrophage colony stimulatory factor and interferon-gamma trigger distinct mechanisms for augmentation of beta-amyloid-induced microglia-mediated neurotoxicity.
Dysregulated stimulation of microglia, the resident macrophages in the brain, can lead to excessive induction of inflammatory agents and subsequently damage to neurons. Fibrillar beta-amyloid peptide (fA beta), a major component of senile plaques in Alzheimer's disease (AD) brain, is known to induce microglial-mediated neurotoxicity under certain conditions. Microglial 'priming' by macrophage colony stimulatory factor (MCSF) or interferon-gamma (IFN gamma) appears to be required for this fA beta-induced microglia mediated neurotoxicity in vitro. We report here that while both MCSF and IFN gamma induce microglial-mediated fA beta neurotoxicity, their mechanisms of toxicity differ. The enhancement of neurotoxicity by IFN gamma or MCSF is not due to enhanced A beta ingestion by microglia or to the direct effect of proinflammatory cytokine production. The neurotoxicity resulting from IFN gamma/fA beta treatment was blocked by pretreatment with nitric oxide synthase inhibitor L-N-5-(1-iminoethyl) ornithine hydrochloride (L-NIO), consistent with a role for nitric oxide in the IFN gamma-mediated toxicity mechanism. In contrast, no induction of nitric oxide production was detected for microglia treated with MCSF/fA beta. Furthermore, inhibiting the generation of reactive oxygen species (ROS) using the specific NADPH oxidase inhibitor apocynin reversed fA beta/MCSF-induced neurotoxicity while L-NIO had little effect. As MCSF is endogenously expressed within the brain, and both its level and that of the MCSF receptor are dramatically increased in the AD brain, the neurotoxicity resulting from ROS release by fA beta/MCSF coactivated microglia may be a more appropriate model for assessing fA beta-induced microglial-mediated neuropathology in AD.
Amyloid beta-Peptides↗
CD45 modulates galectin-1-induced T cell death: regulation by expression of core 2 O-glycans.
Galectin-1 induces death of immature thymocytes and activated T cells. Galectin-1 binds to T cell-surface glycoproteins CD45, CD43, and CD7, although the precise roles of each receptor in cell death are unknown. We have determined that CD45 can positively and negatively regulate galectin-1-induced T cell death, depending on the glycosylation status of the cells. CD45(+) BW5147 T cells lacking the core 2 beta-1,6-N-acetylglucosaminyltransferase (C2GnT) were resistant to galectin-1 death. The inhibitory effect of CD45 in C2GnT(-) cells appeared to require the CD45 cytoplasmic domain, because Rev1.1 cells expressing only CD45 transmembrane and extracellular domains were susceptible to galectin-1 death. Moreover, treatment with the phosphotyrosine-phosphatase inhibitor potassium bisperoxo(1,10-phenanthroline)oxovanadate(V) enhanced galectin-1 susceptibility of CD45(+) T cell lines, but had no effect on the death of CD45(-) T cells, indicating that the CD45 inhibitory effect involved the phosphatase domain. Expression of the C2GnT in CD45(+) T cell lines rendered the cells susceptible to galectin-1, while expression of the C2GnT in CD45(-) cells had no effect on galectin-1 susceptibility. When CD45(+) T cells bound to galectin-1 on murine thymic stromal cells, only C2GnT(+) T cells underwent death. On C2GnT(+) cells, CD45 and galectin-1 co-localized in patches on membrane blebs while no segregation of CD45 was seen on C2GnT(-) T cells, suggesting that oligosaccharide-mediated clustering of CD45 facilitated galectin-1-induced cell death.
Animals↗
Expression of a specific glycosyltransferase enzyme regulates T cell death mediated by galectin-1.
Galectin-1 induces apoptosis of immature thymocytes and activated T cells, suggesting that galectin-1 regulates cell death in the thymus during selection and in the periphery following an immune response. Although it is known that galectin-1 recognizes lactosamine (Gal-GlcNAc) as a minimal ligand, this disaccharide is ubiquitously expressed on a variety of cell surface glycoproteins. Thus, susceptibility to galectin-1 may be regulated by the presentation of lactosamine on specific oligosaccharide structures created by specific glycosyltransferase enzymes. The core 2 beta-1, 6-N-acetylglucosaminyltransferase (core 2 GnT) creates a branched structure on O-glycans that can be elongated to present multiple lactosamine sequences. In the thymus, the core 2 GnT is expressed in galectin-1-sensitive thymocyte subsets. In the periphery, an oligosaccharide epitope created by the core 2 GnT is expressed on galectin-1-sensitive activated T-cells. In this report, we demonstrate that expression of the core 2 GnT was necessary and sufficient for galectin-1-induced death of murine T cell lines. In addition, overexpression of the core 2 GnT in mice increased the susceptibility of double positive thymocytes to galectin-1. These data demonstrate that expression of a specific glycosyltransferase can control susceptibility to galectin-1, suggesting that developmentally regulated glycosyltransferase expression may be a mechanism to modulate cell death during T cell development and function.
Amino Sugars↗
Differentiating between memory and effector CD8 T cells by altered expression of cell surface O-glycans.
Currently there are few reliable cell surface markers that can clearly discriminate effector from memory T cells. To determine if there are changes in O-glycosylation between these two cell types, we analyzed virus-specific CD8 T cells at various time points after lymphocytic choriomeningitis virus infection of mice. Antigen-specific CD8 T cells were identified using major histocompatibility complex class I tetramers, and glycosylation changes were monitored with a monoclonal antibody (1B11) that recognizes O-glycans on mucin-type glycoproteins. We observed a striking upregulation of a specific cell surface O-glycan epitope on virus-specific CD8 T cells during the effector phase of the primary cytotoxic T lymphocyte (CTL) response. This upregulation showed a strong correlation with the acquisition of effector function and was downregulated on memory CD8 T cells. Upon reinfection, there was again increased expression of this specific O-glycan epitope on secondary CTL effectors, followed once more by decreased expression on memory cells. Thus, this study identifies a new cell surface marker to distinguish between effector and memory CD8 T cells. This marker can be used to isolate pure populations of effector CTLs and also to determine the proportion of memory CD8 T cells that are recruited into the secondary response upon reencounter with antigen. This latter information will be of value in optimizing immunization strategies for boosting CD8 T cell responses.
Animals↗
A role for perforin in downregulating T-cell responses during chronic viral infection.
Cytotoxic T cells secrete perforin to kill virus-infected cells. In this study we show that perforin also plays a role in immune regulation. Perforin-deficient (perf -/-) mice chronically infected with lymphocytic choriomeningitis virus (LCMV) contained greater numbers of antiviral T cells compared to persistently infected +/+ mice. The enhanced expansion was seen in both CD4 and CD8 T cells, but the most striking difference was in the numbers of LCMV-specific CD8 T cells present in infected perf -/- mice. Persistent LCMV infection of +/+ mice results in both deletion and anergy of antigen-specific CD8 T cells, and our results show that this peripheral "exhaustion" of activated CD8 T cells occurred less efficiently in perf -/- mice. This excessive accumulation of activated CD8 T cells resulted in immune-mediated damage in persistently infected perf -/- mice; approximately 50% of these mice died within 2 to 4 weeks, and mortality was fully reversed by in vivo depletion of CD8 T cells. This finding highlights an interesting dichotomy between the role of perforin in viral clearance and immunopathology; perforin-deficient CD8 T cells were unable to clear the LCMV infection but were capable of causing immune-mediated damage. Finally, this study shows that perforin also plays a role in regulating T-cell-mediated autoimmunity. Mice that were deficient in both perforin and Fas exhibited a striking acceleration of the spontaneous lymphoproliferative disease seen in Fas-deficient (lpr) mice. Taken together, these results show that the perforin-mediated pathway is involved in downregulating T-cell responses during chronic viral infection and autoimmunity and that perforin and Fas act independently as negative regulators of activated T cells.
Animals↗
Alterations in cell surface carbohydrates on T cells from virally infected mice can distinguish effector/memory CD8+ T cells from naive cells.
Glycosylation changes on surface molecules of T cells affect cell trafficking and function and may be useful in discriminating between naive, effector, and memory T cells. To analyze oligosaccharide structures on T cells activated in vivo, we examined alterations in sialic acid residues on T cells following infection of mice with lymphocytic choriomeningitis (LCMV), vaccinia virus, and vesicular stomatitis virus. We found that the majority of CD8 T cells from mice acutely infected with these viruses showed increased binding to peanut agglutinin (PNA). All of the PNAhighCD8 T cells from infected mice were CD44high, indicating that glycosylation changes were occurring on activated T cells. There was also an increase in the PNAhighCD4 T cell population in virally infected mice. Increased PNA binding to activated CD8 T cells correlated with higher endogenous neuraminidase levels in these cells. This higher neuraminidase activity most likely contributed to the PNAhigh phenotype by cleaving sialic acid residues off the core-1 O-glycans or glycoproteins destined for the cell surface. A PNAhighCD8 T cell population persisted in immune mice that had cleared the LCMV infection. When spleen cells from immune mice were sorted into PNAhigh and PNAlow populations, >95% of the LCMV-specific memory CD8 T cells segregated with the PNAhigh population. This shows that virus-specific memory CD8 T cells remain hyposialylated and can be distinguished from naive CD8 T cells based on PNA binding. Thus, PNA can be used as a marker for Ag-experienced T cells.
Animals↗
Human metabotropic glutamate receptor 1: mRNA distribution, chromosome localization and functional expression of two splice variants.
We have isolated clones from a human brain cDNA library coding for two splice variants of mGluR1. The combined sequences account for 6864 base pairs (bp) of the approximately 7 kilobase (kb) transcript seen on northern blots of human brain mRNA. The distribution of mGluR1 mRNA in human brain is similar to that found in rat brain and the gene for mGluR1 is localized on human chromosome 6. The mRNA for mGluR1 alpha contains an open reading frame that codes for a 1194 amino acid protein, which is slightly smaller than rat mGluR1 alpha. The major structural difference noted between the human and rat mGluR1 is a deletion of 21 nucleotides which would result in the loss of seven amino acids in the middle of a proline- and glutamine-rich region of the C-terminal tail of mGluR1 alpha. The 85 bp exon that results in the HmGluR1 beta splice variant was found to code for a protein with two amino acid differences compared to the rat receptor. Functional and pharmacological characterization of heterologously expressed human mGluR1 was performed using electrophysiological recordings from Xenopus oocytes and calcium imaging in HEK-293 cells. No major differences were found in the response of human mGluR1 to typical agonists and antagonists compared to the rat, or in the behavior of the two splice variants.
Alternative Splicing↗
Electrophysiological actions of GABAB agonists and antagonists in rat dorso-lateral septal neurones in vitro.
1. The actions of GABAB-receptor agonists and antagonists on rat dorso-lateral septal neurones in vitro were recorded with intracellular microelectrodes. 2. In the presence of 1 microM tetrodotoxin to prevent indirect neuronal effects caused by action potential-dependent neurotransmitter release, bath application of baclofen (0.1-30 microM) or SK&F 97541 (0.01-3 microM) evoked concentration-dependent hyperpolarizations which reversed close to the potassium equilibrium potential; the EC50S were 0.55 and 0.05 microM, respectively. No significant desensitization was observed during prolonged agonist exposure (< or = 10 min). 3. Hyperpolarizations induced by baclofen were antagonized in a competitive manner by the following GABAB-receptors antagonists (calculated pA2 values in parentheses): CGP 36742 (4.0), 2-OH saclofen (4.2), CGP 35348 (4.5), CGP 52432 (6.7) and CGP 55845A (8.3). Responses to SK&F 97541 were also antagonized by CGP 55845A (pA2 = 8.4). 4. The amplitude of the late, GABAB receptor-mediated inhibitory postsynaptic potential (i.p.s.p.) was reduced by the GABAB antagonists as follows (means +/- s.e.mean): CGP 55845A (1 microM) 91 +/- 5%, CGP 52432 (1 microM) 64 +/- 5%, CGP 35348 (100 microM) 82 +/- 5%, CGP 36742 (100 microM) 76 +/- 8%, and 2-OH saclofen (100 microM) 68 +/- 3%. 5. It is concluded that neurones in the rat dorso-lateral septal nucleus express conventional GABAB receptors, which are involved in the generation of slow inhibitory postsynaptic potentials. CGP 55845A is the most potent GABAB receptor antagonist described in this brain area.
Analysis of Variance↗
Aliphatic and heterocyclic analogues of arecaidine propargyl ester. Structure-activity relationships of mono- and bivalent ligands at muscarinic M1 (M4), M2 and M3 receptor subtypes.
The pharmacological profiles of tertiary and quaternary monovalent (1b-6b) and bivalent ligands (7a-12b), closely related to arecaidine propargyl ester (CAS 35516-99-5, APE, 1a), were evaluated at muscarinic receptors in rat superior cervical ganglia (M1), rabbit was deferens (M1/M4-like), guinea-pig atria (M2) and guinea-pig ileum (M3). In the monovalent ligand series (1a-6b) APE (1a) displayed the highest potency at all three muscarinic receptors [M2 (-log EC50 = 8.12) > or = M3 (-log EC50 = 7.77) = M1/M4 (-log EC50/vas deferens = 7.72)], whereas in the bivalent ligand series (7a-12b) arecaidine 2-butyne-1,4-diyl bisester (bisABE, 7a) was the most potent agonist with functional selectivity for M1/M4 (-log EC50/vas deferens = 6.94) and M2 receptors (-log EC50 = 7.10) over M3 receptors (-log EC50 = 6.27). On ganglia bisABE elicited M2 receptor-mediated hyperpolarisations, which were followed by long-lasting pirenzepine-sensitive depolarisations. However, the potency at M1 receptors in ganglia of APE (-log EC50 = 6.96) and bisABE (-log EC50 = 5.69) was lower than that in rabbit vas deferens. All bivalent molecules exhibited decreased potencies when compared with their monovalent analogues. However, a change in potency profiles was often obtained. The quaternary isonicotinic acid 2-butyne-1,4-diyl bisester (10b) displayed some functional selectivity for M2 receptors (-log EC50 = 5.78) [6- to 9-fold over M1/M4 (-log EC50/vas deferens = 5.03) and M3 receptors (-log EC50 = 4.83)] without showing nicotinic effects.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Transient and long-lasting actions of 5-HT on rat dentate gyrus neurones in vitro.
1. The actions of 5-hydroxytryptamine (5-HT) on rat dentate gyrus neurones were measured with conventional intracellular recording techniques in brain slices maintained in vitro at 32 degrees C. 2. Bath application of 5-HT (0.3-100 microM) hyperpolarized the membrane potential and reduced the input resistance; these effects persisted in tetrodotoxin (1 microM) and were abolished by MDL 73,005EF, a 5-HT1A receptor antagonist. 3. Local application of 5-HT via a pressure pipette also elicited a hyperpolarization and a reduction in resistance, and evoked a transient 'burst' of spontaneous inhibitory postsynaptic potentials (IPSPs) which were blocked by tetrodotoxin or bicuculline. 4. The 'burst' of IPSPs was subject to desensitization. It was completely abolished in the presence of the 5-HT3 receptor antagonist dolasetron. 5. In some cells, a longer lasting increase in spontaneous IPSP frequency was observed during application of 5-HT; this effect was blocked by the 5-HT2 receptor antagonist MDL 100,907. 6. 5-HT (30 microM) shortened the decay time constants of the glutamatergic and GABAergic evoked EPSPs and IPSPs without changing their amplitudes. 7. It is concluded that 5-HT hyperpolarizes granule cells via postsynaptic 5-HT1A receptors and increases spontaneous GABA release from inhibitory interneurones via the activation of 5-HT3 receptors and/or 5-HT2 receptors.
Animals↗
Involvement of muscarinic M2 and M3, but not of M1 and M4 receptors in vagally stimulated contractions of rabbit bronchus/trachea.
The inhibition of preganglionic and postganglionic contractions of the rabbit isolated bronchus/trachea by antagonists with selectivity for different muscarinic receptor subtypes was compared with their affinities at M1, M2, M3 and M4 receptors. Neither M1/M3 receptor-unselective antagonists (atropine, hexahydro-siladifenidol, thiazinamium, p-fluoro-hexahydro-sila-difenidol) nor antagonists with selectivity for the M1 over M3 subtype ((+)-biperiden, UH-AH 37, telenzepine, o-methoxy-sila-hexocyclium, pirenzepine) consistently showed a preferential inhibition of the response to preganglionic over postganglionic stimulation. Potencies for inhibition of contraction to preganglionic stimulation by antagonists discriminating more than threefold both between M1 and M3, and between M3 and M2 receptors (hexocyclium, (+)-biperiden, UH-AH 37, telenzepine, o-methoxy-silahexocyclium, p-fluoro-hexahydro-sila-difenidol, pirenzepine) are most consistent with affinities at smooth muscle M3 receptors as determined on methacholine-contracted rabbit trachea. Antagonists with a 10-fold higher affinity at M2 over M3 receptors enhanced contractions to field stimulation (AQ-RA 741 = AF-DX 384 = idaverine > himbacine = imperialine = AF-DX 116 = methoctramine >> gallamine), whereas antagonists with a selectivity profile of M4 > or = M3 > M2 (hexahydro-sila-difenidol, pirenzepine, dicyclomine) failed to increase the contractions. Secoverine (selectivity profile M4 > M2 > M3) enhanced contractions at concentrations consistent with its M2 receptor affinity. These results (1) exclude a ganglionic M1 receptor modulating excitatory vagal neurotransmission but (2) suggest the presence of an inhibitory prejunctional M2 rather than an M4 receptor and (3) identify a postjunctional smooth muscle M3 receptor in rabbit bronchus/trachea.
Animals↗
Differential effects of centrally-active antihypertensives on 5-HT1A receptors in rat dorso-lateral septum, rat hippocampus and guinea-pig hippocampus.
1. The electrophysiological responses elicited by 5-hydroxytryptamine1A-(5-HT1A) receptor agonists in rat and guinea-pig CA1 pyramidal neurones and rat dorso-lateral septal neurones were compared in vitro by use of conventional intracellular recording techniques. 2. In the presence of 1 microM tetrodotoxin (TTX), to prevent indirect effects, 5-HT, N,N-dipropyl-5-carboxamidotryptamine (DP-5-CT) and 8-hydroxy-2(di-n-propylamino) tetralin (8-OH-DPAT) hyperpolarized the neurones from rat and guinea-pig brain. 3. The hypotensive drug flesinoxan, a selective 5-HT1A receptor agonist, hyperpolarized neurones in all three areas tested; however, another hypotensive agent with high affinity at 5-HT1A-receptors, 5-methyl-urapidil, hyperpolarized only the neurones in rat hippocampus and septum. 4. In guinea-pig hippocampal neurones, 5-methyl-urapidil behaved as a 5-HT1A-receptor antagonist. 5. The relative efficacies (5-HT = 1) of DP-5-CT, 8-OH-DPAT, flesinoxan and 5-methyl-urapidil at the three sites were: rat hippocampus, 1.09, 0.7, 0.5 and 0.24; rat septum, 0.88, 0.69, 0.82 and 0.7; guinea-pig hippocampus, 1.0, 0.69, 0.89 and 0, respectively. 6. It is concluded that the hypotensive agents flesinoxan and 5-methyl-urapidil appear to have different efficacies at 5-HT1A receptors located in different regions of the rodent brain. Whether these regional and species differences arise from receptor plurality or variability in intracellular transduction mechanisms remains to be elucidated.
8-Hydroxy-2-(di-n-propylamino)tetralin↗
[A new approach to the brachial plexus: clinical results].
The paper reports the results of a new brachial plexus blockade technique using a supraclavicular route which was carried out in 74 patients. From the analysis of results it can be seen that the technique is comparable to that of Moore and Winnie in terms of the success of the blockade. However, this technique appears to be safer in relation to complications such as pneumothorax and subarachnoid injection.
Brachial Plexus↗
Characterization of the novel 5-HT3 antagonists MDL 73147EF (dolasetron mesilate) and MDL 74156 in NG108-15 neuroblastoma x glioma cells.
In radioligand binding experiments, MDL 73147EF and MDL 74156 inhibited the binding of [3H]GR65630 to 5-hydroxy-tryptamine3 (5-HT3) binding sites on membranes prepared from NG108-15 neuroblastoma x glioma cells. The calculated dissociation constants (KI) were 20.03 +/- 6.58 and 0.44 +/- 0.18 nM, respectively (means +/- S.E.M., n = 6 and 9, respectively). Application of 5-HT (10-50 microM) to voltage-clamped NG108-15 cells elicited a rapidly desensitizing inward membrane current, characteristic for the activation of 5-HT3 receptors. The 5-HT-induced membrane current was suppressed in a reversible, concentration-dependent manner by MDL 73147EF and MDL 74156EF. The concentrations required to block half the 5-HT response (IC50) were 3.8 and 0.1 nM, respectively. It is concluded that both compounds are potent and reversible antagonists at 5-HT3 receptors in this neuroblastoma cell line.
Animals↗
Actions of 5-hydroxytryptamine and 5-HT1A receptor ligands on rat dorso-lateral septal neurones in vitro.
1. The actions of 5-hydroxytryptamine (5-HT) and some 5-HT1A receptor ligands on neurones in the rat dorso-lateral septal nucleus were recorded in vitro by intracellular recording techniques. 2. In the presence of tetrodotoxin (1 microM) to block any indirect effects, bath application of 5-HT (0.3-30 microM) hyperpolarized the neurones in a concentration-dependent manner and reduced membrane resistance. The hyperpolarization did not exhibit desensitization and was sometimes followed by a small depolarization. 3. The 5-HT1A receptor ligands, 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), N,N-dipropyl-5-carboxamidotryptamine (DP-5-CT) and buspirone but not the non-selective 5-HT1 receptor agonist, 1-m-trifluoromethylphenylpiperazine (TFMPP), also hyperpolarized the neurones. 4. 5-HT, 8-OH-DPAT and DP-5-CT appeared to act as full agonists whereas buspirone behaved as a partial agonist. The estimated EC50S were: DP-5-CT 15 nM, 8-OH-DPAT 110 nM, 5-HT 3 microM and buspirone 110 nM. 5. At a concentration of 3 microM, the putative 5-HT1A receptor antagonists, spiperone, methiothepin, NAN-190 (1-(2-methoxyphenyl)-4-[4-(2-pthalimido)butyl]piperazine) and MDL 73005EF (8-[2-(2,3-dihydro-1,4-benzodioxin-2-yl-methylamino)ethyl]-8- azaspiro[4,5]decane-7,9-dione methyl sulphonate), produced a parallel rightward shift in the concentration-response curve to 5-HT with no significant reduction in the maximum response. The estimated pA2 values were: NAN-190 6.79, MDL 73005EF 6.59, spiperone 6.54 and methiothepin 6.17.6. The 5-HT2/5-HTlc receptor antagonist, ketanserin (3 microM) and the 5HT3 receptor antagonist, tropisetron (3 microM) did not antagonize the 5-HT-induced hyperpolarizations; however, ketanserin blocked the depolarization which sometimes followed the hyperpolarization.7. It is concluded that the 5-HT-induced membrane hyperpolarization of rat dorso-lateral septal neurones is mediated by 5-HTA receptors.
Animals↗
Electrophysiology of the 5-HT1A ligand MDL 73005EF in the rat hippocampal slice.
The actions of 5-hydroxytryptamine (5-HT) and the 5-HT1A receptor ligand MDL 73005EF on neuronal activity in the CA1 region of rat hippocampal slices in vitro were recorded using intra- and extracellular recording techniques. 5-HT (1-30 microM) hyperpolarised the pyramidal neurones in a concentration-dependent manner and reduced membrane resistance and action potential after-hyperpolarisations (AHPs). MDL 73005EF (1-30 microM) had no clear effects on membrane potential, membrane resistance or AHPs. However, prior application of 3 microM MDL 73005EF to the slices for 10-60 min antagonised the hyperpolarisation induced by 30 microM 5-HT but not the reduction in spike AHP or the hyperpolarisation induced by the GABAB receptor agonist baclofen. MDL 73005EF and the 5-HT1A/2 receptor antagonist spiperone (both 3 microM) reduced the frequency and amplitude of spontaneous inhibitory (bicuculline-sensitive) postsynaptic potentials. Extracellular recordings of population action potentials revealed that MDL 73005EF did not prevent the induction or maintenance of hippocampal long-term potentiation or exhibit local anaesthetic properties. It is concluded that MDL 73005EF is an antagonist at 5-HT1A receptors on hippocampal CA1 pyramidal neurones.
Action Potentials↗
Actions of the phosphodiesterase inhibitor zardaverine on guinea-pig ventricular muscle.
The positive inotropic action of the phosphodiesterase inhibitor zardaverine was investigated in guinea-pig heart muscle. In right papillary muscles, 1-30 microM zardaverine reversibly increased the force of contraction in a concentration-dependent manner. This effect was accompanied by a shortening of contraction and relaxation times. Resting membrane potential was unchanged, whereas action potential amplitude was significantly increased and duration was reduced. In papillary muscles partially depolarised with 22 mM K+, zardaverine (10 and 30 microM) restored slow action potentials, which were not influenced by cimetidine, propranolol or prazosin but were blocked by the calcium channel blocker (+)-nitrendipine or the muscarinic agonist carbachol. cAMP-specific phosphodiesterase III, isolated from guinea-pig ventricular muscle was inhibited by zardaverine as was cAMP-specific phosphodiesterase IV, isolated from dog trachea (IC50s: 0.5 and 0.8 microM, respectively). The results suggest that the observed positive inotropic and electrophysiological effects result from an inhibition of cellular phosphodiesterase.
1-Methyl-3-isobutylxanthine↗