Impaired Blood Flow Autoregulation Research Articles

Why is delirium more frequent in the elderly?

An aging-related reduction in the brain’s functional reserve may explain why delirium is more frequent in the elderly than in younger people insofar as the reserve becomes inadequate to cover the metabolic requirements that are critically increased by stressors. The aim of this paper is to review the normal aging-related changes that theoretically compromise complex mental activities, neuronal and synaptic densities, and the neurocomputational flexibility of the functional reserve. A pivotal factor is diminished connectivity, which is substantially due to the loss of synapses and should specifically affect association systems and cholinergic fibres in delirious patients. However, micro-angiopathy with impaired blood flow autoregulation, increased blood/brain barrier permeability, changes in cerebrospinal fluid dynamics, weakened mitochondrial performance, and a pro-inflammatory involution of the immune system may also jointly affect neurons and their synaptic assets, and even cause the progression of delirium to dementia regardless of the presence of co-existing plaques, tangles, or other pathological markers. On the other hand, the developmental growth in functional reserve during childhood and adolescence makes the brain increasingly resistant to delirium, and residual reserve can allow the elderly to recover. These data support the view that functional reserve is the variable that confronts stressors and governs the risk and intensity of and recovery from delirium. Although people of any age are at risk of delirium, the elderly are at greater risk because aging and age-dependent structural changes inevitably affect the brain’s functional reserve.

Double trouble: managing diabetic emergencies in patients with heart failure

Double trouble: managing diabetic emergencies in patients with heart failure

Impaired Autoregulation of Blood Flow at the Optic Nerve Head During Vitrectomy in Patients With Type 2 Diabetes

To determine whether type 2 diabetes mellitus (T2DM) influences autoregulation of optic nerve head (ONH) blood flow during vitrectomy. Cohort study. Thirteen eyes of 13 subjects with T2DM and 30 eyes of 30 controls without T2DM undergoing vitrectomy for epiretinal membrane or macular hole were included. Following 25 gauge vitrectomy, we measured the mean blur rate (MBR), an index of ONH blood flow, in the vascular area (vascular MBR) and in the tissue area (tissue MBR) using laser speckle flowgraphy. We performed measurements before and 5 and 10minutesafter intraocular pressure (IOP) elevation of approximately 15mm Hg; both parameters represent relative values (%, compared with baseline). We calculated the vascular MBR recovery rate as (vascular MBR at 10min-vascular MBR at 5min)/(vascular MBR at baseline-vascular MBR at 5min). Vascular MBR in T2DM subjects was significantly lower than that in controls at 5 and 10minutes after IOP elevation (P= .0328 and P < .0001, respectively). Tissue MBR was also significantly lower in T2DM subjects than in controls at both time points (P= .0253 and P= .0004, respectively). Vascular MBR recovery rate was significantly lower in the T2DM than in the control group (P= .0090). Furthermore, the vascular MBR recovery rate was significantly negatively correlated with hemoglobin A1c and fasting plasma glucose levels (P= .0284 and P= .0381, respectively). T2DM is associated with impaired ONH blood flow autoregulation in both vascular and tissue areas when subjected to change in IOP duringvitrectomy.

Role of endothelin in diabetic retinopathy.

Endothelin-1 (ET-1) is a 21 amino acid peptide originally purified from conditioned medium of cultures of porcine aortic endothelial cells. It is now known that there are three endothelin genes in the human genome (ET-1, ET-2, and ET-3 genes). ET-1 and ET-2 are both strong vasoconstrictors, whereas ET-3 is a potentially weaker vasoconstrictor compared to the other two isoforms. Besides being a very potent vasoconstrictor, ET-1 also acts as a mitogen on the vascular smooth muscle and thus it may play a role in the development of vascular diseases. There is evidence that impaired auto-regulation of blood flow is involved in the pathogenesis of diabetic microangiopathy. It is known that the ability of the diabetic's circulation to distribute blood is affected, especially during increased blood flow. In most tissues this causes no serious burden, but three tissues are usually susceptible to disturbance. They are the retina, renal cortex, and peripheral nerves. Retinal vascular auto-regulation is defined as the ability of the blood vessels to keep blood flow constant under varying perfusion pressure in order to match it to tissue oxygen and metabolic requirements. The failure of auto-regulation is an important and often early feature of diabetic retinopathy. Since human retina vessels lack extrinsic innervation, retinal vessel calibre and local blood flow are normally regulated by non-nervous mechanisms intrinsic to the retina. There is now a considerable body of evidence suggesting that retinal pericytes are the main regulators of vascular tone in the retinal capillaries because they contain components of contractile proteins similar to vascular smooth muscle cells and because they also possess ET-1 receptors. Furthermore. ET-1 has been shown to cause vasoconstriction of retinal vessels as well as to have mitogenic effects on retinal pericytes. Hence, alterations in the pericyte-ET interaction may have a role causing early hemodynamic and histopathological abnormalities found in diabetic retinopathy. On the contrary, Chakrabarti et al. demonstrate that retinas from the chronic diabetic BB/W rats (6 months) show an increase in ET-1, ET-3, ET(A) receptor and ET(B) receptor mRNA expressions when compared to those from control rats. Similar results are noted by them using immunohistochemical methods. Finally, an increased ocular, and retina tissue levels of ET-1 in diabetic rats have also been reported by Chakravarthy et al., as well as by Takagi et al. All of these findings suggest that endothelins may also be involved in the pathogenesis of more advanced diabetic retinopathy, such as capillary occlusion and subsequent neovascularization. This review summarizes the reported literature on the role of ET-1 in the development of diabetic retinopathy.

Evaluation of cerebrovascular reactivity in children [corrected] with chronic renal failure.

Developmental disturbances and encephalopathy have been observed in children with chronic renal failure (CRF). The aim of this study was to investigate the efficiency of the cerebral circulation in uremic children. The study group consisted of 10 children with CRF on conservative treatment, 8 children on continuous ambulatory peritoneal dialysis (CAPD), and 8 children on maintenance hemodialysis (HD). Examination was performed using a TC2-64B, EME Doppler flowmeter machine and capnograph Datex, Normocap. Blood flow velocity in both middle cerebral arteries (MCA), at rest and after spontaneous hyperventilation for 30 s, was analyzed. The vascular reactivity coefficient was calculated as the percentage ratio of decline of blood flow velocity in MCA to PCO2 decrease. Baseline mean blood flow velocities of MCA in euvolemic children under conservative treatment and on CAPD were significantly higher than those in children on HD and healthy control children. The highest value of the vascular reactivity coefficient was significantly higher in the group of children with CRF on conservative and CAPD treatment, than in children on HD and healthy controls. We suggest that hyperreactivity of the cerebral circulation could be the result of impaired autoregulation of blood flow. Evaluation of cerebrovascular reactivity in uremic children requires further examination.

Abnormalities of microcirculation in glaucoma: facts and hints.

Many risk factors associated with glaucoma have been identified recently. The best known of these is increased intraocular pressure (IOP). Among the others, however, vascular risk factors play a major role. Although such vascular factors were already postulated more than 100 years ago, only recent technical developments have afforded systematic investigations of associated microcirculatory disturbances and basic principles of blood flow regulation. In glaucoma, besides IOP, vascular dysregulation (such as local vasospasm and systemic hypotension, resulting in impaired autoregulation of blood flow in the optic nerve head, the choroid, and other ocular tissues) seems to be a major risk factor. However, multiple coacting factors, which are not limited to the eye but are, rather, symptoms of a systemic disease, seem to be involved in the damaging process.

Impaired vasoconstriction to endothelin 1 in patients with NIDDM.

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.

Glucose Decreases Intracellular Free Calcium and pH in Cultured Rat Aortic Vascular Smooth Muscle Cells: Role of Ca&lt;sup&gt;2+&lt;/sup&gt;-ATPase

Early diabetes mellitus leading to hyperglycemia in both animals and man is associated with impaired blood flow autoregulation. The mechanisms underlying such alterations, however, are unclear, although a role for VSM cells and alterations in [Ca2+]i homeostasis are likely candidates. The present study investigates the effect of elevated extracellular glucose concentrations on [Ca2+]i and intracellular pH (pHi) in cultured rat aortic VSM cells. The VSM cells were coloaded with Fura-2 and SNARF-1 for simultaneous [Ca2+]i and pHi measurements, respectively. VSM cells were treated with glucose concentrations from 0 to 23 mM. The results indicate that glucose induces a decrease in both [Ca2+]i and pHi in a concentration-dependent manner. The effects of glucose on [Ca2+]i and pHi were fully reversible. To investigate whether the [Ca2+]i decreases were due to activation of Ca2+-ATPase by glucose, we used Ca2+-ATPase inhibitors: thapsigargin (TG), cyclopiazonic acid (CPA) and 2,5-di-(tert-butyl)-l,4-benzo-hydroquinone (BHQ). Pretreatment with either TG, CPA, or BHQ abolished the glucose-induced [Ca2+]i and pHj decrease. The effect of drugs on [Ca2+]i and pHi following glucose was drug-dependent. These data indicate that glucose and [Ca2+]i are linked, and may be explained by direct coupling of glycolysis to the activity of Ca2+-ATPase. We concluded that: (l)VSM cells respond to glucose treatment with rapid and sustained decreases in both pHi and [Ca2+]i; (2) the magnitudes of the effects of glucose on pH i and [Ca2+]i were concentration dependent and fully reversible, and (3) the glucose-induced [Ca2+]i decrease was abolished by Ca2+-ATPase inhibitors. The alterations in pHi and [Ca2+]i induced by glucose may be relevant for the decrease in vascular tone observed in early diabetes mellitus.

Effect of elevated extracellular glucose concentrations on transmembrane calcium ion fluxes in cultured rat VSMC

Blood flow autoregulation is impaired in early diabetes mellitus, predisposing the renal microcirculation to injury. These hemodynamic changes have been strongly implicated in the development and progression of diabetic glomerulopathy. Blood flow autoregulation is predominantly a myogenic reflex which is strongly dependent on Ca2+ uptake by vascular smooth muscle cells (VSMC). Because impaired blood flow autoregulation may be responsive to glycemic control, the present study examined the effects of elevated extracellular glucose concentrations on basal, voltage sensitive and receptor operated Ca2+ uptake by VSMC. Confluent cultured rat VSMC were exposed to: (1) control medium (CM; 5 mM glucose); (2) high glucose medium (HGM; 10 to 30 mM glucose); or (3) osmotic control medium (OCM; glucose 5 mM + L-glucose 25 mM or mannitol 25 mM). A threshold glucose concentration of 15 mM markedly and maximally depressed basal Ca2+ uptake by VSMC (HGM 52% vs. CM). In addition, HGM significantly depressed voltage sensitive Ca2+ uptake by VSMC as determined by responses to BAY K 8644 (10(-7) M) or high extracellular [K+] (65 mM, HGM 50% vs. CM). HGM similarly depressed pressor hormone-stimulated Ca2+ uptake (AVP or Ang II 10(-7) M) by VSMC. The effects of HGM on Ca2+ uptake were time exposure dependent and reversible. Ca2+ uptake by VSMC in the presence of OCM did not differ from CM. Elevated extracellular glucose concentrations thus exert a direct and profound effect on basal, voltage sensitive and receptor operated Ca2+ uptake by VSMC. These observations may provide a biochemical basis for glucose-induced dysregulation of regional blood flow autoregulation in early diabetes mellitus.

Impaired autoregulation of blood flow in subcutaneous tissue of long-term type 1 (insulin-dependent) diabetic patients with microangiopathy: an index of arteriolar dysfunction.

Autoregulation of blood flow in subcutaneous tissue was studied at the level of the lateral malleolus in eight long-term Type 1 (insulin-dependent) diabetic patients with clinical microangiopathy, eight short-term Type 1 diabetic patients without clinical microangiopathy and seven healthy control subjects. Blood flow was measured by the local 133Xenon washout technique. Mean arterial blood pressure was reduced by a maximum of 23 mmHg by elevating the limb above heart level and elevating to a maximum of 70 mmHg by head-up tilt; in the latter position venous pressure was kept constant and low by activation of the leg muscle vein pump (heel raising). Mean arterial blood pressure was thus varied between 60 and 160 mmHg. In normal and short-term diabetic subjects blood flow remained within 10% of control values during the changes in arterial blood pressure. In six of the eight Type 1 diabetic patients with clinical microangiopathy, autoregulation of blood flow was impaired, blood flow changing approximately 20% per 10 mmHg change in arterial blood pressure; the slope of the autoregulation curves was significantly higher compared with the two control groups (p less than 0.02). Resting mean arterial blood pressure was significantly elevated in long-term diabetic patients (median: 107 mmHg) compared with short-term diabetic (median: 85 mmHg) and control subjects (median: 91 mmHg) (p less than 0.01 and p less than 0.02, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Impaired autoregulation of blood flow in skeletal muscle and subcutaneous tissue in long-term Type 1 (insulin-dependent) diabetic patients with microangiopathy.

Autoregulation of blood flow was studied in skeletal muscle and subcutaneous tissue in seven Type 1 (insulin-dependent) diabetic patients (median age: 36 years) with nephropathy and retinopathy and in eight normal subjects of the same age. Blood flow was measured by the local 133Xe washout technique. Reduction in arterial perfusion pressure was produced by elevating the limb 20 and 40 cm above heart level. Blood flow remained within 10% of control values when the limb was elevated in normal subjects. In five of the seven diabetic subjects blood flow fell significantly in both tissues when the limb was elevated 40 cm indicating impaired autoregulation. The results suggest that intrinsic vascular (arteriolar) mechanisms (myogenic and/or metabolic) underlying the normal autoregulatory response are defective in some diabetic patients with microangiopathy.

Renal Failure Limiting Antihypertensive Therapy as an Indication for Renal Revascularization

Although surgical repair of renal artery stenosis occasionally improves renal function, it is not yet known when revascularization is indicated for that reason. We report the results observed in a patient with renovascular hypertension and additional stenosis in the contralateral kidney whose renal function deteriorated on repeated occasions during antihypertensive therapy. Renal hemodynamic studies during sodium nitroprusside infusion showed severely impaired autoregulation of blood flow, and glomerular filtration rate was corrected after revascularization of the contralateral kidney alone. After surgery, normal BPs were tolerated without loss of function. These findings demonstrate a specific clinical indication for renal revascularization to preserve kidney function.

Impaired autoregulation of blood flow and glomerular filtration rate in the isolated dog kidney depleted of renin.

The effect of renin depletion on autoregulation of renal blood flow and glomerular filtration rate was examined in an isolated perfused kidney preparation. Group 1 dogs received a normal-sodium diet, group 2 dogs received deoxycorticosterone acetate (DOCA) and a high-sodium diet, group 3 dogs received DOCA and a sodium-deficient diet, group 4 dogs received a high-sodium diet without DOCA, and dogs in groups 5 and 6 were treated just like dogs in groups 1 and 2, respectively. Renin release was stimulated by decreasing renal arterial pressure to 50 mm Hg. An increase in renal arterial pressure from 100 to 160 mm Hg was associated with an impaired autoregulatory response in kidneys from group 2 dogs and in two kidneys from group 4 dogs; these kidneys exhibited suppressed or absent renin release in response to a decrease in renal arterial pressure. A separate group of experiments demonstrated that DOCA plus a high-sodium diet completely depleted the kidney of renin stores, indicating that decreased renin secretion reflected depletion of renal renin content. Infusing angiotensin II (0.22 ± 0.06 µg/min) into the renal artery of group 2 kidneys did not normalize the autoregulatory response. A decrease in renal arterial pressure from 150 to 50 mm Hg was associated with impaired autoregulation of glomerular filtration rate and renal blood flow in kidneys from group 6 dogs; renin secretion was undetectable in these kidneys. All kidneys from groups 1, 3, and 5 and the remaining six kidneys from group 4 exhibited a normal autoregulatory response and normal renin release. In groups 1-3, zonal blood flow was measured using the radiolabeled microsphere technique. Only in group 2 did a significant redistribution of fractional blood flow from the inner to the outer cortex occur. These experiments demonstrate that renin depletion impairs the capacity of the kidney to autoregulate blood flow and glomerular filtration rate; thus the data are consistent with the hypothesis that the renin-angiotensin system participates in the autoregulatory response.

The influence of the polar anastomotic vessels on autoregulation and the urinary excretion of water and sodium by perfused cat kidneys

1. Cat kidneys have been perfused from pump-oxygenator and from heart-lung circuits.2. Kidneys perfused from the pump-oxygenator circuit excreted more water and sodium and showed higher values for sodium: potassium in urine than kidneys perfused from heart-lung circuits. Renal plasma flow and the clearances of creatinine and p-aminohippuric acid were similar for preparations perfused by the two different methods.3. Dorsal and ventral polar anastomotic vessels appeared to communicate directly with sheaves of vasa recta in the kidneys of young cats through interlobar vessels.4. Ligature of these polar anastomotic vessels impaired autoregulation of blood flow in perfused cat kidneys.5. Open drainage from these polar vessels during perfusion increased the rates of excretion of water and sodium.6. Histological preparations made from kidneys perfused from pump-oxygenator and from heart-lung circuits for periods of 5-6(1/2) hr showed that the nephrons remain undamaged. The diameters of the tubules correlated with the rates of urine flow immediately before fixation.