UMLS:C0011849 - FACTA Search

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Query: UMLS:C0011849 (diabetes)
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To determine whether insulin has a vasodilator action on the artery and vein, the effects of insulin at varying concentrations (120 microU/ml, 1.2 mU/ml, 12 mU/ml, and 120 mU/ml) on vasoconstriction by norepinephrine (NE) and angiotensin II (ANG II) were studied in the isolated rabbit femoral artery and vein. Helical strips were suspended in an organ bath filled with modified Krebs solution (pH 7.4), were gassed with 95% O2/5% CO2 at 36 degrees C, and isotonic contractions were measured. Insulin significantly and dose dependently inhibited the vasoconstriction induced by NE (10(-8) M for the artery and 10(-7) M for the vein) at greater than or equal to 1.2 mU/ml for both the artery and vein and the vasoconstriction induced by ANG II (3 x 10(-10) M for the artery and 3 x 10(-9) M for the vein) at greater than or equal to 1.2 mU/ml for the artery and greater than or equal to 12 mU/ml for the vein. The results indicate that insulin has an inhibitory effect on NE- and ANG II-induced contraction in both the artery and vein, and this appeared to be a contributory factor in the hypotensive effect observed in diabetic patients treated with insulin.
Diabetes 1988 Aug
PMID:Effects of insulin on vasoconstrictive responses to norepinephrine and angiotensin II in rabbit femoral artery and vein. 329 27

Hypertonic saline (HS) and angiotensin II (ANG II) administered centrally or peripherally produce a forebrain-mediated central nervous system-(CNS) dependent pressor action. Although the majority of these effects are due to increased central sympathetic drive and inhibition of the cardiac baroreceptor reflex, evidence from peripheral infusions of vasopressin (Vp) receptor antagonists have suggested that part of the blood pressure increase may be due to circulating Vp. We now report that blockade of CNS Vp receptors in rats, via a fourth ventricle infusion of a Vp receptor antagonist, attenuated greater than 70% of the pressor response to lateral ventricle infusion of HS, ANG II, or hypertonic glucose (HG). Intravenous administration of the Vp antagonist could block only 40% of the HS response. When lateral ventricle infusion of HS was performed in rats with a hereditary lack of Vp (diabetes insipidic rats) no pressor response was obtained. Because centrally administered Vp has autonomic nervous system effects that are similar to those induced by HS or ANG II, our results suggest that CNS Vp may provide a link between forebrain acting pressor agents and autonomic nervous system regulation. Finally, HG produced a pressor effect that had an equivalent peak response to HS. However, unlike the HS response, the pressor effect to HG returned to base line within approximately 5 min during a 10-min infusion. Thus there appears to be a quantitative difference in the pressor responses produced by activation of sodium vs. osmoreceptors.
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PMID:Activation of the central vasopressin system: a common pathway for several centrally acting pressor agents. 375 82

Density and affinity of glomerular angiotensin II (ANG II) receptors were determined in normal, untreated, and insulin-treated streptozotocin-diabetic rats 3-4 wk after the onset of diabetes mellitus. With low, intermediate, and high salt intake, angiotensin II receptor density varied inversely with the plasma renin concentration (PRC) in normal, insulin-treated, and untreated diabetic rats. PRC values with all three dietary regimens were lower in the untreated diabetic rats when compared with the other groups. Despite lower plasma renin concentration, however, untreated diabetic rats were also found to have significantly lower glomerular ANG II receptor concentrations at all levels of salt intake. On a normal salt intake, glomerular ANG II receptor density was reduced significantly in untreated diabetic rats (853 +/- 74 (SE) fmol/mg protein), compared with insulin-treated diabetic rats (1,185 +/- 118 fmol/mg) and normal controls (1,058 +/- 83 fmol/mg). ANG II receptor affinity did not change with alternations in salt intake or degree of diabetic control. Reduced glomerular ANG II receptor density in the presence of a suppressed renin-ANG II axis may underlie the altered renal vascular responsiveness to ANG II known to occur in diabetes mellitus.
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PMID:Reduced glomerular angiotensin II receptor density in early untreated diabetes mellitus in the rat. 633 Nov 95

Angiotensin converting enzyme (ACE) inhibitors not only reduce angiotensin II (ANG II) levels but also inhibit kinin degradation. The relative roles of ANG II and bradykinin in the acute action of ACE inhibitors on renal hemodynamic parameters in rats after 3 wk of diabetes were explored using antagonists of the ANG II type 1 (AT1) and the bradykinin B2 receptors. Conscious control and streptozotocin diabetic male Sprague-Dawley rats were randomized to receive vehicle, the ACE inhibitor, ramiprilat, the B2-receptor blocker, HOE-140, the AT1-receptor blocker, valsartan, or the combination of ramiprilat and HOE-140. Systolic blood pressure, glomerular filtration rate (GFR), renal plasma flow (RPF), filtration fraction and urinary flow, and sodium excretion were assessed before and during treatment. Diabetic animals had higher GFR and a tendency toward increased RPF and filtration fraction compared with control animals. Acute ramiprilat infusion decreased GFR significantly in diabetic but not in control animals. Valsartan and the combination of ramiprilat and HOE-140 reduced blood pressure to a similar degree to ramiprilat alone, yet did not reduce GFR. No decrease in GFR was observed in any control rat groups. Ramiprilat decreased RPF in diabetic rats but increased RPF in control rats. No such effects on RPF were observed with valsartan. HOE-140 alone did not influence any renal parameter in the diabetic rats. Diabetic rats had increased urinary flow and sodium excretion, but these parameters were not influenced by any drug regimen.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Acute renal hemodynamic effects of ACE inhibition in diabetic hyperfiltration: role of kinins. 773 15

There is evidence that the renin-angiotensin system may be involved in the metabolic as well as the cardiovascular features of diabetes and that pressor doses of angiotensin II (ANG II) increase insulin sensitivity in parallel with blood pressure (BP) in healthy subjects, but the effects of ANG II on insulin sensitivity have not been previously reported in patients with non-insulin-dependent diabetes mellitus (NIDDM). In a randomized, double-blind, placebo-controlled, crossover study, 11 patients with NIDDM attended 3 study days to evaluate the effects of a 3-h infusion of subpressor and pressor doses of ANG II on whole body insulin sensitivity using the euglycemic hyperinsulinemic clamp. BP and heart rate were recorded, and blood samples were collected for serum insulin, C-peptide, potassium, catecholamines, plasma renin activity, and plasma ANG II concentrations. Plasma levels of ANG II (means +/- SD) were 9 +/- 4, 29 +/- 9, and 168 +/- 47 pmol/ml after placebo, low dose infusion, and high dose infusion, respectively. The higher dose of ANG II was associated with significant increases in BP (e.g., 18 mmHg systolic BP at 150 min) and plasma aldosterone. Whole body insulin sensitivity was 23.8 +/- 12.7 mumol glucose.kg-1.min-1 after placebo and 30.6 +/- 12.7 and 27.2 +/- 13.3 following low and high dose ANG II infusions, respectively (P < 0.05, analysis of variance). In summary, acute infusion of ANG II, with or without an increase in BP, increases insulin sensitivity in normotensive patients with NIDDM.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1994 Dec
PMID:Pressor and subpressor doses of angiotensin II increase insulin sensitivity in NIDDM. Dissociation of metabolic and blood pressure effects. 795 97

Recent evidence indicates a role for the renin-angiotensin system (RAS) in the pathogenesis of glomerular injury in diabetes. To further explore the RAS in diabetes, studies were conducted in nondiabetic control rats and in moderately hyperglycemic diabetic (DM) rats. In DM rats, both acute and chronic therapy with the specific angiotensin II (ANG II) receptor antagonist losartan did not affect glomerular hyperfiltration or hyperperfusion but selectively normalized the glomerular capillary hydraulic pressure and ultrafiltration coefficient. To determine the basis of intrarenal hemodynamic responsiveness to RAS inhibition, we conducted biochemical, molecular biological, and immunohistochemical studies to assess endogenous RAS activity. Values for plasma renin concentration and serum angiotensin-converting enzyme (ACE) activity in DM rats were normal. In contrast, intrarenal renin protein content, and renin and angiotensinogen mRNAs, were increased in DM rats, suggesting disproportionate activation of the intrarenal RAS. Total renal ACE activity was significantly reduced in DM rats, but immunohistochemical studies indicated redistribution of ACE in the diabetic kidney. Proximal tubule ACE activity was reduced, but ACE immunostaining intensity was enhanced in glomeruli and renal vasculature. Together, these observations indicate increased RAS activity in those sites (glomeruli and vasculature) most likely to regulate hemodynamic function, potentially explaining the prominent responses to pharmacological blockade of ANG II formation and/or action.
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PMID:Renal renin-angiotensin system in diabetes: functional, immunohistochemical, and molecular biological correlations. 823 77

Genotypic abnormalities of the renin-ANG system have been suggested as a risk factor for the development of diabetic nephropathy. Cleavage of angiotensinogen is the rate-limiting step in the activation of the renin-ANG system. The TT genotype of a polymorphism encoding threonine instead of methionine (M235T) has been associated not only with increased plasma angiotensinogen concentration but also with essential hypertension. In addition, a polymorphism in the angiotensinogen gene substituting methionine for threonine (T174M) has been associated with hypertension in nondiabetic populations. We studied the relationship between these polymorphisms in the angiotensinogen gene in IDDM patients with diabetic nephropathy (121 men, 74 women, age 40.9 +/- 10 years, diabetes duration 27 +/- 8 years). There was no difference in M235T genotype distribution between IDDM patients with diabetic nephropathy and those with normoalbuminuria: 73/97/25 (37/50/13%) vs. 67/95/23 (36/52/12%) had MM/MT/TT genotypes, respectively. No difference in distribution of T174M genotypes between nephropathic and normoalbuminuric IDDM patients was observed either: 148/44/1 (77/23/0.5%) vs. 141/42/2 (76/23/1%) had TT/TM/MM genotypes, respectively. In patients with nephropathy, systolic blood pressure was higher (161 +/- 22 mmHg [mean +/- SD]) in patients carrying TT genotype of the M235T angiotensinogen polymorphism as compared with patients with MM or MT genotypes (150 +/- 23 mmHg; P = 0.03). We conclude that neither the M235T nor the T174M polymorphism in the angiotensinogen gene contributes to genetic susceptibility to diabetic nephropathy in white IDDM patients, whereas the TT genotype of the M235T is associated with elevated blood pressure in patients with diabetic nephropathy.
Diabetes 1996 Mar
PMID:Angiotensinogen gene polymorphisms in IDDM patients with diabetic nephropathy. 859 44

The effect of 4 weeks streptozotocin-induced diabetes on ocular vascular resistance responses to noradrenalin (NA), adrenalin (A), phenylephrine (PHE), isoproterenol (ISOP), prostaglandin F2 alpha (PGF2 alpha). 5-hydroxytryptamine (5-HT) and angiotensin II (ANG II), was determined using a newly-developed, isolated, arterially-perfused rat eye preparation, by comparing responses from control and diabetic eyes. After extensive preliminary experiments to establish optimum parameters, the ophthalmic artery of enucleated control and diabetic rat eyes was cannulated and the retinal and uveal vasculature perfused at a constant flow with Na(+)-Krebs solution after streptozotocin-induced diabetes had been established for 4 weeks. The eyes were maintained in an environment-controlled organ bath. Perfusion pressure was monitored as increasing log M concentrations of agonists were added to the perfusate. Total ocular resistance could be calculated from knowledge of flow and pressure. In control eyes, NA, A, PHE, PGF2 alpha, and 5-HT all produced dose-dependent increases in total vascular resistance, with the following order of potency: NA = A > 5-HT > PHE = PGF2 alpha at 10(-4) M. The ocular circulation was not sensitive to isoproterenol and angiotensin II. In diabetic eyes responses to NA, A, PGF2 alpha and 5-HT were altered. Diabetic responses to NA and A had lower thresholds with larger resistance increases at low concentrations. However, the rate of increase in resistance with concentration was more gradual in diabetic eyes so that at 10(-4) M control responses were larger. Diabetic resistance responses to PGF2 alpha had the same threshold as in control eyes, but were greater in magnitude with an earlier peak at 10(-4) M. In contrast diabetic resistance responses to 5-HT were reduced, peaked at a lower resistance at 10(-4) M, but had the same threshold as those in the control eye. Basal vascular resistances in control: 3.14 +/- 0.32 mmHg min microliter-1 (n = 28), and diabetic eyes: 3.44 +/- 0.19, mmHg min microliter-1 (n = 36), were not significantly different. Vasoactivity in the early diabetic eye is disturbed with the effective balance between different agonists altered in favour of catecholamines at physiological concentrations. This may be related to the early changes in blood flow and oxygen distribution already reported in the rat eye, as well as changes to autonomic function. The isolated perfused rat eye is a valuable technique for investigating such vascular reactivity in animal models of retinal disease.
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PMID:Altered vasoactivity in the early diabetic eye: measured in the isolated perfused rat eye. 884 42

Accumulation of matrix proteins is a prominent feature of diabetic nephropathy. Glomerular visceral epithelial cells (GVECs) are important contributors to extracellular matrix (ECM) production in the glomerulus. Factors involved with increased accumulation of ECM proteins are high glucose, angiotensin II (ANG II), and transforming growth factor (TGF)-beta. Therefore, we investigated the effects of high glucose and ANG II on fibronectin and TGF-beta production by human GVECs in vitro. We found that ANG II had no effect on the production of fibronectin and TGF-beta by GVECs. Using reverse transcriptase-polymerase chain reaction analysis, no ANG II receptor could be detected on these cells. However, high glucose induced a twofold increase in fibronectin (P < 0.01) and a three- to sixfold increase in TGF-beta (P < 0.001) production. Similar results were obtained by analyzing the mRNA levels of fibronectin (increased 2.7-fold) and TGF-beta (increased 3.5-fold). Addition of increasing concentrations of rTGF-beta to control cells resulted in increased fibronectin production. Neutralizing antibodies against TGF-beta significantly reversed the increase in fibronectin protein and mRNA caused by high glucose back to control levels. We conclude that high glucose concentrations stimulate the synthesis of fibronectin and that this effect is mediated by induction of TGF-beta. These results suggest that in diabetic nephropathy, high glucose levels play a role in changing the matrix composition of the glomerular basement membrane through induction of TGF-beta. Our results indicate that a contribution to this process by an effect of ANG II on GVECs seems unlikely.
Diabetes 1997 May
PMID:Regulation of glomerular epithelial cell production of fibronectin and transforming growth factor-beta by high glucose, not by angiotensin II. 913 52

Classically, the renin-angiotensin system (RAS) in diabetes was thought to be suppressed, and relatively unimportant in the regulation of hemodynamics and the development of complications. However, recent developments have caused reconsideration of this notion. Studies of pharmacological interruption of the RAS with angiotensin converting enzyme (ACE) inhibition have implicated this hormonal system in the progression of diabetic nephropathy, both experimentally and clinically. Preliminary evidence also suggests a beneficial effect of angiotensin II (ANG II) receptor antagonists. The relative roles of the systemic versus intrarenal RAS in the pathogenesis of diabetic nephropathy have recently been evaluated. Although plasma renin level is generally low, it is not yet clear whether RAS component processing is normal in diabetes; there may be subtle changes in ANG II metabolism that sustain relatively higher plasma ANG II levels. Furthermore, the intrarenal RAS may not be suppressed. Renal renin levels tend to be disproportionately elevated, as compared with plasma renin values. Renal ANG II levels are normal, and renal mRNAs for RAS components have been variable. In general, lack of RAS suppression (despite plasma volume and increased exchangeable sodium) may indicate inappropriate activity of the RAS in diabetes. RAS-mediated injury may occur via stimulation of a number of sclerosing mediators, and there is evidence that hyperglycemia acts synergistically with ANG II to promote cellular injury. Finally, various RAS candidate genes for development of diabetic nephropathy have been examined and, although controversy remains, ACE gene polymorphisms may be involved. Together, these recent investigations lend further support to the notion that the RAS plays an important role in diabetic nephropathy, and are beginning to shed light on the mechanisms of progressive renal injury.
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PMID:Role of angiotensin II in diabetic nephropathy. 931 12

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