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Cachexia, a devastating wasting syndrome characterized by severe weight loss with specific losses of muscle and adipose tissue, is driven by reduced food intake, increased energy expenditure, excess catabolism, and inflammation. Cachexia is associated with poor prognosis and high mortality and frequently occurs in patients with cancer, chronic kidney disease, infection, and many other illnesses. There is no effective treatment for this condition. Hypothalamic melanocortins have a potent and long-lasting inhibitory effect on feeding and anabolism, and pathophysiological processes increase melanocortin signaling tone, leading to anorexia, metabolic changes, and eventual cachexia. We used 3 rat models of anorexia and cachexia (LPS, methylcholanthrene sarcoma, and 5/6 subtotal nephrectomy) to evaluate efficacy of TCMCB07, a synthetic antagonist of the melanocortin-4 receptor. Our data show that peripheral treatment using TCMCB07 with intraperitoneal, subcutaneous, and oral administration increased food intake and body weight and preserved fat mass and lean mass during cachexia and LPS-induced anorexia. Furthermore, administration of TCMCB07 diminished hypothalamic inflammatory gene expression in cancer cachexia. These results suggest that peripheral TCMCB07 treatment effectively inhibits central melanocortin signaling and therefore stimulates appetite and enhances anabolism, indicating that TCMCB07 is a promising drug candidate for treating cachexia., Introduction Cachexia is a devastating and multifactorial wasting syndrome, consisting of anorexia, loss of adipose tissue and lean body mass, and a paradoxical increase in energy expenditure and catabolism that [...]

Effects of anesthetics on systemic hemodynamics in mice. Am J Physiol Heart Circ Physio1287: H1618-H1624, 2004. First published May 20, 2004; 10.1152/ajpheart.01192.2003.--The aim of this study was to compare the systemic hemodynamic effects of four commonly used anesthetic regimens in mice that were chronically instrumented for direct and continuous measurements of cardiac output (CO). Mice (CD-1. Swiss, and C57BL6 strains) were instrumented with a transit-time flow probe placed around the ascending aorta for CO measurement. An arterial catheter was inserted into the aorta 4 or 5 days later for blood pressure measurements. After full recovery, hemodynamic parameters including stroke volume, heart rate, CO, mean arterial pressure (MAP). and total peripheral resistance were measured with animals in the conscious state. General anesthesia was then induced in these mice using isoflurane (Iso), urethane, pentobarbital sodium, or ketamine-xylazine (K-X). The doses and routes of administration of these agents were given as required for general surgical procedures in these animals. Compared with the values obtained for animals in the conscious resting state, MAP and CO decreased during all anesthetic interventions, and hemodynamic effects were smallest for Iso (MAP, -24 [+ or -] 3%; CO, -5 [+ or -] 7%; n - 15 mice) and greatest for K-X (MAP, -51 [+ or -] 6%; CO, 37 [+ or -] 9%; n = 8 mice), respectively. The hemodynamic effects of K-X were fully antagonized by administration of the [[alpha].sub.2]-receptor antagonist atipamezole (n = 8 mice). These results indicate that the anesthetic Iso has fewer systemic hemodynamic effects in mice than the nonvolatile anesthetics. anesthesia; analgesia; buprenorphine; isoflurane; urethane; ketamine; xylazine: pentobarbital

A study was conducted on male mRen-2 transgenic rats to investigate the impact of salt loading on acute and chronic cardiovascular parameters and endocrine and body fluid electrolyte responses using a chronic blood pressure monitoring system. The findings provide further proof that central angiotensin systems are critical in the regulation of osmotic responsiveness and that the renin gene may be a candidate marker for salt-sensitive hypertension.

The anteroventral third ventricle (AV3V) is the main site of control for cardiovascular and fluid or metabolic functions in response to direct osmotic stimulation. An assessment of the secretion of plasma peptides such as vasopressin into the supraoptic nucleus following systemic and direct osmotic stimulation shows that the AV3V region is essential in the regulation of central peptide release into the posterior pituitary and the extracellular space of the hypothalamic supraoptic nuclei.

A study of the influence of chronic hypertonic NaCl consumption on the levels of oxytocin (OT) and vasopressin (VP) mRNAs in rats with anterior third ventricular region (AV3V) lesions reveals that the plasma levels of VP and OT are unaltered, while hypothalamic VP and OT mRNA levels enhance in response to the salt challenge. The elimination of the neuro-secretory response to chronic salt consumption and the retention of molecular endocrine response indicates the presence of distinct osmoreceptor mechanisms that regulate the effects of sodium on OT and VP neurons.

Studies on the osmotic stimulation of supraoptic nuclear reveal that the process may trigger central peripheral vasopressin release with the nucleus. The peripheral effects of vasopressin release and mean arterial pressure are due to sodium brain, and blood microanalysis may be useful for stimulating specific brain regions.

Cachexia, a devastating wasting syndrome characterized by severe weight loss with specific losses of muscle and adipose tissue, is driven by reduced food intake, increased energy expenditure, excess catabolism, and inflammation. Cachexia is associated with poor prognosis and high mortality and frequently occurs in patients with cancer, chronic kidney disease, infection, and many other illnesses. There is no effective treatment for this condition. Hypothalamic melanocortins have a potent and long-lasting inhibitory effect on feeding and anabolism, and pathophysiological processes increase melanocortin signaling tone, leading to anorexia, metabolic changes, and eventual cachexia. We used 3 rat models of anorexia and cachexia (LPS, methylcholanthrene sarcoma, and 5/6 subtotal nephrectomy) to evaluate efficacy of TCMCB07, a synthetic antagonist of the melanocortin-4 receptor. Our data show that peripheral treatment using TCMCB07 with intraperitoneal, subcutaneous, and oral administration increased food intake and body weight and preserved fat mass and lean mass during cachexia and LPS-induced anorexia. Furthermore, administration of TCMCB07 diminished hypothalamic inflammatory gene expression in cancer cachexia. These results suggest that peripheral TCMCB07 treatment effectively inhibits central melanocortin signaling and therefore stimulates appetite and enhances anabolism, indicating that TCMCB07 is a promising drug candidate for treating cachexia. [ABSTRACT FROM AUTHOR]

Owen, Medge D., Can B. Unal, Michael F. Callahan, Kavita Trivedi, Catherine York, and William R. Millington. Glycyl-glutamine inhibits the respiratory depression, but not the antinociception, produced by morphine. Am J Physiol Regulatory Integrative Comp Physiol 279: R1944-R1948, 2000.--Glycyl-glutamine (Gly-Gln; [Beta]-[endorphin.sub.30-31]) is an endogenous dipeptide that is synthesized through the posttranslational processing of [Beta]-endorphin in brain stem regions that control respiration and autonomic function. This study tested the hypothesis that Gly-Gln administration to conscious rats will prevent the respiratory depression caused by morphine without affecting morphine antinociception. Rats were administered Gly-Gln (1-100 nmol) or saline (10 [micro] l) intracerebroventricularly followed, 5 min later, by morphine (40 nmol icv). Arterial blood gases and pH were measured immediately before Gly-Gln and 30 min after morphine injection. Gly-Gln pretreatment inhibited morphine-induced hypercapnia, hypoxia, and acidosis significantly. The response was dose dependent and significant at Gly-Gln doses as low as 1 nmol. In contrast, Gly-Gln (1-300 nmol) had no effect on morphine-evoked antinociception in the paw withdrawal test. When given alone to otherwise untreated animals, Gly-Gln did not affect nociceptive latencies or blood gas values. These data indicate that GlyGln inhibits morphine-induced respiratory depression without compromising morphine antinociception. opioid; [Beta]-endorphin; proopiomelanocortin; dipeptide; respiratory depression

Oliverio, Michael I., Marielle Delnomdedieu, Christopher F. Best, Ping Li, Mariana Morris, Michael F. Callahan, G. Allan Johnson, Oliver Smithies, and Thomas M. Coffman. Abnormal water metabolism in mice lacking the type 1A receptor for ANG II. Am. J. Physiol. Renal Physiol. 278: F75-F82, 2000.--Mice lacking [AT.sub.1A] receptors for ANG II have a defect in urinary concentration manifested by an inability to increase urinary osmolality to levels seen in controls after thirsting. This defect results in extreme serum hypertonicity during water deprivation. In the basal state, plasma vasopressin levels are similar in wild-type controls and Agtr1a -/- mice. Plasma vasopressin levels increase normally in the [AT.sub.1A] receptor-deficient mice after 24 h of water deprivation, suggesting that the defect in urine concentration is intrinsic to the kidney. Using magnetic resonance microscopy, we find that the absence of [AT.sub.1A] receptors is associated with a modest reduction in the distance from the kidney surface to the tip of the papilla. However, this structural abnormality seems to play little role in the urinary concentrating defect in Agtr1a -/- mice since the impairment is largely reproduced in wild-type mice by treatment with an [AT.sup.1]-receptor antagonist. These studies demonstrate a critical role for the [AT.sup.1A] receptor in maintaining inner medullary structures in the kidney and in regulating renal water excretion. gene targeting; urinary concentration; magnetic resonance microscopy; papilla; vasopressin