Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Several dominant mutations at the murine agouti locus cause a syndrome of marked obesity and insulin resistance. We have recently reported that intracellular free Ca2+ concentration ([Ca2+]i) is elevated in viable yellow mice. Because [Ca2+]i has a key role in the pathogenesis of insulin resistance, obesity, and hypertension, the role of the purified agouti gene product in regulating [Ca2+]i was evaluated in a number of cell types. Purified murine agouti induced slow, sustained increases in [Ca2+]i in A7r5 vascular smooth muscle cells and 3T3-L1 adipocytes in a dose-dependent fashion. In L6 skeletal myocytes, agouti stimulated an increase in [Ca2+]i with an apparent concentration eliciting 50% of the maximal response (EC50) of 62 nM. This response was substantially inhibited by Ca2+ entry blockade with nitrendipine. To determine whether melanocortin receptors play a role in agouti regulation of [Ca2+]i, we examined the effect of melanocortin peptides and agouti in cells stably transfected with human melanocortin receptors. Human embryonic kidney cells (HEK-293 cells) transfected with either the human melanocortin 1 receptor (MC1R) or melanocortin 3 receptor responded to human agouti with slow, sustained increases in [Ca2+]i, whereas nontransfected HEK-293 cells with no melanocortin receptors did not respond to agouti. Dose-response curves in the MC1R line showed that agouti had an EC50 of 18 nM, which is comparable to that for agouti antagonism of (125)I-Nle,D-Phe-alpha-melanocyte-stimulating hormone binding in the same cell line. This direct effect of agouti on stimulating increases in [Ca2+]i suggests a potential mechanism for agouti-induced insulin resistance.
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PMID:Agouti regulation of intracellular calcium: role of melanocortin receptors. 912 42

This study examined control of cardiovascular and renal function during chronic melanocortin-3/4 receptor (MC3/4-R) activation or inhibition. Arterial and venous catheters were implanted in Sprague-Dawley rats for measurements of mean arterial pressure (MAP) and heart rate (HR) 24 h/d and for intravenous infusions, and the lateral ventricle was cannulated for chronic intracerebroventricular (ICV) infusions. In experiment 1, after a 5-day control period, rats were administered the MC3/4-R agonist MTII (n=7, 10 ng/h ICV) or 0.9% saline (n=6, ICV) for 14 days, followed by a 5-day recovery period. In experiment 2, after a 5-day control period, rats were administered the MC3/4-R antagonist SHU-9119 (n=7, 1 nmol/h ICV) or 0.9% saline vehicle (n=7, ICV), or pair-fed during SHU-9119 infusion (n=5, 1 nmol/h ICV) for 12 days, followed by a 5-day recovery period. MC4-R activation transiently decreased food intake from 23+/-1 to 10+/-2 g/d. Despite the hypophagia, MC3/4-R activation increased MAP by 7+/-1 mm Hg. MC3/4-R inhibition for 12 days increased food intake from 21+/-1 to 35+/-4 g/d, decreased HR by 53+/-11 bpm, and caused no change in MAP despite the marked weight gain. In rats that were pair-fed to prevent increased food intake, MC3/4-R inhibition further decreased HR (-87+/-9 bpm), whereas MAP was unchanged. Thus, chronic hypothalamic MC3/4-R activation raises arterial pressure despite decreased food intake, whereas MC3/4-R inhibition causes marked weight gain without raising arterial pressure. These observations are consistent with the hypothesis that an intact hypothalamic MC3/4-R may be necessary for excess weight gain to raise arterial pressure.
Hypertension 2003 Mar
PMID:Hypothalamic melanocortin receptors and chronic regulation of arterial pressure and renal function. 1262 94

The gamma-melanocyte-stimulating hormone (gamma-MSH) is a natriuretic peptide derived from the N-terminal region of proopiomelanocortin (POMC). Evidence suggests that it may be part of the coordinated response to a low-sodium diet (LSD). We tested the effect of the HSD (8% NaCl) compared with LSD (0.07%) on mean arterial pressure (MAP) in mice with targeted disruption of the PC2 gene (PC2(-/-)), necessary for processing of POMC into gamma-MSH, or the melanocortin receptor 3 gene (Mc3r(-/-); the receptor for MSH). In wild-type mice, HSD for 1 week did not alter MAP versus LSD mice, but plasma gamma-MSH immunoreactivity was more than double the LSD value. In contrast, in PC2(-/-) mice, MAP on the LSD was not greater than in wild-type mice, but plasma gamma-MSH was reduced to one-seventh the wild-type value. On the HSD, MAP rose to a markedly hypertensive level while plasma gamma-MSH concentration remained severely depressed. Intravenous infusion of gamma-MSH (0.2 pmol/min) for 30 min to PC2(-/-) mice after 1 week of HSD lowered MAP from hypertensive levels to normal; infusion of alpha-MSH at the same rate had no effect. Injection of 60 fmol of gamma-MSH into the lateral cerebral ventricle of hypertensive mice also lowered MAP to normal. Administration of a stable analogue of gamma-MSH intra-abdominally by microosmotic pump to PC2(-/-) mice prevented the development of hypertension when ingesting the HSD. In mice with targeted disruption of the Mc3r gene, the HSD also led to marked hypertension accompanied by elevated plasma levels of gamma-MSH; infusion of exogenous gamma-MSH to these mice had no effect on MAP. These results strongly suggest that PC2-dependent processing of POMC into gamma-MSH is necessary for the normal response to the HSD. gamma-MSH deficiency results in marked salt-sensitive hypertension that is rapidly improved with exogenous gamma-MSH through a central site of action. alpha-MSH infused at the same rate had no effect on MAP, indicating that the hypertension is a specific consequence of impaired POMC processing into gamma-MSH. Absence of Mc3r produces gamma-MSH resistance and hypertension on the HSD. These findings demonstrate a novel pathway mediating salt-sensitivity of blood pressure.
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PMID:Genetic disruption of gamma-melanocyte-stimulating hormone signaling leads to salt-sensitive hypertension in the mouse. 1269 27

Acute studies have shown that MC3/4-R stimulation increases sympathetic activity, but the role of adrenergic activation in mediating the cardiovascular and renal responses to chronic melanocortin 3- and 4-receptor (MC3/4-R) activation is unknown. The present study tested whether chronic MC3/4-R activation raises blood pressure and whether these changes are attenuated by alpha1+beta-adrenergic blockade. Rats were instrumented with an intracerebroventricular (ICV) cannula and arterial and venous catheters for measurements of mean arterial pressure (MAP) and heart rate (HR) 24 hours per day, and intravenous infusions. After control measurements, rats were intravenously infused with either saline vehicle (n=7) or alpha1+ beta-adrenergic antagonists (n=6, terazosin+propranolol, 10 mg/kg per day each) for 21 days. Five days after starting the vehicle or adrenergic blockade, the MC3/4-R agonist, MTII (10 ng/h), was infused ICV for 11 days followed by a 5-day recovery period. Another group of rats was infused with the adrenergic antagonists for 21 days but received the saline vehicle ICV for 11 days (n=7). MC3/4-R activation decreased food intake from 21+/-1 to 8+/-2 g/d by day 3 of MC3/4-R activation, and increased MAP and HR by an average of 8+/-2 mm Hg and 9+/-5 bpm, respectively. Adrenergic blockade did not alter the MC3/4-R-mediated decrease in food intake but abolished the increases in MAP and HR (1+/-2 mm Hg and -12+/-5 bpm, respectively, compared with control). ICV vehicle infusion during adrenergic blockade did not alter food intake or MAP. Glomerular filtration rate was unchanged in both the vehicle-infused and adrenergic blocked rats during MC3/4-R activation. These results indicate that the chronic actions of MC3/4-R activation on MAP and HR are mediated by adrenergic activation.
Hypertension 2004 Feb
PMID:Role of adrenergic activity in pressor responses to chronic melanocortin receptor activation. 1470 60

Alpha-, beta-, and gamma-melanocyte stimulating hormones (MSHs) are melanotropin peptides that are derived from the ACTH/beta-endorphin prohormone proopiomelanocortin (POMC). They have been highly conserved through evolutionary development, although their functions in mammals have remained obscure. The identification in the last decade of a family of five membrane-spanning melanocortin receptors (MC-Rs), for which the melanotropins are the natural ligands, has permitted the characterization of a number of important actions of these peptides, although the physiological function(s) of gamma-MSH have remained elusive. Much evidence indicates that gamma-MSH stimulates sympathetic outflow and raises blood pressure through a central mechanism. However, this review focuses on newer cardiovascular and renal actions of the peptide, acting in most cases through the MC3-R. In rodents, a high-sodium diet (HSD) increases the pituitary abundance of POMC mRNA and of gamma-MSH content and results in a doubling of plasma gamma-MSH concentration. The peptide is natriuretic and acts through renal MC3-Rs, which are also upregulated by the HSD. Thus the system appears designed to participate in the integrated response to dietary sodium excess. Genetic or pharmacologic induction of gamma-MSH deficiency results in marked salt-sensitive hypertension that is corrected by the administration of the peptide, probably through a central site of action. Deletion of the MC3-R also produces salt-sensitive hypertension, which, however, is not corrected by infusion of the hormone. These observations in aggregate suggest the operation of a hormonal system important in blood pressure control and in the regulation of sodium excretion. The relationship of these two actions to each other and the significance of this system in humans are important questions for future research.
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PMID:Gamma-MSH, sodium metabolism, and salt-sensitive hypertension. 1476 63

The melanocortin receptor (MCR) pathway has been identified as participating in several physiologically important pathways including pigmentation, energy homeostasis, inflammation, obesity, hypertension, and sexual function. All the endogenous MCR agonists contain a core His-Phe-Arg-Trp sequence identified as important for receptor molecular recognition and stimulation. Several structure-activity studies using the Ac-His-d-Phe-Arg-Trp-NH2 tetrapeptide template have been performed in the context of modifying N-terminal 'capping' groups and amino acid constituents. Herein, we report the synthesis and pharmacologic characterization of modified Xaa-d-Phe-Arg-Trp-NH2 (Xaa = His or Phe) melanocortin tetrapeptides (N-site selective methylation, permethylation, or amide bond reduction) at the mouse MC1, MC3, MC4 and MC5 receptors. The modified peptides generated in this study resulted in equipotent or reduced MCR potency when compared with control ligands. The reduced amide bond analog of the Phe-d-Phe-Arg-Trp-NH2 peptide converted its agonist activity into an antagonistic at the central mMC3 and mMC4 receptors involved in the regulation of energy homeostasis, while retaining full agonist activity at the peripheral MC1 and MC5 receptors.
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PMID:Synthesis and activity of the melanocortin Xaa-d-Phe-Arg-Trp-NH tetrapeptides with amide bond modifications. 1504 39

The present study examined whether blockade of melanocortin receptors subtypes 3 and 4 (MC3/4-R) inhibits chronic cardiovascular and dietary responses to leptin infusion. A cannula was placed in the lateral ventricle of male Sprague-Dawley rats for chronic intracerebroventricular (ICV) infusion via osmotic minipump, and arterial and venous catheters were implanted for measurement of mean arterial pressure (MAP) and heart rate (HR) 24 h/d and IV infusions. After a 5-day control period, rats received (1) 0.9% saline vehicle ICV for 12 days plus leptin (1 microg/kg per minute IV, n=5) during the final 7 days; (2) MC3/4-R antagonist SHU-9119 (1 nmol/h ICV) for 12 days plus leptin (1 microg/kg per minute IV, n=6) during the final 7 days; and (3) SHU-9119 (1 nmol/h ICV, n=8) for 12 days. Leptin infusion in vehicle-treated rats caused a small increase in MAP (5+/-1 mm Hg) despite reduced food intake (23+/-1 to 10+/-1 g/d) and decreased body weight (-6%+/-1%). SHU-9119 infusion completely prevented the cardiovascular and dietary actions of leptin, leading to increased food intake (23+/-1 to 49+/-4 g/d) and body weight (+30%+/-2%), markedly decreased HR (-77+/-9 bpm), and caused a decrease in MAP (-6+/-1 mm Hg). Similar results were observed when SHU-9119 was infused alone in vehicle-treated rats. Leptin decreased plasma insulin to 30% of control values, an effect that was also abolished by SHU-9119 treatment, which caused a 5-fold increase in plasma insulin concentration. Thus, MC3/4-R antagonism completely blocked the chronic cardiovascular, satiety, and metabolic effects of leptin, suggesting that the hypothalamic melanocortin system plays an important role in mediating these actions of leptin.
Hypertension 2004 Jun
PMID:Role of hypothalamic melanocortin 3/4-receptors in mediating chronic cardiovascular, renal, and metabolic actions of leptin. 1512 76

Genetic knockout and null mutations of melanocortin system components lead to phenotypes that recapitulate the metabolic syndrome such as obesity, hypertension and insulin resistance. Since stress is known to modify metabolic and cardiovascular function, we hypothesized the involvement of the neural melanocortin system in the stress response. Male rats were subjected to rapid-eye-movement sleep deprivation stress and the levels of proopiomelanocortin (POMC), MC3R, MC4R and MC5R transcripts in the hypothalamic-pituitary-adrenal axis (HPA) determined by real-time PCR. Increased levels of POMC transcripts were observed in the hypothalamus and adrenal gland tissues but there were no significant changes in the expression of the receptors genes. Whereas MC3R and MC5R are expressed in all HPA tissues, MC4R seems to be restricted mainly to the hypothalamus. It is possible that melanocortin receptors function in different aspects of the neuron. In vitro studies showed similar cellular distribution patterns for MC3R and MC4R and sequence analyses revealed strong conservation of the putative G-protein coupled receptors (GPCR) C-terminal membrane localization signal, EX(3-7)II/L motif, in MC3R, MC4R and MC5R. These data suggest that the physiological roles of neural melanocortin receptors, MC3R and MC4R, are likely determined by distinct tissue distribution patterns and suggest a role for hypothalamic and intra-adrenal melanocortin systems in the manifestation of stress related pathologies.
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PMID:Neural melanocortin receptors are differentially expressed and regulated by stress in rat hypothalamic-pituitary-adrenal axis. 1564 Nov 61

Previous studies suggest that blockade of melanocortin 3 and 4 receptors (MC3/4-R) markedly attenuates the chronic hypertensive effects of leptin. Although obesity has been reported to be associated with leptin "resistance," it is unclear whether obesity alters the cardiovascular and metabolic effects of chronic MC3/4-R activation. Therefore, we tested whether the cardiovascular and metabolic actions of MC3/4-R activation are attenuated in Sprague-Dawley rats fed a high-fat diet (HF, n=6) compared with rats fed a standard chow (NF, n=6) for 12 months. A 21G steel cannula was placed in the lateral ventricle for ICV infusion, and arterial and venous catheters were implanted for measurement of mean arterial pressure (MAP) 24 hours/day and IV infusions. After a 5-day control period, rats were infused with MC3/4-R agonist melanotan II (10 ng/h, ICV), for 10 days followed by a 5-day recovery period. HF rats were heavier (558+/-21 versus 485+/-13 g) with 140% more visceral fat than NF rats, hyperleptinemic (8.9+/-0.5 versus 2.7+/-0.5 ng/mL), and insulin resistant. HF rats also had higher MAP (109+/-3 versus 100+/-1 mm Hg). Chronic melanotan II infusion significantly increased MAP in HF and NF (7+/-2 and 6+/-1 mm Hg), decreased caloric intake (-32+/-2 and -25 +/-2 kcal/day), and reduced insulin levels in both groups by approximately 50%. Thus, the metabolic and cardiovascular actions of chronic MC3/4-R activation are preserved in diet-induced obesity, supporting a potential role for the hypothalamic melanocortin system in obesity hypertension.
Hypertension 2006 Feb
PMID:Does obesity induce resistance to the long-term cardiovascular and metabolic actions of melanocortin 3/4 receptor activation? 1638 May 16

Melanocortins play a central role in autonomic modulation of metabolism by acting through a family of highly homologous G protein-coupled receptors. Studies with gene knockout mice have implicated neural melanocortin receptors, MC3R and MC4R, in the etiology of obesity, insulin resistance, and salt-sensitive hypertension. In an attempt to better understand the mechanisms of function of these receptors, we expressed MC3R and MC4R in neuronal cells and demonstrated their co-localization to several membrane regions. We now show that in cultured neuronal cells, MC3R localizes to lipid rafts and undergoes endocytic internalization upon activation by gamma-MSH through a protein kinase-sensitive pathway. The appearance of the internalized receptor in lysosomes suggests that it is subsequently degraded. The expression of protein kinase A regulatory subunits and of c-Jun and c-Fos was analyzed by either immunoblotting or real-time PCR. No discernable changes were observed in the expression levels of these protein kinase A and protein kinase C responsive genes. Immunohistochemical studies showed a robust expression of MC3R protein in brain nuclei with relevance to cardiovascular function and fluid homeostasis further supporting the notion that the physiological effects of melanocortins on the cardiovascular system arise from effects on the central nervous system.
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PMID:Activation and endocytic internalization of melanocortin 3 receptor in neuronal cells. 1740 38


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