A role for endothelin in malignant phase hypertension has been suggest
ed on the basis of reported increases of circulating plasma immunoreac
tive endothelins in animal models. Recently, a hypertensive rat model
that exhibits a genetically determined tendency for developing spontan
eous onset malignant hypertension has been described. Expression of th
e three genes endothelin-1, endothelin-2, and endothelin-3 was quantif
ied in the kidney by specific RNase protection assays in rats with est
ablished malignant hypertension, in rats with benign hypertension with
and without a genetic susceptibility to malignant hypertension, and i
n normotensive Sprague-Dawley rats. Endothelin-1 mRNA levels were sign
ificantly elevated in the group with malignant hypertension compared w
ith the other three groups. For determination of whether endothelin-1-
mediated effects were crucial in the transition from benign to maligna
nt phase hypertension, an oral nonspecific combined endothelin-A and e
ndothelin-B receptor antagonist (bosentan) was given to hypertensive r
ats susceptible to malignant hypertension. No hypotensive effects were
observed, and no significant difference in the incidence of malignant
hypertension was observed between treated and control groups. In conc
lusion, although increased endothelin-1 mRNA expression was found in k
idney tissue from rats developing malignant hypertension, blockade of
endothelin-1-mediated effects did not prevent the transition from beni
gn phase hypertension. Hence, increased renal endothelin-1 expression
in this model of malignant hypertension does not appear to have a caus
ative role and may simply reflect cellular damage and ischemia.