Inhibition of aortic histamine synthesis by α-hydrazinohistidine inhibits increased aortic albumin accumulation in experimental diabetes in the rat
Diabetologia
Inhibition of aortic histamine synthesis by -hydrazinohistidine inhibits increased aortic albumin accumulation in experimental diabetes in the rat
T. M. Hollis a n d S. A. Strickberger 0
0 Department of Biology,Mueller Laboratory,The PennsylvaniaState University , UniversityPark , USA
Summary. We examined the interrelationship between inhibition of aortic histamine synthesis through inhibition of aortic hisfidine decarboxylase and intra-aortic albumin accumulation in rats made diabetic by a jugular vein injection of 60 mg/kg of streptozotocin under ether anesthesia. Animals were held for 4 weeks following overt manifestation of diabetes. At the end of 3 weeks, at least six animals in each of the diabetic and non-diabetic groups received intra-peritoneal injections of a-hydrazinohistidine (25 mg/kg at 12 h) for the last 7days. Aortic albumin accumulation was measured by quantification of aortic uptake of fluorescein isothiocyanate conjugated to rat serum albumin injected in the jugular vein 1 h before sacrifice. The aortic albumin mass transfer and flux rates of the diabetic group were more than 300% higher than that of the control group; a-hydrazinohistidine treated dia-
Diabetes; histamine synthesis; aortic albumin accumulation; aortic permeability; atherosclerosis; atherogenesis
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9 Springer-Verlag1985
F r o m epidemiological studies it is n o w well established
that diabetes is one i m p o r t a n t risk factor o f
atherosclerotic vascular disease [
1-5
]. Diabetic subjects show
m o r e a d v a n c e d atherosclerosis a n d have m o r e severe
atherosclerosis at any given age t h a n their non-diabetic
c o u n t e r p a r t s ; vascular complications o f atherosclerosis
are the principle event responsible for increased
diabetic mortality [
2-6
].
The interrelationship between diabetes and
atherosclerosis is p o o r l y u n d e r s t o o d . In part this stems f r o m a
basic lack o f u n d e r s t a n d i n g o f the mechanisms o f
atherogenesis; equally important, however, is the lack o f
studies directed towards e x a m i n a t i o n o f changes in
arterial wall metabolism which are atherogenic and which
are exaccerbated in diabetes mellitus.
O u r laboratory has b e e n examining the possibility
that increased arterial wall histamine synthesis m a y
mediate increased endothelial permeability to m a c r o m o l e
cules in diabetes as well in other atherogenic states such
as hypercholesteremia. F o r example, we have recently
r e p o r t e d in experimental diabetes that b o t h aortic
endothelial and s m o o t h muscle histamine synthesis are
increased, histamine catabolism is decreased, and the
inbetic rats had aortic albumin mass transfer rates equivalent to
control values. The aortic filbumin content was nearly tenfold
higher in untreated diabetic rats, but again treatment with
ahydrazinohistidine returned this to control values. These data
offer strong support to the premise that accelerated aortic
histamine synthesis, which occurs in experimental diabetes, is an
important mediator of increased aortic macromolecule
uptake, and as such, may be one component of the multitude of
factors responsible for increased susceptibility of
atherosclerosis among individuals having diabetes mellitus.
tracellular histamine content o f b o t h cell types is
increased p r o p o r t i o n a t e l y [
7
]. Furthermore, we have
s h o w n that in cholesterol-induced atherosclerosis in
rabbits, partial inhibition o f the increased aortic
histamine synthesis b y a - h y d r a z i n o h i s t i d i n e ( a - H H )
produces a 51% decrease in aortic albumin accumulation
and a 63% decrease in the severity o f atherosclerosis [
8
].
M o s t recently, we have shown that a - H H prevents the
increase in the aortic endothelial a n d s m o o t h muscle
cell histamine content in experimental diabetes, despite
the persistence o f severe diabetes [
9
]. The present study
was designed to determine w h e t h e r the increased aortic
albumin a c c u m u l a t i o n occurring in diabetes can be
prevented by the administration o f a - H H , a relatively
specific inhibitor o f histidine decarboxylase [
10, 11
].
Materials and methods
Animals
Male Wistar rats with initial body weights of 200-230g were used in
this study. Animals were divided into four treatment groups with at
least six animals (n = 6) per group. The treatment groups consisted of
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untreated animals (controls, n = 7), non-diabetic animals receiving
aHH (n = 7), diabetic animals (n =9), and diabetic animals receiving
a - H H (n =6).
Diabetes was induced under light anaesthesia by jugular vein
injection of streptozotocin (Sigma Chemicals, St. Louis, Missouri,
60 mg/kg in acid saline, 0.5 ml, pH 4.5), followed by an
intra-peritoneal injection of glucose (1.75 g/kg, 40% solution). All control animals
were weight-mateched and received a sham injection of acid saline
only. All animals were fed Purina Rat Chow (Ral (...truncated)