Histamine synthesis and catabolism in various tissues in diabetic rats.
TL;DR: It is concluded that tissue histamine synthesis is significantly increased in diabetic animals and that this increase is most marked in the aorta, which may contribute to the pathogenesis of endothelial damage in diabetic microangiopathy and macroANGiopathy.
Abstract: In view of the observations that (1) plasma histamine concentrations are significantly higher in diabetic patients and diabetic rats than those in controls, and (2) tissue concentrations of histamine are elevated in rats with experimental diabetes, we have investigated histamine synthesis, as reflected by histidine decarboxylase (HDC) activity, and histamine catabolism, as reflected by histaminase activity, in various tissues of the diabetic rat. Rats with streptozotocin-induced diabetes mellitus (DM) showed an increase in histamine synthesis in various tissues; this was most marked in the aorta and to a lesser, but significant, extent in the kidneys, lungs, and heart, but not in the brain, stomach, or skin. Tissue content of histamine was significantly increased in all tissues except the stomach and skin. We conclude that tissue histamine synthesis is significantly increased in diabetic animals and that this increase is most marked in the aorta. The elevation in HDC activity in these tissues probably accounts for the increase in tissue and plasma concentrations of histamine in diabetic animals, since there is no change in histamine catabolism. This increase in histamine synthesis and release may contribute to the pathogenesis of endothelial damage in diabetic microangiopathy and macroangiopathy.
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TL;DR: A role for a relative or absolute increase in NO production in the pathogenesis of early diabetic vascular dysfunction is suggested and the possibility that inhibition of diabetic vascular functional changes by aminoguanidine may reflect inhibition of NO synthase activity rather than, or in addition to, prevention of AGE formation is raised.
Abstract: This study was undertaken to compare the ability of two guanidine compounds (aminoguanidine and methylguanidine), with different in vitro effects on NO synthase activity and AGE formation, to inhibit diabetic vascular dysfunction developing early after the onset of diabetes. In rats with STZ-induced diabetes of 5-wk duration, regional vascular [125I]albumin permeation was increased about two- to threefold in ocular tissues, sciatic nerve, and aorta; in general, both guanidine compounds normalized albumin permeation in diabetic rats without affecting it in controls. Methylguanidine was only ∼7% as effective as aminoguanidine as an inhibitor of AGE formation from L-lysine and G6P; both compounds were poor inhibitors of AR. Methylguanidine was ∼1–5% as potent as aminoguanidine and L-NMMA as an inhibitor of the cytokine- and endotoxin-inducible isoform of NO synthase. In contrast, the potency of methylguanidine as an inhibitor of the constitutive isoform of NO synthase was comparable to that of aminoguanidine, and both guanidine compounds were much less effective than L-NMMA. These observations suggest a role for a relative or absolute increase in NO production in the pathogenesis of early diabetic vascular dysfunction and raise the possibility that inhibition of diabetic vascular functional changes by aminoguanidine may reflect inhibition of NO synthase activity rather than, or in addition to, prevention of AGE formation.
326 citations
Cites background from "Histamine synthesis and catabolism ..."
...metabolism (11,12); and 5) relative or absolute changes in the production of vasoactive substances such as prostanoids, NO, endothelin, and histamine (13-18)....
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TL;DR: It is demonstrated, for the first time, that the H4 receptor is expressed in the kidney mainly by resident renal cells of the loop of Henlé and that this receptor is significantly overexpressed in diabetic animals, thus suggesting a possible role in the pathogenesis of diabetes-associated renal disease.
Abstract: Objective and design
The renal expression of H1 and H2 receptors has previously been demonstrated, while that of the H4 receptor has been poorly investigated, and thus the aim of this research was to investigate the expression of the H4 receptor in the kidney of diabetic rats.
22 citations
TL;DR: An interesting upsurge in the field which provides scope for new insights into the role of histamine in diabetes is revealed.
21 citations
Cites background from "Histamine synthesis and catabolism ..."
...For instance, a significant drop in intestinal diamine oxidase (DAO) activity [7] 79 as well as an increase of histidine decarboxylase (HDC) activity in various tissues [12] were 80 observed, thus providing evidence for a nascent histamine pool....
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TL;DR: Results suggest that salivary histamine may serve as a predictive index in the prevention of periodontal disease.
Abstract: Background: Some previous investigations underscored the role of histamine in periodontal disease, especially in diabetic patients, but the behavior of this inflammatory mediator in the early phases of periodontal involvement remains unclear. The aim of the present study was to correlate the presence of histamine in saliva with clinical parameters in healthy, periodontitis-affected, and diabetic subjects to ascertain whether this amine may serve as a predictive index of periodontal risk.Methods: For this purpose, subjects were selected as follows: 1) with newly diagnosed type 2 diabetes mellitus; 2) with neither diabetes nor periodontitis; 3) with no diabetes but with chronic, untreated periodontal disease. Histamine salivary levels were measured at the initial time (T0) and after 6, 12, and 24 months using high-performance liquid chromatography. The main periodontal indexes were recorded at the same time intervals.Results: At T0, a very typical shape of the histamine chromatogram was found for all patien...
20 citations
TL;DR: In a diabetic mouse model, SPC levels are increased and SPC TGF-β/BMP-6 expression is modulated, which may contribute to exaggerated intimal hyperplasia in diabetes as bone marrow derived cells home to sites of neointima formation.
Abstract: Diabetic patients experience exaggerated intimal hyperplasia after endovascular procedures. Recently it has been shown that circulating smooth muscle progenitor cells (SPC) contribute to intimal hyperplasia. We hypothesized that SPC differentiation would be increased in diabetes and focused on modulation of TGF-β/BMP-6 signaling as potential underlying mechanism. We isolated SPC from C57Bl/6 mice with streptozotocin-induced diabetes and controls. SPC differentiation was evaluated by immunofluorescent staining for αSMA and collagen Type I. SPC mRNA expression of TGF-β and BMP-6 was quantified using real-time PCR. Intima formation was assessed in cuffed femoral arteries. Homing of bone marrow derived cells to cuffed arterial segments was evaluated in animals transplanted with bone marrow from GFP-transgenic mice. We observed that SPC differentiation was accelerated and numeric outgrowth increased in diabetic animals (24.6 ± 8.8 vs 8.3 ± 1.9 per HPF after 10 days, p < 0.05). Quantitative real-time PCR showed increased expression of TGF-β and decreased expression of the BMP-6 in diabetic SPC. SPC were MAC-3 positive, indicative of monocytic lineage. Intima formation in cuffed arterial segments was increased in diabetic mice (intima/media ratio 0.68 ± 0.15 vs 0.29 ± 0.06, p < 0.05). In GFP-chimeric mice, bone marrow derived cells were observed in the neointima (4.4 ± 3.3 cells per section) and particularly in the adventitia (43.6 ± 9.3 cells per section). GFP-positive cells were in part MAC-3 positive, but rarely expressed α-SMA. In conclusion, in a diabetic mouse model, SPC levels are increased and SPC TGF-β/BMP-6 expression is modulated. Altered TGF-β/BMP-6 expression is known to regulate smooth muscle cell differentiation and may facilitate SPC differentiation. This may contribute to exaggerated intimal hyperplasia in diabetes as bone marrow derived cells home to sites of neointima formation.
17 citations
Cites background from "Histamine synthesis and catabolism ..."
...Importantly, plasma histamine levels and HDS activity in various tissues are increased in diabetes [22]....
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References
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Journal Article•
TL;DR: Procedures are described for measuring protein in solution or after precipitation with acids or other agents, and for the determination of as little as 0.2 gamma of protein.
289,852 citations
TL;DR: In a sixteen year follow-up study in Framingham, it was found that diabetics in general show an increased morbidity and mortality from all cardiovascular causes and Insulin-treated diabetic women showed the greatest relative mortality from coronary heart disease.
Abstract: In a sixteen year follow-up study in Framingham, it was found that diabetics in general show an increased morbidity and mortality from all cardiovascular causes. Insulin-treated diabetic women showed the greatest relative mortality from coronary heart disease. Diabetics were found to have higher lipid values, more hypertension and more obesity, even prior to diagnosis. When all the associated risk factors, individually or together, were taken into consideration their presence could not entirely explain the increase in cardiovascular morbidity and mortality experienced by the diabetic. An as yet unknown factor appears to be present in diabetics that could be responsible for much of the higher incidence of cardiovascular complications in diabetics.
1,667 citations
TL;DR: The early components of atherosclerosis induced by chronic hypercholesterolemla centered around the monocyte-macrophage and its interaction with endothelium In the induction of the fatty streak, and subsequent changes that lead to macrophage-smooth muscle Interactions, platelet-macrophic interactions, and platelets-endothelial interactions appeared to set the stage for the development of more advanced proliferatlve lesions.
Abstract: Morphologic studies resulting from events that occur during the development of the lesions of atherosclerosis were studied in chronic, diet-induced hypercholesterolemia in a series of nonhuman primates. Within 12 days of hypercholesterolemia in Macaca nemestrina, monocytes became adherent to the surface of the endothelium. These monocytes appeared to migrate subendothelially, accumulate lipid, and become lipid-laden macrophages (foam cells). Within a month, a "serofibrinous insudate" formed together with variable numbers of subendothelial lipid-laden macrophages. By the second month, foam cells increased in number, often in multilayers, to form a fatty streak. Concomitantly, the luminal surface of the arteries became increasingly irregular due to the subendothelial accumulation of foam cells. Numerous monocytes continued to attach to the endothelial surface over the fatty streaks, and many of them appeared to enter the intima and participate in the growth of the fatty streaks. Lipid-laden smooth muscle cells appeared in small numbers and formed two to four layers between the macrophages and the internal elastic lamella at 2 to 3 months. During the third month of hypercholesterolemia, endothelial cell continuity over the lipid-laden macrophages became interrupted, exposing the underlying foam cells to circulating blood. Foam cells were then readily observed in whole blood smears, suggesting that many of the lipid-laden macrophages leave the intima and enter the circulation. After 4 months, significant endothelial denudation was found in the iliac artery and many exposed macrophages were covered by adherent platelets in the form of a mural thrombus. Thus, the early components of atherosclerosis induced by chronic hypercholesterolemia centered around the monocyte-macrophage and its interaction with endothelium in the induction of the fatty streak. Subsequent changes that lead to macrophage-smooth muscle interactions, platelet-macrophage interactions, and platelet-endothelial interactions appeared to set the stage for the development of more advanced proliferative lesions.
981 citations
TL;DR: In this paper, morphologic and statistical evidence is presented, to suggest that endothelial cells contract under the influence of mediators, and that this contraction causes the formation of intercellular gaps.
Abstract: Previous work has shown that endogenous chemical mediators, of which histamine is the prototype, increase the permeability of blood vessels by causing gaps to appear between endothelial cells. In the present paper, morphologic and statistical evidence is presented, to suggest that endothelial cells contract under the influence of mediators, and that this contraction causes the formation of intercellular gaps. Histamine, serotonin, and bradykinin were injected subcutaneously into the scrotum of the rat, and the vessels of the underlying cremaster muscle were examined by electron microscopy. To eliminate the vascular collapse induced by routine fixation, in one series of animals (including controls) the root of the cremaster was constricted for 2–4 min prior to sacrifice, and the tissues were fixed under conditions of mild venous congestion. Electron micrographs were taken of 599 nuclei from the endothelium of small blood vessels representing the various experimental situations. Nuclear deformations were classified into four types of increasing tightness (notches, foldsl closing folds, and pinches. In the latter the apposed surfaces of the nuclear membrane are in contact). It was found that: (1) venous congestion tends to straighten the nuclei in al groups; (2) mediators cause a highly significant increase in the number of pinches (P < 0.001), also if the vessels are distended by venous congestion; (3) fixation without venous congestion causes vascular collapse. The degree of endothelial recoil, as measured by nuclear pinches, is very different from that caused by mediators (P < 0.001). (4) Pinched nuclei are more frequent in leaking vessels, and in cells adjacent to gaps (P < 0.001); (5) mediators also induce, in the endothelium, cytoplasmic changes suggestive of contraction, and similar to those of contracted smooth muscle; (6) there is no evidence of pericyte contraction under the conditions tested. Occasional pericytes appeared to receive fine nerve endings. Various hypotheses to explain nuclear pinching are discussed; the only satisfactory explanation is that which requires endothelial contraction.
820 citations
TL;DR: The use of rat kidney instead of guinea pig brain as the source of histamine- N -methyltransferase for the enzymatic assay of histamines was found to improve the sensitivity of the assay.
304 citations