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)

To investigate the intrarenal endothelin 1 (ET-1) synthesis in streptozocin (STZ) diabetic rats with moderate hyperglycemia, we measured plasma ET-1, renal ET-1 mRNA, and renal tissue ET-1 levels. The renal ET-1 mRNA expression progressively decreased from the 2nd to the 6th week after induction of diabetes by STZ. The renal ET-1 mRNA expression and the renal tissue ET-1 content were significantly reduced in 8 diabetic rats with a mean blood glucose level of 21.0 +/- 0.4 mM as compared with 7 normal rats sacrificed at the 6th week after STZ or citric buffer injection. The reduction of renal ET-1 and mRNA levels was ameliorated in 9 diabetic rats with a mean blood glucose level of 6.9 +/- 0.7 mM after strict glycemic control by insulin treatment. Kidney weight and glomerular filtration rate in moderately hyperglycemic rats were significantly increased as compared with normal rats at the 6th week after STZ injection. The mean plasma ET-1 levels in moderately hyperglycemic diabetic rats were not different from those of the other two groups. This study demonstrates that moderate hyperglycemia in diabetic rats is associated with a reduction in renal ET-1 synthesis. Whether decreased renal ET-1 synthesis is an adaptive phenomenon of a renal hemodynamic change during the early stage of diabetes is worthy of further investigation.
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PMID:Decrease of renal endothelin 1 content and gene expression in diabetic rats with moderate hyperglycemia. 747 56

The effects of non-insulin-dependent diabetes mellitus (NIDDM) were investigated on the reactivity of human internal mammary artery (IMA) and saphenous vein (SV) rings obtained from coronary artery patients (CAP) undergoing coronary artery bypass surgery. In the presence of endothelium, the maximal contractile response and sensitivity (pD2) of IMA or SV to NA and ET-1 significantly increased in CAP with NIDDM relative to CAP only (controls). Removal of the endothelium markedly and significantly enhanced the maximal contractile response and sensitivity of IMA or SV to NA in CAP only, but did not induce a significant alteration in CAP with NIDDM compared to that in the presence of endothelium. The maximal contractile response and sensitivity of diabetic vessels with or without endothelium to NA were similar to values of corresponding vessels without endothelium obtained from nondiabetic CAP. The maximum contractions developed by NA or ET-1 were much greater in SV than that determinated in the IMA. Acetylcholine (ACh) and histamine produced endothelium-dependent relaxations in precontracted IMA and these effects of ACh and histamine significantly decreased in CAP with NIDDM. Endothelium-dependent relaxations stimulated by ACh were more pronounced in IMA than that determinated in the SV. In precontracted SV, histamine induced marked contractions that were significantly greater in CAP with NIDDM relative to CAP only. Endothelium-independent relaxations of vessels to sodium nitroprusside (SNP) were not influenced by NIDDM. Data indicate that NIDDM causes a deficit in the vasorelaxant activity of endothelium, leading to an increase in contractility of human IMA and SV. Data also suggest that IMA can be a better choice of graft for coronary occlusive disease than SV, specially in patients with NIDDM.
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PMID:Effects of non-insulin dependent diabetes mellitus on the reactivity of human internal mammary artery and human saphenous vein. 760 92

1. The effects of the non-selective endothelin (ET) receptor (ETA/ETB) antagonist, bosentan, on sciatic nerve dysfunction in experimental diabetes were investigated. 2. Rats with 5-6 weeks untreated streptozotocin-diabetes exhibited characteristic slowed motor nerve conduction velocity (mean +/- s.d., 36.6 +/- 3.4 m s-1) and nerve laser Doppler flux (197 +/- 64 arbitrary units) compared to age-matched control animals (42.7 +/- 2.4 m s-1 and 398 +/- 77 arbitrary units, respectively). Preventative treatment of diabetic rats with bosentan at 100 mg kg-1 day-1 p.o. attenuated both these deficits (39.7 +/- 3.0 m s-1 and 305 +/- 56 arbitrary units, respectively) without affecting mean arterial pressure. 3. In control and untreated diabetic rats, ET-1, 1 nmol kg-1 i.v., caused an initial hypotension (duration, 30 +/- 13 and 26 +/- 9 s, respectively; change in mean arterial pressure, -27 +/- 13 and -25 +/- 7 mmHg, respectively) followed by prolonged hypertension (change in mean arterial pressure, 52 +/- 18 and 31 +/- 5 mmHg, respectively). Effectiveness of the chronic bosentan treatment was demonstrated by inhibition of the hypotensive response to ET-1 in treated diabetic rats (duration, 5 +/- 2 s; change in mean arterial pressure, -4 +/- 2 mmHg) although the hypertension was unaltered (change in mean arterial pressure, 32 +/- 9 mmHg). 4. Acute i.v. administration of 10 mg kg-1 bosentan caused variable and transient rises in nerve laser Doppler flux in control (78 +/- 63 arbitrary units) and untreated diabetic rats (93 +/- 77 arbitrary units). Acute bosentan blocked the hypotensive response to subsequent ET-1 administration and attenuated the later hypertension (change in mean arterial pressure, 21 +/-9 mmHg in control, 29 +/- 10 mmHg in diabetic).5. Our results indicate that oral treatment of diabetic rats with an ET receptor antagonist can improves ciatic nerve perfusion and conduction, suggesting that the vasoconstrictor action of endogenous ET may contribute to peripheral nerve dysfunction in experimental diabetes.
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PMID:Effects of endothelin receptor antagonism with bosentan on peripheral nerve function in experimental diabetes. 767 Jul 40

In diabetes, loss of renal arteriolar smooth-muscle cell contractility leads to intraglomerular hypertension. In glomeruli isolated from streptozotocin (STZ)-induced diabetic rats, the mesangial cells (smooth muscle-like) display loss of contractile responsiveness to angiotensin II. This study examines the mechanistic relationship between altered mesangial cell contractility and vasopressor hormone-stimulated Ca2+ signaling in high glucose. Glomeruli were isolated from normal or STZ-induced diabetic rats to observe ex vivo mesangial cell contractile function. Also, rat mesangial cells were cultured (10-20 passages) in normal (5.6 mmol/l) or high (10-25.6 mmol/l) glucose for 1-5 days. Reduction of glomerular volume and decreased planar surface area of cultured mesangial cells in response to vasoconstrictor stimulation over 60 min were measured by videomicroscopy and personal computer-based morphometry. Contraction of glomeruli isolated from STZ-administered rat in response to endothelin (ET)-1 (0.1 mumol/l) or the Ca2+ ionophore A23187 (5 mumol/l) was impaired significantly compared with that in normal glucose. In the presence of arginine vasopressin (AVP) (1.0 mumol/l) or ET-1 (0.1 mumol/l), mesangial cells demonstrated a dose-dependent loss of contractile response to increasing glucose concentrations (5.6-25.6 mmol/l) within 24 h of high-glucose exposure, which was sustained for 5 days. Mesangial cells in high glucose were consistently smaller in size compared with those in normal glucose. Mesangial cells were preloaded with myo-[2-3H]inositol and intracellular [3H] inositol phosphate release in response to AVP (1.0 mumol/l) was analyzed by Dowex chromatography. Comparing cells in normal (5.6 mmol/l) verus high (25.6 mmol/l) glucose, we observed no significant difference in stimulated inositol phosphate levels from 10 to 60 s.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1995 Jul
PMID:Glomerular mesangial cell altered contractility in high glucose is Ca2+ independent. 778 43

Insulin and insulin-like growth factor I (IGF-I) exhibit vasoactivity. To examine the role of the endothelium in mediating the vascular responses to insulin and IGF-I, we exposed both isolated intact rat mesenteric arteries and rat aortic rings to these growth factors in the presence and absence of endothelium. Perfusion of rat mesenteric arteries with insulin, IGF-I, or IGF-II resulted in the potentiation of arginine vasopressin (AVP)-induced vasoconstriction. Of these growth factors, IGF-I was the most potent, with a significant effect at 0.6 nM and maximal effects at 6.0 nM, followed by IGF-II and insulin. Endothelial denudation or addition of cycloheximide prevented the growth-factor effects. Tissue cGMP levels in the mesenteric artery were minimally affected by growth factors. Insulin and IGF-I vascular effects were not inhibited by BQ123, an endothelin (ET) antagonist that blocked ET-1 enhancement of AVP response. Perfusion of mesenteric arteries with IGF-I for 1 h did not alter vessel ET-1 or ET-1 mRNA contents. Addition of indomethacin markedly inhibited the IGF-I effect on AVP contraction. Thus, the mesenteric vascular effect of insulin and IGF-I is not associated with ET-1 release but appears to link to an increased release of an endothelial-derived contracting factor or the decreased production of an endothelial-derived relaxing factor from the cyclooxygenase pathway. In contrast to their action in the mesenteric artery, insulin (exceeding 100 nM) and IGF-I (1-30 nM) attenuated AVP- and norepinephrine-induced contraction in rat aortic rings. Endothelial-denudation abolished this effect.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1994 Aug
PMID:Endothelial-dependent vascular effects of insulin and insulin-like growth factor I in the perfused rat mesenteric artery and aortic ring. 803 96

Endothelin, a vasoconstrictor peptide secreted from endothelial cells, has been thought to play a role in various forms of vascular disease. Diabetes mellitus is well known for its association with accelerated atherosclerosis and microvascular damage. Although the basis for the vessel insult is multifactorial, hyperinsulinemia is thought to contribute by an unknown mechanism. In this study, we sought to determine whether insulin stimulates the production and secretion of ET-1 as a possible basis for the association of hyperinsulinemia and vascular disease. We demonstrated that insulin significantly stimulates the gene expression and secretion of ET-1 from cultured BAEC, and that insulin increases ET-1 mRNA expressed in BBCEC. Insulin caused a maximal twofold inducement above control ET-1 mRNA expression in a dose-related fashion in BAEC. The increased mRNA resulted from increased transcription, as determined by nuclear run-off studies. Increased ET-1 mRNA was seen after 4 h of incubation with insulin: the peak occurred at 6-8 h and persisted for 24 h. Insulin caused as much as a fourfold stimulation of ET-1 secretion from BAEC in a dose-related fashion, including a twofold increase at a physiological concentration (10(-9) M): The increase began at 1 h of incubation and continued for the entire 24-h incubation period. The insulin-induced increases in both ET-1 mRNA and ET-1 protein secretion were significantly attenuated by genistein, a tyrosine kinase inhibitor. This stimulation probably occurred through the insulin receptor, because IGF-1 had no effect on ET-1 gene expression or secretion from these cells.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1993 Feb
PMID:Insulin stimulates production and secretion of endothelin from bovine endothelial cells. 842 73

Endothelial cell damage, which is associated with local thrombin formation and inflammation, can lead to the release of endothelium-synthesized factors into plasma, such as vWFAg, TM, ACE and ET-1. These markers of endothelial damage are increased in some patients with diabetes mellitus, but the differences with normal are often small and not closely correlated with the severity of microvascular disease, as judged from the degree of albuminuria and the severity of retinopathy. Prorenin, which may also be related to abnormal endothelial cell function or endothelial damage, is elevated in many patients with diabetes, both type I and II, and its level is more closely correlated with the severity of microvascular disease. It is already elevated at an early stage. Further studies will reveal whether, in diabetes, an increased plasma prorenin is a reliable predictor of progressive microvascular disease. It is even conceivable that prorenin is not only a marker of diabetic microvascular disease but also has a role in its pathogenesis, via local proteolytic or non-proteolytic prorenin activation.
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PMID:Renin-angiotensin system components and endothelial proteins as markers of diabetic microvascular disease. 851 38

Microvascular disease is an important cause of morbidity in diabetes. There is evidence that impaired autoregulation of blood flow is involved in the pathogenesis of diabetic microangiopathy. The vascular endothelium plays a central role in the regulation of vascular tone. Endothelin (ET)-1 is a potent endothelium-derived vasoconstrictor substance that contributes to basal vascular tone. Impaired vasoconstriction in response to endogenous ET could result in hyperperfusion and subsequent microvascular damage. The purpose of our study was to determine whether vascular responses to locally administered ET-1 are impaired in NIDDM. Nine patients with NIDDM and 12 control subjects underwent cannulation of the nondominant brachial artery. Forearm blood flow (FBF) was measured at baseline and during the drug infusion using strain-gauge venous occlusion plethysmography. ET-1 (5 pmol/min) was infused for 60 min at a rate of 1 ml/min. FBF was measured during the first 5 min of the infusion and at 5-min intervals thereafter. Results were expressed as change in FBF from baseline (ml.100 ml-1.min-1) and were analyzed using repeated measures analysis of variance and Dunnett's test of multiple comparisons. Control subjects showed a gradual onset of vasoconstriction in response to ET-1, which reached maximum at 35 min (1.1 ml.100 ml-1.min-1; P < 0.01). There was no reduction in FBF in response to ET-1 in the diabetic group. The differences between the diabetic and control groups were significant (P < 0.03). In conclusion, ET-1 infused locally at 5 pmol/min does not cause vasoconstriction in patients with NIDDM.
Diabetes 1996 Jan
PMID:Impaired vasoconstriction to endothelin 1 in patients with NIDDM. 852 53

The effect of insulin to attenuate the Ca2+ and contractile response of vascular smooth muscle to a number of agonists has been described previously, but the Ca2+ regulatory mechanisms of insulin action remain unclear. We determined the effect of a physiological insulin concentration (300 pmol/l) on the Ca2+ response of vascular smooth muscle cells of the porcine right coronary artery to endothelin 1 (ET-1); furthermore, we examined the cellular Ca2+ stores affected by insulin (i.e., Ca2+ stores releasable by inositol 1,4,5-trisphosphate, caffeine, and ionomycin). We measured the Ca2+ responses of acutely isolated single smooth muscle cells with the fluorescent Ca2+ indicator Fura-2. Acute insulin exposure (20 min) significantly attenuated the Ca2+ response of single smooth muscle cells to 10 nmol/l ET-1. This inhibitory effect of insulin was observed both in the presence and absence of extracellular Ca2+. In contrast with the effects on ET-1-induced Ca2+ responses, insulin did not inhibit the Ca2+ response to 5 mmol/l caffeine, an agent that directly releases sarcoplasmic reticulum Ca2+ stores. Insulin was also without effect on the total cellular Ca2+ store released by 1 micromol/l ionomycin, a Ca2+-transporting ionophore. When ET-1 and caffeine were given in succession, a sizable caffeine-sensitive Ca2+ store could be released from insulin-treated cells but not control cells, indicating that the sarcoplasmic reticulum Ca2+ store of insulin-treated cells was not depleted by ET-1. Generalized depletion of the sarcoplasmic reticulum Ca2+ store is not one of the cellular mechanisms involved in the effect of insulin on coronary smooth muscle; instead, the effect may be due to an inhibitory influence on transmembrane signal transduction, such as diminished ET-1-induced inositol 1,4,5-trisphosphate production or reduced ability of this phosphoinositol to release stored Ca2+.
Diabetes 1996 Jul
PMID:Effects of a physiological insulin concentration on the endothelin-sensitive Ca2+ store in porcine coronary artery smooth muscle. 866 36

The normal functional state of the vasculature and the events leading to the development of significant arterial disease involve the interaction of important vasoactive substances, which play important modulating or initiating roles in the development of hypertension and arteriosclerosis. Three endothelins have now been identified, of which ET-1 is the best characterized. ET-1 is produced by epithelial, mesangial, neuronal and glial, and liver cells, and is the most potent vasoconstrictor yet found. Each endothelin is derived from a different gene on separate chromosomes, and each binds to at least 2 types of receptor. The plasma half-life of ET-1 is about 7 min, and this provides a rapid mechanism for adjusting vascular resistance or blood pressure. The actions of endothelin are mediated through several pathways of postreceptor signaling, including activation of the mitogen-activated protein kinase cascade, which give rise to its growth-stimulating properties. Secretion of ET-1 from cultured endothelial cells is stimulated by a wide range of substances, and is inhibited by some prostaglandins. Endothelin in turn stimulates secretion of nitric oxide, arginine vasopressin and atrial natriuretic peptide, and participates in the hormonal control of salt and water balance. Hypoxia and ischemia augment ET-1 secretion, as does insulin, and this could play a role in the accelerated vascular disease of diabetes. ET-1 also causes bronchoconstriction and has been implicated in the development of acute asthma, primary pulmonary hypertension and pulmonary fibrosis. Its role in hypertension is still debatable, though most of the manifestations of congestive heart failure can theoretically be explained by the actions of ET-1. Endothelin also has extensive renovascular and parenchymal effects in the kidney. It is hoped that a fuller understanding of the role of endothelins in normal or pathologic vasculature will lead to effective therapy based on antagonism or augmentation of specific functions.
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PMID:Endothelins as cardiovascular peptides. 873 84


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