Effects of chronic endothelin blockade in an insulin resistant and
hyperinsulinemic rodent model of hypertension.
Verma, Subodh, Sanjay Bhanot, and John H. McNeill.
Division of Pharmacology and Toxicology, Faculty of Pharmaceutical
Sciences, The University of British Columbia, Vancouver, B.C. Canada
V6T 1Z3
APStracts 2:0283H, 1995.
The fructose-induced hypertensive (FH) rat is a widely used model to
study the inter-relationship between hyperinsulinemia and
hypertension. Although hyperinsulinemia is believed to be pathogenic
in the development of high blood pressure in these rats, the exact
mechanisms involved remain to be defined. Recent studies suggesting
that plasma insulin may modulate ET-1 release both in-vitro and in
-vivo led us to hypothesize that hyperinsulinemia may provide a
continual stimulus for ET-1, which may increase blood pressure by
altering ET-1 plasma and/or blood vessel levels. To examine the
validity of our hypothesis, we studied the effects of chronic
endothelin (ET) receptor blockade (by using bosentan, a non
competitive ET antagonist) on plasma insulin levels, plasma ET-1
levels, blood vessel ET content and blood pressure in FH rats. Male
Sprague Dawley rats were divided into four experimental groups:
control (C, n=9), control-treated (CT, n=10), fructose (F, n=10) and
fructose-treated (FT, n=10). At week 6 (weeks denote age of rats),
chronic bosentan treatment was initiated in the CT and FT groups at a
dose of 100mg/kg/day (p.o). At week 7, rats in the F and FT groups
were started on a 66% fructose diet. For the next three weeks, weekly
measurements of plasma insulin, plasma glucose, and systolic BP were
performed. At week 15, the entire mesenteric vascular bed was
dissected out for determination of blood vessel ET content. Plasma
for ET determination was also collected at week 15. Bosentan
treatment caused sustained decreases in blood pressure in the FT
group (130+/-4 vs. untreated F 149+/-2, P<0.001) but had no
effect in the control group. The F rats had a higher total mesenteric
ET-1 content when compared to the C rats (21.5+/-3.2 vs. C 14.1+/-2.1
fmol, P<0.05). Treatment of the F rats with bosentan (FT) did
not alter the total mesenteric ET-1 content (18.8+/-5, P>0.05
vs. untreated F). The treatment did not affect plasma glucose,
insulin or ET levels in any group. These data suggest that fructose
feeding causes an increase in blood vessel ET content, which may be
important in causing increases in blood pressure in these rats.
Whether ET represents an intermediate linking hyperinsulinemia to
hypertension in rats, or operates as an independent hypertensinogenic
mechanism remains to be determined. However, the data suggests that
ET-1 may be involved in the development of high BP in this rodent
model of hypertension.
Received 13 February 1995; accepted in final form 20 June 1995.
APS Manuscript Number H131-5.
Article publication pending Am. J. Physiol. (Heart Circ. Physiology).
ISSN 1080-4757 Copyright 1995 The American Physiological Society.
Published in APStracts on 11 July 1995.