Phe(2)-nle(4)-acth(1-24)

Objective: The authors investigated the effects of ACTH-(1-24) and a high-viscosity solution in the restoration of microvascular function during resuscitation. They injected NG-monomethyl-L-arginine (L-NMMA) and superoxide dismutase (SOD) before ACTH-(1-24) in hamsters resuscitated with the hyperviscous solution to determine the role of ROS and NO in ACTH-(1-24) protective mechanism in the cheek pouch. Hemorrhagic shock (HS) was induced by withdrawing blood to reduce mean arterial pressure (MAP) to 30 mm Hg for 45 min. Methods: Animals were injected with ACTH-(1-24) and resuscitated with dextran of low molecular weight (70 kDa) and a small amount (4%) of dextran of high molecular weight (500 kDa) plus ACTH-(1-24), or autologous (shed) blood withdrawn during HS. Microvascular effects were characterized by measuring blood flow, perfused capillary length (PCL), arteriolar diameter, and red blood cell (RBC) velocity. ROS were assayed at the beginning and after 45 min of HS and after 10 and 90 min of resuscitation. Results: Resuscitation with either shed blood or dextrans 70/500 resulted in the restoration of MAP, whereas PCL, RBC velocity, and arterial diameter decreased significantly. ROS increased significantly after HS, 10 and 45 min of resuscitation. ACTH-(1-24) plus dextrans 70/500 increased MAP immediately; it increased vasodilation and PCL, and attenuated significantly ROS production and leukocyte adhesion during resuscitation. L-NMMA injected after 30 min of HS did not change the protection exerted by ACTH-(1-24) and dextrans 70/500, while SOD increased their protective effects. Conclusions: ACTH-(1-24) appears to enhance the protective effects on the endothelium exerted by increased plasma viscosity by significantly decreasing the oxidative stress and the leukocyte adhesion during resuscitation.

The melanocortin-5 receptor (MC5R) has been implicated in the regulation of exocrine gland secretion, immune regulation, and muscle fatty acid oxidation in mammals. Melanocortin-2 receptor accessory protein 2 (MRAP2) can modulate trafficking, ligand binding, and signaling of melanocortin receptors. To explore potential interaction between ricefield eel (Monopterus albus) MC5R and MRAP2s (maMC5R, maMRAP2X1, and maMRAP2X2), herein we studied the pharmacological characteristics of maMC5R and its modulation by maMRAP2s expressed in the human embryonic kidney cells. Three agonists, α-melanocyte-stimulating hormone (α-MSH), ACTH (1-24), and [Nle4, D-Phe7]-α-MSH, could bind to maMC5R and induce intracellular cAMP production dose-dependently. Compared with human MC5R (hMC5R), maMC5R displayed decreased maximal binding but higher binding affinity to α-MSH or ACTH (1-24). When stimulated with α-MSH or ACTH (1-24), maMC5R showed significantly lower EC50 and maximal response than hMC5R. Two maMRAP2s had no effect on cell surface expression of maMC5R, whereas they significantly increased maximal binding. Only maMRAP2X2 significantly decreased the binding affinity of ACTH (1-24). Both maMRAP2X1 and maMRAP2X2 significantly reduced maMC5R efficacy but did not affect ligand sensitivity. The availability of maMC5R pharmacological characteristics and modulation by maMRAP2s will assist the investigation of its roles in regulating diverse physiological processes in ricefield eel.

1. We investigated the effects of [Nle4,D-Phe7]alpha-melanocyte-stimulating hormone (NDP-MSH), adrenocorticotropin-(1-24) (ACTH-(1-24)) and gamma 2-MSH, three melanocortins with different agonist selectivity for the five cloned melanocortin receptors, on blood pressure and heart rate in conscious, freely moving rats following intravenous administration. 2. As was previously found by other investigators as well as by us gamma 2-MSH, a peptide suggested to be an agonist with selectivity for the melanocortin MC3 receptor, caused a dose-dependent, short lasting pressor response in combination with a tachycardia. Despite the fact that NDP-MSH is a potent agonist of various melanocortin receptor subtypes, among which the melanocortin MC1 receptor, it did not affect blood pressure or heart rate, when administered i.v. in doses of up to 1000 nmol kg-1. 3. ACTH-(1-24) caused a dose-dependent decrease in blood pressure in combination with a dose-dependent increase in heart rate in a dose-range from 15 to 500 nmol kg-1. The cardiovascular effects of ACTH-(1-24) were independent of the presence of the adrenals. 4. Pretreatment with ACTH-(1-24) caused a pronounced, dose-dependent parallel shift to the right of the dose-response curve for the pressor and tachycardiac effects of gamma 2-MSH. The antagonistic effect of ACTH-(1-24) was already apparent following a dose of this peptide as low as 10 nmol kg-1, which when given alone had no intrinsic hypotensive activity. 5. These results form further support for the notion that it is not via activation of one of the as yet cloned melanocortin receptors that gamma-MSH-like peptides increase blood pressure and heart rate. The cardiovascular effects of ACTH-(1-24) seem not to be mediated by the adrenal melanocortin MC3 receptors, for which ACTH-(1-24) is a selective agonist, or by adrenal catecholamines. 6. There appears to be a functional antagonism between ACTH-(1-24) and gamma 2-MSH, two melanocortins derived from a common precursor, with respect to their effect on blood pressure and heart rate. Whether this antagonism plays a (patho)physiological role remains to be shown.