The
endothelins (ET) are potent 21-amino-acid
vasoconstrictor peptides produced in many different tissues, particularly in the endothelium of blood vessels. ET-1 is the main
endothelin secreted by the endothelium, and acts in a paracrine or autocrine fashion on blood vessels by interacting with ETA or ETB receptors on smooth muscle to stimulate contraction or on ETB receptors on endothelial cells to induce the release of
vasorelaxants (
nitric oxide and
prostacyclin). Production of ET-1 is enhanced in several experimental models of
hypertension in the rat, such as
sodium-sensitive forms, e.g.
deoxycorticosterone acetate (
DOCA)-
salt hypertensive,
DOCA-
salt-treated spontaneously hypertensive rats (SHR) and Dahl salt-sensitive rats, as well as other models such as
stroke-prone SHR,
angiotensin II-infused rats and
fructose-fed rats, and possibly 1-K 1C Goldblatt hypertensive rats. In contrast, SHR, 2-K 1C Goldblatt hypertensive rats and
nitric oxide-deficient (
L-NAME-treated) hypertensive rats do not exhibit an ET-1 component.
Endothelin dependency is manifested by excessive vascular growth, particularly in small arteries, and blood pressure lowering and regression of vascular growth
after treatment with
endothelin antagonists. The latter may be combined ETA/ETB or selective ETA antagonists, of which several are orally active and already in clinical development. In humans,
endothelin-dependent vascular tone has been shown in studies of forearm blood flow. Enhanced expression of ET-1
mRNA has been demonstrated in the endothelium of small arteries of patients with moderate to severe
hypertension. In a 4-week trial the combined ETA/ETB antagonist
bosentan reduced the blood pressure of essential hypertensive patients equally to
enalapril.
Bosentan improved hemodynamics in patients with
heart failure in acute and 2-week-long studies.
Endothelin antagonists also offer promise in a rapidly fatal condition,
primary pulmonary hypertension. Thus, the
endothelin system appears to be involved in different forms of
cardiovascular disease in experimental animals and humans, and its interruption offers great promise as a new therapeutic intervention in
hypertension,
heart failure and other diseases.