Preservation of hypoxic pulmonary pressor response in canine pneumococcal pneumonia.

To determine the role of hypoxic pulmonary vasoconstriction in pneumococcal pneumonia, hemodynamic measurements were made in 16 dogs before, and within 36 hours after, intrapulmonary administration of type III pneumococcus. Ten dogs with one lobe or more of pneumonia increased their pulmonary vascular resistances and slightly decreased their arterial O2 tensions. Hypoxia increased and hyperoxia decreased their pulmonary vascular resistances. During O2 breathing, arterial PO2 was less during than before the pneumonia and increased when pulmonary perfusion was diverted away from the diseased lung. In 2 dogs breathing air, forcing the cardiac output through the diseased lung caused an increase in vascular resistance that could clearly be reduced by O2 breathing. In 5 dogs, lung mast cell counts showed no decrease in the lobes with pneumonia. In pneumococcal pneumonia, the hypoxic pulmonary pressor mechanism serves to decrease blood flow to the diseased lobes and, thus, to maintain the arterial PO2. Lung mast cells could participate in this response.     

Cicletanine blunts the pulmonary pressor response to acute hypoxia in rats.

Cicletanine (CIC) recently has been shown to lower systemic arterial pressure in hypertensive animals and man by a mechanism that may involve potentiation of the vasodilator effect of atrial natriuretic peptide (ANP). We previously have shown that ANP prevents acute hypoxia-induced pulmonary vasoconstriction and modulates the severity of chronic hypoxic pulmonary hypertension. The current study tested the hypothesis that CIC inhibits the pulmonary pressor response to acute hypoxia by a cyclic guanosine monophosphate (cGMP)-dependent mechanism. Catheters were placed in the pulmonary arteries of Sprague-Dawley rats through the right jugular vein using a closed chest technique, and in the aorta through the right femoral artery. After a 24 hour recovery, CIC (600 mg/kg) or vehicle was administered orally by gavage to conscious rats 4 hours prior to exposure to 10% oxygen at ambient pressure or to room air. Mean pulmonary arterial pressure (MPAP) and mean systemic arterial pressure (MSAP) and heart rate (HR) were monitored for 3 hours. CIC attenuated the acute pulmonary pressor response to hypoxia (MPAP = 24.5 +/- 1.0 mm Hg in the "hypoxic+CIC" group vs. 29.9 +/- 1.0 mm Hg in the "hypoxic+vehicle" group; p less than 0.05 at 3 hours of hypoxic exposure), but had no significant effect on MSAP or HR. CIC had no effect on MPAP, MSAP, or HR in air control rats. Acute hypoxia caused significant increases in plasma ANP and cGMP and in kidney cGMP content, but CIC administration did not alter these parameters further. This is the first demonstration that acute administration of CIC attenuates the pulmonary pressor response to acute hypoxia in conscious rats.     

Role of erythrocyte deformability in erythrocyte transit time and bioavailability of O2

The bioavailability of oxygen and its transfer towards all of the cells of the body essentially depends on the flow rate of red blood cells in the capillaries, which often have a smaller diameter than the red cell itself. The authors discuss the results obtained for the mean transit time of erythrocytes, based on microfiltration through artificial polycarbonate capillaries with a diameter of 5 microns, a length of 13 microns and a density of 4.10(5) pores/cm2.     

Role of ion channels in acute and chronic responses of the pulmonary vasculature to hypoxia

Localized alveolar hypoxia causes constriction of the small resistance pulmonary arteries, thus diverting the desaturated, mixed-venous blood to better ventilated areas of the lung. Although modulated by endothelial vasoactive substances, the constrictor response to hypoxia is intrinsic to the smooth muscle cell. Ion channels are important elements in two of the three components of the response. Hypoxia inhibits several potassium channels (voltage-gated and TASK), leading to membrane depolarization and calcium entry through L-type channels. It also causes release of calcium from the sarcoplasmic reticulum, with consequent repletion through store-operated calcium channels. Finally, the effect of the rise in cytosolic calcium is amplified by enhanced calcium sensitivity of the actin/myosin interaction, achieved by the hypoxia-induced increase in Rho-kinase activity. The change in oxygen tension that stimulates these three "executive" components is signaled by a change in the redox status of the smooth muscle cell and probably by downstream changes in G-proteins. Ion channels also play a critical role in the vascular remodeling that results in chronic hypoxic pulmonary hypertension, seen when all the pulmonary vascular bed is hypoxic, at high altitude and in patients with chronic lung diseases. The same inhibition of potassium channels and influx of calcium results in high cytosolic levels of potassium and calcium. These, respectively, lead to inhibition of apoptosis and an increase in cellular proliferation. A better understanding of the pathophysiology of hypoxic pulmonary vasoconstriction and vascular remodeling will enable the design of better treatments for hypoxic and other forms of pulmonary hypertension.     

Changes in erythrocyte deformability in Alzheimer's disease

In a previous work we showed an alteration of erythrocyte filtration ability in patients with Alzheimer's disease according to their age and illness duration. This study has for aim to find a criteria of deformability that would be constant in all Alzheimer patients and would show a modification of red cell membranes. The erythrocyte filterability was studied in this present paper, in accord to Reid and Dormandy method using two values of depression (5 and 0 cm of water). These depressions correspond to the physiological values of blood pressure at the level of precapillary and capillary systems. The ratio between the result obtained at 5 cm and the result at 0 cm is constant in normal patient without organic disease and it is independent of age. At the opposite, this ratio increase very significantly in all Alzheimer patients, and this is not correlated to the initial value of filtrability. This ratio could be an index of the alteration of red cell membranes.     

成纤维细胞活化在低氧性肺血管重构中的作用

以往在低氧性肺血管重构机制的研究中,外膜的作用往往被忽略。新近的研究表明,血管外膜特别是其中的成纤维细胞在调节血管功能中发挥着重要的作用。外膜中的成纤维细胞是低氧刺激的首要“损伤感受细胞”,低氧可以激活血管外膜成纤维细胞,活化的成纤维细胞既可以合成分泌细胞生长因子、炎症因子,进而促进中膜血管平滑肌细胞增殖,又可以转分化为平滑肌样细胞（肌纤维母细胞）、分泌胶原蛋白,导致血管重构。因此,低氧导致的成纤维细胞活化及表型转换在肺血管重构中起重要作用,贯穿着低氧性肺血管重构的整个病理过程。     

Erythrocyte deformability and erythrocyte aggregation in preeclampsia

One of the features of preeclampsia is impaired blood rheology due to altered erythrocyte aggregation and erythrocyte deformability. We investigated these two parameters which affect the viscosity of blood, along with serum and intraerythrocytic magnesium concentrations, immunoglobulin titres and fibrinogen concentration in 12 preeclamptic women. Eighteen (18) other non-preeclamptic, gestation-matched women acted as controls. Erythrocyte deformability, expressed as elongation index (EI), and erythrocyte aggregation expressed as aggregation half-time (t 1/2) were measured with the Laser-assisted Optical Rotational Cell Analyser (LORCA). Serum and intraerythrocytic magnesium concentrations were analysed by atomic absorption spectrometry, immunoglobulin titres by radial immunodiffusion and fibrinogen concentration by a clot weight technique. There was no statistically significant difference in these parameters between preeclamptics and controls suggesting that erythrocyte deformability and aggregation as well as serum and intraerythrocytic concentrations, fibrinogen levels and immunoglobulin titres are not altered in preeclampsia. Further investigations are required in severe preeclampsia and in preeclamptic women taking magnesium sulphate supplement.     

Role of extracellular superoxide dismutase in the mouse angiotensin slow pressor response

Low rates of angiotensin II (Ang II) infusion raise blood pressure, renal vascular resistance (RVR), NADPH oxidase activity, and superoxide. We tested the hypothesis that these effects are ameliorated by extracellular superoxide dismutase (EC-SOD). EC-SOD knockout (-/-) and wild type (+/+) mice were equipped with blood pressure telemeters and infused subcutaneously with Ang II (400 ng/kg per minute) or vehicle for 2 weeks. During vehicle infusion, EC-SOD -/- mice had significantly (P<0.05) higher MAP (+/+: 107+/-3 mm Hg versus -/-: 114+/-2 mm Hg; n=11 to 14), RVR, lipid peroxidation, renal cortical p22(phox) expression, and NADPH oxidase activity. Ang II infusion in EC-SOD +/+ mice significantly (P<0.05) increased MAP, RVR, p22(phox), NADPH oxidase activity, and lipid peroxidation. Ang II reduced SOD activity in plasma, aorta, and kidney accompanied by reduced renal EC-SOD expression. During Ang II infusion, both groups had similar values for MAP (+/+ Ang II: 125+/-3 versus -/- Ang II: 124+/-3 mmHg; P value not significant), RVR, NADPH oxidase activity, and lipid peroxidation. SOD activity in the kidneys of Ang II-infused mice was paradoxically higher in EC-SOD -/- mice (+/+: 8.8+/-1.2 U/mg protein(-1) versus -/-: 13.7+/-1.6 U/mg protein(-1); P<0.05) accompanied by a significant upregulation of mRNA and protein for Cu/Zn-SOD. In conclusion, EC-SOD protects normal mice against oxidative stress by attenuating renal p22(phox) expression, NADPH oxidase activation, and the accompanying renal vasoconstriction and hypertension. However, during an Ang II slow pressor response, renal EC-SOD expression is reduced and, in its absence, renal Cu/Zn-SOD is upregulated and may prevent excessive Ang II-induced renal oxidative stress, renal vasoconstriction, and hypertension.     

Microrheologic investigation of erythrocyte deformability in diabetes mellitus

This study was undertaken to determine whether diabetes alters the viscoelastic properties of erythrocytes. The oldest and youngest 10% fractions of circulating red cells were separated by centrifugation of freshly drawn blood obtained from ten diabetics with disease of one to 20 years' duration and from an equal number of age- and sex-matched control subjects. Cells from each fraction were suspended in phosphate- buffered saline, and their rheologic behavior was examined in a rheoscope. The elongation of cells, the percentage of cells that tank- treaded in response to shear stress, tank-treading frequency, and the rate of recovery of cell shape upon cessation of shear stress were determined in the oldest and youngest 10% of cells for diabetics as well as for controls. All four parameters were virtually identical for diabetics and controls. Additional aliquots of cells were taken for assessment of nonenzymatic glucosylation of hemoglobin and cell membrane protein. The absence of any measurable difference in rheologic behavior of cells from diabetic and control subjects, despite substantial differences in nonenzymatic glucosylation of hemoglobin and cell membrane proteins, suggests that the magnitude of glucosylation observed in these cellular constituents does not alter the viscoelastic properties of the cells. The implication of these observations is that microvascular complications of diabetes are not attributable to altered deformability of red cells.     

A hyperactive pulmonary vasculature in response to chronic mitral regurgitation

A subset of patients with mitral valve disease has a marked rise in pulmonary vascular resistance (PVR) that is disproportionate to elevations in pulmonary venous pressure. Termed a "hyperactive" pulmonary vasculature, the elevation in PVR falls promptly and dramatically in response to mitral valve replacement. We report a 55-year-old man with progressive, exertional dyspnea of several months' duration who had signs of congestive heart failure (CHF) with moderate mitral valvular regurgitation and aortic stenosis by echocardiographic interrogation. These lesions in combination, together with his CHF and disproportionate elevation in pulmonary artery systolic pressure (90 mm Hg) and PVR (527 dyne x s x cm(-5)), raised the prospect of valvular replacement. There followed a normalization of PVR and marked improvement in his symptoms and signs of CHF in response to pharmacologic management with an ACE inhibitor, loop diuretic, and aldosterone receptor antagonist to negate any further consideration of surgery.     

肺动脉血管紧张素转换酶在缺氧性肺动脉高压演进过程中的作用

目的探讨肺动脉局部肾素－血管紧张素系统对缺氧性肺动脉高压（ＰＡＨ）的影响。方法采用常压缺氧ＰＡＨ动物模型，观察缺氧后肺动脉收缩压（ＰＡＰｓ）、肺动脉血管紧张素转换酶（ＡＣＥ）活性、胶原蛋白含量（Ｈｐ）及血管平滑肌细胞（ＳＭＣ）超微结构的变化，以及ＡＣＥ抑制剂－西拉普利对以上变化的影响。结果缺氧期间ＰＡＰｓ、ＡＣＥ活性、Ｈｐ显著增高，ＳＭＣ转为分泌型。西拉普利组ＡＣＥ活性下降，ＰＡＰｓ、Ｈｐ降至正常，ＳＭＣ恢复收缩表型。结论肺动脉ＡＣＥ参与缺氧性ＰＡＨ形成、转归过程中肺动脉胶原代谢、ＳＭＣ表型变化的调节。     

Modulation of erythrocyte deformability by PKC activity

The interactions between membrane, peripheral and cytoskeleton proteins are responsible for the maintenance of erythrocyte deformability (EEI) and some of these interactions are modulated by PKC activity. Protein band 3 of the erythrocyte membrane is phosphorylated by phosphotyrosine kinases (PTK) and dephosphorylated by phosphotyrosine phosphatase (PTP). It was previously described by us a signal transduction mechanism that describes a possible pathway connecting an erythrocyte external membrane protein, acetylcholinesterase (AChE), with protein band 3. So how does PKC activity modulate EEI when protein band 3 is phosphorylated or dephosphorylated in absence or presence of AChE effectors?To answer this we used phorbol 12-myristate 13-acetate (PMA) as an activator and chelerythrine chloride as inhibitor of PKC and also band 3 modulators of band 3 phosphorylation degree, in presence and absence of AChE effectors in order to measure in whole blood samples EEI. Our results showed that erythrocyte deformability was significantly (i) decreased by inhibition of PKC, in absence and presence of AChE inhibitor velnacrine (ii) increased with PMA in absence and presence of ACh and (iii) decreased in presence of calpeptin in absence and presence of either chelerythrine or PMA. These results establish dependence between cytoskeleton proteins, PKC activity, band 3 phosphorylation degrees and EEI. Better understanding of those proteins interactions on transduction mechanisms might trigger possible targets for drug action that would modulate EEI.     

The effect of malonyldialdehyde on erythrocyte deformability

The addition of malonyldialdehyde (5-20 micro M) to human erythrocytes results in a marked decrease in cellular deformability as measured with a counter-rotating, cone plate Rheoscope when low shear forces (2.5-25 dynes/sq cm) are applied. At high shear forces (125-500 dynes/sq cm), malonyldialdehyde at 5 micro M had no effect on deformability, although at concentrations of 10 and 20 micro M a small but statistically significant decrease was evident. These effects of this crosslinking agent are observed in the absence of alterations in cell volume and intracellular viscosity. The results obtained are in accord with the view that the polymerization of membrane constituents may contribute to the events that lead to the removal from the circulation of either aging cells or cells exposed to peroxidation-initiating agents.     

Role of pentose phosphate pathway-derived NADPH in hypoxic pulmonary vasoconstriction

We have previously shown that pentose phosphate pathway (PPP) inhibitors, 6-aminonicotinamide (6-AN) and epiandrosterone (EPI), markedly reduce hypoxic pulmonary vasoconstriction (HPV). Although it has been suggested that changes in the NADPH/NADP+ ratio and redox status are involved in the mechanism of HPV, the role of PPP-derived NADPH in this phenomenon is not known. The aim of this study, therefore, was to investigate the role of PPP-derived NADPH in HPV using isolated rat pulmonary arteries (PA) and perfused rat lungs. The NADPH/NADP+ ratio and NADPH levels in PA and lungs exposed to hypoxia increased 2-fold and 7-fold, respectively, compared to time-matched normoxic controls. Both hypoxia-induced increases in lung NADPH levels and lung perfusion pressure were inhibited by 6-AN (500 microM) or EPI (300 microM). The chemical inhibitors of PPP and hypoxia similarly decreased lung tissue NOx levels by approximately 50%. In contrast, hypoxia increased the lung soluble guanylate cyclase (sGC) activity (from 22.9+/-6.3 to 57.1+/-7.6 pmol/min/g), which was prevented by PPP inhibitors. ODQ, a sGC inhibitor, potentiated HPV. These results suggest that while PPP-derived NADPH may play a significant role in HPV, it may also moderate the magnitude of HPV through activation of the NO-sGC-cGMP vasodilation pathway.     

Role of adenosine in the hypoxic ventilatory response of the newborn piglet

The role of intracerebral adenosine levels in the control of ventilatory response to hypoxia was explored in 15 spontaneously breathing intubated piglets, 1–5 days old, sedated with chloral hydrate. Respiration was recorded via by a pneumotachograph. In all animals exposed to hypoxia (12% 0₂) for 10 minutes. There was an initial increase in ventilation followed by a late decrease (the biphasic ventilatory response). Both intravenous caffeine citrate (20 mg/kg) and an Fi_ico of 0.05 separately abolished or attenuated the late ventilatory depression associated with hypoxia. In the same piglets, the administration of 10 pg dipyridamole, a competitive inhibitor of adenosine receptors, directly into the cerebral ventricles abolished the hyperventilatory response to hypoxia. Conversely, the use of 20 μg intraventricular 8-phenyltheophylline abolished the late ventilatory depression associated with hypoxia. Neither drug had a direct effect on ventilation at the time of injection. These results suggest that adenosine is a part of the diphasic ventilatory response to hypoxia. Pediatr Pulmonol. 1994; 17:50–55. © 1994 Wiley-Liss, Inc.     

Role of histamine in the hypoxic vascular response of the lung.

The lung vasculature responds to alveolar hypoxia by constriction and when the hypoxia is localized to one region of the lung, vasoconstriction is also localized to that region. Histamine has been alleged to have a role in the vasoconstrictor response with generalized alveolar and thus systemic hypoxia, but the role for histamine is not clear in localized alveolar hypoxia. Studies were, therefore, undertaken to determine the contribution of histamine to the localized pulmonary vasoconstrictor response to hypoxia. A divided tracheal cannula was used in anesthetized dogs which allowed for ventilation of one lung with oxygen to maintain normal systemic oxygenation (mean PaO2 =73 mm Hg) while the other lung was ventilated with nitrogen as an alveolar hypoxic stimulus. Perfusion to each lung was determined with the 133Xe technique utilizing external counters over the chest. Perfusion (Q) was decreased by 32% (P = 0.002) to the hypoxic lung after 10 minutes of unilateral nitrogen breathing. After intravenous infusion of 20 mg of chlorpheniramine maleate, a potent antihistamine, the decrease in Q to the hypoxic lung was unchanged at 30%. After 40-100 mg chlorpheniramine the decrease in perfusion was again unchanged at 34%. Therefore a significant role was not demonstrated for histamine in the regional pulmonary vasoconstrictor response to alveolar hypoxia in the absence of systemic hypoxemia.