RESUMEN
The gut hormone cholecystokinin (CCK) acts at subdiaphragmatic vagal afferents to induce renal and splanchnic sympathoinhibition and vasodilatation, via reflex inhibition of a subclass of cardiovascular-controlling neurons in the rostroventrolateral medulla (RVLM). These sympathoinhibitory and vasodilator responses are blunted in obese, hypertensive rats and our aim in the present study was to determine whether this is attributable to (i) altered sensitivity of presympathetic vasomotor RVLM neurons, and (ii) aberrant peripheral or central signalling mechanisms. Using a diet-induced obesity model, male Sprague-Dawley rats exhibited either an obesity-prone (OP) or obesity-resistant (OR) phenotype when placed on a medium high fat diet for 13-15 weeks; control animals were placed on a low fat diet. OP animals had elevated resting arterial pressure compared to OR/control animals (P < 0.05). Barosensitivity of RVLM neurons was significantly attenuated in OP animals (P < 0.05), suggesting altered baroreflex gain. CCK induced inhibitory responses in RVLM neurons of OR/control animals but not OP animals. Subdiaphragmatic vagal nerve responsiveness to CCK and CCK1 receptor mRNA expression in nodose ganglia did not differ between the groups, but CCK induced significantly less Fos-like immunoreactivity in both the nucleus of the solitary tract and the caudal ventrolateral medulla of OP animals compared to controls (P < 0.05). These results suggest that blunted sympathoinhibitory and vasodilator responses in obesity-related hypertension are due to alterations in RVLM neuronal responses, resulting from aberrant central but not peripheral signalling mechanisms. In obesity, blunted sympathoinhibitory mechanisms may lead to increased regional vascular resistance and contribute to the development of hypertension.
Asunto(s)
Barorreflejo , Hipertensión/etiología , Bulbo Raquídeo/fisiopatología , Inhibición Neural , Obesidad/complicaciones , Transducción de Señal , Sistema Nervioso Simpático/fisiopatología , Animales , Presión Arterial , Colecistoquinina/farmacología , Modelos Animales de Enfermedad , Hipertensión/metabolismo , Hipertensión/fisiopatología , Masculino , Bulbo Raquídeo/efectos de los fármacos , Bulbo Raquídeo/metabolismo , Inhibición Neural/efectos de los fármacos , Ganglio Nudoso/metabolismo , Ganglio Nudoso/fisiopatología , Obesidad/metabolismo , Obesidad/fisiopatología , Proteínas Proto-Oncogénicas c-fos/metabolismo , Ratas Sprague-Dawley , Receptor de Colecistoquinina A/genética , Receptor de Colecistoquinina A/metabolismo , Sistema Nervioso Simpático/efectos de los fármacos , Sistema Nervioso Simpático/metabolismoRESUMEN
The gut and kidney command >50% of cardiac output postprandially, highlighting the importance of these vascular beds in cardiovascular homeostasis. The gastrointestinal peptide cholecystokinin (CCK) induces vagally mediated splanchnic sympathoinhibition that is attenuated in animals fed a medium high-fat diet (MHFD); therefore, our aim was to determine whether renal sympathetic nerve discharge (RSND) responses to CCK are also affected by this diet, and whether these changes are associated with obesity and hypertension. Another aim was to determine whether regional vasodilator responses to CCK are affected in obesity-related hypertension. In two separate studies, Sprague-Dawley rats were fed either a low-fat diet (LFD; control) or a MHFD for 13 weeks, after which MHFD animals were classified as obesity prone (OP) or obesity resistant (OR) based on their weight gain falling into the upper or lower tertile, respectively. Arterial pressure and heart rate were monitored in isoflurane-anaesthetized, artificially ventilated animals, and either RSND or regional vascular responses to CCK (0.1-8 µg kg(-1)) were evaluated. The OP rats had higher baseline arterial pressure compared with control/OR rats (P < 0.05). Administration of CCK inhibited RSND and increased renal vascular conductance in control/OR rats, and these responses were significantly blunted in OP rats (P < 0.05 for all). Baseline arterial pressure was positively correlated with weight gain and inversely correlated with CCK-induced vasodilatation (P < 0.05 for both). We hypothesize that in obesity-related hypertension, disruption of the sympathoinhibitory signals elicited by CCK reduces vasodilatation in the splanchnic/renal regions, leading to increased postprandial vascular resistance.
Asunto(s)
Colecistoquinina/farmacología , Hipertensión/fisiopatología , Riñón/inervación , Obesidad/complicaciones , Sistema Nervioso Simpático/fisiopatología , Animales , Presión Sanguínea/fisiología , Colecistoquinina/fisiología , Dieta con Restricción de Grasas , Dieta Alta en Grasa , Frecuencia Cardíaca , Hipertensión/etiología , Riñón/efectos de los fármacos , Riñón/fisiopatología , Masculino , Obesidad/fisiopatología , Ratas , Ratas Sprague-Dawley , Sistema Nervioso Simpático/efectos de los fármacos , Vasodilatación/efectos de los fármacosRESUMEN
Gastric leptin and cholecystokinin (CCK) act on vagal afferents to induce cardiovascular effects and reflex inhibition of splanchnic sympathetic nerve discharge (SSND) and may act cooperatively in these responses. We sought to determine whether these effects are altered in animals that developed obesity in response to a medium high-fat diet (MHFD). Male Sprague-Dawley rats were placed on a low-fat diet (LFD; n = 8) or a MHFD (n = 24) for 13 wk, after which the animals were anesthetized and artificially ventilated. Arterial pressure was monitored and blood was collected for the determination of plasma leptin and CCK. SSND responses to leptin (15 µg/kg) and CCK (2 µg/kg) administered close to the coeliac artery were evaluated. Collectively, MHFD animals had significantly higher plasma leptin but lower plasma CCK levels than LFD rats (P < 0.05), and this corresponded to attenuated or reversed SSND responses to CCK (LFD, -21 ± 2%; and MHFD, -12 ± 2%; P < 0.05) and leptin (LFD, -6 ± 2%; and MHFD, 4 ± 1%; P < 0.001). Alternatively, animals on the MHFD were stratified into obesity-prone (OP; n = 8) or obesity-resistant (OR; n = 8) groups according to their weight gain falling within the upper or lower tertile, respectively. OP rats had significantly higher resting arterial pressure, adiposity, and plasma leptin but lower plasma CCK compared with LFD rats (P < 0.05). The SSND responses to CCK or leptin were not significantly different between OP and OR animals. These results demonstrate that a high-fat diet is associated with blunted splanchnic sympathoinhibitory responses to gastric leptin and CCK and may impact on sympathetic vasomotor mechanisms involved in circulatory control.
Asunto(s)
Colecistoquinina/fisiología , Grasas de la Dieta/metabolismo , Leptina/fisiología , Nervios Esplácnicos/fisiología , Adiposidad/fisiología , Animales , Circulación Sanguínea/fisiología , Presión Sanguínea/fisiología , Colecistoquinina/sangre , Leptina/sangre , Masculino , Ratas , Ratas Sprague-Dawley/sangre , Aumento de Peso/fisiologíaRESUMEN
Androgen deprivation therapy (ADT) decreases muscle mass and function but no human studies have investigated the underlying genetic or cellular effects. We tested the hypothesis that ADT will lead to changes in skeletal muscle gene expression, which may explain the adverse muscle phenotype seen clinically. We conducted a prospective cohort study of 9 men with localised prostate cancer who underwent a vastus lateralis biopsy before and after 4 weeks of ADT. Next-generation RNA sequencing was performed and genes differentially expressed following ADT underwent gene ontology mining using Ingenuity Pathway Analysis. Differential expression of genes of interest was confirmed by quantitative PCR (Q-PCR) on gastrocnemius muscle of orchidectomised mice and sham controls (n=11/group). We found that in men, circulating total testosterone decreased from 16.5±4.3nmol/L at baseline to 0.4±0.15nmol/L post-ADT (p<0.001). RNA sequencing identified 19 differentially expressed genes post-ADT (all p<0.05 after adjusting for multiple testing). Gene ontology mining identified 8 genes to be of particular interest due to known roles in androgen-mediated signalling; ABCG1, ACTC1, ANKRD1, DMPK, THY1, DCLK1, CST3 were upregulated and SLC38A3 was downregulated post-ADT. Q-PCR in mouse gastrocnemius muscle confirmed that only one gene, Actc1 was concordantly upregulated (p<0.01) in orchidectomised mice compared with controls. In conclusion, given that ACTC1 upregulation is associated with improved muscle function in certain myopathies, we hypothesise that upregulation of ACTC1 may represent a compensatory response to ADT-induced muscle loss. Further studies will be required to evaluate the role and function of ACTC1.
Asunto(s)
Actinas/genética , Antagonistas de Andrógenos/farmacología , Antineoplásicos Hormonales/farmacología , Músculo Esquelético/metabolismo , Neoplasias de la Próstata/genética , Anciano , Antagonistas de Andrógenos/uso terapéutico , Animales , Antineoplásicos Hormonales/uso terapéutico , Expresión Génica/efectos de los fármacos , Humanos , Masculino , Ratones Endogámicos C57BL , Persona de Mediana Edad , Músculo Esquelético/anatomía & histología , Músculo Esquelético/efectos de los fármacos , Orquiectomía , Neoplasias de la Próstata/sangre , Neoplasias de la Próstata/tratamiento farmacológico , Testosterona/sangre , Regulación hacia ArribaRESUMEN
Although it is well established that exogenous androgens have anabolic effects on skeletal muscle mass in humans and mice, data from muscle-specific androgen receptor (AR) knockout (ARKO) mice indicate that myocytic expression of the AR is dispensable for hind-limb muscle mass accrual in males. To identify possible indirect actions of androgens via the AR in neurons to regulate muscle, we generated neuron-ARKO mice in which the dominant DNA binding-dependent actions of the AR are deleted in neurons of the cortex, forebrain, hypothalamus, and olfactory bulb. Serum testosterone and luteinizing hormone levels were elevated twofold in neuron-ARKO males compared with wild-type littermates due to disruption of negative feedback to the hypothalamic-pituitary-gonadal axis. Despite this increase in serum testosterone levels, which was expected to increase muscle mass, the mass of the mixed-fiber gastrocnemius (Gast) and the fast-twitch fiber extensor digitorum longus hind-limb muscles was decreased by 10% in neuron-ARKOs at 12 weeks of age, whereas muscle strength and fatigue of the Gast were unaffected. The mass of the soleus muscle, however, which consists of a high proportion of slow-twitch fibers, was unaffected in neuron-ARKOs, demonstrating a stimulatory action of androgens via the AR in neurons to increase the mass of fast-twitch hind-limb muscles. Furthermore, neuron-ARKOs displayed reductions in voluntary and involuntary physical activity by up to 60%. These data provide evidence for a role of androgens via the AR in neurons to positively regulate fast-twitch hind-limb muscle mass and physical activity in male mice.
Asunto(s)
Encéfalo/metabolismo , Actividad Motora/genética , Músculo Esquelético/anatomía & histología , Neuronas/metabolismo , Condicionamiento Físico Animal , Receptores Androgénicos/genética , Andrógenos , Animales , Western Blotting , Retroalimentación Fisiológica , Genotipo , Hormona Luteinizante/metabolismo , Masculino , Ratones , Ratones Noqueados , Fatiga Muscular/genética , Fibras Musculares Esqueléticas , Fuerza Muscular/genética , Tamaño de los Órganos/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Testosterona/metabolismoRESUMEN
Gastric leptin elicits its cardiovascular and splanchnic sympathoinhibitory responses via a vagal afferent mechanism, however the latter are blunted/abolished in animals fed a medium high fat diet (MHFD). In a diet-induced obesity model we sought to determine whether the renal sympathetic nerve discharge (RSND) and regional vasodilator responses to gastric leptin are also affected by diet and/or obesity. The diet induced obesity model was used in 2 separate studies. After 13 weeks on a MHFD the animals were classified as either obesity prone (OP) or obesity resistant (OR) depending on their weight gain. Control animals were fed a low fat diet for an equivalent period. Arterial pressure (AP) and heart rate (HR) were monitored in isoflurane-anaesthetised, artificially ventilated animals and RSND or regional vascular responses to leptin (15 µg/kg) administered close to the coeliac artery were evaluated. OP rats had higher baseline AP compared to control/OR rats (P<0.05). Close arterial leptin inhibited RSND in control animals but this response was abolished in OR and OP animals (P<0.01 for both). Leptin administration increased renal vascular conductance in control animals but this response was significantly attenuated only in OP animals (P<0.05). The vasodilator response in the superior mesenteric artery was not significantly different in any of the groups (P>0.05). Together these results suggest that, while the renal sympathoinhibitory responses to gastric leptin are affected by diet, the vasodilator responses to leptin in the renal vascular bed are only affected in OP animals. These changes may impact on cardiovascular homeostatic mechanisms in obesity.