Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0042373 (vascular disease)
17,070 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In Alzheimer's dementia (AD) the Primum Movens is Amyloid (AM) production on precapillaries: Dyshoric Angiopathy, and capillaries: Senile Plaques (SP) producing Blood-Brain-Barrier (BBB) disturbances, entry in the brain of toxic metals which displace the zinc. Cerebral AM alone may be asymptomatic. Clinical symptoms (Amnesia, Instrumental Disorders) appear when AM induces Neighbouring neuritic alterations: Paired Hellical Filaments (PHF) and Distant neuronal body lesions: Neurofibrillary Tangles (NFT). The AM is coded by a locus on the chromosome 21 and a duplication of this locus should be the etiology of cerebral AM in AD. In AD cerebral zinc decreases particularly in the hippocampus. The zinc-enzyme Superoxyde-Dismutase (SOD) is coded by a locus also on the chromosome 21 near AM and the plasma level of SOD is high in AD. Zinc deposits observed in capillary AM-SP, result probably from the excess of plasmatic SOD. Other metals: Iron, aluminium are also observed in the AM-SP and their excess in the brain may be related to the decrease of zinc by metal to metal displacement. The decrease of functional zinc in the brain may interfere in the pathogenesis of PHF-NFT by metalotoxicity, neighbouring and distant to AM. Without AM, NFT are produced also by metalotoxicity and therefore brain zinc displacement. a) by lead: Encephalopathia saturnica b) by many metals: Guam Encephalopathy c) by aluminium d) by BBB disturbances leading probably to an abnormal entry of metals in the brain (Dementia Pugilistica, viral encephalitides). NFT may be produced by the deficiency of the following zinc enzymes: 1. Those of DNA metabolism, indicating abnormal DNA and therefore abnormal protein synthesis: PHF-NFT. 2. Those of neuronal detoxication: SOD, Carbonic Anhydrase, Lactate Dehydrogenase leading to neuronal toxicity particularly in the hippocampus normally rich in SOD. 3. Of Glutamate (GLU) Dehydrogenase (GDH) resulting in an excitotoxic increase of GLU. 4. Those of the metabolism of neurotransmitters (NT): neuropeptides, Histamine, GABA, Acetylcholine. Therapeutic proposition: a zinc complex crossing the BBB should be useful a) to prevent that the AM produces PHF-NFT by Neighbouring and Distant metalotoxicity and DNA changes; b) to regularise zinc-enzymes of neuronal detoxification and of neurotransmitters metabolisms. Preliminary trials by zinc Aspartate give yet promising results.
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PMID:[Alzheimer's dementia and zinc]. 170 60

Smoking is a primary risk factor in coronary and peripheral vascular disease. However, the precise component of cigarette smoke that contributes to the pathogenesis of vascular disease remains unclear. The goal of this study was to determine the effect of nicotine on endothelium-dependent dilatation of peripheral resistance arterioles in vivo. We measured the diameter of resistance arterioles (approximately 50 microns in diameter) contained within the microcirculation of the hamster cheek pouch in response to endothelium-dependent (acetylcholine and ADP) and -independent (nitroglycerin) agonists before and after an intravenous infusion of vehicle or two concentrations of nicotine. Acetylcholine, ADP, and nitroglycerin produced a dose-related dilatation of the cheek pouch arterioles under control conditions. Endothelium-dependent, but not -independent, dilatation of arterioles was modestly impaired by an infusion of a low concentration of nicotine (1.0 microgram.kg-1.min-1). Infusion of a higher concentration of nicotine (2 micrograms.kg-1.min-1), which increased the plasma level of nicotine to 14 +/- 1.6 ng/ml, produced a profound selective impairment in endothelium-dependent vasodilatation. We suggest that elevations in plasma nicotine may contribute to the pathogenesis of the peripheral vascular disease observed in smokers.
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PMID:Effect of nicotine on endothelium-dependent arteriolar dilatation in vivo. 917 3

ATP-dependent potassium channel blockers used as hypoglycaemic agents may have effects on vascular disease in diabetes mellitus beyond their effect on blood glucose control. This study was designed to determine the effects of treatment with gliclazide on the isolated abdominal aorta of diabetic rabbits in which endothelium-dependent relaxation is impaired by a mechanism involving oxygen-derived free radicals. After induction of diabetes with alloxan, there was no effect of gliclazide (10 mg x kg(-1) day(-1) orally) on blood glucose or insulin levels over a 6 week period. Hence, this permitted an examination of the vascular effects of gliclazide in diabetic rabbits exclusive of metabolic effects. Acetylcholine- and nitric oxide-induced relaxation in aortae from rabbits treated with or without gliclazide were measured in the absence or presence of the nitric oxide synthase inhibitor, N(G)-nitro-L-arginine (L-NAME). Diabetes was associated with significant impairment of acetylcholine-induced endothelium-dependent relaxation of the abdominal aorta which was not significant in diabetic rabbits treated with gliclazide in vivo. Aortae from diabetic rabbits studied in the presence of L-NAME showed an exaggerated contraction to acetylcholine which was prevented in rabbits treated with gliclazide. Gliclazide treatment did not affect the response to acetylcholine of normal rabbit aorta, and gliclazide when added in vitro had no effect on the response of diabetic rabbit aorta, suggesting that the effect of gliclazide was specific to the abnormality arising with diabetes and was not due to an acute effect of the drug. These data indicate that gliclazide, aside from either a direct antioxidant action or an effect on insulin or glucose levels, may ameliorate diabetic endothelial cell dysfunction.
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PMID:Vascular action of the hypoglycaemic agent gliclazide in diabetic rabbits. 949 23

Acetylcholine-induced vasodilatation is impaired in animal models of insulin-dependent diabetes mellitus (IDDM), and may result from altered nitric oxide synthesis or release. The response to intraluminal flow, a more physiologically relevant stimulus for nitric oxide release, is unknown. This study examined flow-induced responses in isolated resistance arteries from male Sprague-Dawley control and streptozotocin-diabetic (45 mg/kg i.v., 4 week duration) rats. Mesenteric arteries (4-5th order) were dissected and cannulated on a pressure myograph (mean internal diameter +/- SEM at 40 mmHg, control 223 +/- 8, n = 9 vs diabetic 239 +/- 12 microm, n = 8, NS). Arteries were preconstricted with noradrenaline (1 micromol/l) and intraluminal pressure raised and maintained at 80 mmHg. Luminal flow was raised in incremental steps (0-1.27 microl/s). Arteries from control animals dilated to flow while arteries from diabetic animals constricted (% change in internal diameter +/- SEM at 0.79 microl/s: control 13.46 +/- 6.52, n = 9 vs diabetic -7.44 +/- 3.38%, n = 8; p < 0.005). Incubation with N(omega)-nitro-L-arginine methyl ester (0.1 mmol/l) abolished flow responses in arteries from controls but not from diabetic rats. In conclusion, impaired flow-induced nitric oxide-mediated vasodilatation may contribute to vascular disease in IDDM.
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PMID:Flow-induced dilatation in isolated resistance arteries from control and streptozotocin-diabetic rats. 949 27

Abnormalities in vascular endothelial function, which occur early in atherosclerosis, may play an etiologic role in the development of the disease or represent a marker for the extent of atherosclerosis. Endothelial dysfunction, usually characterized by demonstration of decreased endothelium-dependent vasorelaxation, may be a sensitive and specific method to detect vascular disease in its earliest stages. In this context, separation of abnormalities in receptor-mediated and flow-mediated endothelium-dependent vasodilatory responses may allow for the most accurate characterization of endothelial dysfunction. In 35 patients undergoing routine annual cardiac catheterization after heart transplantation, changes in epicardial lumen area and coronary blood flow in response to intracoronary administration of adenosine, acetylcholine, and nitroglycerin were measured simultaneously using an intravascular ultrasound (IVUS) catheter positioned over a Doppler flow wire in the left anterior descending coronary artery. The combination of these techniques allowed for distinction between receptor-mediated and flow-mediated endothelium-dependent vascular responses. Peak flow with the endothelium-independent resistance vessel dilator adenosine occurred at 18+/-2 sec; the maximal lumen area response occurred later, at 43+/-11 sec (P < 0.001). Acetylcholine, an endothelium-dependent small- and large-vessel vasodilator, caused an immediate increase in both flow and lumen area, but a second peak of dilation was observed, and maximal area occurred 46 sec after maximal flow (54+/-14 vs. 100+/-26 sec, P < 0.001). Simultaneous IVUS and Doppler flow measurements after infusion of vasoactive agents allows for distinction between and evaluation of the relative contribution of agonist-mediated and flow-mediated responses, which may offer important and unique insights into coronary endothelial function.
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PMID:Simultaneous intracoronary ultrasound and Doppler flow studies distinguish flow-mediated from receptor-mediated endothelial responses. 1034 24

Clinical evidence suggests that early endothelial cell (EC) dysfunction may predict the development of graft vascular disease. We wished to assess the early functional and morphological changes in the graft endothelium in a commonly used animal model of graft vascular disease, the rat aortic interposition allograft model. To assess graft EC function, regulation of vascular tone by ECs was monitored in aortic rings from grafts harvested at various times after transplantation (Tx). EC morphology was assessed by silver staining, which was followed by en face inspection of the luminal side of the grafts. Acetylcholine-induced EC-dependent vasorelaxation was reduced in allografts at post-Tx days 7 and 14, whereas in syngeneic grafts EC-dependent relaxation was unaffected at any time after Tx. In separate grafts collected at the same time points, massive leukocyte adhesion at post-Tx day 7 and EC denudation at days 14 and 28 were evident in allografts but not in syngeneic grafts. At post-Tx day 56 (a time at which vessel wall remodeling is pronounced in this model), an intact EC layer covered the grafts. EC dysfunction and morphological changes were prevented by immunosuppression of recipient rats with cyclosporine. Our study shows that Tx-induced EC dysfunction in rat aortic allografts can be observed within 1 week of Tx in rat aortic allografts and that this is occurring concomitantly with enhanced leukocyte adhesion to the graft ECs. These changes occur before any other morphological or functional changes described thus far in this model and appear to be immune-driven. Taken together, these results show that Tx-induced early EC dysfunction, as described in patients, may be studied in the model of rat aortic Tx.
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PMID:Endothelial dysfunction and denudation in rat aortic allografts. 1114 35

Homocysteine is an independent risk factor for atherosclerotic vascular disease. It impairs endothelial function via increasing superoxide production and quenching nitric oxide (NO) release. Tetrahydrobiopterin (BH4) is a critical cofactor that couples nitric oxide synthase and facilitates the production of nitric oxide (vs. superoxide anions). In the first study, the effects of hyperhomocysteinemia (0.1 mM, 3 h) on endothelium-dependent vasorelaxation to ACh and A23187 were examined in isolated segments of rat aortae in the presence or absence of BH4 (0.1 mM). In the second study, the effects of hyperhomocysteinemia (24 h) on nitric oxide production and superoxide release (using lucigenin chemiluminescence) were studied in human umbilical vein endothelial cells in the absence or presence of BH4 (10 microM). Homocysteine incubation impaired receptor-dependent and -independent endothelial function to ACh and A23187. This effect was attenuated by BH4. Furthermore, homocysteine exposure increased superoxide production and impaired agonist-stimulated nitric oxide release. These effects were attenuated by BH4 (p < 0.05). Hyperhomocysteinemia impairs endothelial function, in part due to a diminished bioavailability of BH4 with resultant uncoupling of nitric oxide synthase. BH4 may represent an important target for strategies aimed at improving endothelial dysfunction secondary to hyperhomocysteinemia.
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PMID:Tetrahydrobiopterin attenuates homocysteine induced endothelial dysfunction. 1284 52

Coronary spasm plays an important role in the pathogenesis of not only variant angina but also coronary heart disease in general including acute coronary syndromes. The incidence of coronary spasm in Japanese patients with angina pectoris was about 40%. The total number of patients with angina pectoris increases with old age. The patients' age distribution was relatively younger in the coronary spasm than in the stable effort angina. The vascular endothelium has been reported to be a multifunctional organ whose integrity is essential to normal vascular physiology, and whose dysfunction can be a critical factor in the pathogenesis of vascular disease. Acetylcholine and methacholine cause vasodilation by endothelium-derived relaxing factor when endothelium is functioning normal, whereas they cause vasoconstriction when endothelium is removed or damaged. Coronary spasm can be induced by acetylcholine and methacholine. The patients with coronary spasm may have a disturbance in the endothelial function of the coronary arteries.
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PMID:Endothelial dysfunction and coronary artery spasm. 1503 50

Erectile dysfunction (ED) is another manifestation of vascular disease. We evaluated the natural history of ED in the spontaneously hypertensive rat (SHR) and the respective participation of associated pathophysiological modifications, i.e., endothelial dysfunction and tissue remodeling. SHR and their normotensive counterparts [Wistar-Kyoto rats (WKY)] of 6, 12, and 24 wk of age (n = 12) were used to evaluate erectile function, erectile and aortic tissue reactivity, and remodeling. Erectile responses in SHR are reduced at all ages (P < 0.001). In both aortic and erectile tissues of SHR and WKY, relaxations to ACh are altered progressively with age, although more markedly in SHR. They are decreased at 12 wk of age in erectile tissue of SHR compared with WKY (maximal relaxation: -19.2 +/- 2.8% vs. -28.3 +/- 3.9%, P < 0.001) but only at 24 wk of age in aortas (-47.9 +/- 6.4% vs. -90.5 +/- 2.9%, P < 0.001). Relaxations to sodium nitroprusside are unaltered in aortic rings of both strains but enhanced in erectile tissue of SHR at 12 wk of age. Major modifications in the distribution of collagen I, III, and V in SHR occur in both types of tissue and are detectable sooner in erectile tissue compared with aortic tissue. The onset of ED is detectable before the onset of hypertension in the SHR. Structural and functional alterations, while similar, occur earlier in erectile compared with vascular tissue. If confirmed in humans, ED could be an early warning sign for hypertension, and common therapeutic strategies targeting both ED and hypertension could be investigated.
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PMID:Erectile dysfunction: an early marker for hypertension? A longitudinal study in spontaneously hypertensive rats. 1529 63

We evaluated the endothelial function of thoracic aortas and pulmonary arteries in a population of European wood mice (Apodemus sylvaticus), which exhibit hypercholesterolemia. According to the plasma cholesterol level, mice were divided into two groups: hypercholesterolemic (AHL, total plasma cholesterol 200-300 mg/dl) and normocholesterolemic (ANL, total plasma cholesterol <200 mg/dl). Acetylcholine (ACh) caused endothelium-dependent relaxation of precontracted aortas and pulmonary arteries. Relaxation of the pulmonary artery is completely dependent on nitric oxide. This relaxation was inhibited in AHL pulmonary arteries. On the other hand, part of the ACh-induced relaxation of the thoracic aorta was resistant to N(omega)-nitro-L-arginine (L-NNA). L-NNA-sensitive and -resistant relaxation to ACh were also inhibited in AHL aortas. Inhibition of endothelium-dependent relaxation of the aortas was correlated with total plasma cholesterol level. Endothelium-independent relaxation to sodium nitroprusside (SNP) was similar in AHL and ANL pulmonary arteries, but in the thoracic aorta of AHL mice, the sensitivity to SNP was slightly decreased, without a change in maximal response to SNP. No morphological change was observed in the aortas and the pulmonary arteries from AHL and ANL mice. Thus, AHL mice are valuable as a new experimental model to study the relation of hyperlipidemia to vascular disease since the endothelial function is impaired in these mild hyperlipidemic animals.
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PMID:Impairment of endothelium-dependent relaxation of aortas and pulmonary arteries from spontaneously hyperlipidemic mice (Apodemus sylvaticus). 1761 85


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