Role of endothelin-1 in stress response in the central nervous system

• Published in: American journal of physiology. Regulatory, integrative and comparative physiology integrative and comparative physiology, 2000-08, Vol.279 (2), p.515-R521
• Main Authors: Kurihara, Yukiko, Kurihara, Hiroki, Morita, Hiroyuki, Cao, Wei-Hua, Ling, Guang-Yi, Kumada, Mamoru, Kimura, Sadao, Nagai, Ryozo, Yazaki, Yoshio, Kuwaki, Tomoyuki
• Format: Article
• Language: English
• Subjects: Animals; Brain - metabolism; Catecholamines - metabolism; Endothelin-1 - genetics; Endothelin-1 - physiology; Methoxyhydroxyphenylglycol - metabolism; Mice; Mice, Inbred C57BL; Mice, Inbred ICR; Mice, Knockout - genetics; Reference Values; Stress, Physiological - physiopathology
• ISSN: 0363-6119; 1522-1490
• DOI: 10.1152/ajpregu.2000.279.2.r515

Departments of 1  Cardiovascular Medicine and 2  Physiology, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655,  3  St. Luke's College of Nursing, Tokyo 104-0044; 4  Division of Cardiovascular Biology and 6  Department of Physiology, Chiba University School of Medicine, Chiba 260-8670; and 5  The Hospital International Medical Center of Japan, Tokyo 162-8655, Japan Endothelin (ET)-1 is a 21-amino acid peptide that induces a variety of biological activities, including vasoconstriction and cell proliferation, and its likely involvement in cardiovascular and other diseases has recently led to broad clinical trials of ET receptor antagonists. ET-1 is widely distributed in the central nervous system (CNS), where it is thought to regulate hormone and neurotransmitter release. Here we show that CNS responses to emotional and physical stressors are differentially affected in heterozygous ET-1-knockout mice, which exhibited diminished aggressive and autonomic responses toward intruders (emotional stressors) but responded to restraint-induced (physical) stress more intensely than wild-type mice. This suggests differing roles of ET-1 in the central pathways mediating responses to different types of stress. Hypothalamic levels of ET-1 and the catecholamine metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) were both increased in wild-type mice subjected to intruder stress, whereas MHPG levels were not significantly affected in ET-1-knockout mice. Furthermore, immunohistochemical analysis showed that ET-1 and tyrosine hydroxylase, an enzyme in the catecholamine synthesis pathway, were colocalized within certain neurons of the hypothalamus and amygdala. Our findings suggest that ET-1 modulates central coordination of stress responses in close association with catecholamine metabolism. knockout mice; catecholamine * Y. Kurihara, H. Kurihara, and T. Kuwaki contributed equally to this work.