Outcomes of lung transplantation for pleuroparenchymal fibroelastosis: A French multicentric retrospective study.

BACKGROUND: Pleuroparenchymal fibroelastosis (PPFE) has no currently available specific treatment. Benefits of lung transplantation (LT) for PPFE are poorly documented. METHODS: We conducted a nation-wide multicentric retrospective study in patients who underwent lung or heart-lung transplantation for chronic end-stage lung disease secondary to PPFE between 2012 and 2022 in France. RESULTS: Thirty-one patients were included. At transplantation, median age was 48 years [IQR 35-55]. About 64.5% were women. Twenty-one (67.7%) had idiopathic PFFE. Sixteen (52%) had bilateral LT, 10 (32%) had single LT, 4 (13%) had lobar transplantation and one (3%) had heart-lung transplantation. Operative mortality was 3.2%. Early mortality (<90 days or during the first hospitalization) was 32%. Eleven patients (35.5%) underwent reoperation for hemostasis. Eight (30.8%) experienced bronchial complications. Mechanical ventilation time was 10 days [IQR 2-55]. Length of stay in intensive care unit and hospital were 34 [IQR 18-73] and 64 [IQR 36-103] days, respectively. Median survival was 21 months. Post-transplant survival rates after 1, 2, and 5 years were 57.9%, 42.6% and 38.3% respectively. Low albuminemia (p = 0.046), FVC (p = 0.021), FEV1 (p = 0.009) and high emergency lung transplantation (p = 0.04) were associated with increased early mortality. Oversized graft tended to be correlated to a higher mortality (p = 0.07). CONCLUSION: LT for PPFE is associated with high post-operative morbi-mortality rates. Patients requiring high emergency lung transplantation with advanced disease, malnutrition, or critical clinical status experienced worse outcomes. GOV IDENTIFIER: NCT05044390.

[Short-term results of video-assisted lung cancer surgery in octogenarians]. / Morbi-mortalité de la résection pulmonaire pour cancer par chirurgie vidéo-assistée chez l'octogénaire.

INTRODUCTION: Due to an increase in life expectancy, onco-pulmonologists and thoracic surgeons are more frequently faced with octogenarian patients with lung cancer. In this age group, treatment modalities may need to be revised because of the increasing presence of comorbidities. Surgery remains the reference treatment for early stage disease, but mortality rates and postoperative complications are higher in this group of patients. One of the solutions to reduce the operative risk would be to develop videoassisted thoracoscopic pulmonary resection surgery. The aim of this study was to evaluate the results of this form of lung cancer surgery in octogenarians. METHODS: All patients 80 years old or more who underwent videoassisted lung cancer surgery from 2014 to 2018 at Lyon University Hospital were included. Wedge resections and diagnostic procedures were excluded. RESULTS: Nineteen patients (13 men, 6 women) were included. The median age was 82 years old. All patients had undergone videoassisted lobectomy. Three patients required conversion to thoracotomy (15.8%). All patients underwent complete resection (R0). One patient had N1 lymph node involvement, all others were N0. The postoperative complication rate was 68.4%, the majority of which were grade II of the Clavien classification. Perioperative mortality was 5.3%. CONCLUSIONS: Videoassisted lung cancer resection in a selected population of octogenarians is associated with satisfactory short-term results. It is reasonable to favour minimally invasive techniques in this population, even if the proof of their superiority has not yet been firmly established.

Transcatheter aortic valve implantation: a safe and efficient procedure to treat an aortic valve stenosis before lung cancer resection.

A 75 year old man presented with left upper lobe squamous cell carcinoma. Severe aortic stenosis has been discovered during preoperative assessment. In this situation, two therapeutic strategies are described: concomitant or two-staged procedures. The debate has not yet led to the conclusion on whether preferably performing one or the other. Furthermore, in an oncologic context, using cardiopulmonary bypass is still controversial. So, thoracic and cardiac surgeons jointly proposed to the patient a transcatheter aortic valve implantation followed, 72 h later, by lung cancer resection. This case report describes a way to treat both diseases avoiding cardiopulmonary bypass adverse effects and without delaying lung cancer treatment.

Metachronous single lung transplantation after contralateral pneumonectomy. A ''big'' challenge?

Single lung transplantation for cystic fibrosis is an uncommon therapy. Contralateral pneumonectomy is, in these cases, rarely done before transplantation. Herein, we report the case of a single lung transplantation in a patient who had previously a contralateral pneumonectomy.

Atrial fibrillation is associated with hypermethylation in human left atrium, and treatment with decitabine reduces atrial tachyarrhythmias in spontaneously hypertensive rats.

Atrial fibrillation (AF) is the most common cardiac arrhythmia. As the molecular mechanisms underlying the pathology are largely unknown, this cardiac arrhythmia remains difficult to treat. To identify specific molecular actors involved in AF, we have performed a transcriptomic analysis on left atrium (LA) from patients with valvular heart disease with or without AF. We showed that 1627 genes had altered basal expression level in LA tissue of AF patients compared with the control group. The significantly enriched gene ontology biological process "anatomical structure morphogenesis" contained the highest number of genes in line with changes in structure that occur when the human heart remodels following AF development (ie, LA dilatation and interstitial fibrosis). We then focused the study on Pitx2 (paired-like homeodomain 2), being the most altered transcription factor in LA from AF patients and from which compelling evidence have indicated that its reduced expression can be considered as a marker for the disease. In addition, its expression was inversely correlated with LA size. We demonstrated that AF is associated with Pitx2 promoter hypermethylation both in humans and arrhythmic aging spontaneously hypertensive rats. Chronic administration of a DNA methylation inhibitor (ie, 5-Aza-2'-deoxycitidine) improved ECG arrhythmic profiles and superoxide dismutase activities and reduced fibrosis in the left ventricle of spontaneously hypertensive rats. Taken together, these data support the notion that AF is associated with epigenetic changes in LA and provide a proof-of-concept that hypomethylating agents have to be considered in the treatment of atrial arrhythmias.

[Long-term results of lung cancer surgery in octogenarians]. / Résultats à long terme de la chirurgie de résection pulmonaire pour cancer chez l'octogénaire.

INTRODUCTION: This retrospective study was undertaken to evaluate late results of lung cancer surgery in octogenerians. METHODS: All patients 80years old or more who underwent a lung resection for cancer from 2000 to 2010 at Lyon University Hospital were included. No patients were treated with video-assisted surgery. Wedge resections were excluded. RESULTS: Sixty-three patients (42 men, 21 women) were operated. The median age was 82years. Operative mortality was 4.7%. The rate of perioperative complications was 49%. The late survival was 34% at 5years. Five-year survival by nodal involvement was N0, 36%; N1, 29%; N2 20%, P<0.05. Patients with a squamous cell carcinoma (24) had a better long-term survival than patients with an adenocarcinoma (30), 33% and 25% respectively at 5years, P<0.05. The rate of recurrence was 33.9%. CONCLUSIONS: Surgical treatment of lung cancer in selected population of octogenerians is associated with satisfactory early and long-term results. Survival is influenced by nodal involvement and by the pathologic type of the cancer.

[Indications of lung transplantation: Patients selection, timing of listing, and choice of procedure]. / Indications de la transplantation pulmonaire : sélection des candidats, critères d'inscription en liste d'attente, choix du type d'intervention.

Lung transplantation (LT) is now considered as an excellent treatment option for selected patients with end-stage pulmonary diseases, such as COPD, cystic fibrosis, idiopathic pulmonary fibrosis, and pulmonary arterial hypertension. The 2 goals of LT are to provide a survival benefit and to improve quality of life. The 3-step decision process leading to LT is discussed in this review. The first step is the selection of candidates, which requires a careful examination in order to check absolute and relative contraindications. The second step is the timing of listing for LT; it requires the knowledge of disease-specific prognostic factors available in international guidelines, and discussed in this paper. The third step is the choice of procedure: indications of heart-lung, single-lung, and bilateral-lung transplantation are described. In conclusion, this document provides guidelines to help pulmonologists in the referral and selection processes of candidates for transplantation in order to optimize the outcome of LT.

Thymoma associated with autoimmune diseases: 85 cases and literature review.

OBJECTIVES: To describe the clinical features, treatment, and outcome of autoimmune diseases (AD) in a cohort of patients with thymoma. DESIGN: Pathological records from three university hospitals, between 2005 and 2011, were reviewed to identify patients with thymoma. Patients with thymoma and AD were compared with patients with thymoma without AD. RESULTS: 47/85 (55%) cases of thymoma had AD, including myasthenia gravis (MG) (n=33), Hashimoto's thyroiditis (n=4), Isaac's syndrome (n=3), Morvan syndrome (n=2), pure red cell aplasia (n=2), systemic lupus (n=2), lichen planus (n=2), and one case of each following conditions: aplastic anemia, autoimmune hemolytic anemia, Good's syndrome, pemphigus, autoimmune hepatitis, Graves' disease, limbic encephalitis, and inflammatory myopathy. Six patients (7%) presented at least 2 ADs. The median duration of follow-up after surgery was 60 months (40-78 months). In 32 patients, the diagnosis of AD preceded the diagnosis of thymoma, in 9 patients, thymoma was diagnosed at the same time as the AD and 7 patients had been operated on when they developed an AD. We found a significative difference on the Masaoka stage between the MG patients and the patients who present another AD (p=0.028). No risk factor for developing an AD after thymectomy was identified. CONCLUSIONS: We describe here the long-term follow-up of a large series of AD related to thymoma. Our results confirm previous data concerning AD occurrence in patients with thymoma and suggest that preexisting autoimmunity is not a risk factor for developing autoimmune manifestations after thymectomy.

[Graft-versus-host disease, a rare complication of lung transplantation]. / La maladie du greffon contre l'hôte, graft-versus-host disease, une complication exceptionnelle de la transplantation pulmonaire.

Graft-versus-host disease (GVHD) is a classic and frequent multisystemic complication of bone marrow allografts. It has also been reported after the transplantation of solid organs such as the liver or gut. Recent cases of GVHD have been reported after lung and heart-lung transplant. Skin, liver, gastrointestinal tract and bone marrow are the organ preferentially affected by GVHD. Corticosteroid is the first line treatment of GVHD. The prognosis reported in solid organ transplants is poor with infectious complications favoured by immunosuppressive therapy. In this article, we report a case of a patient with cystic fibrosis who presented a probable GVHD 18 months after a lung transplant and a literature review of similar cases.

Role of matrix metalloproteinases in blood flow-induced arterial enlargement: interaction with NO.

Tears in the internal elastic lamina (IEL) can be observed after chronic increases in arterial blood flow, suggesting a potential role for matrix metalloproteinases (MMPs) in flow-induced vascular remodeling. We undertook to study this phenomenon by constructing an arteriovenous fistula (AVF) between the left common carotid artery (CCA) and the external jugular vein in rabbits. The diameter of the flow-loaded left CCA increased by 13.6+/-1.8% by day 3 after construction of the AVF compared with the right CCA (n=4, P:<0.01) and by 40.7+/-7.5% by day-15 (n=10, P:<0.0001). Increased CCA diameter also coincided with IEL fragmentation. Three days after construction of the AVF, gelatin zymography of protein extracts from left CCAs of untreated rabbits showed a significant increase in the 62-kDa (active MMP-2) activity and the appearance of a lytic band at 92 kDa (pro-MMP-9). In further experiments, MMP activity was inhibited by treatment with doxycycline (DOX) or BB-94, a specific MMP inhibitor. The increase in the 62-kDa gelatinolytic band was abolished in DOX- and BB-94-treated rabbits. The 92-kDa gelatinolytic band was also reduced in DOX-treated animals. Furthermore, both increased left CCA diameter and IEL fragmentation were abolished in DOX- and BB-94-treated rabbits. To evaluate whether nitric oxide was involved in blood flow-induced MMP activation, the rabbits were treated with N:(G)-nitro-L-arginine methyl ester to inhibit nitric oxide synthesis. MMP activities were significantly decreased in the left CCAs of N:(G)-nitro-L-arginine methyl ester-treated animals. Hence, blood flow-induced MMP activation is critical in flow-induced vascular enlargement and IEL fragmentation, and blood flow-induced nitric oxide participates in MMP activation.

FDG-PET improves tumour detection in patients with paraneoplastic neurological syndromes.

To determine the usefulness of [18F]fluorodeoxyglucose (FDG) whole body FDG-PET in the diagnosis of tumours in patients with paraneoplastic neurological syndromes (PNS), we prospectively studied 20 patients with paraneoplastic antibodies in whom conventional imaging gave negative or inconclusive results for the presence of tumour. All 20 patients had neurological manifestations compatible with PNS and well-characterized paraneoplastic antibodies (12 anti-Hu, one anti-Hu and anti-CV2, one anti-CV2, four anti-Yo, one anti-Ri and one anti-amphiphysin). The mean delay between the onset of neurological symptoms and FDG-PET was 10 months (range 1-54). In these 20 patients, abnormal uptake was demonstrated in 18 patients, with some patients having abnormal signal in several areas. We observed abnormal uptake in the mediastinum (13 cases), lung (two cases), breast (two cases), parotid gland (one case), or the cervical, supraclavicular or axillary lymph nodes (seven cases). Following FDG-PET, the histological diagnosis of the tumour was made in 14 patients (small cell lung carcinoma in eight cases, breast adenocarcinoma in two, lung adenocarcinoma in two, axillary metastasis of ovary carcinoma in one, and malignant thymoma in one). Two other patients with abnormal FDG uptake showed radiological evidence of lung cancer, but a histological diagnosis could not be obtained. In two other patients, initial FDG-PET showed abnormal FDG uptake that was not confirmed a few months later by repeat FDG-PET. In the two patients with negative FDG-PET, peritoneal carcinomatosis was diagnosed in one and no tumour was found in the other. In our series, the sensitivity of FDG-PET for tumour detection was >83% demonstrating a clear role of this technique in the management of patients with PNS. However, in our series, the specificity of FDG uptake was only 25% due to unexplained abnormal FDG uptake in three patients and in abnormal FDG uptake due to a benign tumour in one patient. Over the study period, we saw 73 other patients with PNS and paraneoplastic antibodies. A tumour was demonstrated in 71 out of 73 by conventional techniques. Since false-positive and false-negative results are possible with FDG-PET and in most patients with PNS, the tumour is demonstrated by conventional techniques, we believe that FDG-PET should be reserved, at the moment, for patients with well-defined PNS antibodies when conventional imaging fails to identify a tumour or when lesions are difficult to biopsy.

Management of emerging multidrug-resistant tuberculosis in a low-prevalence setting.

Multidrug-resistant (MDR) tuberculosis (TB) is an emerging concern in communities with a low TB prevalence and a high standard of public health. Twenty-three consecutive adult MDR TB patients who were treated at our institution between 2007 and 2013 were reviewed for demographic characteristics and anti-TB treatment management, which included surgical procedures and long-term patient follow-up. This report of our experience emphasizes the need for an individualized approach as MDR TB brings mycobacterial disease management to a higher level of expertise, and for a balance to be found between international current guidelines and patient-tailored treatment strategies.

Blockade of cyclosporine-induced vasoconstriction by the calcium channel blocker diltiazem in dogs.

The calcium channel blocker diltiazem has been shown to reduce cyclosporine toxicity both in clinical and in experimental studies. To determine the effect of diltiazem administration on cyclosporine vasoconstriction and on renal release of endothelin, we administered cyclosporine in models of renal and hind limb autoperfusion in the dog. Infusion of cyclosporine in the hind limb (20 mg) during diltiazem perfusion caused an average increase of 6 +/- 2 mm Hg in hind limb perfusion pressure compared with 17 +/- 2 mm Hg before diltiazem, a significant difference (p < 0.05). Similarly, injections of cyclosporine (10 mg) in the kidney during diltiazem infusion caused an average increase of 26 +/- 4 mm Hg in renal perfusion pressure compared with 83 +/- 13 mm Hg before diltiazem infusion, a significant decrease in the renal vascular response (p < 0.05). On the other hand, sodium nitroprusside did not change the renal vasoconstriction to cyclosporine, which suggests a specific effect of diltiazem. Serum levels of endothelin in renal venous blood increased from 0.5 +/- 0.4 pg/ml to 3.8 +/- 0.6 pg/ml with cyclosporine, despite diltiazem infusion. Therefore, although the calcium channel blocker diltiazem effectively decreases cyclosporine-induced renal and hind limb vasoconstriction, it does not act by preventing endothelin release induced by cyclosporine stimulation.

Flow-induced release of endothelium-derived relaxing factor during pulsatile bypass: experimental study in the fetal lamb.

OBJECTIVE: This study was initiated to test the hypothesis that fetal hemodynamic changes observed under pulsatile flow bypass might be related to the release of endothelium-derived relaxing factor through oscillating shear stress. METHODS: Normothermic bypass was instituted in utero in 21 preterm fetal lambs for a 1-hour period through the right atrium and main pulmonary artery. Ultrasonic flowmeters were positioned around the descending aorta and the umbilical artery. The circuit consisted of an oxygenator and a pump set to either continuous flow (n = 7) or pulsatile flow (n = 7) and adjusted to maintain a fetal main arterial pressure of 50 mm Hg. In seven other animals, endothelium-derived relaxing factor was blocked by a continuous infusion of N omega-nitro-L-arginine after 30 minutes of pulsatile flow. RESULTS: During the first 30 minutes of bypass, pump flows were significantly lower in the continuous-flow group than in the pulsatile-flow or blocked-flow groups (respectively, 612 +/- 144, 907 +/- 153 and 987 +/- 228 ml/min), with similar changes in aortic and umbilical flows. Systemic vascular resistances were significantly lower in the pulsatile-flow and blocked-flow groups than in the continuous-flow group (550 +/- 106 vs 821 +/- 212 dynes/sec/cm-5). However, after blockade of endothelium-derived relaxing factor, resistances increased gradually in the blocked-flow group to reach the level of that of the continuous-flow group at the end of bypass (943 +/- 77 vs 556 +/- 143 dynes/sec/cm-5 in the pulsatile-flow group). CONCLUSIONS: Blockade of endothelium-derived relaxing factor after 30 minutes of pulsatile flow returns fetal hemodynamics to continuous flow conditions. The specific inhibitor of endothelium-derived relaxing factor used in this experiment suggests that nitric oxide may be released by fetal endothelium during pulsatile bypass.

Long-term clinical and hemodynamic evaluation of porcine valved conduits implanted from the right ventricle to the pulmonary artery.

OBJECTIVE: This retrospective study was initiated to evaluate the long-term results of valved prosthetic conduits implanted in the right ventricular outflow tract in patients with complex ventricular-pulmonary discontinuity. METHODS: A cohort of 103 patients out of 127 (24 early deaths, 19%) operated on between 1973 and 1996 with porcine valved conduits was available for evaluation, with a follow-up ranging from 1 to 21.6 years (mean follow-up 8.4 +/- 6 years). A total of 74 hemodynamic studies were performed after the operation, 50 patients having undergone at least 1 cardiac catheterization during the follow-up period. RESULTS: There were 16 late deaths, and the actuarial survivals, including early mortality, were 72.9% +/- 4% at 5 years, 63.1% +/- 5% at 10 years, and 58.2% +/- 5% at 15 years, at which time 20 patients were still available for review and exposed to the risk of dying. The mean peak systolic gradient across the right ventricular outflow tract was plotted as a function of time, showing a gradual increase and a significant step-up after the eighth year, from 43 +/- 36 to 69 +/- 19 mm Hg (P < .005). Reoperation was required for progressive conduit obstruction between 1.1 and 17.7 years after implantation (mean 7.4 +/- 4.8 years) in 25 patients (24%, 70% CL 15%-33%), with generally very few symptoms, or for residual ventricular septal defect in 3 patients. Freedom from reoperation was 79.5% +/- 5% at 10 years and 65.8% +/- 7% at 15 years. CONCLUSIONS: Porcine conduits may represent a valuable alternative to biologic substitutes with similar long-term results. Given the few symptoms, progressive conduit stenosis after the eighth postoperative year imposes a yearly noninvasive patient evaluation during the follow-up.

Experimental right ventricle to pulmonary artery discontinuity: outcome of polyurethane valved conduits.

OBJECTIVE: The ideal substitute for the treatment of ventricle-pulmonary artery discontinuity remains a topic of controversy, because of calcifications and degeneration of biologic substitutes leading to subsequent reoperations. Because polyurethane valves used in ventricular assist devices show a satisfactory biocompatibility, the aim of this study was to evaluate a valved conduit composed of a Dacron graft incorporating a trileaflet 25 mm polyurethane valve. METHODS: The conduit was implanted between the right ventricle and the main pulmonary artery in adult sheep, with ligation of the proximal pulmonary artery. The animals received no medications. Serial hemodynamic data were collected at the time of implantation and at postoperative intervals of 6 and 12 months. RESULTS: The peak pressure gradient across the valve increased significantly between implantation (0.17 +/- 5.6 mm Hg) and 6 months after operation (7.3 +/- 3 mm Hg, p = 0.0007) and remained stable thereafter (6.7 +/- 3 mm Hg at 12 months), whereas the cardiac output remained unchanged (4.6 +/- 0.6 L/min at implantation, 4 +/- 0.6 L/min at 6 months, and 3.9 +/- 1.1 L/min at 12 months). At the completion of the study, valve samples were processed and vapor coated with carbon for microscopic examination. There was one instance of nonadherent thrombus formation inside a cusp but no structural failures. The other valves were free of calcium deposits and no significant amounts of phosphorus could be detected by scanning electron microscopy and energy dispersive spectrometry. CONCLUSIONS: These data demonstrate the good hemodynamic performance, low thrombogenicity, and acceptable durability of the polyurethane valves implanted in the right side of the heart in a chronic sheep model.

Better preservation of endothelial function and decreased activation of the fetal renin-angiotensin pathway with the use of pulsatile flow during experimental fetal bypass.

OBJECTIVE: Pulsatile flow was shown to overcome the progressive rise in peripheral and placental vascular resistances observed during steady-flow bypass, this rise being counteracted by inhibition of nitric oxide synthase. This study quantifies the release of endothelial vasoactive substances during a 60-minute in utero model of fetal bypass. METHODS: Fetuses were randomly allocated into 1 of 2 groups (steady flow, n = 8, or pulsatile flow, n = 13) and subjected to bypass through central cannulation and perfusion with either a centrifugal or pulsatile (125 beats x min(-1)) blood pump. RESULTS: Lactate concentration was high, starting at fetal exteriorization and increasing during fetal preparation in the 2 groups. Once bypass was established, the rise was significant only in the steady-flow group. Plasma nitric oxide metabolites, similar before bypass, reached higher levels during pulsatile flow at the end of bypass (99+/-9 vs. 82+/-23 micromol x L(-1); P =.037). Levels of urinary nitric oxide metabolites were significantly higher in the pulsatile-flow than in the steady-flow group (764+/-143 vs. 508+/-240 micromol x L(-1); P =.005). Plasma cyclic guanosine monophosphate levels increased after 30 minutes of bypass in the pulsatile-flow group (25+/-18 vs. 12+/-8 pmol x mL(-1); P =.004), and urinary cyclic guanosine monophosphate excretion was higher in the pulsatile-flow group (517+/-450 vs. 118+/-78 pmol x mL(-1); P =.024). Plasma endothelin-1 levels increased in the 2 groups and were higher in the steady-flow group at 30 minutes (27+/-5 vs. 23+/-2 pg x mL(-1); P =.04) and 60 minutes of bypass (39+/-7 vs 32 +/- 6 pg x mL(-1); P =.04). Plasma renin concentration increased significantly during bypass only in the steady-flow group (26+/-10 vs. 57+/-42 in ng A1 x mL(-1) x h(-1); P =.04). CONCLUSIONS: Improved placental and peripheral perfusion during fetal pulsatile-flow bypass may be mediated by preservation of fetal/maternal endothelial nitric oxide biosynthetic mechanisms and/or decreased activation of the fetal renin-angiotensin pathway.

Effects of various flow types on maternal hemodynamics during fetal bypass: is there nitric oxide release during pulsatile perfusion?

OBJECTIVE: This study investigates the role of various flow conditions on maternal hemodynamics during fetal cardiopulmonary bypass. METHODS: Normothermic fetal bypass was conducted under pulsatile, or steady flow, for a 60-minute period. Fetal lamb preparations were randomly assigned to 1 of the 3 groups: steady flow (n=7), pulsatile flow (n=7), or pulsatile blocked flow bypass (n=7), where fetuses were perfused with Nomega-nitro-L-arginine after the first 30 minutes of pulsatile flow to assess the potential role of endothelial autacoids. RESULTS: Maternal oximetry and pressures remained unchanged throughout the procedure. Under fetal pulsatile flow, maternal cardiac output increased after 20 minutes of bypass and remained significantly higher than under steady flow at minute 30 (8.8+/-0.7 L x min(-1) vs 5.9+/-0.5 L x min(-1), P=.02). Maternal cardiac output in the pulsatile group also remained higher than in both steady and pulsatile blocked flow groups, reaching respectively 8.7+/-0.9 L x min(-1) vs 5.8+/-0.4 L x min(-1) (P=.02) and 5.9+/-0.3 L min(-1) (P=.01) at minute 60. Maternal systemic vascular resistances were significantly lower under pulsatile than under steady flow after 30 minutes and until the end of bypass (respectively, 9.1+/-0.6 IU vs 12.7+/-1.1 IU, P=.02 and 8.9+/-0.5 IU vs 12.9+/-1.2 IU, P=.01). Infusion of Nomega-nitro-L-arginine was followed by an increase in systemic vascular resistances from 9.3+/-0.7 IU, similar to that of the pulsatile group, to 13.5+/-1 IU at 60 minutes, similar to that of the steady flow group. CONCLUSIONS: Maternal hemodynamic changes observed under fetal pulsatile flow are counteracted after infusion of Nomega-nitro-L-arginine, suggesting nitric oxide release from the fetoplacental unit under pulsatile fetal flow conditions.

Role of thromboxane and angiotensin in cyclosporine-induced renal vasoconstriction in the dog.

Cyclosporine is associated with renal insufficiency characterized by a reduction in glomerular filtration rate that may result from renal vasoconstriction. Injection of cyclosporine in the isolated renal artery perfused at a constant flow induces a potent dose-dependent vasoconstriction of renal arterial vessels in the dog. The present study was designed to investigate the role of thromboxane A2, angiotensin, and endothelial-dependent vasodilation in the cyclosporine-induced renal vasoconstriction. A specific thromboxane A2-receptor antagonist (pinane-thromboxane A2), administered at a dose of 150 micrograms, significantly decreased the renal vasoconstriction response to cyclosporine from 103 +/- 26 mm Hg to 45 +/- 11 mm Hg (p < 0.05), with cyclosporine serum levels at the end of injection averaging 382 +/- 105 and 421 +/- 150 nmol/L before and after injection of the antagonist. In contrast, pharmacologic blockade of angiotensin receptors by saralasin had no effect on the cyclosporine arterial vasoconstriction in the kidney. The endothelium-dependent vasodilation to acetylcholine was not modified during cyclosporine injection. Thus cyclosporine renal vasoconstriction appears independent of the renin-angiotensin system and of endothelium-dependent vasodilation. It is at least partly mediated by thromboxane A2. Prevention of cyclosporine vasoconstriction by thromboxane A2-receptor antagonist may likely be possible, with more potent agents having more affinity to thromboxane A2 renal receptors.

Pentoxifylline decreases cyclosporine-induced renal endothelin release and vasoconstriction.

Cyclosporine (CSA) causes an acute vasoconstriction of renal artery and a significant increase in renal endothelin release. Pentoxifylline, a vasodilator, has been suggested to prevent CSA toxicity. To study the effect of pentoxifylline treatment on CSA-related vasoconstriction and endothelin release, a model of renal autoperfusion in the dog was used. Oral pentoxifylline at the dose of 400 mg three times daily for 3 days was given to 15 dogs. Pure powder CSA (10 mg) was injected into the isolated renal artery perfused at constant flow; changes in perfusion pressure reflected variations in vascular resistance. In the pentoxifylline-treated group (15 dogs), the infusion of CSA caused an average increase of 27 +/- 8 mm Hg in renal perfusion pressure, compared with 60 +/- 10 mm Hg in a control group of 8 untreated animals (p < or = 0.05). Plasma concentration of endothelin in the renal vein increased from an average of 1.2 +/- 0.2 pg/mL before to 2.4 +/- 0.5 pg/mL after CSA administration (p < or = 0.05) in the control group, whereas it did not change significantly in the pentoxifylline-treated group. Thus, oral pretreatment with pentoxifylline significantly decreased the renal vasoconstriction and endothelin release due to CSA administration.