RESUMEN
The consumption of alcohol and caffeine affects the lives of billions of individuals worldwide. Although recent evidence indicates that caffeine impairs the reinforcing properties of alcohol, a characterization of its effects on alcohol-stimulated mesolimbic dopamine (DA) function was lacking. Acting as the pro-drug of salsolinol, alcohol excites DA neurons in the posterior ventral tegmental area (pVTA) and increases DA release in the nucleus accumbens shell (AcbSh). Here we show that caffeine, via antagonistic activity on A2A adenosine receptors (A2AR), prevents alcohol-dependent activation of mesolimbic DA function as assessed, in-vivo, by brain microdialysis of AcbSh DA and, in-vitro, by electrophysiological recordings of pVTA DA neuronal firing. Accordingly, while the A1R antagonist DPCPX fails to prevent the effects of alcohol on DA function, both caffeine and the A2AR antagonist SCH 58261 prevent alcohol-dependent pVTA generation of salsolinol and increase in AcbSh DA in-vivo, as well as alcohol-dependent excitation of pVTA DA neurons in-vitro. However, caffeine also prevents direct salsolinol- and morphine-stimulated DA function, suggesting that it can exert these inhibitory effects also independently from affecting alcohol-induced salsolinol formation or bioavailability. Finally, untargeted metabolomics of the pVTA showcases that caffeine antagonizes alcohol-mediated effects on molecules (e.g. phosphatidylcholines, fatty amides, carnitines) involved in lipid signaling and energy metabolism, which could represent an additional salsolinol-independent mechanism of caffeine in impairing alcohol-mediated stimulation of mesolimbic DA transmission. In conclusion, the outcomes of this study strengthen the potential of caffeine, as well as of A2AR antagonists, for future development of preventive/therapeutic strategies for alcohol use disorder.
RESUMEN
The use of hypoxic devices among athletes who train in normobaric hypoxia has become increasingly popular; however, the acute effects on heart and brain metabolism are not yet fully understood. This study aimed to investigate the mitochondrial bioenergetics in trained male and female Wistar rats after acute hypoxia training. The experimental plan included exercising for 30 min on a treadmill in a Plexiglas cage connected to a hypoxic generator set at 12.5% O2 or in normoxia. After the exercise, the rats were sacrificed, and their mitochondria were isolated from their brains and hearts. The bioenergetics for each complex of the electron transport chain was tested using a Clark-type electrode. The results showed that following hypoxia training, females experienced impaired oxidative phosphorylation through complex II in heart subsarcolemmal mitochondria, while males had an altered ADP/O in heart interfibrillar mitochondria, without any change in oxidative capacity. No differences from controls were evident in the brain, but an increased electron transport system efficiency was observed with complex I and IV substrates in males. Therefore, the study's findings suggest that hypoxia training affects the heart mitochondria of females more than males. This raises a cautionary flag for female athletes who use hypoxic devices.
RESUMEN
Hemodynamic changes during exercise in acute hypoxia (AH) have not been completely elucidated. The present study aimed to investigate hemodynamics during an acute bout of mild, dynamic exercise during moderate normobaric AH. Twenty-two physically active, healthy males (average age; range 23-40 years) completed a cardiopulmonary test on a cycle ergometer to determine their maximum workload (Wmax). On separate days, participants performed two randomly assigned exercise tests (three minutes pedaling at 30% of Wmax): (1) during normoxia (NORMO), and (2) during normobaric AH at 13.5% inspired oxygen (HYPO). Hemodynamics were assessed with impedance cardiography, and peripheral arterial oxygen saturation (SatO2) and cerebral oxygenation (Cox) were measured by near-infrared spectroscopy. Hemodynamic responses (heart rate, stroke volume, cardiac output, mean arterial blood pressure, ventricular emptying rate, and ventricular filling rate) were not any different between NORMO and HYPO. However, the HYPO test significantly reduced both SatO2 (96.6 ± 3.3 vs. 83.0 ± 4.5%) and Cox (71.0 ± 6.6 vs. 62.8 ± 7.4 A.U.) when compared to the NORMO test. We conclude that an acute bout of mild exercise during acute moderate normobaric hypoxia does not induce significant changes in hemodynamics, although it can cause significant reductions in SatO2 and Cox.
Asunto(s)
Consumo de Oxígeno , Saturación de Oxígeno , Adulto , Ejercicio Físico/fisiología , Prueba de Esfuerzo , Hemodinámica/fisiología , Humanos , Hipoxia , Masculino , Oxígeno , Consumo de Oxígeno/fisiología , Adulto JovenRESUMEN
Energy drinks are very popular nonalcoholic beverages among adolescents and young adults for their stimulant effects. Our study aimed to investigate the effect of repeated intraoral Red Bull (RB) infusion on dopamine transmission in the nucleus accumbens shell and core and in the medial prefrontal cortex and on cardiac contractility in adult rats exposed to chronic RB consumption. Rats were subjected to 4 weeks of RB voluntary consumption from adolescence to adulthood. Monitoring of in vivo dopamine was carried out by brain microdialysis. In vitro cardiac contractility was studied on biomechanical properties of isolated left-ventricular papillary muscle. The main finding of the study was that, in treated animals, RB increased shell dopamine via a nonadaptive mechanism, a pattern similar to that of drugs of abuse. No changes in isometric and isotonic mechanical parameters were associated with chronic RB consumption. However, a prolonged time to peak tension and half-time of relaxation and a slower peak rate of tension fall were observed in RB-treated rats. It is likely that RB treatment affects left-ventricular papillary muscle contraction. The neurochemical results here obtained can explain the addictive properties of RB, while the cardiovascular investigation findings suggest a hidden papillary contractility impairment.
RESUMEN
Acute hypoxia (AH) is a challenge to the homeostasis of the cardiovascular system, especially during exercise. Research in this area is scarce. We aimed to ascertain whether echocardiographic, Doppler, and tissue Doppler measures were able to detect changes in systolic and diastolic functions during the recovery after mild exercise in AH. Twelve healthy males (age 33.5 ± 4.8 years) completed a cardiopulmonary test on an electromagnetically braked cycle-ergometer to determine their maximum workload (Wmax). On separate days, participants performed randomly assigned two exercise sessions consisting in 3 min pedalling at 30% of Wmax: (1) one test was conducted in normoxia (NORMO) and (2) one in normobaric hypoxia with FiO2 set to 13.5% (HYPO). Hemodynamics were assessed with an echocardiographic system. The main result was that the HYPO session increased parameters related to myocardial contractility such as pre-ejection period and systolic myocardial velocity with respect to the NORMO test. Moreover, the HYPO test enhanced early transmitral filling peak velocities. No effects were detected for left ventricular volumes, as end-diastolic, end-systolic, and stroke volume were similar between the NORMO and the HYPO test. Results of the present investigation support the hypothesis that a brief, mild exercise bout in acute normobaric hypoxia does not impair systolic or diastolic functions. Rather, it appears that stroke volume is well preserved and that systolic and early diastolic functions are enhanced by exercise in hypoxia.
RESUMEN
NEW FINDINGS: What is the central question of this study? In the papillary muscle from type I diabetic rats, does diabetes-associated altered ventricular function result from changes of acto-myosin interactions and are these modifications attributable to a possible sarcomere rearrangement? What is the main finding and its importance? For the first time, we showed that type-I diabetes altered sarcomeric ultrastructure, as seen by transmission electron microscopy, consistent with physiological parameters. The diabetic condition induced slower timing parameters, which is compatible with a diastolic dysfunction. At the sarcomeric level, augmented ß-myosin heavy chain content and increased sarcomere length and crossbridges' number preserve myocardial stroke and could concur to maintain the ejection fraction. ABSTRACT: We investigated whether diabetes-associated altered ventricular function, in a type I diabetes animal model, results from a modification of acto-myosin interactions, through the in vitro recording of left papillary muscle mechanical parameters and examination of sarcomere morphology by transmission electron microscopy (TEM). Experiments were performed on streptozotocin-induced diabetic and age-matched control female Wistar rats. Mechanical isometric and isotonic indexes and timing parameters were determined. Using Huxley's equations, we calculated mechanics, kinetics and energetics of myosin crossbridges. Sarcomere length and A-band length were measured on TEM images. Type I and III collagen and ß-myosin heavy chain (MHC) expression were determined by immunoblotting. No variation in resting and developed tension or maximum extent of shortening was evident between groups, but diabetic rats showed lower maximum shortening velocity and prolonged timing parameters. Compared to controls, diabetics also displayed a higher number of crossbridges with lower unitary force. Moreover, no change in type I and III collagen was associated to diabetes, but pathological rats showed a two-fold enhancement of ß-MHC content and longer sarcomeres and A-band, detected by ultrastructural morphometry. Overall, these data address whether a preserved systolic function accompanied by an altered diastolic phase results from a recruitment of super-relaxed myosin heads or the phosphorylation of the regulatory light chain site in myosin. Although the early signs of diabetic cardiomyopathy were well expressed, the striking finding of our study was that, in diabetics, sarcomere modification may be a possible compensatory mechanism that preserves systolic function.
Asunto(s)
Diabetes Mellitus Experimental , Sarcómeros , Animales , Diabetes Mellitus Experimental/metabolismo , Femenino , Contracción Miocárdica/fisiología , Ratas , Ratas Wistar , Sarcómeros/metabolismo , EstreptozocinaRESUMEN
BACKGROUND: We recently showed that striatal overexpression of brain derived neurotrophic factor (BDNF) by adeno-associated viral (AAV) vector exacerbated L-DOPA-induced dyskinesia (LID) in 6-OHDA-lesioned rats. An extensive sprouting of striatal serotonergic terminals accompanied this effect, accounting for the increased susceptibility to LID. OBJECTIVE: We set to investigate whether the BDNF effect was restricted to LID, or extended to dyskinesia induced by direct D1 receptor agonists. METHODS: Unilaterally 6-OHDA-lesioned rats received a striatal injection of an AAV vector to induce BDNF or GFP overexpression. Eight weeks later, animals received daily treatments with a low dose of SKF82958 (0.02âmg/kg s.c.) and development of dyskinesia was evaluated. At the end of the experiment, D1 and D3 receptors expression levels and D1 receptor-dependent signaling pathways were measured in the striatum. RESULTS: BDNF overexpression induced significant worsening of dyskinesia induced by SKF82958 compared to the GFP group and increased the expression of D3 receptor at striatal level, even in absence of pharmacological treatment; by contrast, D1 receptor levels were not affected. In BDNF-overexpressing striata, SKF82958 administration resulted in increased levels of D1-D3 receptors co-immunoprecipitation and increased phosphorylation levels of Thr34 DARPP-32 and ERK1/2. CONCLUSION: Here we provide evidence for a functional link between BDNF, D3 receptors and D1-D3 receptor close interaction in the augmented susceptibility to dyskinesia in 6-OHDA-lesioned rats. We suggest that D1-D3 receptors interaction may be instrumental in driving the molecular alterations underlying the appearance of dyskinesia; its disruption may be a therapeutic strategy for treating dyskinesia in PD patients.
Asunto(s)
Factor Neurotrófico Derivado del Encéfalo/metabolismo , Cuerpo Estriado/metabolismo , Agonistas de Dopamina/farmacología , Discinesia Inducida por Medicamentos/metabolismo , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D3/metabolismo , Animales , Benzazepinas/farmacología , Factor Neurotrófico Derivado del Encéfalo/efectos de los fármacos , Cuerpo Estriado/efectos de los fármacos , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades/inducido químicamente , Discinesia Inducida por Medicamentos/etiología , Inmunoprecipitación , Oxidopamina , Ratas , Receptores de Dopamina D1/efectos de los fármacos , Receptores de Dopamina D3/efectos de los fármacosRESUMEN
No data are available on whether a diet deficient of the essential fatty acids is able to modulate tissue levels of endocannabinoids and congeners. Male rats fed for 12 weeks a diet deficient of essential fatty acids, palmitic and oleic acids (EFAD), replaced with saturated fatty acids (SAFA), showed lowered n-3 and n-6 PUFAs levels in plasma, liver and adipose tissue, with concomitant steep increase of oleic and mead acids, while in hypothalamus no changes in PUFA concentration were detected and only palmitoleic acid was found increased. We found a reduction of anandamide and palmitoylethanolamide in liver and brain, while oleoylethanolamide increased significantly in liver and adipose tissue, associated to a 50 % body weight decrease. Changes in N-acylethanolamide profile may contribute to body weight reduction distinctive of EFA deficiency.
Asunto(s)
Ácidos Araquidónicos/análisis , Endocannabinoides/análisis , Etanolaminas/análisis , Ácidos Grasos Esenciales/deficiencia , Ácidos Grasos/administración & dosificación , Ácidos Oléicos/análisis , Ácidos Palmíticos/análisis , Alcamidas Poliinsaturadas/análisis , Tejido Adiposo/química , Amidas , Animales , Peso Corporal/efectos de los fármacos , Química Encefálica , Ácidos Grasos Omega-3/sangre , Ácidos Grasos Omega-3/química , Ácidos Grasos Omega-6/sangre , Ácidos Grasos Omega-6/química , Hígado/química , Masculino , RatasRESUMEN
This study provides information about baseline mechanical properties of the entire muscle and the molecular contractile mechanism in human ureter smooth muscle and proposed to investigate if changes in mechanical motor performance in different regions of isolated human ureter are attributable to differences in myosin crossbridge interactions. Classic mechanical, contraction and energetic parameters derived from the tension-velocity relationship were studied in ureteral smooth muscle strips oriented longitudinally and circularly from abdominal and pelvic human ureter parts. By applying of Huxley's mathematical model we calculated the total working crossbridge number per mm(2) (Ψ), elementary force per single crossbridge (Π0), duration of maximum rate constant of crossbridge attachment 1/f1 and detachment 1/g2 and peak mechanical efficiency (Eff.max). Abdominal longitudinal smooth muscle strips exhibited significantly higher maximum isometric tension and faster maximum unloaded shortening velocity compared to pelvic ones. Contractile differences were associated with significantly higher crossbridge number per mm(2). Abdominal longitudinal muscle strips showed a lower duration of maximum rate constant of crossbridge attachment and detachment and higher peak mechanical efficiency than pelvic ones. Such data suggest that the abdominal human ureter showed better mechanical motor performance mainly related to a higher crossbridge number and crossbridge kinetics differences. Such results were more evident in the longitudinal rather than in the circular layer.
RESUMEN
BACKGROUND: Ureteral peristalsis is the result of coordinated mechanical motor performance of longitudinal and circular smooth muscle layer of the ureter wall. The main aim of this study was to characterize in smooth muscle of proximal segments of human ureter, the mechanical properties at level of muscle tissue and at level of myosin molecular motors. METHODS: Ureteral samples were collected from 15 patients, who underwent nephrectomy for renal cancer. Smooth muscle strips longitudinally and circularly oriented from proximal segments of human ureter were used for the in vitro experiments. Mechanical indices including the maximum unloaded shortening velocity (Vmax), and the maximum isometric tension (P0) normalized per cross-sectional area, were determined in vitro determined in electrically evoked contractions of longitudinal and circular smooth muscle strips. Myosin cross-bridge (CB) number per mm2 (Ψ) the elementary force per single CB (Ψ) and kinetic parameters were calculated in muscle strips, using Huxley's equations adapted to nonsarcomeric muscles. RESULTS: Longitudinal smooth muscle strips exhibited a significantly (p<0.05) faster Vmax (63%) and a higher P0 (40%), if compared to circular strips. Moreover, longitudinal muscle strips showed a significantly higher unitary force (Ψ) per CB. However, no significant differences were observed in CB number, the attachment (f1) and the detachment (g2) rate constants between longitudinal and circular muscle strips. CONCLUSIONS: The main result obtained in the present work documents that the mechanical, energetic and unitary forces per CB of longitudinal layer of proximal ureter are better compared to the circular one; these preliminary findings suggested, unlike intestinal smooth muscle, a major role of longitudinal smooth muscle layer in the ureter peristalsis.
Asunto(s)
Actomiosina/fisiología , Miosinas/fisiología , Peristaltismo/fisiología , Uréter/fisiología , Adulto , Fenómenos Biomecánicos , Estimulación Eléctrica , Femenino , Humanos , Técnicas In Vitro , Contracción Isométrica , Masculino , Persona de Mediana Edad , Músculo Liso/fisiologíaRESUMEN
Impaired functions of myocardial muscle cells in human and animals, is a primary defect associated with idiopathic dilated cardiomyopathy (DCM). The pathophysiological mechanisms implicated in the DCM are yet to be clarified and an effective therapy is still not available. The BIO TO-2 cardiomyopathic Syrian Hamsters (CMSHs) represent an animal model of idiopathic DCM. The aim of this study was to investigate the effect of long-term treatment (2 months) with propionyl-L-carnitine (PLC), coenzyme Q(10), omega-3 fatty acids and a combination of these three agents (formulation HS12607) on mechanical properties and acto-myosin crossbridges (CBs) kinetics of left ventricular (LV) papillary muscle from control and treated 10 month old BIO TO-2 CMSHs. Isometric and isotonic contractile properties of isolated papillary muscle from control and treated CMSHs were investigated, and acto-myosin CB number, force and kinetics were calculated using Huxley's equations. Mechanical parameter values were higher in treated than in control hamsters, particularly when substances were administered together in a coformulation (HS12607). Compared to control, HS12607-treated papillary muscles showed a significant increase of maximum peak isometric tension (P(o)) (30.06 +/- 4.91 vs. 19.74 +/- 5.00 mN/mm(2)), maximum extent of muscle shortening (0.13 +/- 0.03 vs. 0.07 +/- 0.02 L/L(max)), maximum unloaded shortening velocity (1.18 +/- 0.24 vs. 0.53 +/- 0.13 L/L(max) s(-1)) and maximum peak of power output (5.52 +/- 1.61 vs. 1.58 +/- 0.83). The curvature of the hyperbolic force-velocity relationships did not differ between control and treated hamsters. When compared to controls, acto-myosin CB number increased in treated hamsters [(6.67 +/- 1.91) 10(10)/mm(2) vs. (3.55 +/- 2.08) 10(10)/mm(2)], whereas the unitary force of single CB was similar in control and treated animals. The peak value of the rate constant for CB attachment (f(1)) and detachment (g(2)) was higher in treated animals when compared to control. (93.87 +/- 25.82 vs.47.28 +/- 10.88 s(-1) and 214.40 +/- 44.64 vs. 95.56 +/- 23.49 s(-1), respectively). In conclusion, the present study illustrates that supplementation with PLC, CoQ(10) and omega-3 fatty acids improved motor parameters, energetic, and CB kinetics of BIO TO-2 CMSH papillary muscle indicating that these naturally occurring substances may be a valid adjuvant to conventional therapy in DCM.
Asunto(s)
Cardiomiopatías/tratamiento farmacológico , Carnitina/análogos & derivados , Ácidos Grasos Omega-3/uso terapéutico , Músculos Papilares/efectos de los fármacos , Ubiquinona/análogos & derivados , Animales , Antiinflamatorios no Esteroideos/uso terapéutico , Carnitina/uso terapéutico , Cricetinae , Técnicas In Vitro , Masculino , Mesocricetus , Ubiquinona/uso terapéutico , Vitaminas/farmacologíaRESUMEN
The inability of heart muscle to generate ventricular pressure to adequately propel blood through the cardiovascular system is a primary defect associated with congestive heart failure (CHF). Force-frequency relationship (FFR) is one of the main cardiac defects associated with congestive heart failure. Thus FFR is a convenient methodological tool for evaluating the severity of muscle contractile dysfunction and the effectiveness of therapeutic agents. Papillary muscle isolated from BIO TO-2 cardiomyopathic Syrian hamsters (CMSHs), show a depressed FFR and represents an animal model of human idiopathic dilated cardiomyopathy. In the present study we investigated the effect of CoQ10, omega-3 fatty acids, propionyl-L-carnitine (PLC) and a combination of these 3 agents (formulation HS12607) on FFR in 8 month old BIO TO-2 CMSHs. Papillary muscles isolated from the anesthetized animals were placed in an incubation bath and attached to an isometric force transducer. A digital computer with an analog/digital interface allowed control of both muscle developed force and electrical stimulus parameters. Force-frequency response was evaluated, at Lmax, with increasing frequencies: 0.06, 0.12, 0.25, 0.5, 1, 2 and 4 Hz. HS12607-treatment produced a positive inotropic effect resulting in a significant enhancement (p < 0.05) of the peak force at the highest frequencies (1-4 Hz). In the range of frequency of 1-4 Hz also CoQ10 and omega-3 significantly (p < 0.05) attenuated the fractional decline in developed force. The significant improvement (p < 0.05) of the timing parameter peak rate of tension rise (+ T') and peak rate of tension fall (-T') indicating a faster rate of muscle contraction and relaxation respectively, found in CoQ10, omega-3 and PLC-treated CMSHs, may be due to the positive effects of these substances on sarcoplasmic reticulum functions. These findings suggest that naturally occurring CoQ10, omega-3 and PLC, particularly when administered together in a coformulation, might be a valid adjuvant to conventional therapy in dilated cardiomyopathy especially when considering that they are natural substances, devoid of side effects.
Asunto(s)
Carnitina/análogos & derivados , Ácidos Grasos Omega-3/farmacología , Contracción Miocárdica/efectos de los fármacos , Músculos Papilares/efectos de los fármacos , Ubiquinona/análogos & derivados , Animales , Cardiomiopatías/tratamiento farmacológico , Cardiomiopatías/fisiopatología , Cardiomiopatía Dilatada/tratamiento farmacológico , Cardiomiopatía Dilatada/fisiopatología , Carnitina/farmacología , Cricetinae , Masculino , Mesocricetus , Modelos Animales , Contracción Miocárdica/fisiología , Músculos Papilares/fisiología , Estimulación Química , Ubiquinona/farmacologíaRESUMEN
Trace amine-associated receptors, a novel class of G-protein coupled receptors which respond to trace amines but not to classical biogenic amines, have been found to be expressed in heart. Therefore, we investigated the cardiac effects of the trace amines p-tyramine, beta-phenylethylamine, octopamine, and tryptamine. Isolated rat hearts were perfused in the presence of trace amines, monitoring the hemodynamic variables. In addition, radioligand binding experiments with [3H]-p-tyramine and [125I]-3-iodothyronamine were performed in rat ventricular tissue. Octopamine, beta-phenylethylamine, and tryptamine produced a dose-dependent negative inotropic effect as shown by reduced cardiac output (IC(50)=109 microM, 159 microM, and 242 microM, respectively). In the same preparation a similar effect was produced by thyronamine and 3-iodothyronamine, with IC(50)=94 microM and 27 microM, respectively. The negative inotropic effect of octopamine was confirmed in a papillary muscle preparation. All trace amines except tryptamine increased the heart rate, but this action could be attributed to their sympathomimetic properties, since it was abolished by propranolol. The negative inotropic effect of trace amines was significantly increased by the tyrosine kinase inhibitor genistein. Specific and saturable binding of [(3)H]-p-tyramine and [125I]-3-iodothyronamine was observed in ventricular tissue. While [3H]-p-tyramine was displaced by 3-iodothyronamine, [(125)I]-3-iodothyronamine was not displaced by p-tyramine. In conclusion, trace amines and thyronamines are negative inotropic agents. Their effect appears to be mediated by a subtype of trace amine-associated receptor which is characterized by the rank of potency: 3-iodothyronamine > thyronamine = octopamine = beta-phenylethylamine, while tryptamine and p-tyramine are significantly less active.
Asunto(s)
Aminas Biogénicas/farmacología , Corazón/efectos de los fármacos , Receptores de Amina Biogénica/efectos de los fármacos , Receptores Acoplados a Proteínas G/metabolismo , Tironinas/farmacología , Antagonistas Adrenérgicos beta/farmacología , Animales , Aminas Biogénicas/antagonistas & inhibidores , Presión Sanguínea/efectos de los fármacos , Gasto Cardíaco/efectos de los fármacos , Circulación Coronaria/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Masculino , Miocardio/metabolismo , Músculos Papilares/efectos de los fármacos , Propranolol/farmacología , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Ratas , Ratas Wistar , Receptores Acoplados a Proteínas G/efectos de los fármacos , Simpatomiméticos/farmacología , Tiramina/metabolismoRESUMEN
Mechanisms underlying dilated cardiomyopathy (DCM) are poorly understood and effective therapy is still unavailable. The aim of this study was to examine the heart ultrastructure and dynamic of BIO T0-2 cardiomyopathic hamsters, an animal model of DCM, and to study in these animals, the effects of a co-formulation (HS12607) of propionyl-L-carnitine, coenzyme Q(10) and omega-3 fatty acids on cardiac mechanical parameters. Sarcomere length, Frank-Starling mechanism and force-frequency relations were studied on isolated ventricular papillary muscle from age-matched BIO F1B normal Syrian hamsters, BIO T0-2 control and BIO T0-2 HS12607-treated cardiomyopathic Syrian hamsters. At the optimum length to maximum active force, electron microscopy of left ventricular papillary muscle revealed that seven out of ten muscles studied showed shorter sarcomeres (1.20 +/- 0.29 microm), and the remaining three showed longer sarcomeres (2.80 +/- 0.13 microm), compared to those of normal hamsters (2.05 +/- 0.06 microm, n = 10). Severe alterations of the Frank-Starling mechanism, force-frequency relations and derivative parameters of contractile waves were also observed in vitro in the BIO T0-2 control hamsters. Long-term (8 weeks) treatment with HS12607 prevented alterations in sarcomere length in the BIO T0-2 cardiomyopathic hamsters; the Frank-Starling mechanism and force-frequency relations were also significantly (P < 0.05) improved in these hamsters. Therefore results of the present study strongly suggest the need for clinical studies on metabolic therapeutic intervention in the effort to stop the progression of dilated cardiomyopathy.
Asunto(s)
Cardiomiopatía Dilatada/tratamiento farmacológico , Carnitina/análogos & derivados , Ácidos Grasos Omega-3/uso terapéutico , Ubiquinona/análogos & derivados , Animales , Cardiomiopatía Dilatada/patología , Cardiomiopatía Dilatada/fisiopatología , Carnitina/uso terapéutico , Cricetinae , Modelos Animales de Enfermedad , Estimulación Eléctrica , Masculino , Mesocricetus , Contracción Miocárdica/efectos de los fármacos , Músculos Papilares/efectos de los fármacos , Sarcómeros/efectos de los fármacos , Sarcómeros/ultraestructura , Ubiquinona/uso terapéuticoRESUMEN
The compound N-piperidinyl-[8-chloro-1-(2,4-dichlorophenyl)-1,4,5,6-tetrahydrobenzo [6,7]cyclohepta[1,2-c]pyrazole-3-carboxamide] (NESS 0327) was synthesized and evaluated for binding affinity toward cannabinoid CB1 and CB2 receptor. NESS 0327 exhibited a stronger selectivity for CB1 receptor compared with N-piperidinyl-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (SR 141716A), showing a much higher affinity for CB1 receptor (Ki = 350 +/- 5 fM and 1.8 +/- 0.075 nM, respectively) and a higher affinity for the CB2 receptor (Ki = 21 +/- 0.5 nM and 514 +/- 30 nM, respectively). Affinity ratios demonstrated that NESS 0327 was more than 60,000-fold selective for the CB1 receptor, whereas SR 141716A only 285-fold. NESS 0327 alone did not produce concentration-dependent stimulation of guanosine 5'-O-(3-[35S]thio)-triphosphate ([35S]GTPgammaS) binding in rat cerebella membranes. Conversely, NESS 0327 antagonized [R(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrolol [1,2,3-de]-1,4-benzoxazin-yl]-(1-naphthalenyl)methanone mesylate] (WIN 55,212-2)-stimulated [35S]GTPgammaS binding. In functional assay, NESS 0327 antagonized the inhibitory effects of WIN 55,212-2 on electrically evoked contractions in mouse isolated vas deferens preparations with pA2 value of 12.46 +/- 0.23. In vivo studies indicated that NESS 0327 antagonized the antinociceptive effect produced by WIN 55,212-2 (2 mg/kg s.c.) in both tail-flick (ID50 = 0.042 +/- 0.01 mg/kg i.p.) and hot-plate test (ID50 = 0.018 +/- 0.006 mg/kg i.p.). These results indicated that NESS 0327 is a novel cannabinoid antagonist with high selectivity for the cannabinoid CB1 receptor.
Asunto(s)
Piperidinas/síntesis química , Pirazoles/síntesis química , Receptor Cannabinoide CB2 , Receptores de Droga/antagonistas & inhibidores , Animales , Unión Competitiva , Cannabinoides/química , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Masculino , Ratones , Piperidinas/química , Piperidinas/farmacología , Pirazoles/química , Pirazoles/farmacología , Receptores de Cannabinoides , Receptores de Droga/metabolismoRESUMEN
A coformulation of essential factors, i.e. propionyl-L-carnitine (PLC), coenzyme Q10 (CoQ10), nicotinamide (NAM), riboflavin and pantothenic acid, was administered orally to Wistar rats for 7 weeks and its efficacy was tested through in vivo and in vitro techniques in improving motor functions of striated, cardiac and smooth musculature of the rat. In vivo experiments showed that long-term supplementation significantly improved horizontal locomotor activity by about 19% in male and 26% in female rats. Maximum values of shortening velocity, work and power were significantly increased (P<.05) in papillary muscle isolated from treated rats. A positive inotropic effect was also observed on colonic smooth muscle strips upon treatment. Work was the most affected parameter and it increased by 160% in smooth muscle from treated animals. The present results indicate that supplementation with the combination of the above mentioned substances elicits positive functional changes on motor performance of skeletal, cardiac and smooth muscle of the rat.