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.