Inhibition of aortic histamine synthesis by α-hydrazinohistidine inhibits increased aortic albumin accumulation in experimental diabetes in the rat

Diabetologia, May 1985

We examined the interrelationship between inhibition of aortic histamine synthesis through inhibition of aortic histidine 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 α-hydrazinohistidine (25 mg/kg at 12 h) for the last 7 days. 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; α-hydrazinohistidine treated diabetic rats had aortic albumin mass transfer rates equivalent to control values. The aortic albumin content was nearly tenfold higher in untreated diabetic rats, but again treatment with α-hydrazinohistidine 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.

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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 - 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 ::?..:.:t o x E vo if) n, O t3.. 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)


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T. M. Hollis, S. A. Strickberger. Inhibition of aortic histamine synthesis by α-hydrazinohistidine inhibits increased aortic albumin accumulation in experimental diabetes in the rat, Diabetologia, 1985, pp. 282-285, Volume 28, Issue 5, DOI: 10.1007/BF00271686