Biomedical subjects

Y Naka

Publications and source records attributed to Y Naka.

At least 55 records · Page 3Linked to original sources

PubMed1997

Failure to express the P-selectin gene or P-selectin blockade confers early pulmonary protection after lung ischemia or transplantation.

Endothelial P-selectin expression contributes to the first wave of neutrophil (polymorphonuclear leukocyte: PMN) influx in several inflammatory conditions. Although remote tissue ischemia, such as a crush injury to the hindlimb, may result in P-selectin-mediated pulmonary leukosequestration, it is not known whether the lungs exhibit a similar response after hypothermic preservation or when subjected to a direct ischemic insult. To determine if P-selectin may mediate early primary graft failure, left lungs harvested from male Lewis rats were preserved for 6 hr at 4 degrees C and transplanted orthotopically into isogeneic recipients. Recipients immunodepleted of PMNs before transplantation demonstrated improved graft function; pulmonary vascular resistance was reduced approximately 6-fold, arterial oxygenation was increased approximately 3-fold, and recipient survival was increased approximately 4-fold (P < 0.05, 0.05, and 0.005, respectively). Administration of a blocking anti-P-selectin IgG 10 min before reperfusion diminished graft PMN infiltration and resulted in improved graft function and recipient survival compared with controls. To establish the role of P-selectin in normothermic pulmonary ischemia, mice were subjected to temporary left pulmonary artery ligation. After functional removal of the nonischemic right lung, mice deletionally mutant for the P-selectin gene (P-selectin-/-) exhibited reduced PMN infiltration (approximately 2-fold), improved arterial oxygenation (approximately 2-fold), and improved survival (approximately 3-fold) compared with P-selectin +/+ control mice (P < 0.05, 0.01, and 0.05, respectively). These studies isolate and identify the central role of a single gene product (P-selectin) in early PMN recruitment and tissue injury after frank pulmonary ischemia and in the setting of lung transplantation after hypothermic preservation.

Animals↗

PubMed1997

The effect of endovascular therapy for cerebral arterial spasm, its limitation and pitfalls.

PURPOSE: The effect of endovascular treatment for vasospasm was investigated by analysing the results of patients treated in Wakayama City in 1994. MATERIALS AND METHODS: Ninety nine patients with ruptured cerebral aneurysms, who survived more than one week and were treated in Wakayama City in 1994, were studied. Twenty five patients caused symptomatic vasospasm and 25 were treated by endovascular therapy, percutaneous transluminal angioplasty (PTA) and/or intra-arterial papaverine infusion (IAP). PTA was performed for proximal vasospasm which located in the main arterial trunk, such as ICA, M1, BA (n = 3). IAP was chosen for distal vasospasm which located mainly in the M2, A1, A2 (n = 12). PTA and/or IAP was performed for diffuse vasospasm which located in proximal and distal arteries (n = 10). RESULTS: In the proximal vasospasm group, all patients were good to moderately disabled on the Glasgow outcome scale (GOS). In the distal vasospasm group, 8 patients were good to moderately disabled, and 4 patients were severely disabled. The overall results were as follows: 17 (68%), good to moderately disabled, 4 (16%), severely disabled, 4 (16%), dead. The morbidity and mortality rate was 8/25 (32%) in symptomatic spasm group. CONCLUSION: PTA was very effective especially for proximal vasospasm, but IAP was not always effective for distal or diffuse vasospasm. Diffuse vasospasm revealed a high mortality rate in spite of the endovascular therapy.

Adult↗

PubMed1997

Circulatory resuscitation with left ventricular assist device support reduces interleukins 6 and 8 levels.

BACKGROUND: Elevated tumor necrosis factor serum levels have been reported in patients with severe congestive heart failure. This study was designed to characterize the cytokine profile in patients with acute circulatory collapse. METHODS: Blood drawn from 14 consecutive patients within 24 hours before undergoing left ventricular assist device placement and after at least 30 days of mechanical assistance or before transplantation was assayed for levels of interleukin 6, interleukin 8, and tumor necrosis factor-alpha. RESULTS: Interleukin 6 level was elevated in 11 (79%), interleukin 8 in 10 (71%), and tumor necrosis factor in 2 (14%) of the 14 patients. After hemodynamic recovery, interleukin 6 levels decreased from 33.6 +/- 9 pg/mL to 11.3 +/- 4 pg/mL (p = 0.05) and interleukin 8 levels decreased from 122 +/- 34 pg/mL to 19.7 +/- 8 pg/mL (p = 0.005). Tumor necrosis factor-alpha levels did not vary significantly; they were associated with infection in 2 left ventricular assist device recipients and normalized after left ventricular assist device support. All patients had resolution of circulatory shock after mechanical support and had improvement in parameters of end-organ function. CONCLUSIONS: Circulatory shock treated with left ventricular assist device placement is associated with a proinflammatory response similar to that seen in septic shock. The decrease in cytokine serum levels that follows hemodynamic recovery suggests that these cytokines may be markers of tissue damage and may modulate cardiac dysfunction.

Biomarkers↗

PubMed1997

Exacerbation of cerebral injury in mice that express the P-selectin gene: identification of P-selectin blockade as a new target for the treatment of stroke.

There is currently a stark therapeutic void in the treatment of evolving stroke. Although P-selectin is rapidly expressed by hypoxic endothelial cells in vitro, the functional significance of P-selectin expression in stroke remains unexplored. In order to identify the pathophysiological consequences of P-selectin expression and to identify P-selectin blockade as a potential new approach for the treatment of stroke, experiments were performed using a murine model of focal cerebral ischemia and reperfusion. Early P-selectin expression in the postischemic cerebral cortex was demonstrated by the specific accumulation of radiolabeled anti-murine P-selectin IgG, with the increased P-selectin expression localized to the ipsilateral cerebral microvascular endothelial cells by immunohistochemistry. In experiments designed to test the functional significance of increased P-selectin expression in stroke, neutrophil accumulation in the ischemic cortex of mice expressing the P-selectin gene (PS +/+) was demonstrated to be significantly greater than that in homozygous P-selectin-null mice (PS -/-). Reduced neutrophil influx was accompanied by greater postischemic cerebral reflow (measured by laser Doppler) in the PS -/- mice. In addition, PS -/- mice demonstrated smaller infarct volumes (5-fold reduction, P<.05) and improved survival compared with PS +/+ mice (88% versus 44%, P<.05). Functional blockade of P-selectin in PS +/+ mice using a monoclonal antibody directed against murine P-selectin also improved early reflow and stroke outcome compared with control mice, with reduced cerebral infarction volumes noted even when the blocking antibody was administered after occlusion of the middle cerebral artery. These data are the first to demonstrate a pathophysiological role for P-selectin in stroke and suggest that P-selectin blockade may represent a new therapeutic target in the treatment of stroke.

Animals↗

PubMed1996

Hypoxia-induced exocytosis of endothelial cell Weibel-Palade bodies. A mechanism for rapid neutrophil recruitment after cardiac preservation.

The period of hypoxia is an important priming event for the vascular dysfunction that accompanies reperfusion, with endothelial cells (ECs) and neutrophils (PMNs) playing a central role. We hypothesized that EC Weibel-Palade (WP) body exocytosis during the hypoxic/ischemic period during organ preservation permits brisk PMN recruitment into postischemic tissue, a process further amplified in an oxidant-rich milieu. Exposure of human umbilical vein ECs to a hypoxic environment (pO2 approximately 20 torr) stimulated release of von Willebrand factor (vWF), stored in EC WP bodies, as well as increased expression of the WP body-derived PMN adhesion molecule P-selectin at the EC surface. Increased binding of 111In-labeled PMNs to hypoxic EC monolayers (compared with normoxic controls) was blocked with a blocking antibody to P-selectin, but was not affected by a nonblocking control antibody. Although increased P-selectin expression and vWF release were also noted during reoxygenation, hypoxia alone (even in the presence of antioxidants) was sufficient to increase WP body exocytosis. To determine the relevance of these observations to hypothermic cardiac preservation, during which the pO2 within the cardiac vasculature declines to similarly low levels, experiments were performed in a rodent (rat and mouse) cardiac preservation/transplantation model. Immunodepletion of recipient PMNs or administration of a blocking anti-P-selectin antibody before transplantation resulted in reduced graft neutrophil infiltration and improved graft survival, compared with identically preserved hearts transplanted into control recipients. To establish the important role of endothelial P-selectin expression on the donor vasculature, murine cardiac transplants were performed using homozygous P-selectin deficient and wild-type control donor hearts flushed free of blood/platelets before preservation/transplantation. P-selectin-null hearts transplanted into wild-type recipients demonstrated a marked (13-fold) reduction in graft neutrophil infiltration and increased graft survival compared with wild-type hearts transplanted into wild-type recipients. To determine whether coronary endothelial WP exocytosis may occur during cardiac preservation in humans, the release of vWF into the coronary sinus (CS) was measured in 32 patients during open heart surgery. CS samples obtained at the start and conclusion of the ischemic period demonstrated an increase in CS vWF antigen (by ELISA) consisting of predominantly high molecular weight multimers (by immunoelectrophoresis). These data suggest that EC WP exocytosis occurs during hypothermic cardiac preservation, priming the vasculature to recruit PMNs rapidly during reperfusion.

Animals↗

PubMed1996

Cerebral protection in homozygous null ICAM-1 mice after middle cerebral artery occlusion. Role of neutrophil adhesion in the pathogenesis of stroke.

Acute neutrophil (PMN) recruitment to postischemic cardiac or pulmonary tissue has deleterious effects in the early reperfusion period, but the mechanisms and effects of neutrophil influx in the pathogenesis of evolving stroke remain controversial. To investigate whether PMNs contribute to adverse neurologic sequelae and mortality after stroke, and to study the potential role of the leukocyte adhesion molecule intercellular adhesion molecule-1 (ICAM-1) in the pathogenesis of stroke, we used a murine model of transient focal cerebral ischemia consisting of intraluminal middle cerebral artery occlusion for 45 min followed by 22 h of reperfusion. PMN accumulation, monitored by deposition of 111In-labeled PMNs in postischemic cerebral tissue, was increased 2.5-fold in the ipsilateral (infarcted) hemisphere compared with the contralateral (noninfarcted) hemisphere (P < 0.01). Mice immunodepleted of neutrophils before surgery demonstrated a 3.0-fold reduction in infarct volumes (P < 0.001), based on triphenyltetrazolium chloride staining of serial cerebral sections, improved ipsilateral cortical cerebral blood flow (measured by laser Doppler), and reduced neurological deficit compared with controls. In wild-type mice subjected to 45 min of ischemia followed by 22 h of reperfusion, ICAM-1 mRNA was increased in the ipsilateral hemisphere, with immunohistochemistry localizing increased ICAM-1 expression on cerebral microvascular endothelium. The role of ICAM-1 expression in stroke was investigated in homozygous null ICAM-1 mice (ICAM-1 -/-) in comparison with wild-type controls (ICAM-1 +/+). ICAM-1 -/- mice demonstrated a 3.7-fold reduction in infarct volume (P < 0.005), a 35% increase in survival (P < 0.05), and reduced neurologic deficit compared with ICAM-1 +/+ controls. Cerebral blood flow to the infarcted hemisphere was 3.1-fold greater in ICAM-1 -/- mice compared with ICAM-1 +/+ controls (P < 0.01), suggesting an important role for ICAM-1 in the genesis of postischemic cerebral no-reflow. Because PMN-depleted and ICAM-1-deficient mice are relatively resistant to cerebral ischemia-reperfusion injury, these studies suggest an important role for ICAM-1-mediated PMN adhesion in the pathophysiology of evolving stroke.

Animals↗

PubMed1996

In vitro evaluation of neonatal human immunity against the pig.

The critical shortage of organ donors has greatly limited the number of clinical allotransplantations. This is particularly true for neonatal patients, for whom xenotransplantation could provide an alternative therapeutic option to allotransplantation. The role of neonatal infant immunity in xenotransplantation is not, however, clearly understood. We examined both the proliferative responses of human neonatal lymphocytes to pig aortic endothelial cells and serum levels of neonatal natural antipig xenoantibody. Neonatal human lymphocytes and serum were isolated from umbilical cord blood. Adult human lymphocytes and serum were used as controls. A one-way xenogeneic mixed lymphocyte-endothelial cell reaction was performed, and lymphocyte proliferation was measured by tritiated thymidine uptake. Neonatal human lymphocytes recognized and proliferated in response to pig aortic endothelial cells (mean 63,926 +/- 26,054 counts per minute). The level of xenogeneic mixed lymphocyte-endothelial cell reaction of neonatal lymphocytes was significantly lower (p < 0.004) than that of adult human lymphocytes (mean 122,444 +/- 33,132 counts per minute). An enzyme-linked immunosorbent assay was performed to determine the binding of natural immunoglobulin M and G antibodies to pig endothelial cells. Whole-cell enzyme-linked immunosorbent assay demonstrated neonatal human serum to contain very low binding levels of natural antipig immunoglobulin M xenoantibody compared with adult serum. Like adult serum, neonatal human serum contained natural antipig immunoglobulin G xenoantibody. Neonatal serum was not cytotoxic to pig endothelial cells, suggesting that immunoglobulin G was not the predominant xenoreactive antibody. To assess whether neonatal pig endothelial cells also expressed xenoantigens, adult and neonatal cultured pig endothelial cells were examined by enzyme-linked immunosorbent assay with adult human serum. Adult human natural immunoglobulin M xenoantibody recognized not only adult pig endothelial cell xenoantigens but also neonatal pig endothelial cell xenoantigens. The binding levels of adult natural antipig immunoglobulin M xenoantibodies to adult and neonatal pig endothelial cells were similar, suggesting that neonatal pig aortic endothelial cells express xenoantigens. The findings of low binding levels of cytotoxic antipig immunoglobulin M xenoantibody and low levels of lymphocyte xenoreactivity to pig endothelial cells in human neonates suggests that pig organs may eventually be a suitable source of xenografts for human neonates.

Adult↗

PubMed1996

cAMP-mediated vascular protection in an orthotopic rat lung transplant model. Insights into the mechanism of action of prostaglandin E1 to improve lung preservation.

Prostaglandin E1 (PGE1) is often added to the donor pulmonary flush solution to enhance clinical lung preservation for transplantation. Although PGE1 is thought to act as a pulmonary vasodilator during the harvest period, the precise mechanism(s) of action whereby PGE1 enhances lung preservation is unknown. Because cAMP levels decline in endothelial and vascular smooth muscle cells exposed to hypoxia, we hypothesized that a PGE1-mediated increase in cAMP levels within the preserved lungs might improve pulmonary vascular homeostasis following lung transplantation. Rat lungs demonstrated a time-dependent decline in cAMP levels during hypothermic storage, with cAMP levels significantly increased by PGE1 supplementation (approximately 2-fold by 6 hours, P < .0005). To test whether augmenting cAMP levels may enhance lung preservation, experiments were performed using an orthotopic rat left lung transplant model. Compared with controls, supplementing the preservation solution with the membrane-permeable cAMP analogue dibutyryl-cAMP resulted in dose-dependent preservation enhancement, marked by reduced pulmonary vascular resistance (6.0-fold, P < .01), improved arterial oxygenation (3.0-fold, P < .01), reduced graft neutrophil infiltration (1.5-fold, P < .05), and improved recipient survival (7.0-fold, P < .005). Similar preservation enhancement was observed with another cAMP analogue (8-bromo-cAMP) or the phosphodiesterase inhibitor indolidan. Stimulating the cAMP second messenger system by PGE1 supplementation resulted in marked hemodynamic benefits and improved recipient survival, in parallel with reduced graft neutrophil infiltration, vascular permeability, and platelet deposition. These beneficial effects of PGE1 were abrogated by simultaneous administration of the cAMP-dependent protein kinase antagonist Rp-cAMPS. Although an arterial vasodilator (minoxidil) resulted in significant pulmonary vasodilation during harvest, it lacked other nonvasodilating effects of PGE1 and resulted in poor preservation. These data show that harvest vasodilation by itself is insufficient to enhance lung preservation and that PGE1 enhances lung preservation by stimulating the cAMP-dependent protein kinase and promoting non-vasodilatory mechanisms of pulmonary protection.

Alprostadil↗

PubMed1996

Measuring activities of daily living among haemophiliacs.

To explore the activities of daily living (ADL) status and/or changes in functional limitations among haemophiliacs, 97 patients were studied longitudinally using a 41-item checklist. The total number of data items was 239 with repeated inquiries. Hierarchical factor analyses yielded a clear separation of items into five factors by the analogous trunk and limb motion, and the existence of one higher-order factor which indicated that the items measured the same underlying concept. Analyses of ratings showed that in haemophiliacs full flexion of the lower limbs was easily limited, and this deterioration was difficult to prevent. The functional limitation level differed significantly by age group, but some patients showed a slight improvement in a follow-up observation. The ADL of haemophiliacs should be explored separately for trunk and limb motion, not for the traditional categories.

Activities of Daily Living↗

PubMed1995

Ischemia-induced interleukin-8 release after human heart transplantation. A potential role for endothelial cells.

BACKGROUND: Interleukin-8 (IL-8) secreted from endothelial cells is a powerful neutrophil chemoattractant and activator. We hypothesized that human endothelial cells deprived of oxygen would secrete IL-8, which might translate into elevated IL-8 production after cardiac ischemia. Furthermore, we hypothesized that coronary sinus (CS) IL-8 levels would be particularly high after cardiac preservation for transplantation, due to extended ischemic times. METHODS AND RESULTS: Human saphenous vein endothelial cells exposed to a hypoxic environment (PO2 < 20 mm Hg) demonstrated a time-dependent release of IL-8 (measured by ELISA) into the culture supernatant as early as 4 hours after exposure. To determine whether cardiac preservation in humans was associated with IL-8 production, we obtained CS blood samples 5 minutes after reperfusion in a consecutive series of patients after they underwent cardiac transplantation (CTX, n = 20) or elective cardiac surgery (non-CTX, n = 21). CTX patients demonstrated significantly higher CS IL-8 levels than non-CTX patients (325 +/- 123 versus 50 +/- 17 ng/mL, respectively, P < .05). Further analysis of the CS samples revealed that a biochemical marker of myocyte injury (myoglobin) was similarly elevated in the CTX patients compared with the non-CTX patients (3340 +/- 625 versus 1151 +/- 525 ng/mL, respectively, P < .05). CONCLUSIONS: These differences may reflect the longer ischemic times of CTX compared with non-CTX hearts (161 +/- 10 versus 80 +/- 6 minutes, P < .0001) and suggest that the neutrophil chemoattractant/activator IL-8 may contribute to myocyte injury after prolonged hypothermic cardiac ischemia, as occurs during human cardiac transplantation.

Aged↗

PubMed1995

Hypoxia and modification of the endothelium: implications for regulation of vascular homeostatic properties.

Hypoxia is a common denominator of ischemic microenvironments. Endothelium subjected to oxygen deprivation maintains cell viability and basic biosynthetic mechanisms, but displays multiple changes in properties relevant to vascular homeostasis, including suppression of the anticoagulant cofactor thrombomodulin, decreased barrier function, and generation of proinflammatory cytokines. Diminished intracellular cAMP during the period of hypoxia and lowered nitric oxide/cGMP in the subsequent reperfusion period are proposed as fundamental mechanisms driving vascular dysfunction impacting on coagulation, permeability, vasomotor tone and leukocyte adhesivity. The period of organ preservation for transplantation, recognized to be associated with hypoxia, primes mechanisms leading to subsequent vascular dysfunction which can be ameliorated by buttressing cAMP and nitric oxide/cGMP intra- and intercellular second messenger systems. A mechanism likely to contribute to hypoxia-mediated generation of cytokines, such as interleukin 6, is activation of the transcription factor NF-IL-6, which occurs in oxygen deprivation. These data indicate that study of cellular mechanisms of endothelial perturbation in hypoxia is likely to provide insights ultimately applicable to ischemia-induced vascular damage.

Animals↗

PubMed1995

Inhaled nitric oxide fails to confer the pulmonary protection provided by distal stimulation of the nitric oxide pathway at the level of cyclic guanosine monophosphate.

It has been suggested that inhaled nitric oxide gas may be beneficial after lung transplantation, because endogenous levels of pulmonary nitric oxide decline rapidly after reperfusion. However theoretical concerns remain about the formation of highly toxic oxidants during the quenching of nitric oxide by superoxide. To determine whether distal stimulation of the nitric oxide-cyclic guanosine monophosphate pathway at the level of cyclic guanosine monophosphate might confer the beneficial vascular effects of nitric oxide without its potential toxicities, we studied an orthotopic rat left lung transplant model. In this model, hemodynamic and survival measurements can be obtained independent of the native right lung. Lungs were preserved for 6 hours at 4 degrees C in Euro-Collins solution alone (control, n = 6) or supplemented with the cyclic guanosine monophosphate analog, 8-(4-chlorophenylthio)-guanosine-3',5'-cyclic guanosine monophosphate (cGMP, n = 4). In additional experiments in which lungs were preserved with Euro-Collins solution alone, inhaled nitric oxide was administered during reperfusion (NO, n = 12). Thirty minutes after transplantation and ligation of the native right pulmonary artery, pulmonary vascular resistance, arterial oxygenation, graft neutrophil infiltration (myeloperoxidase activity), and recipient survival were evaluated. Cyclic guanosine monophosphate decreased pulmonary vascular resistance (1.1 +/- 0.2 vs 12.1 +/- 6.3 mm Hg/ml/min, p < 0.05), improved oxygen tension (369 +/- 56 vs 82.8 +/- 48 mm Hg, p < 0.05), reduced myeloperoxidase activity (1.7 +/- 0.3 vs 3.1 +/- 0.9 delta Abs 460 nm/min, p < 0.05), and improved recipient survival (100% vs 0%, p < 0.005) compared with Euro-Collins solution alone (control group). Animals receiving inhaled nitric oxide during reperfusion did not differ from control animals with respect to any of these parameters. These data suggest that distal stimulation of the nitric oxide-cyclic guanosine monophosphate pathway at the level of cyclic guanosine monophosphate has a protective effect that is not seen with inhaled nitric oxide in the immediate pulmonary reperfusion period.

Administration, Inhalation↗

PubMed1995

Nitroglycerin maintains graft vascular homeostasis and enhances preservation in an orthotopic rat lung transplant model.

Transplanted lungs often fail during the peritransplantation period for poorly understood reasons. Because the nitric oxide pathway regulates pulmonary vascular tone, helps to maintain the integrity of the endothelial barrier, and modulates neutrophil adhesivity and activation, we hypothesized that perturbation of this pathway during the preservation and reperfusion of transplanted lungs might play a critical role in mediating early graft failure. To evaluate whether supplementing the preservation solution with the nitric oxide donor nitroglycerin enhances lung preservation for transplantation, we obtained hemodynamic measurements in a model of orthotopic left lung transplantation in the rat after ligation of the native right pulmonary artery. In these experiments, recipient survival and hemodynamics depended solely on the transplanted lung. The left lung was harvested from 22 rats, flushed with either lactated Ringer's solution alone (control, n = 11) or Ringer's solution supplemented with nitroglycerin (0.1 mg/ml, n = 11), preserved for 4 hours at 4 degrees C, and then transplanted using a rapid cuff technique for bronchial and vascular anastomoses. Nitroglycerin significantly improved arterial blood oxygenation (339 +/- 66 versus 130 +/- 12 mm Hg, p < 0.05), increased pulmonary arterial flow (7.6 +/- 1.9 versus 0.9 +/- 0.2 ml/min, p < 0.005), decreased pulmonary vascular resistance (1.7 +/- 0.4 versus 6.6 +/- 1.9 x 10(3) Wood units, p < 0.05), and enhanced recipient survival (64% versus 0%, p < 0.05). Control grafts had significantly greater neutrophil accumulation (50% greater as quantified by myeloperoxidase activity, p < 0.05) than grafts preserved in the presence of nitroglycerin. These studies show that supplementation of the preservation solution with the nitric oxide donor nitroglycerin maintains graft vascular homeostasis and significantly improves pulmonary function and recipient survival after transplantation.

Animals↗

PubMed1995

Selective reduction of PVR by inhalation of a cGMP analogue in a porcine model of pulmonary hypertension.

Selective reduction of pulmonary vascular resistance (PVR) remains a therapeutic goal for the treatment of pulmonary hypertension, but current therapeutic options remain limited. Although the gas nitric oxide (NO) selectively dilates the pulmonary vascular bed, it requires special equipment for administration, has a short biologic half-life, and is potentially toxic. We hypothesized that stimulation of the NO pathway at the level of its second messenger, guanosine 3',5'-cyclic monophosphate (cGMP), by targeted pulmonary delivery of a membrane-permeable nonhydrolyzable cGMP analogue would cause selective pulmonary vasodilation. Pulmonary hypertension was induced in 21 pigs by the intravenous infusion of a thromboxane A2 analogue (9,11-dideoxy-9 alpha,11 alpha-epoxymethanoprostaglandin F2 alpha). Inhaled 8-bromoguanosine 3',5'-cyclic monophosphate (8-BrcGMP) lowered PVR in a time- and dose-dependent manner, with maximal effect achieved after 20 min. Compared with physiological saline control, 8-BrcGMP inhalation (3.0 micrograms/kg) lowered PVR by 25 +/- 3% (P < 0.01), whereas there was no significant decline in systemic vascular resistance (4 +/- 6%); mean pulmonary arterial pressure declined 13 +/- 3% (P < 0.01), whereas there was little change in mean arterial pressure; cardiac output increased 10 +/- 4% (P < 0.05). PVR did not decrease after inhalation of noncyclic 8-bromoguanosine 5'-monophosphate, indicating that stimulation of the NO-cGMP pathway beyond the level of NO results in pulmonary vasodilation independent of stimulation of purinergic receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Inhalation↗

PubMed1995

Enhanced preservation of orthotopically transplanted rat lungs by nitroglycerin but not hydralazine. Requirement for graft vascular homeostasis beyond harvest vasodilation.

Nitric oxide (NO) produced within the lungs maintains pulmonary vascular homeostatic properties, modulating leukocyte traffic, platelet aggregation, and vasomotor tone. Because reactive oxygen intermediates generated during reperfusion react rapidly with available NO, we hypothesized that the NO donor nitroglycerin (NTG) would enhance lung preservation for transplantation by improving graft blood flow and reducing graft neutrophil and platelet sequestration. By use of an orthotopic rat left lung transplant model, with ligation of the native right pulmonary artery to ensure that recipient survival and physiological measurements depend entirely on the transplanted lung, transplants were performed in 70 male Lewis rats after 6-hour 4 degrees C preservation in Euro-Collins solution (EC) alone or EC with supplemental NTG. Compared with EC alone, supplemental NTG significantly increased pulmonary arterial flow (2.2 +/- 1.4 to 21.4 +/- 2.9 mL/min, P < .01), decreased pulmonary vascular resistance (7.4 +/- 2.0 to 1.4 +/- 0.1 x 10(3) Woods units, P < .05), improved arterial oxygenation (163 +/- 57 to 501 +/- 31 mm Hg, P < .01), and enhanced recipient survival (17% to 100%, P < .001). These beneficial effects of NTG were dose dependent over a range of 0.001 to 0.1 mg/mL. Although NTG caused significant pulmonary vasodilation during the harvest/flushing period, the direct-acting vasodilator hydralazine caused greater vasodilation than did NTG but was associated with poor graft function, elevated pulmonary vascular resistance, and poor recipient survival. To explore nonvasodilator protective mechanisms of NTG, graft neutrophil and platelet sequestration were studied; supplemental NTG significantly reduced both neutrophil and platelet accumulation compared with either hydralazine or EC alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1995

[Endovascular treatment of cerebral vasospasm with intra-arterial papaverine infusion].

Thirty-one cases of cerebral vasospasm following subarachnoid hemorrhage were treated with intraarterial papaverine infusion. Symptomatic cases were nineteen, and asymptomatic cases were twelve. Papaverine (120 mg/saline 50 ml, 30 min) was injected superselectively to vasospastic vessels through a microcatheter. The rate of symptomatically improved cases was 63% initially, but about two thirds of those cases had recurrence within a day. The 63% of symptomatic cases showed infarction in spite of papaverine infusion. Three cases of recurrent vasospasm after intra-arterial papaverine underwent PTA and showed good dilatation of vasospastic vessels. The complications of our intra-arterial papaverine were hypotension in two cases, convulsion in one case and transient disturbed consciousness in one case. We experienced no fatal complications. Overall outcome was ADL1 (19%), ADL2 (25%), ADL3 (44%), ADL4 (0%), ADL5 (6%), and death (6%). Since the effect of intra-arterial papaverine infusion is of short duration and weak, combination of PTA and papaverine may be necessary. It is recommended to use papaverine for vasospasm in distal arteries such as M2, A1, A2, and to carry out PTA for proximal arteries such as ICA and M1.

Adult↗

PubMed1995

[Amnestic syndrome after right temporo-occipital subcortical hemorrhage].

A case of right temporo-occipital subcortical hemorrhage with amnestic syndrome was reported. A 65-year-old woman presented with visual disturbance and headache. CT and MRI demonstrated a hemorrhagic lesion in the right occipital lobe involving parahippocampal gyrus. Neurological examination on admission revealed left homonymous hemianopsia and anterograde and retrograde amnesia. Neuropsychological examination revealed marked recent memory disturbance, but she had visual retention and verbal retention, and her value in WAIS (Wechsler Adult Intelligence Scale) was normal. After 40 days, she was discharged without improvement of amnesia. These findings suggest that the cortico-medial temporal lobe pathway was disturbed by subcortical hemorrhage, and we think there are connective fibers between visual and verbal memory systems. This is the first report of hippocampal amnesia following temporo-occipital subcortical hemorrhage.

Aged↗

PubMed1994

The nitric oxide/cyclic GMP pathway in organ transplantation: critical role in successful lung preservation.

Reestablishment of vascular homeostasis following ex vivo preservation is a critical determinant of successful organ transplantation. Because the nitric oxide (NO) pathway modulates pulmonary vascular tone and leukocyte/endothelial interactions, we hypothesized that reactive oxygen intermediates would lead to decreased NO (and hence cGMP) levels following pulmonary reperfusion, leading to increased pulmonary vascular resistance and leukostasis. Using an orthotopic rat model of lung transplantation, a porphyrinic microsensor was used to make direct in vivo measurements of pulmonary NO. NO levels measured at the surface of the transplanted lung plummeted immediately upon reperfusion, with levels moderately increased by topical application of superoxide dismutase. Because cGMP levels declined in preserved lungs after reperfusion, this led us to buttress the NO pathway by adding a membrane-permeant cGMP analog to the preservation solution. Compared with grafts stored in its absence, grafts stored with supplemental 8-Br-cGMP and evaluated 30 min after reperfusion demonstrated lower pulmonary vascular resistances with increased graft blood flow, improved arterial oxygenation, decreased neutrophil infiltration, and improved recipient survival. These beneficial effects were dose dependent, mimicked by the type V phosphodiesterase inhibitor 2-o-propoxyphenyl-8-azapurin-6-one, and inhibited by a cGMP-dependent protein kinase antagonist, the R isomer of 8-(4-chlorophenylthio)guanosine 3',5'-cyclic monophosphorothioate. Augmenting the NO pathway at the level of cGMP improves graft function and recipient survival following lung transplantation.

Amino Acid Oxidoreductases↗