Cardiovascular effects of melanocortins.

Melanocortins (MSH's) are three structurally related peptides derived from proopiomelanocortin. They regulate several physiologic functions including energy metabolism, appetite, and inflammation. Recent work in rodents has also identified important effects of MSH's, particularly γ-MSH, on sodium metabolism and blood pressure regulation. Normal rats and mice respond to a high sodium diet with an increase in the plasma concentration of γ-MSH, and remain normotensive, while those with genetic or pharmacologic γ-MSH deficiency become hypertensive on a high sodium diet. This hypertension is corrected by exogenous administration of the peptide. Mice lacking the γ-MSH receptor (the melanocortin 3 receptor, Mc3r) also become hypertensive on a high sodium diet but remain so when administered γ-MSH, and infusions of physiologic levels of the peptide stimulate urinary sodium excretion in normal rats and mice, but not in mice with deletion of Mc3r. The salt-sensitive hypertension in rodents with impaired γ-MSH signaling appears due to stimulation of noradrenergic activity, since plasma noradrenaline is increased and the hypertension is rapidly corrected with infusion of the α-adrenoceptor antagonist phentolamine. In contrast to the antihypertensive property of physiologic levels of γ-MSH, intravenous or intracerebroventricular injections of high levels of the peptide raise blood pressure. This occurs in mice lacking Mc3r, indicating an interaction with some other central receptor. Finally, the salt-sensitive hypertension in rodents with disruption of γ-MSH signaling is accompanied by insulin resistance, an observation which offers a new window into the study of the association of salt-sensitive hypertension with insulin resistance and type II diabetes.

Increased renal phosphodiesterase-5 activity mediates the blunted natriuretic response to a nitric oxide donor in the pregnant rat.

Pregnancy is characterized by plasma volume expansion and renal sodium retention with loss of natriuretic response to atrial natriuretic peptide due to increased medullary phosphodiesterase-5 (PDE5). Here, we determined whether natriuretic responses to nitric oxide (NO) are also blunted in pregnancy due to increased PDE5. Anesthetized 16-day pregnant and virgin rats were studied at baseline and during intrarenal infusion of the NO donor spermine NONOate (2.5 nmol/min), the PDE5 inhibitor sildenafil (SILD; 0.5 µg/min), or a combination. The right (noninfused) kidney served as a control. Intrarenal NONOate had no effect on mean arterial pressure (MAP); however, SILD reduced MAP in virgin rats, and the combination of NONOate+SILD reduced MAP in both virgin and pregnant rats. Neither NONOate nor SILD altered glomerular filtration rate. NONOate and SILD each stimulated sodium excretion (U(Na)V) and fractional excretion of sodium (FE(Na)) in virgin rats, but the combination did not result in an additional natriuretic response. However, NONOate infusion did not increase U(Na)V or FE(Na) in pregnant rats, but the natriuretic response to NONOate was restored with SILD, and SILD alone produced a natriuresis during pregnancy. Sodium nitroprusside (10(-4) mol/l)-stimulated cGMP accumulation from inner medullary collecting duct cells was blunted in cells from pregnant vs. virgin or postpartum rats and was restored by treatment with the PDE5 inhibitor DMPPO (10(-7) mol/l). Therefore, increased intrarenal PDE5 mediates the blunted natriuretic response to NO, and loss of responsiveness to the cGMP-dependent, natriuretic agents may contribute to volume expansion during pregnancy.

Evidence for a noradrenergic mechanism causing hypertension and abnormal glucose metabolism in rats with relative deficiency of gamma-melanocyte-stimulating hormone.

A close association between salt-sensitive hypertension and insulin resistance has been recognized for more than two decades, although the mechanism(s) underlying this relationship have not been elucidated. Recent data in mice with genetic disruption of the gamma-melanocyte-stimulating hormone (gamma-MSH) system suggest that this system plays a role in the pathophysiological relationship between hypertension and altered glucose metabolism during ingestion of a high-sodium diet (8% NaCl, HSD). We tested the hypothesis that these two consequences of interrupted gamma-MSH signalling were the result of sympathetic activation by studying rats treated with the dopaminergic agonist bromocriptine (5 mg kg(-1) i.p., daily for 1 week; Bromo) to cause relative gamma-MSH deficiency. Bromo-treated rats fed the HSD developed hypertension and also exhibited fasting hyperglycaemia (P < 0.005) and hyperinsulinaemia (P < 0.025). Furthermore, Bromo-treated rats on the HSD had impaired glucose tolerance and blunted insulin-mediated glucose disposal. Intravenous infusion of gamma(2)-MSH, or of the alpha-adrenergic receptor antagonist phentolamine, to Bromo-HSD rats lowered both mean arterial pressure (MAP) and blood glucose to normal after 15 min (P < 0.001 versus control), but had no effect in rats receiving vehicle and fed the HSD; gamma(2)-MSH infusion also reduced the elevated plasma noradrenaline to control levels in parallel with the reductions in MAP and blood glucose concentration. Infusion of hydralazine to Bromo-HSD rats lowered MAP but had only a trivial effect on blood glucose. We conclude that rats with relative gamma-MSH deficiency develop abnormal glucose metabolism, with features of insulin resistance, in association with hypertension when ingesting the HSD. Elevated plasma noradrenaline concentration in Bromo-HSD rats is normalized by gamma(2)-MSH infusion, suggesting that an adrenergic mechanism may link the salt-sensitive hypertension and the impaired glucose metabolism of relative gamma-MSH deficiency.

Tonicity-dependent induction of Sgk1 expression has a potential role in dehydration-induced natriuresis in rodents.

In various mammalian species, including humans, water restriction leads to an acute increase in urinary sodium excretion. This process, known as dehydration natriuresis, helps prevent further accentuation of hypernatremia and the accompanying rise in extracellular tonicity. Serum- and glucocorticoid-inducible kinase (Sgk1), which is expressed in the renal medulla, is regulated by extracellular tonicity. However, the mechanism of its regulation and the physiological role of hypertonicity-induced SGK1 gene expression remain unclear. Here, we identified a tonicity-responsive enhancer (TonE) upstream of the rat Sgk1 transcriptional start site. The transcription factor NFAT5 associated with TonE in a tonicity-dependent fashion in cultured rat renal medullary cells, and selective blockade of NFAT5 activity resulted in suppression of the osmotic induction of the Sgk1 promoter. In vivo, water restriction of rats or mice led to increased urine osmolality, increased Sgk1 expression, increased expression of the type A natriuretic peptide receptor (NPR-A), and dehydration natriuresis. In cultured rat renal medullary cells, siRNA-mediated Sgk1 knockdown blocked the osmotic induction of natriuretic peptide receptor 1 (Npr1) gene expression. Furthermore, Npr1-/- mice were resistant to dehydration natriuresis, which suggests that Sgk1-dependent activation of the NPR-A pathway may contribute to this response. Collectively, these findings define a specific mechanistic pathway for the osmotic regulation of Sgk1 gene expression and suggest that Sgk1 may play an important role in promoting the physiological response of the kidney to elevations in extracellular tonicity.

Abnormal glucose metabolism in hypertensive mice with genetically interrupted gamma-melanocyte stimulating hormone signaling fed a high-sodium diet.

BACKGROUND: Rodents with deficiency of or resistance to the proopiomelanocortin-derived peptide gamma-melanocyte stimulating hormone (gamma-MSH) develop marked salt-sensitive hypertension. We asked whether this hypertension was accompanied by abnormal glucose metabolism. METHODS: gamma-MSH-deficient Pc2(-/-) mice, and resistant Mc3r(-/-) mice were studied acutely for measurement of blood pressure and glucose and insulin concentrations after > or =1 week of a high-sodium diet (HSD; 8% NaCl) compared to a normal-sodium diet (NSD; 0.4% NaCl). Mc3r(-/-) also underwent glucose tolerance test (GTT) and insulin tolerance test. RESULTS: Both knockout strains were hypertensive and also exhibited fasting hyperglycemia and hyperinsulinemia on the HSD. Mc3r(-/-) mice on the HSD had impaired glucose tolerance and insulin-mediated glucose disposal compared to wild-type mice on either the HSD or the NSD, or to Mc3r(-/-) mice on the NSD. CONCLUSIONS: These results indicate an interaction of interrupted gamma-MSH signaling with the HSD to cause hypertension on the one hand and abnormal glucose metabolism, with the characteristics of insulin resistance, on the other. Further study of the nature of this interaction should provide new insight into the mechanisms by which salt-sensitive hypertension and insulin resistance are linked.

Prevention of salt-induced hypertension by an analog of gamma-melanocyte-stimulating hormone in the rat.

BACKGROUND: Rats with suppression of pituitary intermediate lobe (IL) function by treatment with the dopaminergic agonist bromocriptine develop salt-sensitive hypertension accompanied by a deficiency of gamma-melanocyte-stimulating hormone (gamma-MSH). METHODS: To study the time course, and establish the causal role, of gamma-MSH deficiency in the development of salt-sensitive hypertension, we instrumented 12 male Sprague-Dawley rats with radiotelemetry transmitters to record intraaortic mean arterial pressure (MAP). One week later, they were placed on a high-sodium diet (8% NaCl, HSD) and received daily intraperitoneal injections of bromocriptine (5 mg/kg). The rats were also implanted with micro-osmotic pumps to deliver either a stable analog of gamma-MSH ([Nle3, D-Phe6]-gamma-MSH, NDP-gamma-MSH) at 12 pmol/h or normal saline vehicle. RESULTS: In vehicle-treated rats on the HSD and receiving bromocriptine injections, MAP rose so that it was significantly greater than that in NDP-gamma-MSH-treated animals by Day 4, and reached a stable plateau of approximately 135 mm Hg between Days 7 and 14. After Day 14, bromocriptine injections were stopped, and MAP in vehicle-infused rats fell progressively despite continued ingestion of the HSD, so that by Day 18, MAP was no longer different from NDP-gamma-MSH-infused animals. The MAP in the latter group did not vary significantly from the control level of 101+/-4 mm Hg throughout the 21 days of the experiment. CONCLUSIONS: These results indicate that gamma-MSH deficiency is a consequence of the bromocriptine treatment responsible for the salt-sensitive hypertension, and these results also identify the time course during which this hypertension develops.

Cardiovascular and renal actions of melanocyte-stimulating hormone peptides.

PURPOSE OF REVIEW: Melanocyte stimulating hormones (MSHs, melanocortins) have important roles in feeding and energy metabolism and in inflammation. Recent observations have uncovered major functions for these peptides, particularly gamma-MSH, in cardiovascular regulation and sodium metabolism. RECENT FINDINGS: Both alpha- and gamma-MSH acutely elevate blood pressure and heart rate through central stimulation of sympathetic nervous outflow. This action of alpha-MSH is mediated by the melanocortin 4 receptor (MC4R), whereas sympathetic nervous stimulation by gamma-MSH does not involve its receptor MC3R but rather is likely due to activation of a sodium channel in the central nervous system. In contrast, gamma-MSH deficiency in rodents, or disruption of MC3R, leads to marked salt-sensitive hypertension, again through a central mechanism: a small dose of exogenous peptide delivered into the cerebroventricular system of mice with gamma-MSH deficiency restores blood pressure to normal. This salt-sensitive hypertension is accompanied by the development of insulin resistance; the mechanism linking these two consequences of a high-salt diet is not yet known but may involve activation of the sympathetic nervous system. SUMMARY: The study of MSH peptides in blood pressure regulation offers a new opportunity to gain insight into the mechanisms underlying salt sensitivity and its link to insulin resistance, and to new therapies.

Central receptors mediating the cardiovascular actions of melanocyte stimulating hormones.

OBJECTIVE: Alpha and gamma-melanocyte stimulating hormones (MSH) are peptides that possess potent hypertensinogenic actions when injected intravenously or intracerebroventricularly. We sought to define the central receptor(s) mediating these cardiovascular actions. METHODS: We gave bolus injections of synthetic alpha or gamma-MSH intravenously or intracerebroventricularly to anesthetized wild-type (Mc3r+/+, Mc4r+/+) mice and mice with targeted disruption of the gamma-MSH receptor (Mc3r-/-) or the melanocortin 4 receptor (Mc4r-/-). RESULTS: Gamma-MSH injected intravenously increased mean arterial pressure (MAP) and heart rate (HR) dose-dependently, with the effect being evident at 10 mol/kg; the maximum increase, at 10 mol/kg, was 38 mmHg in both strains from similar control MAP. Parallel increases in HR also occurred. Injection of the sodium channel blocker, benzamil, 4 microg/kg intracerebroventricularly, before intravenous gamma-MSH completely prevented the increases in MAP and HR in both strains. Injection of 2 x 10 mol/g body weight alpha-MSH intravenously had no effect on MAP or HR in Mc4r wild-type or -/- mice. However, the same dose given intracerebroventricularly to wild-type mice increased MAP from 76 +/- 4 to 95 +/- 5 mmHg at 10 min (P < 0.01) and HR from 416 +/- 15 to 480 +/- 15 beats/min (P < 0.01). In Mc4r-/- mice, the intracerebroventricular administration of the peptide did not alter these variables, in contrast to the results in wild-type mice. CONCLUSION: Both MSH peptides exert their hypertensinogenic effects through central sites of action, which probably reflect the activation of sympathetic outflow. The actions of intracerebroventricular alpha-MSH appear to be mediated via Mc4r, whereas those of gamma-MSH are independent of its receptor Mc3r, but reflect the activation of a sodium channel in the central nervous system. These results help to reconcile the hypertensive action of gamma-MSH injections with the hypertension observed in states of gamma-MSH deficiency.

Modulation by dietary sodium intake of melanocortin 3 receptor mRNA and protein abundance in the rat kidney.

Gamma-melanocyte stimulating hormone (gamma-MSH) is a circulating natriuretic peptide hormone derived from proopiomelanocortin (POMC); its concentration in plasma and pituitary POMC mRNA abundance, increase in rats ingesting a high-sodium diet (HSD, 8% NaCl) compared with a low-sodium diet (LSD, 0.07% NaCl). RT-PCR of rat kidney RNA demonstrated reaction products of the expected size in both cortex and medulla for MC3-R, MC4-R, and MC5-R mRNA; no signal for MC1-R or MC2-R was detected. Relative to beta-actin or cyclophilin, abundance of the three receptor transcripts after 1 wk of the LSD was approximately equal in both cortex and medulla. After 1 wk of the HSD, mRNA abundance of MC4-R and MC5-R was unchanged, whereas that of MC3-R in medulla more than doubled, the ratio of MC3-R/beta-actin signal increasing from 0.38 +/- 0.04 on LSD to 0.84 +/- 0.04 on HSD (P < 0.001). No significant increase occurred in the cortex. The increase in MC3-R expression induced by dietary sodium was observed in inner medullary collecting duct (IMCD) cells isolated from the kidneys of HSD rats, suggesting that these cells were the major site of receptor expression in the medulla. Immunoblots of whole medullary and IMCD cell homogenates detected MC3-R immunoreactive protein; its expression was twice as great in samples from HSD vs. LSD rat kidneys, paralleling the increase in MC3-R mRNA abundance on the HSD. No changes in MC4-R or MC5-R protein expression were observed. Incubation of IMCD cell suspensions with increasing concentrations of gamma2-MSH led to increased cAMP accumulation, with values from rats on the HSD being roughly double the values from LSD rats. Intrarenal infusion of gamma2-MSH (500 fmol/min) increased sodium and cAMP excretion from the infused but not contralateral kidney of HSD rats, while having no effect in LSD rats. These data show that MC3-R is expressed in rat IMCD cells in a manner modulated by dietary sodium intake. Because MC3-R is the receptor with which gamma-MSH interacts, our findings suggest the existence of a sodium-regulating system, activated in response to a HSD, which increases urinary sodium excretion to balance the high-sodium intake.

1,25 dihydroxyvitamin d amplifies type a natriuretic peptide receptor expression and activity in target cells.

1,25 dihydroxyvitamin D (VD) has been shown to exert a number of beneficial effects on cardiovascular function, including reduction in BP and inhibition of cardiac hypertrophy. In an effort to identify a possible mechanistic link between VD and these salutary effects, the role of VD in controlling the activity and expression of the type A natriuretic peptide receptor (NPR-A), a receptor that signals reductions in BP and suppression of cellular growth in the myocardium and vascular wall, was investigated. VD, as well as the nonhypercalcemic analogue RO-25-6760, increased NPR-A-dependent cyclic guanosine monophosphate production and NPR-A gene expression in cultured rat aortic smooth muscle cells. The increase in NPR-A expression was associated with an increase in NPR-A gene promoter activity that was critically dependent on the presence of a functional VD receptor response element located approximately 495 bp upstream from the transcription start site of the gene. This element was associated with the VD receptor/retinoid X receptor complex in vitro. Mutation of this element resulted in complete elimination of the VD-dependent induction of the NPR-A gene promoter but did not affect osmotic stimulation of the promoter. Treatment of rats with RO-25-6760 for 7 d increased the atrial natriuretic peptide-dependent excretion of sodium and cyclic guanosine monophosphate without affecting mean arterial BP or plasma calcium levels. This was associated with a twofold increase in NPR-A mRNA levels in the inner medulla. Amplification of NPR-A activity represents a plausible mechanism to account for at least some of the beneficial effects that VD exerts on cardiovascular function.

Appetite and inflammation, nutrition, anemia, and clinical outcome in hemodialysis patients.

BACKGROUND: Malnutrition-inflammation complex syndrome, an outcome predictor in maintenance hemodialysis (MHD) patients, may be related to anorexia. OBJECTIVES: We examined whether subjectively reported appetite is associated with adverse conditions and increased morbidity and mortality in MHD patients. DESIGN: A cohort of 331 MHD outpatients was asked to rate their recent appetite status on a scale from 1 to 4 (very good, good, fair, and poor appetite, respectively). Anemia indexes and nutritional and inflammatory markers-including serum concentrations of C-reactive protein, tumor necrosis factor alpha, and interleukin 6-were measured. The malnutrition-inflammation score was used to evaluate the malnutrition-inflammation complex syndrome, and the SF36 questionnaire was used to assess quality of life (QoL). Mortality and hospitalization were followed prospectively for up to 12 mo. RESULTS: Patients were aged 54.5 +/- 14.4 y. Diminished appetite (fair to poor) was reported by 124 patients (38%). Hemoglobin, protein intake, and QoL scores were progressively lower, whereas markers of inflammation, malnutrition-inflammation scores, and the required erythropoietin dose were higher across the worsening categories of appetite. The adjusted odds ratios of diminished versus normal appetite for increased serum tumor necrosis factor alpha and C-reactive protein concentrations were significant. Significant associations between a poor appetite and an increased rate of hospitalization and mortality were observed. The hazard ratio of death for diminished appetite was 4.74 (95% CI: 1.85, 12.16; P = 0.001). CONCLUSION: Diminished appetite (anorexia) is associated with higher concentrations of proinflammatory cytokines and higher levels of erythropoietin hyporesponsiveness and poor clinical outcome, including a 4-fold increase in mortality, greater hospitalization rates, and a poor QoL in MHD patients. Appetite status may yield significant insight into the clinical status of dialysis patients.

Comparing outcome predictability of markers of malnutrition-inflammation complex syndrome in haemodialysis patients.

BACKGROUND: Markers of malnutrition-inflammation complex syndrome (MICS) are reported to predict mortality and hospitalization in maintenance haemodialysis (MHD) patients. However, it is not clear which one is a more sensitive and stronger predictor of outcome. METHODS: We examined the utility of 10 markers of MICS as predictors of prospective mortality and hospitalization, which included malnutrition-inflammation score (MIS), a fully quantitative score adopted from subjective global assessment, and serum levels of C-reactive protein (CRP), interleukin-6 (IL-6), tumour necrosis factor-alpha (TNF-alpha), albumin, pre-albumin, total iron binding capacity, creatinine, total cholesterol and normalized protein nitrogen appearance. A cohort of 378 MHD patients, who were randomly selected from eight DaVita dialysis facilities in the South Bay Los Angeles area, was studied. RESULTS: Patients, aged 54.5+/-14.7 years, included 53% men, 47% Hispanics, 30% African-Americans and 55% diabetics, who had undergone MHD for 37+/-34 months. Over a 12-month follow-up, 39 patients died and 208 were hospitalized at least once. Multivariate Cox and Poisson models that included 11 covariates [gender, age, race, ethnicity, diabetes, dialysis vintage, Charlson co-morbidity index (CCI), insurance status, Kt/V, body mass index and history of cardiovascular disease] were explored for the highest quartiles of inflammatory markers or the lowest quartiles of nutritional markers. The magnitude of relative risk of death and hospitalization was greatest for MIS, CRP and IL-6. In extended multivariate models that included all 10 MICS markers and 11 additional covariates simultaneously, CRP, MIS and CCI were the only consistent predictors of mortality and hospitalization, and their outcome predictabilities were superior to serum albumin. CONCLUSIONS: The MIS appears to be a useful, short-term tool to risk-stratify MHD patients and may circumvent the need for measuring inflammatory markers such as CRP or IL-6.

Increased activity of cGMP-specific phosphodiesterase (PDE5) contributes to resistance to atrial natriuretic peptide natriuresis in the pregnant rat.

Increased cGMP-specific phosphodiesterase (PDE5) activity in renal inner medullary collecting duct (IMCD) cells contributes to resistance to atrial natriuretic peptide (ANP) and the excessive sodium retention seen in experimental nephrotic syndrome and liver cirrhosis. Normal pregnancy is also accompanied by sodium retention and plasma volume expansion, and pregnant rats are resistant to the natriuretic action of ANP. The authors investigated a possible role of increased renal PDE5 activity in the physiologic sodium retention of normal rat pregnancy. The natriuresis and increased urinary cGMP excretion (U(cGMP)V) evoked by acute volume expansion (a measure of renal responsiveness to endogeneous ANP) was blunted in 16-d pregnant versus virgin rats, despite equivalent increases in circulating ANP in pregnants and virgins. The ANP-dependent cGMP accumulation in isolated IMCD cells from pregnants was blunted versus virgins and restored by the PDE5-selective antagonist DMPPO (10(-7) mol/L). PDE5 activity in vitro and PDE5 protein abundance in IMCD were greater in pregnants. Four days postpartum, volume expansion natriuresis, U(cGMP)V, and PDE5 protein levels in IMCD cell homogenates had returned to virgin values. These results demonstrate that normal rat pregnancy leads to in vivo and in vitro renal resistance to ANP, in association with heightened activity of the cGMP-specific PDE5 in IMCD. This may contribute to the physiologic sodium retention of normal pregnancy.

Gamma-MSH, sodium metabolism, and salt-sensitive hypertension.

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.

A low, rather than a high, total plasma homocysteine is an indicator of poor outcome in hemodialysis patients.

An increased level of total plasma homocysteine (tHcy) is a risk factor for poor cardiovascular outcome in the general population. However, a decreased, rather than an increased, tHcy concentration may predict poor outcome in maintenance hemodialysis (MHD) patients, a phenomenon referred to as reverse epidemiology. Associations were examined between tHcy level and markers of malnutrition-inflammation complex syndrome and 12-mo prospective hospitalization and mortality in 367 MHD patients, aged 54.5 +/- 14.7 (mean +/- SD) years, who included 199 men and 55% individuals with diabetes. tHcy was 24.4 +/- 11.8 micro mol/L, and 94% of the patients had hyperhomocysteinemia (tHcy >13.5 micro mol/L). tHcy had weak to moderate but statistically significant bivariate and multivariate correlations with some laboratory markers of nutrition (serum albumin, prealbumin, creatinine, and urea nitrogen) but no significant correlation with serum C-reactive protein or two proinflammatory cytokines (IL-6 and TNF-alpha). During 12 mo of follow-up, 191 MHD patients were hospitalized, 37 died, nine underwent renal transplantation, and 38 transferred out. Hospitalization rates were significantly higher in patients with lower tHcy levels. Mortality rate in the lowest tHcy quartile (17.4%) was significantly higher compared with other three quartiles (6.5 to 9.8%; Kaplan-Meier P = 0.04). Relative risk of death for the lowest tHcy quartile, even after adjustment for case-mix and serum albumin, was 2.27 (95% confidence interval, 1.14 to 4.53; P = 0.02). Hence, tHcy may be a more exclusive nutritional marker in MHD patients with no association with inflammatory measures. Despite a very high prevalence of hyperhomocysteinemia in MHD patients, lower values of tHcy are paradoxically associated with increased hospitalization and mortality. The lowest tHcy quartile confers a twofold increase in risk of death independent of hypoalbuminemia. The nutritional feature of tHcy in MHD patients may explain its reverse association with outcome.

Association between serum ferritin and measures of inflammation, nutrition and iron in haemodialysis patients.

BACKGROUND: Serum ferritin is a frequently used marker of iron status in dialysis patients. Iron administration is to be withheld for ferritin values >800 ng/ml according to K/DOQI guidelines. We hypothesized that such non-iron-related factors as elements of the malnutrition-inflammation complex syndrome (MICS) may increase serum ferritin concentration independently of iron status. METHODS: We studied 82 prevalent maintenance haemodialysis (MHD) patients (including 43 men), aged 55.7 +/- 15.3 years. The inflammatory and nutritional status was evaluated by serum C-reactive protein (CRP), Subjective Global Assessment (SGA) and its newer, fully quantitative versions, i.e. Dialysis Malnutrition Score (DMS) and Malnutrition-Inflammation Score (MIS). RESULTS: All but six patients had been on maintenance doses of intravenous iron dextran (between 100 and 200 mg/month) during the 10 weeks prior to the measurements. Serum ferritin levels were increased across SGA categories: (ANOVA P-value 0.03). Both unadjusted and multivariate adjusted correlation coefficients (r) for serum ferritin and CRP vs pertinent values were statistically significant for DMS and MIS and some other measures of nutritional status and iron indices. After deleting 10 MHD patients with either iron deficiency (ferritin <200 ng/ml) or iron overload (ferritin >2000 ng/ml), in the remaining 72 MHD patients both bivariate and multivariate correlations were much stronger and statistically significant (r = -0.33 and -0.29, respectively, P < 0.01). A multivariate model showed simultaneous, significant correlations between serum ferritin and both markers of inflammation and iron status independent of each other. After dividing the 72 MHD patients into two groups of serum ferritin based on a K/DOQI recommended serum ferritin cut-off of 800 ng/ml, the MIS and logarithm of serum CRP were significantly higher in the higher ferritin group. CONCLUSIONS: Serum ferritin values in the range of 200-2000 ng/ml may be increased due to non-iron-related factors including elements of MICS.

Suppression of gamma-melanocyte-stimulating hormone secretion is accompanied by salt-sensitive hypertension in the rat.

Gamma-melanocyte-stimulating hormone (gamma-MSH) is a natriuretic peptide derived from proopiomelanocortin (POMC) in the pituitary neurointermediate lobe (NIL); its plasma concentration in rats doubles after ingestion of a high (HSD; 8% NaCl) compared with a low sodium diet (LSD; 0.07%). Because NIL function is regulated through dopaminergic pathways, we asked whether dopaminergic stimulation with bromocriptine (5 mg/kg IP daily for 1 week) or inhibition with haloperidol (5 mg/kg IP for 1 week) alters the gamma-MSH response to a HSD. In vehicle-treated rats, plasma gamma-MSH and NIL gamma-MSH content on the HSD were both markedly elevated over values in rats on the LSD (P<0.001); no difference in mean arterial pressure (MAP) occurred. In haloperidol-treated rats on the LSD, both plasma gamma-MSH and NIL gamma-MSH content were greater than in vehicle-treated rats (P<0.05) and did not increase further on the HSD; MAP was also no different. In bromocriptine-treated rats, neither plasma gamma-MSH nor NIL gamma-MSH content increased on the HSD versus LSD, and MAP was markedly elevated on the HSD (132+/-3 versus 106+/-3 mm Hg, P<0.001). Intravenous infusion of gamma-MSH (0.4 pmol/min) to bromocriptine-treated rats on the HSD restored plasma gamma-MSH concentration to a level appropriate for the HSD and lowered MAP from 131+/-6 to 108+/-5 mm Hg (P<0.01). These results demonstrate that the increases in NIL content and plasma concentration of gamma-MSH normally occurring during ingestion of the HSD are prevented by dopaminergic suppression of NIL function. This results in deficiency of gamma-MSH on the HSD and is accompanied by elevated blood pressure, which is corrected by infusion of the peptide. gamma-MSH may be an important component in the normal response to a HSD; interruption of this response leads to salt-sensitive hypertension.

Genetic disruption of gamma-melanocyte-stimulating hormone signaling leads to salt-sensitive hypertension in the mouse.

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.