Biomedical subjects

J M Launay

Publications and source records attributed to J M Launay.

At least 37 records · Page 2Linked to original sources

PubMed2000

Serotonin 2B receptor is required for heart development.

Several lines of evidence suggest that the serotonin (5-hydroxytryptamine, 5-HT) regulates cardiovascular functions during embryogenesis and adulthood. 5-HT binds to numerous cognate receptors to initiate its biological effects. However, none of the 5-HT receptor disruptions in mice have yet resulted in embryonic defects. Here we show that 5-HT(2B) receptor is an important regulator of cardiac development. We found that inactivation of 5-HT(2B) gene leads to embryonic and neonatal death caused by heart defects. 5-HT(2B) mutant embryos exhibit a lack of trabeculae in the heart and a specific reduction in the expression levels of a tyrosine kinase receptor, ErbB-2, leading to midgestation lethality. These in vivo data suggest that the Gq-coupled receptor 5-HT(2B) uses the signaling pathway of tyrosine kinase receptor ErbB-2 for cardiac differentiation. All surviving newborn mice display a severe ventricular hypoplasia caused by impaired proliferative capacity of myocytes. In adult mutant mice, cardiac histopathological changes including myocyte disarray and ventricular dilation were consistently observed. Our results constitute genetic evidence that 5-HT via 5-HT(2B) receptor regulates differentiation and proliferation of developing and adult heart. This mutation provides a genetic model for cardiopathy and should facilitate studies of both the pathogenesis and therapy of cardiac disorders in humans.

Animals↗

PubMed2000

Chromosomes 4 and 13 in beta-carboline-induced seizures in mice: benzodiazepine binding.

Methyl beta-carboline-3-carboxylate (beta-CCM) is a ligand for the benzodiazepine (BZD) binding site of the GABA-A receptors with convulsive properties. We provided evidence for the involvement of a fragment of mouse chromosomes 4 and 13 in beta-CCM-induced seizures in a previous paper. Here, we analyzed, through [3H]-flumazenil binding, whether central BZD binding sites could be involved in the physiological processes underlying these differences of genetic sensitivities. In the JE/Le strain, where the effects of the chromosome 4 fragment can be analyzed, we found associations between [3H]-flumazenil binding and the convulsive action of beta-CCM. On the contrary, this no longer holds true in C3XtEso strain, where the effects of the chromosome 13 fragment were observed.

Animals↗

PubMed2000

First report of polymorphisms in the prion-like protein gene (PRND): implications for human prion diseases.

The aim of this study was to investigate the possible involvement of genetic variation in the prion-like protein gene (PRND), which encodes the doppel protein (Dpl), in the aetiology of human prion diseases. Patients with sporadic, infectious or genetic forms of human prion diseases and controls were systematically screened, using the single-strand conformational polymorphism method, for genetic variants of the PRND gene. Four polymorphisms in PRND (three structural changes, T26M, P56L and T174M and a silent polymorphism, T(174)T) were detected. No strong association was found between any of these polymorphisms and human prion diseases but certain PRND alleles may be useful markers for tracing the chromosomal ancestry of PRNP mutations. Although genetic variation in PRND does not seem to play a major role in the pathogenesis of prion diseases, this first report of PRND polymorphisms may open up new possibilities for investigating the involvement of such polymorphisms in other human diseases.

Alleles↗

PubMed2000

Functional expression of P-glycoprotein and multidrug resistance-associated protein (Mrp1) in primary cultures of rat astrocytes.

Although it has been well established that the drug efflux pump P-glycoprotein (P-gp) protects the brain against the entry of cytotoxic drugs, its real in situ localization, i.e., at brain capillary endothelial cells or on astrocyte foot processes, is still controversial. The aim of this study was to compare the expression of P-gp and of multidrug resistance-associated protein (Mrp1), another drug efflux pump, in cultured neonatal rat brain astrocytes and in cultured brain capillary endothelial cells. Reverse transcriptase-polymerase chain reaction (RT-PCR) analysis showed that the mdr1b gene was preferentially expressed in astrocytes, whereas both mdr1a and mdr1b mRNA were detected in endothelial cells. Moreover, the mrp1 gene encoding Mrp1 was expressed in both cell types. Western blotting analysis revealed higher expression of P-gp in endothelial cells as compared with astrocytes, but higher expression of Mrp1 in astrocytes. Moreover, P-gp and Mrp1 expression was not modified in more differentiated astrocytes obtained when cultured with db-cAMP for 48 hr. Our functional analysis of P-gp showed a modest effect of P-gp modulators (CsA, verapamil, PSC 833) on the uptake of colchicine (a substrate of P-gp) by astrocytes, whereas they increased by about 50% the uptake of vincristine (a common substrate of P-gp and MRP) by astrocytes. MRP modulators (genistein, probenecid, and sulfinpyrazone) did not modify the uptake of colchicine but increased that of vincristine with a major effect found for sulfinpyrazone. Moreover, indomethacin, probenecid, and sulfinpyrazone increased the uptake of fluorescein (a substrate of MRP but not of P-gp). Taken together, our results provide the first biochemical and functional evidence supporting the expression of P-gp and Mrp1 in rat cultured astrocytes.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2000

Ligand interaction with the purified serotonin transporter in solution and at the air/water interface.

The purified serotonin transporter (SERT) was spread at the air/water interface and the effects both of its surface density and of the temperature on its interfacial behavior were studied. The recorded isotherms evidenced the existence of a stable monolayer undergoing a lengthy rearrangement. SERT/ligand interactions appeared to be dependent on the nature of the studied molecules. Whereas an unrelated drug (chlorcyclizine) did not bind to the spread SERT, it interacted with its specific ligands. Compared to heterocyclic drugs, for which binding appeared to be concentration-dependent, a 'two-site' mechanism was evidenced for pinoline and imipramine.

Air↗

PubMed2000

Regulation by neurotransmitter receptors of serotonergic or catecholaminergic neuronal cell differentiation.

The murine F9-derived 1C11 clone exhibits a stable epithelial morphology, expresses nestin, an early neuroectodermal marker, and expresses genes involved in neuroectodermal cell fate. Upon appropriate induction, 100% of 1C11 precursor cells develop neurite extensions and acquire neuronal markers (N-CAM, synaptophysin, gammagamma-enolase, and neurofilament) as well as the general functions of either serotonergic (1C11*(/5HT)) (5HT, 5-hydroxytryptamine) or noradrenergic (1C11**(/NE)) (NE, norepinephrine) neurons. The two programs are shown to be mutually exclusive. 1C11 thus behaves as a neuroepithelial cell line with a dual bioaminergic fate. 1C11*(/5HT) cells implement a functional 5-HT transporter and thereby a complete serotonergic phenotype within 4 days, whereas 5-HT(1B/D), 5-HT(2B), and 5-HT(2A) receptors are sequentially induced. The accurate time schedule of catecholaminergic differentiation was defined. Catecholamine synthesis, storage, and catabolism are acquired within 4 days; the noradrenergic phenotype is complete at day 12 and includes a functional norepinephrine transporter and an alpha(1D)-adrenoreceptor (day 8). The time-dependent onset of neurotransmitter-associated functions proper to either program is similar to in vivo observations. Along each pathway, the selective induction of serotonergic or adrenergic receptors is shown to be an essential part of the differentiation program, since they promote an autoregulation of the corresponding phenotype.

Animals↗

PubMed2000

PDZ-dependent activation of nitric-oxide synthases by the serotonin 2B receptor.

Taking advantage of three cellular systems, we established that 5-HT(2B) receptors are coupled with NO signaling pathways. In the 1C11 serotonergic cell line and Mastomys natalensis carcinoid cells, which naturally express the 5-HT(2B) receptor, as well as in transfected LMTK(-) fibroblasts, stimulation of the 5-HT(2B) receptor triggers intracellular cGMP production through dual activation of constitutive nitric-oxide synthase (cNOS) and inducible NOS (iNOS). The group I PDZ motif at the C terminus of the 5-HT(2B) receptor is required for recruitment of the cNOS and iNOS transduction pathways. Indeed, the 5-HT(2B) receptor-mediated NO coupling is abolished not only upon introduction of a competitor C-terminal 5-HT(2B) peptide in the three cell types but also in LMTK(-) fibroblasts expressing a receptor C-terminally truncated or harboring a point mutation within the PDZ domain. The occurrence of a direct functional coupling between the receptor and cNOS activity is supported by highly significant correlations between the binding constants of drugs on the receptor and their effects on cNOS activity. The 5-HT(2B)/iNOS coupling mechanisms appear more complex because neutralization of endogenous Galpha(13) by specific antibodies cancels the cellular iNOS response while not interfering with cNOS activities. These findings may shed light on physiological links between the 5-HT(2B) receptor and NO and constitute the first demonstration that PDZ interactions participate in downstream transductional pathways of a G protein-coupled receptor.

Amino Acid Sequence↗

PubMed2000

5-hydroxytryptamine 2B receptor regulates cell-cycle progression: cross-talk with tyrosine kinase pathways.

In this paper, we present evidence that activation of 5-hydroxytryptamine 2B (5-HT2B) receptors by serotonin (5-HT) leads to cell-cycle progression through retinoblastoma protein hyperphosphorylation and through activation of both cyclin D1/cdk4 and cyclin E/cdk2 kinases by a mechanism that depends on induction of cyclin D1 and cyclin E protein levels. The induction of cyclin D1 expression, but not that of cyclin E, is under mitogen-activated protein kinase (MAPK) control, indicating an independent regulation of these two cyclins in the 5-HT2B receptor mitogenesis. Moreover, by using the specific platelet-derived growth factor receptor (PDGFR) inhibitor AG 1296 or by overexpressing a kinase-mutant PDGFR, we show that PDGFR kinase activity is essential for 5-HT2B-triggered MAPK/cyclin D1, but not cyclin E, signaling pathways. 5-HT2B receptor activation also increases activity of the Src family kinase, c-Src, Fyn, and c-Yes. Strikingly, c-Src, but not Fyn or c-Yes, is the crucial molecule between the G(q) protein-coupled 5-HT2B receptor and the cell-cycle regulators. Inhibition of c-Src activity by 4-amino-5-(4-methylphenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP1) or depletion of c-Src is sufficient to abolish the 5-HT-induced (i) PDGFR tyrosine kinase phosphorylation and MAPK activation, (ii) cyclin D1 and cyclin E expression levels, and (iii) thymidine incorporation. This paper elucidates a model of 5-HT2B receptor mitogenesis in which c-Src acts alone to control cyclin E induction and in concert with the receptor tyrosine kinase PDGFR to induce cyclin D1 expression via the MAPK/ERK pathway.

Animals↗

PubMed2000

In vivo regulation of cerebral monoamine oxidase activity in senescent controls and chronically stressed mice by long-term treatment with Ginkgo biloba extract (EGb 761).

It is well recognized that Ginkgo biloba extract (EGb 761) exert beneficial effects against various age-related changes and is able to reduce the negative influence of stress. In view of the age-dependent increase in the activity of the B form of monoamine oxidase (MAO-B) and in view of the anti-stress action of EGb 761 hypothetically attributed to an inhibition of monoamine oxidase by this substance, we investigated the effects of long-term treatment with EGb 761 upon in vivo cerebral MAO-A and -B activities of stressed and unstressed 17- and 18-month-old mice. The stress was a 'chronic mild stress' regimen whose behavioral impact is known to be reduced by EGb 761. The results showed that: (1) EGb761 induced reductions in MAO activity in 18-month-old, but not in 17-month-old mice; the older animals having higher basal MAO activity; (2) in unstressed mice, EGb 761 appeared to reduce the age-induced increase in cerebral MAO activity; (3) MAO-A and -B activities of stressed and treated 18-month-old mice did not differ significantly from the levels observed in unstressed and untreated 17-month-old mice. These results may shed light on the anti-stress effects of Ginkgo biloba extract.

Aging↗

PubMed2000

Tyrosine hydroxylase deficiency unresponsive to L-dopa treatment with unusual clinical and biochemical presentation.

Tyrosine hydroxylase (TH) deficiency is generally considered as a cause of the autosomal recessive form of dopa-responsive dystonia, also known as Segawa disease. Clinical hallmarks comprise parkinsonian and other extrapyramidal symptoms. Biochemically the defect leads to the defective synthesis of catecholamines, in particular dopamine. The diagnosis relies on a characteristic pattern of biogenic amine metabolites exclusively in the CSF and can be confirmed by establishing a mutation in the TH gene. Here we present a patient meeting all diagnostic criteria, including a new homozygous mutation (926T > C) with confirmed parental heterozygosity, extrapyramidal symptoms, but atypical other symptoms with periodic neurological episodes observed every 4 days and unresponsive to dopa treatment. The CSF biochemical abnormalities were severe. Uncharacteristically, a strongly abnormal urinary catecholamine metabolite pattern was also consistently observed. The atypical presentation of this patient shows that the clinical and metabolic phenotype of TH deficiency is more variable than formerly thought, and that the condition should no longer be considered as a treatable disorder per se.

Amino Acid Metabolism, Inborn Errors↗

PubMed2000

Platelet monoamine oxidase B activity is inversely associated with plasma cotinine concentration.

Cigarette smoke but not nicotine inhibits irreversibly platelet monoamine oxidase B (MAO-B) activity. Current smokers have decreased platelet MAO-B activity which normalizes when smokers quit. Normalization of platelet MAO-B activity probably depends on platelet turnover. Platelet MAO-B activity has been found to be correlated with plasma thiocyanate concentration. The aim of this study was to investigate in smokers whether platelet MAO-B activity is related to plasma cotinine concentration, an indirect index of use of smoked tobacco. We determined simultaneously plasma cotinine concentration and platelet MAO-B activity in 85 cigarette smokers [mean (+/- SD) age 39 +/- 8.8 years, 55 men]. Platelet MAO-B activity was lower in male than in female smokers (14.1 +/- 7.9 versus 17.8 +/- 7.2 nmol/h/10(9) platelets, p = 0.03). Platelet MAO-B activity correlated positively with age (r = 0.26, p = 0.01) and inversely with plasma cotinine concentration (r = -0.32, p = 0.002) but not with number of cigarettes smoked or with Fagerström Tolerance Questionnaire score. Multiple linear regression analysis showed that 49% of the age-adjusted variance in platelet MAO-B activity (R2 = 0.489, p < 0.0001) was explained by plasma cotinine concentration (p < 0.001) and gender (p = 0.037). It was concluded that platelet MAO-B activity in smokers is inversely associated with plasma cotinine level, an index of smoked tobacco use. Further studies are needed to investigate whether measurement of platelet MAO-B activity can be used as a long-term index of tobacco use and smoke exposure.

Adult↗

PubMed2000

Changes in benzodiazepine binding in a subkindling situation.

PURPOSE: A low dose of the benzodiazepine receptor inverse agonist methyl beta-carboline-3-carboxylate (beta-CCM) (1 mg/kg) was used to assess [3H]-flumazenil binding in a subkindling situation in Swiss mice. METHODS: The brains were removed, and benzodiazepine receptor binding was studied every second day over 14 days of administration. RESULTS: With each successive trial, Bmax values showed a steady and significant decrease, whereas Kd values showed a steady and significant increase. Behavioral data showed that at this low dose, actual kindling (seizuring) was not reached at the behavioral level. CONCLUSIONS: The findings suggest that decreased gamma-aminobutyric acid (GABA) inhibition may occur even if behavioral effects of kindling are not observed.

Animals↗

PubMed2000

High plasma serotonin levels in primary pulmonary hypertension. Effect of long-term epoprostenol (prostacyclin) therapy.

Elevated plasma serotonin is associated with primary pulmonary hypertension (PPH). To test whether this elevation could be related to platelet activation, the 2 pools of blood serotonin (platelets and plasma) and plasma 5-hydroxyindoleacetic acid (5-HIAA) as well as markers of platelet activation (alpha(IIb)beta(3), CD36, P-selectin, and CD63 membrane epitopes) were measured in 16 patients with severe PPH (group 1) before and at days 10 and 40 of treatment with a continuous infusion of epoprostenol (prostacyclin). The same biological parameters were also measured in 19 healthy subjects (group 2) and in 10 patients after cardiovascular surgery with extracorporeal circulation (group 3), a condition known to profoundly activate the platelets. Twelve PPH patients showed hemodynamic and clinical improvement, 3 remained stable, and 1 had the treatment stopped because of clinical aggravation. At day 0, mean plasma serotonin (5-hydroxytryptamine [5-HT]) concentration was much higher in PPH patients than in normal subjects (34.4+/-21.2 versus 9.1+/-6.0 nmol/L, respectively; P:<0.001) and positively correlated with total pulmonary resistance. The mean platelet 5-HT content was not significantly different in PPH compared with normal individuals. Mean plasma 5-HIAA concentrations were much higher in PPH than in normal patients (162+/-57 versus 61+/-7 nmol/L, respectively; P<0.001). These parameters did not significantly change during epoprostenol treatment. There was no correlation between the changes in plasma 5-HT during treatment and clinical or hemodynamic improvement. In PPH patients, the mean platelet volume significantly decreased (ANOVA, P<0.01) during treatment. Positive correlations were evidenced between the size of platelets and the number of alpha(IIb)beta(3) and CD36 epitopes. When compared with control platelets, the number of alpha(IIb)beta(3) epitopes detected on PPH platelets at day 0 tended to be higher, but this difference did not reach a statistical significance (41 300+/-7140 for PPH patients versus 36 010+/-3930 for control subjects, P=0.069). The number of CD36 epitopes, in the range of controls at day 0 (11 590+/-5080 for PPH patients versus 11 900+/-1790 for control subjects), decreased during treatment (ANOVA, P=0.038) and became significantly low at day 40 (8660+/-3520, P<0.001). The number of CD63 epitopes was not elevated, and P-selectin was never detected at any time point on PPH platelets. This glycoprotein profile indicates that the platelets of PPH patients were not highly activated but had an accelerated turnover and returned to normal under epoprostenol treatment without change of the elevated plasma serotonin, characteristic of PPH. In conclusion, neither platelet activation nor a significant alteration of the 5-HT endothelial metabolism explains the high level of plasma 5-HT in PPH patients. The 5-HT plasma concentration is not a predictive marker of the severity of PPH, and its evolution is independent of the clinical and hemodynamic status. Treatment by a potent antiaggregating agent, epoprostenol, does not affect the increase of plasma 5-HT, despite a therapeutic benefit.

Adult↗

PubMed2000

[Recent data on prion diseases].

The transmissible spongiform encephalopathies (TSEs) or "prions diseases", provokes some controversies about their origins and possible transmission from animals to humans. Important advances were obtained recently on the genetical TSEs with the genotypic diagnosis methods based on the discovery of numerous mutations and inclusions in the PRNP gene coding for prion protein. The possible connection between the bovine spongiform encephalopathy (BSE) and the newvariant of Creutzfeldt-Jakob disease (nv-CJD) ask numerous questions in terms of public health. Lastly, the important problem of biological diagnosis of "prions diseases" presents interesting advances that must be continued and supported by the public health authorities.

Animals↗

PubMed2000

[Biochemical mechanisms in the physiopathology of migraine].

Migraine is one of the few pathologies which gave rise to a tremendous number of physiopathological hypotheses. The variability of its clinical features and of the crisis initiating triggers, together with the numerous functional and/or biological abnormalities reported in migrainous patients, led to multiple 'theories' about migraine. For instance, migraine attacks may be associated with modifications of cerebral blood flow, and/or alterations at the cellular (neuronal and peripheral: platelets, mast cells, etc.) and subcellular (mainly mitochondrial) levels leading to variations of parameters such as serotonin, vasoactive neuropeptides, histamine, nitric oxide, neuroactive amino acids, etc. However, these modifications are mainly related to migraine attacks but not to migrainous patients. These emphasize how important is the distinction between the crisis mechanism(s) and the determinism of migraine illness. Despite the absence of any true animal model of migraine attack, the obtention, through the activation of the trigemino-vascular complex, of an experimental meningeal neurogenic inflammation was a clear breakthrough for the understanding of the migraine attack. Concerning the determinism of migraine, its familial characteristic has been known for a long time, but genetic studies started only recently. Despite some important contributions, the respective roles of genetic and environmental factors, as well as the transmission mode of migraine, remain largely to be determined. Practically, these genetic data, which really concern only a very peculiar form of migraine--the familial hemiplegic one--do not have presently any diagnostic or therapeutic application.

Animals↗

PubMed1999

Decreased serotonin transporter binding in unaffected relatives of manic depressive patients.

BACKGROUND: There are numerous reports of decreased binding to platelet serotonin transporter (5-HTT) in depression, suggesting that it might be considered a trait marker of depression. To further investigate whether reduced 5-HTT function could be an endophenotype in manic depressive illness, we looked for abnormalities of platelet 5-HTT among subjects who are potential carriers of genetic vulnerability to manic depressive illness (MDI). METHODS: Blood samples were obtained from 20 unaffected relatives from families with at least two individuals with bipolar disorder and from 19 control participants. Plasma 5-HIAA, platelet 5-HT, and [3H] imipramine binding were measured. RESULTS: Unaffected relatives manifested lower platelet 5-HTT function than control participants as revealed both by reduced number and diminished affinity of imipramine binding sites and diminished platelet 5-HT content. CONCLUSIONS: These preliminary results suggest that reduced 5-HTT function could be considered a trait marker or an endophenotype in MDI.

Adrenergic Uptake Inhibitors↗

PubMed1999

Evidence for preconditioning by isoflurane in coronary artery bypass graft surgery.

BACKGROUND: Experimentally, isoflurane, a commonly used volatile anesthetic agent, mimics the cardioprotective effects of ischemic preconditioning via a mechanism that could involve the activation of protein kinase C. The present study was designed to assess the clinical relevance of this observation in patients undergoing elective CABG. METHODS AND RESULTS: Twenty patients were included in the study. In 10 of them, preconditioning was elicited after the onset of cardiopulmonary bypass via a 5-minute exposure to isoflurane (2.5 minimum alveolar concentration), followed by a 10-minute washout before aortic cross-clamping and cardioplegic arrest. Ten case-matched control patients underwent an equivalent period (15 minutes) of prearrest isoflurane-free bypass. Outcome measurements included troponin I and creatine kinase-MB isoenzyme (until the third postoperative day) levels and the activity of ecto-5'-nucleotidase, which contributes to adenosine production and is considered to be a reporter of protein kinase C activation, as assessed in right atrial biopsy samples taken before bypass and at the end of the preconditioning protocol (or after 15 minutes of bypass in control patients). Aortic cross-clamping times did not differ between the 2 groups: 52+/-14 and 48+/-14 minutes (mean+/-SD) in control and isoflurane-preconditioned patients, respectively. Likewise, prebypass values of ecto-5'-nucleotidase were similar in control (3.54+/-0.86 nmol x mg protein(-1) x min(-1)) and isoflurane-treated (2.98+/-1.08 nmol x mg protein(-1) x min(-1)) patients. The values subsequently remained unchanged in control patients (3.62+/-0.94 nmol x mg protein(-1) x min(-1)), whereas they significantly increased after isoflurane preconditioning (4.74+/-0. 50 nmol x mg protein(-1) x min(-1); P<0.002 versus baseline values, P<0.004 versus time-matched values in control patients). This was paralleled by a consistently smaller release of troponin I, which yielded an area under the curve and a peak value of 204+/-147 ng x mL(-1) x min(-1) and 3.98+/-2.83 ng/mL, respectively, versus 284+/-136 ng x mL(-1) x min(-1) and 5.88+/-3.64 ng/mL, respectively, in control patients. The release of creatine kinase-MB featured a similar pattern. There were no adverse effects related to isoflurane. CONCLUSIONS: These data support a cardioprotective effect of isoflurane and, more generally, demonstrate the feasibility of pharmacologically preconditioning the human heart during cardiac surgery.

Aged↗

PubMed1999

Opening of potassium channels: the common cardioprotective link between preconditioning and natural hibernation?

BACKGROUND: The tolerance of hibernating mammals to cold hypoxia is related to a factor similar to agonists of delta-opioid receptors. This study was designed to assess whether activation of these receptors could reproduce the protection conferred by ischemic preconditioning and whether such cardioprotection was similarly mediated by an opening of ATP-sensitive potassium (KATP) channels. METHODS AND RESULTS: Thirty-two isolated rat hearts were arrested with and stored in Celsior at 4 degrees C for 5 hours before being reperfused for 2 hours. They were divided into 4 equal groups. Group 1 hearts served as controls. In group 2, ischemic preconditioning was elicited by two 5-minute global ischemia periods interspersed with 5 minutes of reperfusion before arrest. In group 3, hearts were pharmacologically preconditioned with a 15-minute infusion of the delta-opioid receptor agonist D-Ala2-D-Leu5-enkephalin (DADLE; 200 micromol/L). In group 4, the protocol was similar to group 3 except that infusion of DADLE was preceded by infusion of the KATP blocker glibenclamide (50 micromol/L). The salutary effects of both forms of preconditioning were primarily manifest as a better preservation of diastolic function, a reduced myocardial edema, and reduced creatine kinase leakage. This protection was abolished by administration of glibenclamide before DADLE. CONCLUSIONS: These data suggest that activation of delta-opioid receptors improves recovery of cold-stored hearts to a similar extent as ischemic preconditioning, most likely through an opening of KATP channels. This provides a rationale for improving the preservation of hearts for transplantation by pharmacologically duplicating the common pathway to natural hibernation and preconditioning.

Animals↗