RESUMO
UNLABELLED: Melanocortin receptors (MC3/4R) mediate most of the metabolic and cardiovascular actions of leptin. AIM: Here, we tested if MC4R also contributes to leptin's effects on respiratory function. METHODS: After control measurements, male Holtzman rats received daily microinjections of leptin, SHU9119 (MC3/4R antagonist) or SHU9119 combined with leptin infused into the brain lateral ventricle for 7 days. On the 6th day of treatment, tidal volume (VT ), respiratory frequency (fR ) and pulmonary ventilation (VE ) were measured by whole-body plethysmography during normocapnia or hypercapnia (7% CO2 ). Baseline mean arterial pressure (MAP), heart rate (HR) and metabolic rate were also measured. VE , VT and fR were also measured in mice with leptin receptor deletion in the entire central nervous system (LepR/Nestin-cre) or only in proopiomelanocortin neurones (LepR/POMC-cre) and in MC4R knockout (MC4R(-/-) ) and wild-type mice. RESULTS: Leptin (5 µg day(-1) ) reduced body weight (~17%) and increased ventilatory response to hypercapnia, whereas SHU9119 (0.6 nmol day(-1) ) increased body weight (~18%) and reduced ventilatory responses compared with control-PBS group (Lep: 2119 ± 90 mL min(-1) kg(-1) and SHU9119: 997 ± 67 mL min(-1) kg(-1) , vs. PBS: 1379 ± 91 mL min(-1) kg(-1) ). MAP increased after leptin treatment (130 ± 2 mmHg) compared to PBS (106 ± 3 mmHg) or SHU9119 alone (109 ± 3 mmHg). SHU9119 prevented the effects of leptin on body weight, MAP (102 ± 3 mmHg) and ventilatory response to hypercapnia (1391 ± 137 mL min(-1) kg(-1) ). The ventilatory response to hypercapnia was attenuated in the LepR/Nestin-cre, LepR/POMC-cre and MC4R(-/-) mice. CONCLUSION: These results suggest that central MC4R mediate the effects of leptin on respiratory response to hypercapnia.
Assuntos
Leptina/farmacologia , Melanocortinas/metabolismo , Hormônios Estimuladores de Melanócitos/farmacologia , Receptor Tipo 3 de Melanocortina/metabolismo , Receptor Tipo 4 de Melanocortina/metabolismo , Fenômenos Fisiológicos Respiratórios/efeitos dos fármacos , Animais , Peso Corporal/efeitos dos fármacos , Dióxido de Carbono/sangue , Regulação da Expressão Gênica , Hipercapnia/induzido quimicamente , Leptina/administração & dosagem , Masculino , Hormônios Estimuladores de Melanócitos/administração & dosagem , Camundongos , Camundongos Knockout , Ratos , Ratos Sprague-Dawley , Receptor Tipo 3 de Melanocortina/genética , Receptor Tipo 4 de Melanocortina/genéticaRESUMO
Alpha-melanocyte-stimulating hormone (alpha-MSH) is a neuroimmunomodulatory peptide that is involved in the control of host responses trough modulation of production and action of proinflammatory cytokines in inflammatory cells in the periphery and within the central nervous system (CNS). However, little is known about the receptors that mediate the modulatory effects of alpha-MSH in the CNS. The objective of the present study was to establish the specific melanocortin receptors involved in the inhibition by MSH peptides of IL-1beta-induced activation of the HPA. i.c.v. injection of 12.5 ng of IL-1beta caused significant changes in plasma corticosterone, as compared to basal levels. The treatment with gamma-MSH (1 microg), an MC3 receptor agonist, resulted in significant reduction of the IL-1beta-induced plasma corticosterone levels. Administration of the MC3/MC4 receptor antagonist SHU9119 blocked this effect. Besides, treatment with a high dose of alpha-MSH (1 microg) increased plasma corticosterone. When alpha-MSH was given at a lower dose (0.1 microg), it did not modify corticosterone levels but caused an inhibitory effect on the corticosterone release induced by IL-1beta. The administration of SHU9119 or a more selective MC4 receptor antagonist like HS014 blocked the effects of alpha-MSH. In conclusion, our results suggest that both alpha-MSH and gamma-MSH are capable of inhibiting the effect of the IL-1beta on the activation of HPA axis acting at the CNS, and that this effect is mediated by specific central melanocortin receptors.
Assuntos
Corticosterona/sangue , Hipotálamo/metabolismo , Interleucina-1/administração & dosagem , Hipófise/metabolismo , Receptor Tipo 3 de Melanocortina/agonistas , Receptor Tipo 4 de Melanocortina/agonistas , Glândula Tireoide/metabolismo , alfa-MSH/administração & dosagem , gama-MSH/administração & dosagem , Animais , Masculino , Hormônios Estimuladores de Melanócitos/administração & dosagem , Peptídeos Cíclicos/administração & dosagem , Ratos , Ratos Wistar , Receptor Tipo 3 de Melanocortina/antagonistas & inibidores , Receptor Tipo 4 de Melanocortina/antagonistas & inibidoresRESUMO
The aim of the present study was to determine the effect of alpha-MSH on serum LH in order to obtain some clues about the possible, mechanism by which the peptide modifies gonadotropin secretion. Intact female rats treated with alpha-MSH on diestrus 2 afternoon exhibited an increase in serum LH levels at 18 hr on proestrus and an elevated number of ova per rat the day of estrus when compared with saline-treated controls. Moreover, the peptide administered in chronically ovariectomized (CHR-OVX) rats treated with estradiol benzoate (EB) plus low doses of progesterone (P), increased LH in serum as well as P serum levels when compared with levels in CHR-OVX animals treated with EB plus P and saline solution instead of alpha-MSH. It has been shown that LH release is blocked by OVX and adrenalectomy (ADX) on the afternoon of proestrus; this blockade was reversed by an injection of alpha-MSH at the time of the operation. Measurements of P in ADX-OVX animals treated with alpha-MSH showed that P serum levels were maintained for longer periods of time when compared with the P serum levels of ADX-OVX animals treated with saline. On the other hand, alpha-MSH infused into CHR-OVX rats treated with low doses of EB, which can lower serum LH levels, lowered the serum LH even more, although the serum P levels were increased. Finally alpha-MSH did not affect the serum LH levels in diestrous rats. The present results demonstrated that alpha-MSH influences the release of LH by modifying the release and/or the degradation of P. This P, in turn, modifies LH serum concentrations, having either a stimulatory or inhibiting effect on the release of LH, apparently depending on the time period it remains high in serum.