Arginine vasopressin reduces intestinal oxygen supply and mucosal tissue oxygen tension

We investigated intestinal oxygen supply and mucosal tissue PO2 during administration of increasing dosages of continuously infused arginine vasopressin (AVP) in an autoperfused, innervated jejunal segments in anesthetized pigs. Mucosal tissue PO2 was measured by employing two Clark-type surface oxygen electrodes. Oxygen saturation of jejunal microvascular hemoglobin was determined by tissue reflectance spectrophotometry. Microvascular blood flow was assessed by laser-Doppler velocimetry. Systemic hemodynamic variables, mesenteric venous and systemic acid-base and blood gas variables, and lactate measurements were recorded. Measurements were performed at baseline and at 20-min intervals during incremental AVP infusion (n = 8; 0.007, 0.014, 0.029, 0.057, 0.114, and 0.229 IU.kg(-1).h(-1), respectively) or infusion of saline (n=8). AVP infusion led to a significant (P < .05), dose-dependent decrease in cardiac index (from 121 +/- 31 to 77 +/- 27 ml.kg(-1).min(-1) at 0.229 IU.kg(-1).h(-1)) and systemic oxygen delivery (from 14 +/- 3 to 9 +/- 3 ml.kg(-1).min(-1) at 0.229 IU.kg(-1).h(-1)) concomitant with an increase in systemic oxygen extraction ratio (from 31 +/- 4 to 48 +/- 10%). AVP decreased microvascular blood flow (from 133 +/- 47 to 82 +/- 35 perfusion units at 0.114 IU.kg(-1).h(-1)), mucosal tissue PO2 (from 26 +/- 7 to 7 +/- 2 mmHg at 0.229 IU.kg(-1).h(-1)), and microvascular hemoglobin oxygen saturation (from 51 +/- 9 to 26 +/- 12% at 0.229 IU.kg(-1).h(-1)) without a significant increase in mesenteric venous lactate concentration (2.3 +/- 0.8 vs. 3.4 +/- 0.7 mmol/l). We conclude that continuously infused AVP decreases intestinal oxygen supply and mucosal tissue PO2 due to a reduction in microvascular blood flow and due to the special vascular supply in the jejunal mucosa in a dose-dependent manner in pigs.     

Relation between extent of coronary artery disease and blood viscosity.

Blood viscosity (shear rate 100/s) and its major determinants (packed cell volume, plasma fibrinogen concentration, and plasma viscosity) were measured before coronary angiography in 50 men aged 30-55 and related to the extent of coronary artery disease. Twenty-six men had extensive disease (stenosis of two or three major coronary vessels), and 24 had either stenosis of one vessel or no stenosis. The 26 men with extensive disease had significantly higher mean blood viscosity than those with mild or no disease and 25 healthy controls (p less than 0.001). The increased viscosity was due partly to a higher packed cell volume and partly to a higher fibrinogen concentration; plasma viscosity was not significantly increased. These differences could not be explained by smoking history. These results suggest an association between increased blood viscosity and extensive coronary artery disease in men, which merits further investigation.     

Mechanisms of the renal vasodilation caused by insulin in anesthetized pigs

The present study was planned to determine the mechanisms involved in the renal vasodilation caused by insulin. Changes in flow caused by the intravenous infusion of 0.004 IU/kg/min of insulin at constant heart rate, aortic blood pressure, left ventricular contractility and blood levels of glucose and potassium in the left renal artery were assessed using an electromagnetic flowmeter. In ten pigs, infusion of insulin caused an increase in renal blood flow which averaged 12.8% of the control values. After hemodynamic variables had returned to control values, insulin infusion was repeated in five pigs following blockade of alpha-adrenergic receptors with injection of phentolamine into the renal artery and in the other five pigs following blockade of nitric oxide formation with injection in the same artery of Nomega-nitro-L-arginine methyl ester (L-NAME). After blockade of alpha-adrenergic receptors, insulin infusion caused an increase in renal blood flow which averaged 18.1% of the control values, being significantly enhanced with respect to the increase previously obtained in the same pigs. On the contrary, after blockade of nitric oxide formation insulin infusion caused a decrease in renal blood flow which averaged 6.5% of the control values. These responses were respectively abolished by the subsequent injection into the renal artery of L-NAME and phentolamine. The present study showed that the renal vasodilation caused by insulin in the anesthetized pig was the result of two opposite effects which involved a predominant vasodilation mediated by the release of nitric oxide from the endothelium and a sympathetic vasoconstrictor mechanism mediated by alpha-adrenergic receptors.     

Free fatty acids/triglycerides increase ocular and subcutaneous blood flow

Elevated plasma free fatty acids (FFA) induce skeletal muscle insulin resistance and impair endothelial function. The aim of this study was to characterize the acute hemodynamic effects of FFA in the eye and skin. A triglyceride (Intralipid 20%, 1.5 ml/min)/heparin (bolus: 200 IU; constant infusion rate: 0.2 IU. kg(-1). min(-1)) emulsion or placebo was administered to 10 healthy subjects. Measurements of pulsatile choroidal blood flow with laser interferometry, retinal blood flow with the blue field entoptic technique, peak systolic and end diastolic blood velocity (PSV, EDV) in the ophthalmic artery with Doppler sonography, and subcutaneous blood flow with laser Doppler flowmetry were performed during an euglycemic somatostatin-insulin clamp over 405 min. Plasma FFA/triglyceride elevation induced a rise in pulsatile choroidal blood flow by 25 +/- 3% (P < 0.001) and in retinal blood flow by 60 +/- 23% (P = 0.0125). PSV increased by 27 +/- 8% (P = 0.001), whereas EDV was not affected. Skin blood flow increased by 149 +/- 38% (P = 0.001). Mean blood pressure and pulse rate remained unchanged, whereas pulse pressure amplitude increased by 17 +/- 5% (P = 0.019). Infusion of heparin alone had no hemodynamic effect in the eye or skin. In conclusion, FFA/triglyceride elevation increases subcutaneous and ocular blood flow with a more pronounced effect in the retina than in the choroid, which may play a role for early changes of ocular perfusion in the insulin resistance syndrome.     

The action of timoptin peptides on the hemostatic system

Repeated introduction of thymus polypeptide drug thymoptine (8 times every 24 hours, 1 microgram/kg) led to the increase in total and non-enzymatic fibrinolytic activity of blood plasma and the decrease in fibrinogen concentration. Thymoptine could lyse non-stabilized fibrin and cause depolymerization of aggregates of fibrin monomer in virto. Highest depolymerization activity was observed at thymoptine concentration of 10 micrograms/ml.     

Evaluation of various hemorheological parameters in nonagenarians: evidence of an increase of fibrinogen

Cardiovascular disease is the most frequent cause of mortality in the elderly. A reduced microvascular blood flow associated with an increase in atherosclerosis might contribute to age related increases in the incidence of ischemic vascular disease. In order to evaluate the effect of age on some haemorheological parameters, blood and plasma viscosity and fibrinogen have been measured in 10 healthy elderly subjects, aged between 88 and 96 years, compared with 15 healthy young subjects (mean age 37 years). Elderly subjects showed a significant increase in plasma fibrinogen (p less than 0.0005) and a trend to an increase in plasma viscosity, whereas no difference was present in blood viscosity. These data confirm that aging is associated with a greater deal of thrombotic risk factors, the most important of which seems to be fibrinogen.     

Fibrinogen in Obesity Before and After Weight Reduction

Several studies have shown that obesity is associated with atherosclerosis. The reason may be that there is often a gathering together of risk factors for cardiovascular disease in obesity. Recently plasma fibrinogen level has been identified as an important cardiovascular risk factor. The aim of the study was to investigate fibrinogen levels in obesity before and after weight reduction. Obese but otherwise healthy patients with overweight problems were studied. 448 female patients (39.1 ± 13.2 years, body mass index 38.7 kg/m²) and 136 male patients (39.4 ± 12.8 years, body mass index 40.7 kg/m²) were examined after overnight fasting. Sixty patients (44 female, 16 male) were studied after 9.5 ± 6.2 month of dieting (1200 kcal/day: 20% protein, 30% fat and 50% carbohydrates). The weight loss was 16.7 ± 11.0 kg in the female and 16.2 ± 6.7 kg in the male patients, and blood pressure, triglycerides, blood glucose and uric acid had declined. The fibrinogen level correlated with the body mass index, the waist circumference, the hip circumference and the waist to hip ratio. The fibrinogen level also correlated with insulin. A partial correlation of fibrinogen and insulin continued to exist after removing the linear effects of the other variables measured. After weight reduction, the level of fibrinogen was lower. In patients with extreme overweight and high fibrinogen levels, who reduced their BMI by 7.4 ± 1.24 kg/m², the weight loss correlated with the decrease in fibrinogen. The results suggest that fibrinogen is associated with the degree of obesity and with the fasting insulin level. Fibrinogen concentration is lowered by weight reduction. However decrease of fibrinogen was observed only in patients with considerable weight loss.     

Influence of serotonin on myocardial blood flow in the presence and absence of a coronary arterial stenosis: observations in domestic swine

This study tested the hypothesis that 5-HT may impair coronary flow regulation by inappropriately increasing arteriolar tone in the coronary circulation. Ten closed chest, domestic swine were studied both in the presence and in the absence of a severe artificial intraluminal coronary stenosis. A 5-French micromanometer catheter with fluid lumen was placed in the left anterior descending coronary artery and used to record pressure and infuse 5-HT (40 and 100 micrograms/min) into the coronary circulation. For the stenosis phase of the protocol the catheter was embedded in the artificial stenosis. Hemodynamics, regional myocardial blood flow (microsphere technique), coronary vascular resistance, lactate consumption, and oxygen metabolism were measured at control and at 5 min of each 5-HT dose. In the absence of coronary artery stenosis (i.e., full vasodilatory reserve), there was no change in regional myocardial blood flow or coronary vascular resistance during 5-HT infusion. In the presence of a severe coronary stenosis (i.e., limited vasodilator reserve) 5-HT produced a significant (P less than 0.05) decrease versus control in the distal left anterior descending: circumflex zone endocardial blood flow ratio (0.63 +/- 0.19, mean +/- 1 SD, to 0.55 +/- 0.15) and a significant (P less than 0.05) increase versus control in endocardial (50.6 +/- 16.6 to 61.2 +/- 19.8 mm Hg/ml/min/g) and transmural (49.9 +/- 9.5 to 57.2 +/- 12.8) coronary vascular resistance. Thus, 5-HT does not impair coronary flow regulation when full vasodilatory reserve is present. When coronary vasodilatory reserve is impaired by the presence of a severe proximal stenosis, 5-HT causes modest impairment of endocardial flow regulation.     

Hemodynamic aspects of obliterative processes in peripheral blood vessel--rigid and soft narrowing.

Hemodynamic aspects of obliterative processes in peripheral blood vessels were studied on a mechanical model built of distensible tubing, with a fixed peripheral resistance, through which citrated blood was circulated by pulsatile flow. Hemodynamics of progressive focal stenosis, elongated soft stenosis, and elongated rigid stenosis were assessed. By the use of a hydrodynamic model and a series of in vitro experiments, we have measured the pressure and flow characteristics, and calculated the pressure and energy losses for the various stenotic sites. The critical stricture was found to be larger for a rigid stenosis than a soft stenosis. The length of the stenosis was also an important factor. Increasing the length of a rigid stenosis, for example, by 50 percent resulted in an increase of 25 percent in the flow through the stenosis. The energy dissipation was determined as a preferred indication for several parameters such as: pressure drop, pulsed flow, pulse rate, and the geometry and mechanical properties of the stenosis.     

Interleukin-2 and blood brain barrier in cats: pharmacokinetics and tolerance following intrathecal and intravenous administration.

Single bolus doses of glycosylated human interleukin-2 (n IL-2) in the range of 2.8 x 10(3) to 2.0 x 10(6) IU/kg were administered to anesthesized cats via the cephalic vein (n = 10) or using suboccipital puncture (n = 8). CSF (cerebrospinal fluid) and blood samples were collected by repeated puncture. The n IL-2 concentration in four cats was determined on the basis of its biologic activity using 3H-thymidine incorporation into human ConA-blasts and by radioimmunoassay. In additional experiments radioactivity was determined in cerebrospinal fluid and serum after intravenous and intrathecal (i.th.) application of 5.8 x 10(3) - 3.2 x 10(3) IU/kg of 14C-acetyl-n IL-2 in regular time intervals. CSF and serum concentration time-profiles show a biexponential decline in the plasma elimination phase with half-lives of 4 min (alpha-phase) and 90 min (beta-phase) after intravenous and 20-120 min (alpha-phase) and 2-16 hours (beta-phase) after intrathecal application. There is a trend towards longer terminal elimination half-lives with increasing doses. Interleukin-2 is able to penetrate the blood brain barrier from the circulation into the cerebrospinal fluid and vice versa. Due to a slow rate of penetration and rapid elimination from blood only traces of n IL-2 (2-8 IU/ml) are detected in CSF after i.v. injection of 2 x 10(6) IU/kg, whereas concentrations between 400 and 1600 IU/ml are maintained in CSF for several hours following i.th. administration of 2-10 x 10(5) IU/kg.(ABSTRACT TRUNCATED AT 250 WORDS)     

Conebulization of surfactant and urokinase restores gas exchange in perfused lungs with alveolar fibrin formation

Alveolar fibrin generation has been suggested to possess strong surfactant-inhibitory potency. In perfused rabbit lungs, fibrin formation in the alveolar space was induced by sequential ultrasonic aerosolization of fibrinogen and thrombin, and the efficacy of rescue administration of surfactant and urokinase was investigated. Ventilation-perfusion (VA/Q) distribution was assessed by the multiple inert gas elimination technique. Aerosolization of fibrinogen (approximately 20 mg/kg body wt) increased shunt flow to approximately 7%. Sequential nebulization of fibrinogen and thrombin (1.3 U/kg body wt) caused alveolar fibrin deposition, documented immunohistologically, and provoked marked shunt flow, progressing to approximately 22% at the end of the experiments. The hemodynamics were virtually unchanged. Rescue aerosolization of natural bovine surfactant (15 mg/kg body wt) or urokinase-type plasminogen activator (4,500 U/kg body wt), undertaken after fibrin formation, improved gas exchange but progressive shunt flow still occurred (efficacy, surfactant > urokinase). In contrast, conebulization of surfactant and urokinase reversed shunt flow to approximately 7%, with an increased appearance of normal VA/Q matching. We conclude that alveolar fibrin formation is a potent surfactant-inhibitory mechanism in intact lungs, provoking severe VA/Q mismatch with a predominance of shunt flow, and that rescue aerosolization of surfactant plus urokinase may offer restoration of gas exchange under these conditions.     

Effectiveness of weekly subcutaneous recombinant human erythropoietin administration for chemotherapy-induced anemia

The effects of weekly subcutaneousrecombinant human erythropoietin (r-hEPO)administration on anemia during chemotherapy includingcisplatin and 5-fluorouracil in patients with head andneck carcinomas were examined. Weekly subcutaneousr-hEPO administration in cancer patients has not beeninvestigated previously. Patients were treated withr-hEPO 100 IU/kg (2 patients), 200 IU/kg (6 patients),or 400 IU/kg (5 patients), or placebo, andeffectiveness was evaluated by monitoring hemoglobinconcentration changes after administration for 8weeks. Hemoglobin concentrations in all 3 r-hEPOdosage groups were higher than that in the controlgroup during chemotherapy. All r-hEPO doses producedimprovements in the anemia induced by chemotherapy;however, the 400 IU/kg dose was most effective. Therequirement for blood transfusions decreased inpatients receiving r-hEPO therapy, and no significantside-effects were associated with r-hEPOadministration. These results suggest thatchemotherapy-induced anemia can be prevented by weeklysubcutaneous r-hEPO administration.     

Biochemical and thrombolytic properties of a low molecular weight form (comprising Leu144 through Leu411) of recombinant single-chain urokinase-type plasminogen activator

The cDNA encoding a low Mr derivative (residues 144-411) of human single-chain urokinase-type plasminogen activator was cloned, the recombinant low Mr single-chain urokinase-type plasminogen activator (rscu-PA-32k) was expressed in Chinese hamster ovary cells, and the translation product was purified to homogeneity from conditioned cell culture medium. rscu-PA-32k is very similar to intact recombinant single-chain urokinase-type plasminogen activator in terms of its very low activity (120 IU/mg) on a chromogenic substrate for urokinase (pyroglutamylglycylarginine p-nitroanilide), its plasminogen-dependent fibrinolytic activity on fibrin plates (specific activity = 170,000 IU/mg), its plasminogen activating potential, and the lack of specific binding to fibrin. In a rabbit jugular vein thrombosis model, comparable thrombolysis was obtained with rscu-PA-32k as compared to low molecular weight two-chain urokinase (50% lysis at 2.1 and 1.6 mg/kg infused over 4 h). Thrombolysis was associated with much less extensive systemic fibrinogen breakdown with rscu-PA-32k than with two-chain urokinase (residual fibrinogen at 50% lysis of 71 and 10%, respectively). It is concluded that the functional properties of rscu-PA-32k, expressed with a high efficiency, are similar to those of its previously characterized natural counterpart.     

Proceedings: The effects of hypothalamic and reflexogenic hypertension on renal and femoral circulation.

In anaesthetized dogs, electrical stimulation of the median posterior hypothalamus provoked hypertension accompanied by a decrease of renal blood flow and an increase of femoral blood flow. Similar hypothalamic reactions occurred after bilateral cervical vagotomy or after atropine, 2 mg/kg i.v. During reflexogenic hypertension induced by bilateral carotid occlusion in bivagotomized dogs, the renal and femoral blood flows were not significantly modified. The decrease of the renal blood flow and the increase of the femoral blood flow, during hypothalamic stimulation were greatly reduced or reversed after R 28935 equals erythro-1-(1--e12-(1,4-benzodioxan-2-yl)-2-OH-Et]-4-piperidyl)-2-benzimidaxolinone, 80 mug/kg i.v., but not after clonidine, 5 mug/kg i.v.     

阿托伐他汀联合普罗布考对动脉硬化家兔血流及斑块影响

目的:探讨阿托伐他汀钙片联合普罗布考治疗对兔颈动脉斑块稳定性的影响及血液流场改变。方法:选取清洁级日本大耳白兔40只,随机分为正常组、模型组、实验组、对照组,每组10只,复制颈动脉粥样硬化模型。对照组按照阿托伐他汀钙10 mg/(kg·d)的剂量,给兔按照不同体重予以不同药量治疗,将药物以生理盐水稀释至5 mL灌胃,实验组在对照组基础上加用普罗布考片0.25 g/(kg·d),与阿托伐他汀钙一同以生理盐水稀释至5 mL灌胃,模型组及正常组予以5 mL生理盐水灌胃。干预持续4周。用动物超声影像系统对兔进行颈动脉超声检查,彩色多普勒血流显像及血管成像检测颈动脉狭窄程度,血流速度,血流动力学改变。结果:1治疗后实验组阿托伐他汀钙片联合普罗布考治疗对兔颈动脉内-中膜厚度、斑块面积与模型组相比均明显改善,稳定斑块数明显增加,与对照组比较,实验组改善明显,差异有统计学意义(P0.05);2正常组颈动脉正常,治疗后,实验组狭窄明显减轻,血流速度接近正常,对照组有所改善,模型组颈动脉狭窄程度最重,血流速度快,血流动力学发生改变,斑块不稳定性增加,差异有统计学意义(P0.05)。结论:阿托伐他汀钙片联合普罗布考治疗能够有效提高兔颈动脉粥样硬化斑块的稳定性,改善颈动脉狭窄,使血液流速接近正常水平,值得做进一步药理研究及深入探讨。     

Numerical simulation of LDL mass transfer in a common carotid artery under pulsatile flows

Symmetrical 30-60% stenosis in carotid artery with a semi-permeable wall under steady/unsteady flows for Newtonian/non-Newtonian fluids is investigated numerically. The results show that the unsteadiness of blood flow, blood pressure rise and LDL component size increase the luminal concentration, LC, of the surface. The maximum LC occurring immediately after the separation point and the non-Newtonian fluid predicts higher LDL accumulation. LC decreased as the recirculation length is increased and reaches maximum at 40% stenosis. This process is used to estimate the time-dependent growth of the arterial wall.     

Flow of couple stress fluid through stenotic blood vessels

The effects of an axially symmetric mild stenosis on the flow of blood, when blood is represented by a couple stress fluid model, have been studied. It is found that, for a fixed stenosis size, the resistance to flow and wall shear stress increase as the couple stress parameter eta decreases from unity. A comparison of the results with those of the Newtonian case shows that the magnitude of resistance to flow and wall shear under a given set of conditions, is greater in the case of the couple stress fluid model. It is seen that even in the case of a mild stenosis (19% area reduction), resistance to flow and wall shear values are increased over those for no stenosis by 60% and 62%, respectively, when compared with the case of a Newtonian fluid.     

Renal cortical and medullary blood flow responses to L-NAME and ANG II in wild-type, nNOS null mutant, and eNOS null mutant mice

Experiments in wild-type (WT; C57BL/6J) mice, endothelial nitric oxide synthase null mutant [eNOS(-/-)] mice, and neuronal NOS null mutant [nNOS(-/-)] mice were performed to determine which NOS isoform regulates renal cortical and medullary blood flow under basal conditions and during the infusion of ANG II. Inhibition of NOS with N(omega)-nitro-l-arginine methyl ester (l-NAME; 50 mg/kg iv) in Inactin-anesthetized WT and nNOS(-/-) mice increased arterial blood pressure by 28-31 mmHg and significantly decreased blood flow in the renal cortex (18-24%) and the renal medulla (13-18%). In contrast, blood pressure and renal cortical and medullary blood flow were unaltered after l-NAME administration to eNOS(-/-) mice, indicating that NO derived from eNOS regulates baseline vascular resistance in mice. In subsequent experiments, intravenous ANG II (20 ng x kg(-1) x min(-1)) significantly decreased renal cortical blood flow (by 15-25%) in WT, eNOS(-/-), nNOS(-/-), and WT mice treated with l-NAME. The infusion of ANG II, however, led to a significant increase in medullary blood flow (12-15%) in WT and eNOS(-/-) mice. The increase in medullary blood flow following ANG II infusion was not observed in nNOS(-/-) mice, in WT or eNOS(-/-) mice pretreated with l-NAME, or in WT mice administered the nNOS inhibitor 5-(1-imino-3-butenyl)-l-ornithine (1 mg x kg(-1) x h(-1)). These data demonstrate that NO from eNOS regulates baseline blood flow in the mouse renal cortex and medulla, while NO produced by nNOS mediates an increase in medullary blood flow in response to ANG II.     

An increase in startle response in rats administered oxytocin

Twenty-four male albino Wistar rats were allocated to four groups and given either 23.2, 11.6 or 5.8 IU OXT/kg or vehicle (0.9% saline). A significant increase in startle response was observed in the 11.6 and 5.8 IU OXT/kg groups when compared to vehicle. Our results further support the suggestion that OXT is a "stress hormone" by implicating this peptide with increased emotionality/reactivity during a stressful experience.     

Thermogenic effects of dihydrocodeine in the rat

The object of this study was to assess the effects of dihydrocodeine on thermogenesis and brown adipose tissue activity in the rat from measurements of oxygen consumption and blood flow. Acute injection of dihydrocodeine tartrate (s.c.) stimulated resting oxygen consumption (VO2) in Sprague-Dawley rats in a dose-dependent manner (0.5-50 mg/kg), with a peak response (40-45% increase) occurring at 10-25 mg/kg. This effect was also observed in urethane-anaesthetized rats (although the effect was reduced) and in conscious animals following gastric intubation with the drug. Pretreatment of rats with either a beta-adrenergic antagonist (propranolol, 20 mg/kg), ACTH (4 g/kg), or an opiate antagonist (WIN44441-1, 2 mg/kg) significantly reduced the response to dihydrocodeine, whereas corticosterone injection (5 mg/kg) enhanced the effect. Surgical adrenalectomy or hypophysectomy (HYPX) almost completely abolished the thermogenic effect of dihydrocodeine. Dihydrocodeine also stimulated VO2 in lean (58% increase) and genetically obese Zucker rats (69% increase), and in both Zucker genotypes these responses were only slightly affected by HYPX, but enhanced in HYPX rats treated daily with corticosterone (1 mg/kg). Tissue blood flow, assessed from the distribution of radiolabelled microspheres, was unaffected in white adipose tissue, skeletal muscle, testes, kidney, brain, and liver (arterial supply) after a single injection of dihydrocodeine (25 mg/kg), but flow to interscapular and perirenal brown adipose tissue was increased by 9- to 10-fold. Surgical sympathectomy of brown adipose tissue prevented the increase in blood flow.(ABSTRACT TRUNCATED AT 250 WORDS)