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Obesity is a chronic condition whose incidence is growing due to lack of exercise and frequent nutrition disorders. Childhood obesity has reached epidemic proportions worldwide. One of the best treatment methods is physical training. However, conflicting results have been reported regarding its clinical effectiveness. These contrasting findings may be due to the type and intensity of the adopted physical training program. Therefore, the purpose of the current study was to investigate the effect of an 8-week individualized physical training program on endothelial function, blood biomarkers and adipokine levels in obese children with and without metabolic syndrome (MS). One-hundred-and-twenty-two obese adolescents (71 obese without MS and 51 obese with MS) aged 14 ± 2 years were included in this study. The 8-week individualized training program decreased glucose, triglycerides, total cholesterol, low-density lipoprotein cholesterol and leptin in obese subjects with and without MS. However, adiponectin and endothelial-dependent vasodilatation increased in the follow-up study in both groups. Taken together, the findings suggest that individualized training program is an effective means for the treatment of obesity and MS in pediatric populations., Competing Interests: The authors declare no conflict of interest.

Background: The aim of this study was to examine the effects of intense physical training on vascular function in streptozotocin-diabetic rats. We focused on the endothelium-dependent relaxation (EDR) induced by acetylcholine (ACh) and stable ADP adenosine-5'- O - (2-thiodiphosphate) (ADPβS)., Methods: Control or diabetic male Wistar rats (n=44) were randomly assigned to sedentary or trained groups. The training program consisted in a regular period of running on a treadmill during 8 weeks (10° incline and up to 25 m/min, 60 min/day). The reactivity of isolated thoracic aorta rings of healthy, diabetic and/or trained has been tested., Results: ACh and ADPβS-induced EDR were observed in phenylephrine (PE) pre-contracted vessels. As compared to sedentary control group, diabetic rats showed an increase in PE-induced contraction and a decrease in ACh and ADPβS-induced EDR (p<0.05). Moreover, there were no increase in ACh and ADPβS-induced EDR in diabetic rats. N-Nitro-L-Arginine Methyl Ester inhibited the nitric oxide synthase in diabetic and control rats, thereby resulting in a strong inhibition of the EDR induced by ACh and ADPβS (10-6 M)., Conclusion: Diabetes induced an endothelium dysfunction. Nevertheless, our intense physical training was not effective to restore the aorta endothelial function.

This study examined the effects of a dual treatment combining insulin treatment and exercise training on basal cardiac function and signaling pathways involving β3-AR, NOS1, and RyR2 in type 1 diabetic rats. Male Wistar rats were assigned into a diabetic group receiving no treatment (D), an insulin-treated diabetic (Ins), a trained diabetic (TD), and a trained insulin-treated diabetic (TIns) group. Control group (C) was included in order to confirm the deleterious effects of diabetes. Insulin treatment and/or treadmill exercise training were conducted for 8 weeks. Basal cardiac function was evaluated by Langendorff technique. Cardiac protein expression of β3-AR, NOS1, and RyR2 was assessed using Western blots. Diabetes induced a decrease of both basal diastolic and systolic (±dP/dt) cardiac function (P < 0.05). Moreover, diabetes was associated with an increase of β3-AR and NOS1 and a decrease of RyR2 expression (P < 0.05). Although combined treatment was not able to normalize -dP/dt, it succeeded to normalize +dP/dt of diabetic rats. Combined treatment led to an overexpression of RyR2. Effects of this combined treatment on +dP/dt and RyR2 were greater than the effects of insulin and exercise training, applied solely. Treatments, applied solely or in combination, resulted in a complete normalization of β3-AR and in a down-regulation of NOS1 because this protein expression in all treated diabetic rats became lower than control values (P < 0.01). Our study shows that unlike single treatments, dual treatment combining insulin treatment and exercise training was able to normalize basal systolic function of diabetic rats by a specific regulation of β3-AR-NOS1-RyR2 signaling pathways.

Aim: Exercise training is known to improve endothelium-dependent relaxation in the coronary and skeletal muscle arteries. However, the effects of exercise training on peripheral nonworking tissue, including microcirculation, are still unclear. Therefore, we investigated the effect of chronic and regular aerobic exercise on cutaneous microvascular endothelial function in rats., Methods: We assessed the effect of physical training on skin microcirculation in 7 sedentary (SED) and 21 training rats (Wistar-Kyoto), submitted to a treadmill training protocol (15 m/min; 15% incline; 60 min/day; 8 weeks). Training rats were divided into 3 groups, exercising 1 day/week (Ex1), 3 days/week (Ex3) or 5 days/week (Ex5). Cutaneous blood flow was recorded before the beginning of the training protocol, after 4 weeks and at the end of the training program. Hyperemic response (RH) was the flow reaction obtained after sudden release of the garrot. For data analysis, cutaneous vascular conductance (CVC) was indexed as cutaneous blood flow divided by mean arterial blood pressure (in millimeters of mercury, mmHg) and normalized to baseline values., Results: At baseline, CVC was not different among groups (SED or training) at 3 steps of experimental protocol. The hyperemic stimulus significantly increased normalized CVC only in group Ex3 after 4 weeks (P<0.006) and 8 weeks (P<0.006)., Conclusion: Exercise training exerts a generalized effect on the vasculature by increasing endothelial function in vessel beds different from those perfusing actively working muscle. However, some differences exist since training at a frequency of 3 bouts weekly only modifies cutaneous microcirculation.

Background: Moderate physical activity enhances endothelium-dependent vasorelaxation. Whether the frequency of exercise affects endothelial function is unclear. The purpose of this study was to investigate the effects of various frequencies of training on endothelium-dependent vasorelaxation., Design: Male Wistar rats were trained for 8 weeks on a treadmill at various frequencies [1 (Ex1), 3 (Ex3) or 5 days/week (Ex5)] and compared with age-matched sedentary animals (SED). A control group allowed us to assess endothelial function before the exercise protocol. Rings of thoracic aorta were precontracted with phenylephrine., Results: Endothelium-independent relaxation elicited by sodium nitroprusside was similar in all groups. The maximal response elicited by acetylcholine (ACh) was not different between groups, whereas pD2 values (-logEC50, EC50 being the concentration of ACh that elicited 50% of the maximal response) significantly correlated with frequency of training. nitro-L-arginine methyl ester (L-NAME) reduced the relaxation elicited by 10(-7) mol/l ACh or higher in control and all trained groups, and by 10(-6) mol/l ACh or higher in SED group. Indomethacin inhibited the vasodilating response to 10(-7) mol/l ACh or higher in control, SED and Ex1 groups, and to 10(-8) mol/l or more in Ex3 and Ex5 animals. Tetraethylammonium attenuated the response to 10(-6) mol/l ACh or higher in control and SED groups and to 10(-7) mol/l or more in all trained animals., Conclusion: This data suggest that decreased ACh-induced vasorelaxation after physical inactivity may result from impairment of endothelial nitric oxide synthase, prostacyclin and endothelium-derived hyperpolarizing factor pathways. This effect is prevented by training in a frequency-dependent manner.

Objectives: We report in the present study the role of endothelin (ET-1) and ET-1 receptors in the sustained hypoxia-induced systemic hypertension., Methods: Wistar rats were randomly assigned to live continuously in hypobaric hypoxia (CH rats) or normoxia (N rats). At the end of hypoxic stress exposure (5 weeks at 450 mm Hg), measurements of mean systemic arterial pressure were done. The effects of ET-1 in the presence or not of the endothelium and/or of specific ET-A inhibitors (BQ-123) or ET-B inhibitors (BQ-788), have been investigated in an isolated model of rat thoracic aorta. Finally, plasmatic ET-1 concentrations have been determined by assay procedure., Results: Following five weeks of chronic hypoxic stress, CH rats presented a significant increase of mean systemic arterial pressure (N: 129.1+/-6.8 mm Hg vs CH: 152.5+/-3.4 mm Hg; P<0.05). Despite of this hypoxia-induced hypertension, ET-1 plasmatic concentration was not different between N and CH rats. Finally, CH rats presented a reduce response to ET-1 when compared to N rats. This phenomenon seems to be associated to the ET-A vascular smooth muscle cell receptors, since difference between N and CH rats was still present in endothelium denuded aortic rings in the presence or not of the specific ET-B inhibitors (BQ-788). In addition, in the presence of the specific ET-A inhibitor (BQ-123) response to ET-1 was abolished in N and CH rats to the same extent (N:-98%; CH:-99%)., Conclusion: This work clearly suggests that, following long term exposure to hypoxia, ET-1 and ET-1 receptors are not involved in the persistence of systemic hypertension in a rat model, and that chronic exposure to severe hypoxic stress was associated with a downregulation of the ET-A receptors response to ET-1.

1-O-alkylglycerols (alkyl-Gro) are natural etherlipids with multiple biological activities. We previously demonstrated that alkyl-Gro reduce endothelial permeability. Here we showed that alkyl-Gro reduced the basic Fibroblast Growth Factor (bFGF)-stimulated endothelial cell proliferation in a concentration-dependent manner. The effects of 0.5 and 5 ng/ml bFGF on growth were completely suppressed after 72 h-treatment by 50 microM alkyl-Gro. Since bFGF greatly increased (+56%+/-15) the production of 1-O-alkyl-2-acyl-sn-glycerophosphate in alkyl-Gro-treated endothelial cells, our data suggest that the observed effects of alkyl-Gro could be mediated through PLD activation. Inhibition of bFGF-stimulated endothelial proliferation could support anti-angiogenic activity of alkyl-Gro.

We undertook this study to determine whether long-term high intensity exercise would modify cutaneous endothelial-dependent vasodilation. We compared a group of 9 highly trained windsurfers (mean age: 24.5 +/- 1.6 years) to a control group of 8 sedentary individuals (22.9 +/- 0.4 years, NS). Laser Doppler was used to measure cutaneous blood flow in the resting state (baseline), during post-occlusive hyperaemia (endothelium-dependent vasodilation), and local heating to 42 degrees C. Lipid profile was similar in both groups. Resting heart rate was significantly lower in windsurfers. Baseline cutaneous vascular conductance (CVC) values were similar in both groups (0.059 +/- 0.016 and 0.051 +/- 0.009). During reactive hyperaemia, normalized peak CVC value was significantly higher in the windsurfers group (1775.4 +/- 286.9 and 826.4 +/- 121.7 % baseline CVC; p = 0.01). Normalized peak CVC value in response to local heating (42 degrees C) was not significantly different between both groups (2359.4 +/- 346.1 and 1467.7 +/- 282.6 % baseline CVC). Endothelium-dependent vasodilation in cutaneous microcirculation is significantly enhanced in the forearm skin of highly trained windsurfers when compared to sedentary controls.

Alkylglycerols are natural etherlipids abundant in shark liver oil (SLO) in a diacylated form. SLO is known to have antitumor properties and was recently described as an inhibitor of tumor neovascularization. However, most studies did not discriminate between the respective activities of alkylglycerols and of fatty acids, which both have potent biological properties. In this work, a mouse model was used to investigate the antitumor effects of SLO and of alkylglycerols purified from the same source, both administered orally. We demonstrated that either pure alkylglycerols or SLO reduced the tumor growth in a similar manner, suggesting that alkylglycerols were involved in this effect. In alkylglycerol-treated mice, metastasis dissemination was reduced by 64 +/- 8%, whereas SLO effect was 30 +/- 9% below control. Purified alkylglycerols also decreased significantly plasmalogen content in tumors, whereas SLO had no such effect. Finally, we demonstrated that a 5-day treatment with alkylglycerols curtailed the presence in tumors of von Willebrand factor, a marker of endothelial cells. This result suggested an anti-angiogenic effect of alkylglycerols. In summary, alkylglycerols were shown to decrease the growth, vascularization, and dissemination of Lewis lung carcinoma tumors in mice. These findings suggest that the antitumor activity of SLO is likely mediated by the presence of alkylglycerols., (Copyright 2004 Lawrence Erlbaum Associates, Inc.)

Although the neurobiological causative factors are now beginning to be understood, to a large extent the complex mechanisms involved in migraine remain an enigma, with the appearance of a transient unilateral cephalic pain, possibly preceded by a protean aura and associated with several other symptoms. The factors involved include three clinical signs or symptoms, i.e., pain, the aura (focalized neurological and neurosensory signs), and accompanying symptoms (e.g., sensory, psychological, or digestive); and three anatomical sites, i.e., the brain, the meningeal or intracranial vessel and a peripheral cranial nerve, the trigeminus (V). Familial hemiplegic migraine (FHM) has led to a consideration of the genetic origin of ionic channel-dependent pathologies (channelopathies), while certain other arguments which are for the most part indirect favor the hypothesis of abnormalities, again possibly of genetic origin, in the central neurotransmitters (including serotonin), which are involved in the transmission of pain messages and in vasomotor control. However, the main point is that each of the sites involved has its specific pharmacopoeia, which can contribute towards the treatment of migraine.

The effects of adrenomedullin were evaluated in isolated vascular rings from rats treated with monocrotaline (60 mg/kg, s.c.) causing pulmonary hypertension and right ventricular hypertrophy within 3 to 4 weeks. Sham animals (NaCl-treated rats) were used for comparison. The relaxing effects of adrenomedullin (10(-8) M) and acetylcholine (10(-6) M) were determined in thoracic aorta and pulmonary artery rings precontracted with phenylephrine (10(-7) M). In sham animals, adrenomedullin caused significant vasorelaxation of aorta and pulmonary artery although of different amplitude (24 +/- 3% and 40 +/- 2%, respectively). A greater relaxation was observed in response to acetylcholine. Monocrotaline-treated rats exhibited a reduction in adrenomedullin relaxation in pulmonary artery (54 and 68% loss of effect, at 3 and 4 weeks, respectively, P < 0.01 vs. sham) and comparable reductions in acetylcholine responses. The decrease in adrenomedullin relaxing effect was less pronounced in aorta than in pulmonary artery, suggesting a distinct tissue sensitivity to monocrotaline. In contrast, the relaxing effect of acetylcholine on aorta was decreased at 4 weeks (36% reduction, P < 0.01 vs. sham). In this model, the adrenomedullin-induced relaxation of the pulmonary artery was impaired due to a severe endothelial dysfunction which may contribute partly to the evolving pathophysiological process.

This study investigates the effects of agents which act on the production or efficacy of free radicals on the hypoxic responses of rat aorta rings. Under moderate hypoxic conditions, the resting tension of the rings was not changed but in rings precontracted with 5-hydroxytryptamine, there was a relaxation followed by a contraction. Removal of the endothelium with saponin suppressed relaxation to acetylcholine and abolished the contractions produced by hypoxia. In rings with a functional endothelium, hypoxic vasoconstriction was strongly inhibited by mannitol and exifone, but was not reduced by N(G)-nitro-L-arginine methyl ester, superoxide dismutase + catalase, or deferoxamine. Hypoxic vasodilatation was only partially inhibited by mannitol. To conclude, hypoxic constriction of the rat thoracic aorta is largely endothelium-dependent and involves free radicals whereas hypoxic dilatation is partially endothelium-dependent and partially involves free radicals. There is also indirect evidence for lack of direct involvement of nitric oxide/endothelium-derived relaxing factor (NO*/EDRF), hydroxyl radical (OH*) and superoxide anion in the hypoxic constriction and relaxation of the rat aorta.

Purpose: Endothelial P2y purinoceptor stimulation is known to induce vasodilatation mediated by NO release from endothelial cells. We examined the effect of a potent P2y agonist, adenosine-5'-O-(2-thiodiphosphate) (ADPbetaS), on human corporal cavernosal strips and its dependence on a functional endothelial lining., Materials and Methods: The preparations mounted in isometric conditions were precontracted by noradrenaline (NA) at a concentration of 0.1 microM. Increasing concentrations of ADPbetaS from 1 microM to 100 microM were added in the presence and absence of a functional endothelium or in the presence and absence of an NO synthase inhibitor and a selective P2y antagonist. Acetylcholine (Ach)-induced relaxation was used in each experiment for control., Results: In human precontracted corporal cavernosal strips with a functional endothelium (relaxed by acetylcholine) ADPbetaS induces a dose-dependent relaxation with maximal relaxation of 45.5+/-5.0% and an EC50 of 11.7 microM. The relaxant effect of ADPbetaS was reduced by 77.1+/-7.0% by reactive blue 2 (20 microM)(a P2y antagonist). L-NAME (L-Nitro Arginin Methyl Ester), an NO synthase inhibitor (100 microM), reduced Ach- and ADPbetaS- induced relaxations by 86.59+/-3.24% and 86.83+/-0.5% respectively. Ach- and ADPbetaS- induced relaxations were significantly inhibited after dislodging of the endothelial lining of the corporal cavernosal strips, 90.11+/-6.2% and 87.1+/-5% respectively., Conclusions: Human corporal cavernosal strips can be relaxed by stimulation of P2y purinoceptors via NO release. This relaxation is an endothelium-dependent mechanism. Purines may be implicated in physiological erection in man.

Endothelial cells were isolated from bovine thoracic aorta and cultured. Bovine aortic endothelial cells (BAEC) were incubated with radiolabeled arachidonic acid (3H-AA) or eicosapentaenoic acid (14C-EPA) (1 microM) for 3 hr. Both fatty acids were predominantly incorporated into phosphatidylcholine (57 +/- 2% and 62 +/- 2% respectively) and slightly into phosphatidylethanolamine (11 +/- 0.5% and 12 +/- 0.6% respectively). phosphatidylinositol (26 +/- 1.5% and 10 +/- 0.5% respectively) and neutral lipids (6 +/- 0.5% and 15 +/- 1% respectively). After BAEC incubation with 3H-AA for 24 hr with or without EPA (1 microM), the release of radioactive metabolites of AA induced by thrombin (5.5 U/ml) was strongly reduced by the preliminary treatment with EPA (72 +/- 5%). After BAEC incubation with AA, EPA or vehicle (control), endothelin-1 levels were measured by RIA in the culture medium and we observed that: 1) the basal production of endothelin-1 was not modified after either AA or EPA treatment, 2) the thrombin-evoked release of endothelin-1 was significantly reduced by EPA (5.8 +/- 0.82 and 3.8 +/- 0.50 pg/microg proteins in control and EPA-treated cells, respectively); 3) by contrast, AA had no significant effect on the thrombin-evoked release of endothelin-1. In conclusion, EPA reduces strongly the endothelin-1 release but AA is ineffective. This reduction of endothelin-1 release may account partly for some of the vascular effects of EPA.

A possible role of uridine 5'-triphosphate (UTP) and uridine at sympathetic nerve terminals was studied in the rabbit ear artery after incubation of isolated vessels with [3H]uridine or [3H]noradrenaline. It was found that [3H]uridine was taken up by rabbit ear artery. This uptake was largely suppressed after the removal of endothelium and was inhibited by ethidium bromide and dipyridamole. Chemical denervation of the vessels with 6-hydroxydopamine did not reduce the uptake. Following pre-incubation of the isolated vessels with [3H]uridine, there was a release of radioactivity from the superfused rabbit ear artery. UTP, UDP, UMP and uridine were detected by thin layer chromatography both in the superfusate and inside the vessels. Transmural electric stimulation (30 V, 5 Hz) induced a contraction of the vessels but did not increase the release of uridine nucleotides into the superfusate. [3H]Noradrenaline was released during electric stimulation and the addition of UTP (100 microM) had no effects on this release. To conclude, this study shows that in contrast to endothelial cells, the sympathetic nerve terminals of the rabbit ear artery do not take up uridine and do not release uridine-derived nucleotides. UTP at 100 microM is also unable to modulate the evoked release of noradrenaline. These results mainly confine the role of UTP in endothelium-derived vasodilatation via P2Y2 and/or P2Y4 receptors.

1. The endothelium-dependent relaxation of blood vessels induced by P2Y-purinoceptor activation has often been shown to involve prostacyclin and/or nitric oxide (NO) release. In this work, we have investigated the mechanisms involved in the relaxant effect of the P2Y agonist, adenosine -5'-O-(2-thiodiphosphate) (ADP beta S) using two complementary preparations: rat pancreatic vascular bed and aortic ring. 2. On the pancreatic vascular bed, ADP beta S (1.5 and 15 microM) infused for 30 min induced a concentration-dependent vasodilatation; it was progressive during the first 10 min (first period) and sustained from 10 to 30 min (second period). Indomethacin (10 microM) delayed ADP beta S-induced vasodilatation (1.5 and 15 microM) by about 6 min. N omega-nitro-L-arginine methyl ester (L-NAME) (200 microM) suppressed the relaxation for about 5 min but thereafter ADP beta S at the two concentrations progressively induced an increase in the flow rate. Even the co-administration of L-NAME and indomethacin did not abolish the ADP beta S-induced vasorelaxation. 3. On 5-hydroxy tryptamine (5-HT) precontracted rings mounted in isometric conditions in organ baths, we observed that ADP beta S induced a concentration-dependent relaxation of rings with a functional endothelium; this effect was stable for 25 min. The ADP beta S relaxant effect was strongly inhibited by Reactive Blue 2 (30 microM) and was suppressed by pretreatment of rings with saponin (0.05 mg ml-1 for 30 min), which also abolished the acetylcholine-induced relaxation. 4. ADP beta S-induced relaxation of 5-HT precontracted rings is largely inhibited by indomethacin (100 or 10 microM) or L-NAME (100 microM). 5. We conclude that: the ADP beta S-induced relaxation is endothelium-dependent, mediated by P2Y-purinoceptors, and at least in part linked to NO and prostacyclin release, depending on the preparation used. Furthermore, on the pancreatic vascular bed, (an)other mechanism(s) than prostacyclin and NO releases may be involved in ADP beta S-induced vasodilatation.

The effects of melatonin on LH and PRL releases induced by treatment with naloxone, naloxone methyliodide and nalmefene were studied in adult male rats. Subcutaneous melatonin injection (1.4 mg/Kg) had no effect on LH secretion, but caused an inhibition effect (84%) on LH release induced by naloxone (2.4 mg/Kg). Melatonin too totally inhibited LH secretion induced by naloxone methyliodide (2.8 mg/Kg) and nalmefene (2 mg/Kg) when it was simultaneously administered with each opioid receptor antagonist. Melatonin alone had no significant effect on serum PRL levels, but decreased by 25.5% the inhibitory effect potency of nalmefene on PRL secretion after simultaneous injections. The inhibitory effect potency of naloxone on PRL release increased (16%) when it was administered with melatonin. Simultaneous injection of melatonin with naloxone methyliodide inhibited PRL release (78%) while naloxone methyliodide alone did not modify this secretion. The results obtained with a quaternary opioid antagonist indicate that the opioid receptor type which mediates LH and PRL responses is located respectively outside and inside the blood-brain barrier. Our findings show that opiate antagonists and their quaternary ammonium salts affect secretion of LH and PRL through different mechanisms susceptible to the influence of melatonin.

Contractile responses to norepinephrine (noradrenaline, NE 10(-5) M) in the canine saphenous vein (SV) are significantly, although slightly, reduced (14%) when induced in a physiological medium depleted of calcium for 1 hour (+ EGTA). In contrast, they are inhibited by about 75% after 24 hr in calcium free physiological saline solution (P.S.S.). ED50 of norepinephrine in 1-hr calcium-free medium and in normal Ca++ P.S.S. are 6 x 10(-7)M and 4.2 x 10(-7)M, respectively. Two blockers of extracellular calcium entry have also been cited as inhibitors of intracellular calcium pool refilling. At concentrations of 10(-6)M, 10(-5)M and 10(-4)M, diltiazem and nicardipine inhibit the norepinephrine-induced contractions (NIC) in a concentration-dependent manner. At 10(-4)M, the two calcium blockers inhibit the NIC by 70% and by 72% respectively in Ca++ free (+ EGTA) P.S.S. Nifedipine and verapamil only begin to significantly inhibit NIC in Ca++ free (+ EGTA) P.S.S. at concentrations equal to or greater than 10(-5)M. At 10(-4)M concentration, control inhibition in Ca++ free P.S.S. was observed as 60% and 49%, respectively. Contrary to the other 3 calcium antagonists tested, diltiazem antagonises NIC significantly less in calcium-containing medium (45%) than in calcium-free medium (72%). Procaine at a concentration of 10(-3)M, described as sufficient to totally inhibit calcium release from its intracellular storage sites, only inhibits NIC by 52% in calcium free (+ EGTA) P.S.S. These results are consistent with the following conclusion: i) in the canine saphenous vein (SV), NIC is mainly mediated by calcium mobilization from its intracellular storage sites; ii) the calcium antagonists tested here and procaine are unable to totally inhibit, even at high concentrations, the contractions induced via intracellular calcium release; this characteristic is nonsignificant for nifedipine and verapamil at low concentrations (10(-6)M). iii) verapamil and nifedipine, like diltiazem and nicardipine at high concentrations, may not only possess the characteristics of extracellular calcium entry blockers, but also that of partial antagonist of NIC via non specific mechanisms; iv) diltiazem may relax the vascular smooth muscle of SV, not only by the above two properties, but also through another mechanism yet unknown; v) partial persistence of NIC on the SV under conditions of short or long extracellular calcium depletion may be due to a mechanism of intracellular Ca++ recycling, the smooth muscle cell partially retaining its intracellular Ca++.

Cerebral ischaemia induces considerable neurotransmitter exocytosis, mediated by calcium entry in neurones, essentially via the N-type, voltage-dependent channels, which are insensitive to calcium blockers. Nonetheless, these blockers, by unclear mechanisms, exert a neuroprotective effect when used in experimental ischaemic models. On the other hand, the existence of L-type, voltage-dependent channels, the only ones responding to the action of calcium blockers on synapses, argues in favour of their possible concomitant action in certain highly pathological situations. We studied the action of three calcium blockers, nimodipine, diltiazem and verapamil (administered at a concentration of 100 microM directly into the striatum of rats), on the extracellular release of dopamine and serotonin, and on the level of their main metabolites, in a model of transient global cerebral ischaemia (four-vessel occlusion). The total absence of effect of these molecules on neurotransmitter release induced by ischaemia proves the non-involvement of this mechanism in the protective action of calcium entry blockers on ischaemic lesions, and the absence or very weak action of L-type, voltage-dependent presynaptic channels in the striatum of rats.

The effect of naloxone and beta-casomorphin on luteinizing hormone (LH) release from pituitary cell aggregates, obtained by three-dimensional culture, with or without mediobasal hypothalamic fragments was studied in vitro. Short-term naloxone perifusion at a concentration of 10(-5)M did not modify either basal or LHRH-stimulated LH release from the pituitary cell aggregates. In contrast, a 12-min naloxone perifusion at the same concentration caused an increase in LH release in the mediobasal hypothalamic-pituitary cell aggregate axis. This increase was rapid (12-16 min after time pulse), marked [up to 10 times (p less than 0.004) the initial base line], short (return to the base line secretion 32-40 min after the beginning of the time pulse) and dose-dependent, with a rise greater than 1000% at a concentration of 10(-4) (p less than 0.006). The same effect was observed when a second pulse was applied 48 min after the first one. LH release induced by naloxone was antagonized 56 +/- 2% (p less than 0.03) by beta-casomorphin (an exogenous opiate) at a concentration of 10(-5) M. beta-casomorphin alone did not modify LH basal secretion, but inhibited 25.1 +/- 2.4% (p less than 0.008) LH release enhanced by LHRH. These results indicate that naloxone, an opiate antagonist, markedly increases LH release via a mu-type opioid receptor mechanism at the hypothalamic level only, during short-term exposure.

Adenosine triphosphate (ATP) and uridine triphosphate (UTP) receptors were studied by comparing the contractile responses to UTP with those to ATP in the rat tail and femoral arteries and dog saphenous vein, after endothelium removal confirmed by histology, and near abolition of relaxation to acetylcholine. Contractions induced by ATP and UTP were dose dependent, as assessed from preparations at resting tension. Contraction curves were very different: rapid subsidence with ATP and sustained contraction with UTP. In the rat tail artery and the dog saphenous vein, quinidine, nordihydroguaiaretic acid (NDGA) and phentolamine inhibited the contractions induced by ATP, whereas those induced by UTP were only slightly reduced in the presence of NDGA and were not antagonized by quinidine and phentolamine. In all three vessels, alpha-beta methylene ATP induced desensitization to ATP, whereas it did not antagonize the UTP-induced contractions. Reactive blue 2 was incapable of antagonizing contractions to ATP and UTP in these preparations. In addition, UTP-induced contractions were hardly inhibited in a calcium-free Krebs solution, whereas ATP was totally inhibited. We showed that a calcium antagonist, nicardipine, was more potent on the UTP-induced than on the ATP-induced contractions. These results showed the UTP-induced contraction to be mediated by a new class of receptors, qualified here as 'pyrimidinoceptors', for which no antagonist is known. These results were obtained in the tail and femoral arteries of the rat and from the dog saphenous vein. ATP induced contraction in these three vessels via P2x purinoceptors. P2x purinoceptors and 'pyrimidinoceptors' are localized on the vascular smooth muscle.