Natriuretic peptides and adrenomedullin in the vascular system

$6-B2-1-07 CAPILLARY AND INTERSTITIAL RESPONSES TO INFLAMMATION AND BURN INJURY R.K. Reed Department of physiology, University of Bergen, ,~,rstadveien 19, N-5009 Bergen, Norway The tissue response to burn injury and inflammation involve changes at the microvascular barrier and in the interstitium which result in enhanced transcapillary fluid and solute transport which may eventually cause edema. The magnitude of the normal net transcapillary fluid filtration is such that it will turn over the interstitial fluid volume in 12-24 hours in most experimental animals while an even longer time is required in man. The transcapillary net filtration of fluid is the product of the transcapillary net filtration pressure (AP) and the capillary filtration coefficient ("water permeability"). The net capillary filtration pressure is normally 0.5 to 1-2 mmHg in skin (Aukland K & Reed RK, Physiol Rev 7 3 : 1 - 7 8 , 1 9 9 3 ) . The occurrence of edema in skin normally requires a doubling of interstitial fluid volume and when edema forms in a few minutes such as in inflammation and burn injury, the transcapillary fluid filtration must be increased up to several hundred times above normal, and consequently the product of Ap and CFC has increased to the same extent. Since CFC increases by 2-3 times above normal in burn injuries, increased Ap must account for most of the increase in net filtration. In burn injuries interstitial fluid pressure (Pif) decreases from -1 to as low as -I 50 mmHg and will consequently be the main contributor to account for the increased AP. A similar increased negativity of Pif has been found to occur in several inflammatory reactions. Again, the increase in CFC is 2 to 3 times above normal and therefore increased AP is required to explain the rapidity by which edema can form also under these circumstances. Thus, in rat trachea and skin Pif has been observed to fall from -1 mmHg in control to -10 mmHg after e.g. mast cell degranulation, neurogenic inflammation, carageenan and blockade of fibroblast collagen receptors (131integrins). Increased negativity of Pif will therefore contribute actively to enhance edema formation under these circumstances rather then preventing the edema formation which has been the common role assigned to Pif" However, although increased negativity of Pif will contribute to the initial edema formation, the increased interstitial volume will raise Pif' resulting in less negative and eventually positive values as edema has developed. Although increased negativity of Pif participate in generating the edema, once the edema is in a steady state, its maintenance depends upon increased capillary hydrostatic pressure a n d / o r increased capillary filtration coefficient. In general, the capillary responses to injury and inflammation are vasodilation with subsequent increase in capillary hydrostatic pressure and increased permeability to water and macromolecules, both of which will enhance transcapillary transport.

$6-B2-2-01 NATRIURETIC PEPTIDES AND ADRENOMEDULLIN IN THE VASCULAR SYSTEM N. Minamino I , K. Kangawa 1, K. Miyamoto 1, S. Sugo I , H. Shoji I , M. Furuya 2, S. Tanaka2, K. Kitamura 3, T. Eto 3 & H. Matsuo 1 1) National Cardiovascular Center Research Institute, Fujishirodai, Suita, Osaka 565, Japan, 2) Suntory Institute for Biomedical Research, Shimamoto, Osaka, Japan, 3) Department of Medicine, Miyazaki Medical College, Kiyotake, Miyazaki, Japan Natriuretic peptide family comprises A-type (atrial) natriuretic peptide (ANP), B-type (brain) natriuretic peptide (BNP) and C-type natriuretic peptide (CNP). These peptides share a highly homologous 17-residue ring structure but exert different pharmacological activity. CNP specifically binds to a receptor guanylate cyclase, GC-B, while both ANP and BNP act on GC-A receptor. ANP and BNP are mainly produced and secreted into the blood stream from cardiac atrium and ventricle, and participate in the regulation of blood pressure and body fluid volume through circulation system. In contrast, CNP is localized in the central nervous system and has been assumed to function as a neuropeptide. Recently, we have found that CNP specific GC-B receptor is widely distributed not only in the cental nervous system but also in the peripheral tissue. In fact, cultured vascular smooth muscle cells (VSMCs) actively express GC-B receptor and their growth is inhibited by CNP. We further examined effects of CNP on in vivo vascular cell proliferation and found that CNP inhibits air-drying injury induced thickening of VSMCs in carotid artery. These results support that CNP is also synthesized in the peripheral system. To identify CNP-producing tissue or cells, we surveyed for CNP and its mRNA in rat peripheral tissue by using RT-PCR and RIA, and found that CNP gene is expressed in most of the peripheral tissues, including gastrointestinal tract, kidney, lung, testis and aorta, although its expression level is much lower than that in the central nervous system. During a survey for new peptides in the cultured cell lines, we detected production of CNP in phorboi ester (TPA)-treated monoeytie leukemia cell line, THP-1. Production of CNP by THP-1 cells was markedly augmented by treatment of TPA, and THP-1 cells were simultaneously transformed into macrophage-like cells. Based on these results, CNP is deduced to function as a local regulator in the peripheral system, especially in injured or atherosclerotic regions of blood vessel, where monoeyte-maerophage system synthesizes CNP which in turn inhibits the growth of VSMCs expressing GC-B receptor. Adrenomedullin (AM) is a new peptide isolated from pheochromocytoma and adrenal gland, and elicits potent vasorelaxant effect comparable to that of CGRP. Very recently, we found active production of AM in vascular endothelial ceils and VSMCs. Since AM-specific receptors coupled with adenylate cyclases have recently shown to be present on VSMCs, AM secreted from endothelial cells and VSMCs are assumed to function as an autocrine or paracrine factor regulating vascular function.

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