Polymorphism of gene encoding vascular angiotensin II receptor and microangiopathies in patients with insulin-dependent diabetes mellitus

Polymorphism A1166C of the AT1R gene encoding angiotensin vascular receptor [replacement of C (cytosine) for A (adenine)) at position 1166] was compared in patients with insulin-dependent diabetes mellitus (IDDM) complicated by diabetic nephropathy (DN) and in noncomplicated patients (n = 27 and n = 41, respectively) and also in patients with IDDM complicated by diabetic retinopathy (DR) and in correspondent noncomplicated individuals (n = 30 and n = 44, respectively). The frequency of AT1R gene alleles and genotypes in patients with IDDM complicated by DN did not differ significantly from that observed in patients with noncomplicated IDDM. In contrast, in patients with IDDM complicated by retinopathy, a significant decrease in the content of A allele (68.3% against 82.6%) and a significant increase in the content of C allele (31.7% against 17.4%) was found as compared with the control group. Thus, in the Moscow population, A1166C polymorphism of the AT1R gene is not associated with diabetic renal complications but indeed associated with diabetic retinal complications. C allele is a risk factor of DR (the relative risk, RR, is equal to 2.17), and A allele is, in contrast, a protective factor against early retinopathy development (RR is equal to 0.49).     

Adrenal sensitivity to angiotensin II and undiscovered aldosterone stimulating factors in hypertension

We have determined that the adrenal glands of patients with the syndromes of low-renin essential hypertension and idiopathic hyperaldosteronism are abnormally sensitive to the steroidogenic effect of angiotensin II. The mechanism of this heightened responsiveness to angiotensin II is unknown but may be due to the bilateral adrenal hyperplasia present in many patients with these low-renin hypertension syndromes. We have found that metoclopramide, a dopamine antagonist, causes three-fold increases in levels of plasma aldosterone in normal subjects. These increases could not be accounted for by changes in plasma renin activity, ACTH or potassium. Metoclopramide does not stimulate bovine adrenal glomerulosa cells to produce aldosterone in vitro, suggesting that it stimulates the secretion of aldosterone in vivo indirectly, by increasing the levels or the activity of an undefined aldosterone stimulating factor. We have also found that human urine, after partial purification, stimulates bovine adrenal glomerulosa cells to produce aldosterone in vitro. Urine samples from patients with low-renin essential hypertension or idiopathic hyperaldosteronism have more stimulating activity than urine samples from normal subjects. These preliminary findings support the hypothesis that excessive production of an undefined aldosterone stimulating factor may be the basic abnormality in some cases of idiopathic hyperaldosteronism and low-renin essential hypertension.     

Influence of season on plasma antidiuretic hormone, angiotensin II, aldosterone and plasma renin activity in young volunteers

We investigated seasonal changes in hormonal and thermoregulatory responses. Eight volunteers were subjected to the experiment at four times of the year: around the vernal and autumnal equinoxes, and at the summer and winter solstices at latitude 35° N. Plasma antidiuretic hormone (ADH), angiotensin II (ANG II), aldosterone (ALD) and plasma renin activity (PRA) were analyzed before and after water immersion. Seasonal changes in thermoregulatory responses were assessed by measuring core temperature and sweat rate during immersion of the leg in hot water (at 42°C) for 30 min in a room maintained at 26°C. The concentration of plasma ADH and ALD before water immersion was significantly higher in summer than in other seasons. The concentrations of ANG II and PRA did not show seasonal variations. Changes in tympanic temperature during water immersion showed significant differences between seasons, and were higher in winter than in other seasons. The sweat rate was significantly higher in summer than in other seasons. In summary, ADH and ALD concentrations displayed a seasonal rhythm with marked elevation in summer; this may be a compensative mechanism to prevent dehydration from increased sweat loss during summer due to heat acclimatization.     

Increased oxidative damage to all DNA bases in patients with type II diabetes mellitus

Gas chromatography-mass spectrometry was used to measure the oxidative DNA damage in diabetic subjects and controls. Levels of multiple DNA base oxidation products, but not DNA base de-amination or chlorination products, were found to be elevated in white blood cell DNA from patients with type II diabetes as compared with age-matched controls. The chemical pattern of base damage is characteristic of that caused by an attack on DNA by hydroxyl radical. An increased formation of the highly reactive hydroxyl radical could account for many of the reports of oxidative stress in diabetic subjects. There was no evidence of an increased DNA damage by reactive nitrogen or chlorine species.     

Exogenous somatostatin raises plasma insulin levels in patients with insulin-dependent diabetes mellitus

The effect of cyclic somatostatin on circulating insulin levels was studied in eight patients with insulin-dependent diabetes mellitus (IDDM). The study was performed after an overnight fast when their subcutaneous depots of insulin had been depleted during i.v. insulin substitution for 18 hours. A constant rate i.v. insulin infusion (0.4 mU/kg/min) was given for 240 min and somatostatin was co-infused between 60-120 min (100 micrograms/h) and 180-240 min (250 micrograms/h) respectively. Plasma insulin, blood glucose and hematocrit were measured at 15 min intervals. Hematocrit fell from 41.7 to 38.3% during the study period. Somatostatin increased the plasma insulin levels, corrected for the changes of hematocrit, by approximately 8% in the low dose (P less than 0.05) as well as in the high dose (P less than 0.05) period. It is concluded that somatostatin interferes with the clearance of insulin thereby increasing the circulating plasma insulin levels in IDDM patients without residual insulin secretion.     

Magnesium levels in plasma,erythrocyte, and platelet in hypertensive and normotensive patients with type II diabetes mellitus

The authors, by means of a recently introduced method, evaluated the intraplatelet concentrations of magnesium in 45 normotensive patients with type II diabetes mellitus, in 45 hypertensive diabetics and in 15 healthy controls. They also evaluated plasma and erythrocyte concentrations of the cation through direct current plasma spectrometer. Both normotensive and hypertensive diabetics showed a reduction in plasma, erythrocyte, and platelet concentrations of magnesium compared to controls. On the contrary, no significant difference was found between hypertensive and normotensive diabetics with regard to plasma and erythrocyte magnesium, whereas intraplatelet assay of the ion pointed out significantly lower concentrations of magnesium in hypertensive compared to normotensive patients (56.4±9.0 vs 60.7±10.2 μg/10⁸ cells-p<0.05). The authors believe that intraplatelet assay of magnesium may be the most reliable method for the evaluation of the cation in hypertensive diabetics, probably because platelets share common features with smooth muscle cells, including the α-2-adrenoceptor cyclase system and a coupling mechanism concerning the calcium-dependent contraction.     

Effect of aldosterone on vascular angiotensin II receptors in the rat

The effect of aldosterone on the density and affinity of binding sites for 125I-labelled angiotensin II was investigated in a particulate fraction prepared from the rat mesenteric arteriolar arcades. The infusion of aldosterone 6.6 micrograms/h intraperitoneally via Alzet osmotic minipumps for 6 d produced an increase in the density of binding sites for 125I-labelled angiotensin II without change in affinity. After sodium depletion, mesenteric artery angiotensin II receptors were down-regulated as expected. An increase in the number of binding sites could be found when aldosterone was infused into sodium-depleted rats with no change in the elevated plasma renin activity. The intraperitoneal infusion of angiotensin II (200 ng X kg-1 X min-1 for 6 d) simultaneously with aldosterone resulted in down-regulation of vascular angiotensin II receptors, whereas after intravenous angiotensin II infusion (at 60 ng X kg-1 X min-1) the density of angiotensin II binding sites rose with aldosterone infusion. Plasma renin activity (PRA) was reduced and plasma angiotensin II increased in a dose-dependent fashion after angiotensin II infusion. An aldosterone concentration of 3 ng/mL for 18 h produced an increase in the number of angiotensin II binding sites in rat mesenteric artery smooth muscle cells in culture. We conclude that increased plasma aldosterone may result in up-regulation of vascular angiotensin II receptors independently of changes in plasma renin activity, and may in certain physiological states effectively antagonize the down-regulating action of angiotensin II.     

Impaired contractile responsiveness of diabetic glomeruli to angiotensin II: a possible indication of mesangial dysfunction in diabetes mellitus

The contractile function of renal glomerulus was studied in vitro using isolated glomeruli from streptozotocin-diabetic rats. Glomerular contraction was assessed by the reduction of extracellular [3H]inulin space of glomerulus, mostly composing of intracapillary space, produced by angiotensin II. The inulin space was dose-dependently reduced after angiotensin II addition in both diabetic and control rats but the degree of reduction significantly smaller in the former. The radioreceptor assay revealed rather increased angiotensin II receptors in diabetic glomeruli. Since the contractile response of glomerulus to angiotensin II is mediated via mesangial cell contraction, these results suggest the presence of mesangial cell dysfunction in diabetes.     

The triglyceride content of adipocytes and plasma of patients with diabetes mellitus.

In two groups of obese diabetic patients closely matched for age, glucose intolerance and indices of obesity, the group with hypertriglyceridaemia was found to have an increased triglyceride content of adipocytes (p less than 0.001) and raised fasting plasma insulin (p less than 0.02). Plasma insulin did not directly relate to the level of plasma triglyceride (r = +0.28, n = 36, p N.S.) but correlated with the triglyceride content of adipocytes (r = +0.59, n = 37, p less than 0.001). The results suggest that raised plasma insulin is not a primary determinant of the level of plasmatriglyceride but that it may be related by its effect on lipogenesis in adipose and other tissues.     

Effects of static magnetic fields on plasma levels of angiotensin II and aldosterone associated with arterial blood pressure in genetically hypertensive rats

Effects of static magnetic fields (SMFs) on development of hypertension were investigated using young male, stroke resistant, spontaneously hypertensive rats (SHRs) beginning at 7 weeks of age. SHRs were randomly assigned to two different exposure groups or an unexposed group. The SHRs in the exposure groups were constantly exposed to two different types of external SMFs of 3.0-10.0 mT or 8.0-25.0 mT for 12 weeks. The SMFs were generated from permanent magnetic plates attached to the rat cage. The blood pressure (BP) of each rat was determined at weekly intervals using indirect tail-cuff method. The SMFs suppressed and retarded the development of hypertension in both exposed groups to a statistically significant extent for several weeks, as compared with an unexposed group. The antipressor effects were related to the extent of reduction in plasma levels of angiotensin II and aldosterone in the SHRs. These results suggest that the SMFs of mT intensities with spatial gradients could be attributable to suppression of early BP elevation via hormonal regulatory system.     

Decreased sensitivity of platelets to prostacyclin in patients with diabetes mellitus

In order to ascertain the platelet sensitivity to prostacyclin (PGI2) in patients with diabetes mellitus, we determined the percentage inhibition of platelet aggregation and platelet ATP secretion following PGI2 addition in an in vitro system. The percentage inhibition of platelet aggregation caused by PGI2 in final concentration of 1.25, 2.5, or 5.0 ng/ml was significantly lower in diabetics than in healthy controls. That of platelet ATP secretion by 1.25 or 2.5 ng/ml of PGI2 was also significantly lower in diabetics. These data suggested that in patients with diabetes mellitus, the decreased sensitivity of platelets to PGI2 will bring about hypercoagulability and may become one of the risk factors of diabetic microangiopathy in cooperation with lowered vascular PGI2 generation.     

Polymorphism of the angiotensin I-converting enzyme gene in diabetic retinopathy patients and type 2 diabetes mellitus patients with myocardial infarction

The insertion/deletion polymorphism (I/D) of the angiotensin I-converting enzyme gene (ACE) was examined in type I diabetes mellitus patients (DM) with (n = 31), or without (n = 33) retinopathy, and in type 2 DM patients with either myocardial infarction (MI; n = 75), or with (n = 37), or without (n = 178) retinopathy. No association between the ACE gene and retinopathy in type 1 and type 2 DM patients was revealed. In the type 2 DM patients with MI, a statistically significant (P < 0.05) elevation of the D allele frequency (64%) compared to that without MI (55.3%), together with statistically nonsignificant prevalence of the DD homozygotes (41% versus 30.6%) was observed. Our data indicate that the D allele (RR 1.43) and DD genotype (RR 1.75) are risk factors for myocardial infarction in the type 2 DM patients.     

The retinal renin-angiotensin system: roles of angiotensin II and aldosterone

In the present review we examine the experimental and clinical evidence for the presence of a local renin-angiotensin system within the retina. Interest in a pathogenic role for the renin-angiotensin system in retinal disease originally stemmed from observations that components of the pathway were elevated in retina during the development of certain retinal pathologies. Since then, our knowledge about the contribution of the RAS to retinal disease has greatly expanded. We discuss the known functions of the renin-angiotensin system in retinopathy of prematurity and diabetic retinopathy. This includes the promotion of retinal neovascularization, inflammation, oxidative stress and neuronal and glial dysfunction. The contribution of specific components of the renin-angiotensin system is evaluated with a particular focus on angiotensin II and aldosterone and their cognate receptors. The therapeutic utility of inhibiting key components of the renin-angiotensin system is complex, but may hold promise for the prevention and improvement of vision threatening diseases.