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

Endothelin (ET)-1 is a 21-amino acid peptide that induces a variety of biol ogical activities, including vasoconstriction and cell proliferation, and i ts likely involvement in cardiovascular and other diseases has recently led to broad clinical trials of ET receptor antagonists. ET-1 is widely distri buted in the central nervous system (CNS), where it is thought to regulate hormone and neurotransmitter release. Here we show that CNS responses to em otional and physical stressors are differentially affected in heterozygous ET-1 knockout mice, which exhibited diminished aggressive and autonomic res ponses toward intruders (emotional stressors) but responded to restraint-in duced (physical) stress more intensely than wild-type mice. This suggests d iffering roles of ET-1 in the central pathways mediating responses to diffe rent types of stress. Hypothalamic levels of ET-1 and the catecholamine met abolite 3-methoxy-4-hydroxyphenylglycol(MHPG) were both increased in wild-t ype mice subjected to intruder stress, whereas MHPG levels were not signifi cantly affected in ET-1-knockout mice. Furthermore, immunohistochemical ana lysis showed that ET-1 and tyrosine hydroxylase, an enzyme in the catechola mine synthesis pathway, were colocalized within certain neurons of the hypo thalamus and amygdala. Our findings suggest that ET-1 modulates central coo rdination of stress responses in close association with catecholamine metab olism.