Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The role of nitric oxide (NO) in the control of coronary blood flow (CBF) during the development of diabetes is unknown. To study this, mongrel dogs were chronically instrumented using sterile techniques for measurements of systemic hemodynamics and CBF. With heart rate controlled (150 beats/min), veratrine (1-10 micrograms/kg) caused dose-dependent increases in CBF; e.g., 5 mirograms/kg of veratrine increased CBF by 57 +/- 7% from 41 +/- 1.3 ml/min (P < 0.05). The dogs developed diabetes 4-5 wk after injection of alloxan (40-60 mg/kg iv, blood glucose levels were 384 +/- 18 mg/dl). After diabetes the same doses of veratrine caused smaller increases in CBF; i.e., 5 micrograms/kg of veratrine increased CBF by 32 +/- 2% (P < 0.05 compared with control) from 28 +/- 4 ml/min. ACh- and adenosine-induced coronary vasodilation were reduced after diabetes as well. In anesthetized dogs after diabetes, vagal stimulation caused smaller increases in CBF. ACh and bradykinin caused smaller increases in NO(-)(2) production in coronary microvessels from diabetic dogs. Furthermore, despite the fact that mRNA for endothelial cell NO synthase from the aorta was increased twofold with the use of Northern blotting, the protein for aortic endothelial constitutive NO synthase was reduced by 66% after diabetes, as determined by Western blotting. Our results indicate that the NO-dependent coronary vasodilation by the Bezold-Jarisch reflex is impaired in conscious dogs after diabetes. The mechanism responsible for the impaired endothelium-dependent coronary vasodilation is most likely the decreased release of NO from the endothelium.
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PMID:Reduced coronary NO production in conscious dogs after the development of alloxan-induced diabetes. 1040 6

Experiments were designed to investigate the effects of chronic administration of an NO donor, (+/-)-(E)-ethyl-2-[(E)-ethylhydroxyimino]-5-nitro-3-hexeneamide (FK409), on the impairment of the acetylcholine-induced endothelium-dependent relaxations of the aorta, perfused mesenteric arterial bed and perfused kidney that seen in streptozotocin-induced diabetic rats. In aortic strips and in the perfused kidney, the decreased acetylcholine-induced relaxation seen in diabetes was restored to normal by chronic (daily for 4 weeks) administration of FK409 (20 mg/kg or 10 mg/kg, respectively). Acetylcholine increased the NOx (NO2- and NO3-) level in the perfusates from aortic strips, the perfused kidney and the perfused mesenteric arterial bed. These increases were significantly weaker for diabetic rats than for the controls. This effect of diabetes was ameliorated by chronic administration of FK409 (20 mg/kg) in aortic strips and perfused kidney, but not in the perfused mesenteric arterial bed. These results demonstrate that chronic administration of the novel NO releaser FK409 can improve diabetes-impaired endothelium-dependent vasodilatation in the rat aorta and perfused kidney.
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PMID:Effects of chronic treatment with the spontaneous nitric oxide releaser FK409 on vascular responses in established streptozotocin-induced diabetic rat. 1050 39

Zucker rats are a useful model in which to define the mechanisms that link obesity to diabetes and associated cardiovascular disease. The present study tests the hypothesis that diabetic obese (compared with nondiabetic lean) Zucker rats are hypertensive and display a further increase in arterial pressure when fed a high salt diet. Male, nondiabetic lean and diabetic obese Zucker rats were chronically instrumented with telemetry probes and fed a basal salt diet for 3 weeks followed by exposure to a high salt diet for 11 days. On the basal diet, obese (vs lean) rats had significantly higher arterial pressures ( approximately 13 mm Hg), and the high salt diet significantly elevated mean arterial pressure (MAP) in obese (but not lean) Zucker rats ( approximately 12 mm Hg). Blockade of the sympathetic nervous system with hexamethonium caused a significantly larger decrease in MAP in obese (vs lean) Zucker rats fed the basal diet (51 vs 33 mm Hg), but the high salt diet did not increase the hexamethonium-induced reduction in arterial pressure in obese rats. Acute blockade of angiotensin receptors with losartan resulted in similar decreases in MAP in both groups on either diet. Acetylcholine-induced vasodilatory capacity of the carotid artery was significantly less in the obese (vs lean) Zucker rats. Together these data indicate that increased sympathetic nervous system activity and decreased vascular reactivity may contribute to elevated arterial pressure in type 2 diabetic, obese Zucker rats, but the sympathetic nervous system does not appear to contribute to the dietary salt-sensitive hypertension in this model.
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PMID:Elevated sympathetic activity contributes to hypertension and salt sensitivity in diabetic obese Zucker rats. 1064 32

Estrogen deficiency is one of the factors involved in the stress incontinence in postmenopausal women, and estrogens have been used clinically in the treatment of urinary disorders during menopause. Sex hormones seem to be also involved in the diabetic changes of urinary bladder and urethra, because ovariectomy causes an increase in the micturition of streptozotocin-diabetic rats. In the present study diabetic and healthy female rats were used to investigate the effect of 17beta-estradiol on mechanical contractions to norepinephrine and to KCI and relaxations to ATP on isolated proximal urethral preparations as well as on contractions to ACh, ATP and KCl on detrusor smooth muscle strips. The data were compared with those obtained in OVX animals, with or without estradiol replacement. The present study showed that ovariectomy decreased the responses to ATP, NE and KCl in urethral preparations, and responses to ATP, ACh and KCl in bladder strips from both healthy and diabetic rats. Diabetes appeared to potentiate the effect of ovariectomy in both tissues. Estrogen replacement was able to recover functional responses in urethras of healthy rats. In diabetic rats, this treatment partially restored ATP-induced responses in both tissues, almost completely restored those to NE in urethra and those to ACh in bladder. This study clearly indicated that abnormalities of urethra and bladder function caused by ovariectomy can be restored by estrogen treatment also in diabetic animals, at least at an early stage of disease.
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PMID:Diabetes influences the effect of 17beta-estradiol on mechanical responses of rat urethra and detrusor strips. 1079 17

Our previous study indicated that nitric oxide (NO)-dependent coronary vasodilation was impaired in conscious dogs with diabetes. Our goal was to determine whether modulation of O(2) consumption by NO is depressed in canine cardiac muscle after diabetes. Diabetes was induced by injection of alloxan (40-60 mg/kg iv), dogs were killed after diabetes was induced (4-5 wk), and the cardiac muscle from the left ventricle was cut into 15- to 30-mg slices. O(2) uptake by the muscle slices was measured polarographically with a Clark-type O(2) electrode. S-nitroso-N-acetylpenicillamine decreased O(2) consumption in normal and diabetic tissues (10(-4) M, 61 +/- 7 vs. 61 +/- 8%, P > 0.05). Bradykinin (10(-4) M)- or carbachol (CCh, 10(-4) M)-induced inhibition of O(2) consumption was impaired in diabetic tissues (51 +/- 6 vs. 17 +/- 4% or 48 +/- 4 vs. 19 +/- 3%, respectively, both P < 0.05 compared with normal). The inhibition of O(2) consumption by kininogen or kallikrein was depressed in diabetic tissues as well. In coronary microvessels from diabetic dogs, bradykinin or ACh (10(-5) M) caused smaller increases in NO production than those from normal dogs. Our results indicate that the modulation of O(2) consumption by endogenous, but not exogenous, NO is depressed in cardiac muscle from diabetic dogs, most likely because of decreased release of NO from the vascular endothelium.
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PMID:Depressed modulation of oxygen consumption by endogenous nitric oxide in cardiac muscle from diabetic dogs. 1092 49

Gastrointestinal symptoms in diabetic patients are commonplace, and are believed to be due, at least partly, to neuropathy of the gut. In the present study, therefore, some important neurotransmitters in the myenteric plexus were investigated in non-obese diabetic mice, an animal model of human type 1 diabetes. For this purpose, immunocytochemistry was applied on sections from antrum, duodenum and colon, subsequently quantified by computerized image analysis. Whereas the number of vasoactive intestinal peptide (VIP)-positive neurons was increased in antral myenteric ganglia of diabetic mice, there was a decreased density of nerve fibres in muscularis propria. No difference was seen in the VIP of duodenum and colon. Acetylcholine-containing nerve fibres showed an increased volume density in muscularis propria of antrum and duodenum, but a decreased density in colon of diabetic mice, as compared with controls. There was a decreased number of neurons containing nitric oxide synthase (NOS) in myenteric ganglia of antrum and duodenum. No difference was seen in density of NOS-containing nerve fibres in muscularis propria. There was no difference regarding neuropeptide Y (NPY) and galanin between diabetic and control mice; nor was there any difference between pre-diabetic NOD mice and controls regarding all bioactive substances investigated. It is concluded that the diabetic state affects the innervation of gut in this animal model. The present findings may be of some relevance to the gastrointestinal symptoms seen in patients with diabetes.
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PMID:Diabetic state affects the innervation of gut in an animal model of human type 1 diabetes. 1096 18

The effect of chronic treatment with the angiotensin converting enzyme inhibitor, temocapril, on prevention of endothelial dysfunction was evaluated in an experimental model of diabetes mellitus. Endothelium-dependent relaxation to acetylcholine was impaired while endothelium-independent relaxation to nitroglycerin was unaltered in diabetic aortic ring segments. Treatment of diabetic animals with temocapril prevented the impaired endothelium-dependent relaxation without altering responses to nitroglycerin. Acetylcholine-induced relaxation was largely due to nitric oxide (NO)-mediated relaxation; however, a small but significant portion of relaxation in aortic rings from temocapril-treated diabetic rats was resistant to inhibition by the nitric oxide synthase (NOS) inhibitor, L-nitroarginine.
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PMID:Temocapril, an angiotensin converting enzyme inhibitor, protects against diabetes-induced endothelial dysfunction. 1096 53

The aim of the present work was to analyze whether the oral hypoglycemic drug gliclazide affects diabetic endothelial dysfunction in streptozotocin-induced diabetic rats. Gliclazide was compared with glibenclamide, ascorbic acid, and aminoguanidine. An insulin-dependent model of diabetes was selected to exclude insulin-releasing effects of the drugs. Both in isolated aortic segments and mesenteric microvessels, endothelium-dependent relaxation evoked by acetylcholine (ACh, 1 nM to 10 microM) was significantly reduced in vessels from diabetic animals. This impairment was reversed when the segments were previously incubated with 100 U/ml superoxide dismutase. When streptozotocin-induced diabetic rats were orally treated from the time of diabetes induction with gliclazide (10 mg/kg) or ascorbic acid (250 mg/kg), ACh-induced endothelium-dependent relaxation was well preserved both in aortic segments and mesenteric microvessels. In addition, the impaired vasodilatation to exogenous nitric oxide (NO) in aortic segments was also improved in gliclazide-treated diabetic rats. On the other hand, oral treatment with glibenclamide (1 and 10 mg/kg) or aminoguanidine (250 mg/kg) did not produce significant improvements in diabetic endothelial dysfunction. We conclude that gliclazide reverses the endothelial dysfunction associated with diabetes. This effect appears to be due not to the metabolic actions of the drug but rather to its antioxidant properties, as it can be mimicked by other antioxidants. We propose that the mechanism involved is the inactivation of reactive oxygen species, which are increased in diabetes probably as a result of increased early protein glycosylation products, such as glycosylated hemoglobin (HbA(1c)). These effects of gliclazide are not shared by other oral hypoglycemic agent such as glibenclamide, or by blockade of advanced glycosylation end product (AGE) generation with aminoguanidine.
J Diabetes Complications
PMID:Prevention of endothelial dysfunction in streptozotocin-induced diabetic rats by gliclazide treatment. 1100 32

We investigated the changes in arterial blood pressure (BP) and of mesenteric arterial bed (MAB) responsiveness that accompany streptozotocin (STZ)-induced diabetes. BP was recorded by radiotelemetry in conscious animals before and during a 4-week period following induction of the diabetic state with STZ. At the end of this period, the MAB was isolated and perfused under constant flow conditions: perfusion pressure (PP, mmHg) was taken as an index of arteriolar tone. BP was lower (P < 0.05) in STZ-treated diabetic rats (82.9+/-5.0 mmHg) than in vehicle-treated rats (108.9+/-6.3 mmHg). Basal perfusion pressure of the MAB was lower in STZ-treated rats than in control rats and inhibition of nitric oxide (NO) synthesis with N(G)-nitro-L-arginine-methyl-ester and N(G)-nitro-L-arginine (100 microM each) failed to change this relationship. Increases in PP of MAB to phenylephrine (Phe), norepinephrine (NE), and potassium chloride (KCl) were reduced in STZ-treated rats compared with control rats. Inhibition of NO synthesis reduced responses to Phe, NE, and KCL in both STZ and control rats. The reduced responsiveness of STZ rats to Phe, NE, and KCl persisted after inhibition of NO synthesis. Acetylcholine (ACh) evoked relaxation of the MAB in a dose-dependent fashion. Maximal responses to ACh, but not sodium nitroprusside, were lower in STZ rats than in vehicle treated rats. Inhibition of NO synthesis reduced responses to ACh in both STZ and control rats. The reduced responsiveness of STZ rats to ACh persisted after inhibition of NO synthesis. The data demonstrate that STZ-induced diabetes is associated with a fall in blood pressure when pressure is recorded with radiotelemetry. The fall in blood pressure may be related to a non-specific decrease in responsiveness to vasoconstrictor stimuli mediated at least in part by NO-independent mechanisms. A decrease in responsiveness to endothelial dependent vasodilator mechanisms appeared insufficient to restore responsiveness to vasoconstrictor stimuli.
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PMID:Radiotelemetric monitoring of blood pressure and mesenteric arterial bed responsiveness in rats with streptozotocin-induced diabetes. 1100 35

We examined endothelium-dependent relaxation in the aortas and renal arteries of Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a model of non-insulin-dependent diabetes mellitus, in comparison with non-diabetic Long-Evans Tokushima Otsuka rats as controls. Acetylcholine-induced relaxation in both arteries was attenuated, and the attenuation was restored to the control level by indomethacin. The relaxation was inhibited completely in the aortas, but only partially in renal arteries by N(G)-nitro-L-arginine methyl ester, and the degree of the latter inhibition was greater in OLETF rats than in the controls. The relaxation was inhibited by aminoguanidine in both arteries of OLETF rats but not in the controls. Serum NO(2) plus NO(3) levels significantly increased in OLETF rats. These results suggest that impairment of relaxation in OLETF rat arteries is due to increased release of contractile factors but not decreased release of nitric oxide.
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PMID:Altered endothelium-dependent responsiveness in the aortas and renal arteries of Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a model of non-insulin-dependent diabetes mellitus. 1112 Mar 82


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