Profound hypothermia with alpha-stat pH management during open-heart surgery is associated with choreoathetosis.

A retrospective chart review was conducted to examine risk factors associated with the occurrence of choreoathetosis, a rare but significant complication of open-heart surgery in children. Ten children were identified as having developed choreoathetosis after cardiac surgery. Their charts were reviewed and compared with 33 age- and diagnosis-matched controls who underwent open-heart surgery during the same time period. Children with choreoathetosis reached lower rectal and esophageal temperatures (p = 0.0018 for both) and spent a greater portion of total bypass time at lower rectal and esophageal temperatures (p < 0.001 for both). Duration of cooling below 20 degrees C esophageal temperature and PaCO2 at the end of the cooling period were significant predictors of choreoathetosis (p = 0.023 and p = 0.0497, respectively) in a logistic regression model, and a greater fraction of choreoathetosis patients had prior developmental delays (p = 0.017). No difference was found in the age at surgery, duration of bypass, aortic cross-clamp time, arterial pH, PaCO2 or mean arterial pressure. The combination of extended exposure to profound hypothermia and alpha-stat pH management strategy and preexisting developmental delay are associated with the development of choreoathetosis following open-heart surgery 61 in children.

Functional comparison of transmyocardial revascularization by mechanical and laser means.

BACKGROUND: As a result of the clinical benefit observed in angina patients treated by transmyocardial revascularization (TMR) with a laser, interest in mechanical TMR has been renewed. Although the injury induced by mechanical TMR is similar to laser TMR, the resultant impact on myocardial contractility is unknown. The purpose of this study was to determine whether mechanical TMR improves ventricular function as compared with laser TMR in chronically ischemic myocardium. METHODS: After establishing an area of chronic myocardial ischemia, 25 domestic pigs were randomized to treatment by: excimer laser (group I), a hot needle (50 degrees C) (group II), a normothermic needle (group III), an ultrasonic needle (40 KHz) (group IV), or no treatment (group V). All devices create a transmural channel of the same diameter; 22 +/- 1 transmural channels were created in each animal. Regional myocardial contractility was assessed by measuring ventricular wall thickening at rest and with dobutamine stress echocardiography. Six weeks after revascularization, the animals were restudied at rest and with stress. Postsacrifice and histologic analysis of angiogenesis and TMR effects was then assessed. RESULTS: Laser TMR provided significant recovery of ischemic myocardial function. This improvement in contractility after laser TMR was a 75% increase over the baseline function of the ischemic zone (p < 0.01). Mechanical TMR provided no significant improvement in function posttreatment. In fact, TMR achieved with an ultrasonic needle demonstrated a 40% worsening of the contractility versus the pretreatment baseline (p < 0.05). Histologic analysis demonstrated a significant increase in new blood vessels in the ischemic zone after laser TMR, which was not demonstrated for any of the other groups (p < 0.05). Additionally, evaluation of the mechanical TMR channels demonstrated significant scarring, which correlated with the functional results. CONCLUSIONS: Using devices to create an injury analogous to the laser, mechanical TMR failed to improve the function of chronically ischemic myocardium. Only laser TMR significantly improved myocardial function.

Postoperative troponin I values: insult or injury?

BACKGROUND: Troponin I (TnI) is increasingly employed as a highly specific marker of acute myocardial ischemia. The value of this marker after cardiac surgery is unclear. HYPOTHESIS: The purpose of this study was to measure serum TnI levels prospectively at 1, 6, and 72 h after elective cardiac operations. In addition, TnI levels were measured from the shed mediastinal blood at 1 and 6 h postoperatively. Serum values were correlated with cross clamp time, type of operation, incidence of perioperative myocardial infarction, as assessed by postoperative electrocardiograms (ECG) and regional wall motion, as documented by intraoperative transesophageal echocardiography (TEE). METHODS: Sixty patients underwent the following types of surgery: coronary artery bypass graft (CABG) (n = 45), valve repair/replacement (n = 10), and combination valve and coronary surgery (n = 5). Myocardial protection consisted of moderate systemic hypothermia (30-32 degrees C), cold blood cardioplegia, and topical cooling for all patients. RESULTS: Of 60 patients, 57 (95%) had elevated TnI levels, consistent with myocardial injury, 1 h postoperatively. This incidence increased to 98% (59/60) at 6 h postoperatively. There was a positive correlation between the length of cross clamp time and initial postoperative serum TnI (r = 0.70). There was no difference in the serum TnI values whether or not surgery was for ischemic heart disease (CABG or CABG + valve versus valve). There were no postoperative myocardial infarctions as assessed by serial ECGs. There was no evidence of diminished regional wall motion by TEE. Levels of TnI in the mediastinal shed blood were greater than assay in 58% (35/60) of the patients at 1 h and in 88% (53/60) at 6 h postoperatively. Patients who received an autotransfusion of mediastinal shed blood (n = 22) had on average a 10-fold postoperative increase in serum TnI levels between 1 and 6 h. Patients who did not receive autotransfusion average less than doubled their TnI levels over the same interval. At 72 h, TnI levels were below the initial postoperative levels but still indicative of myocardial injury. CONCLUSION: Postoperative TnI levels are elevated after all types of cardiac surgery. There is a strong correlation between intraoperative ischemic time and postoperative TnI level. Further elevation of TnI is significantly enhanced by reinfusion of mediastinal shed blood. Despite these postoperative increases in TnI, there was no evidence of myocardial infarction by ECG or TEE. The postoperative TnI value is even less meaningful after autotransfusion of shed mediastinal blood.

Content of thoracic residency training and its relevance to the practice of medicine.

BACKGROUND: The Thoracic Surgery Directors Association (TSDA) curriculum book provides learning objectives for a thoracic surgery residency. Our purpose was to evaluate the relevance of these objectives through feedback from recent graduates. METHODS: Graduates of multiple TSDA programs were mailed a 50-item questionnaire. Survey items were objectives from the TSDA curriculum book representing six areas of thoracic surgery. Graduates rated each objective for adequacy of instruction and relevance to their current practice on Likert-type scales. RESULTS: Two hundred twenty-eight surveys were included in the analysis. Despite excellent operating room education, graduates across subspecialty lines reported the need for improved education in "nonoperative" subjects. Graduates practicing cardiac surgery reported little relevance of their general thoracic educational experience. Conversely, graduates practicing general thoracic surgery expressed the need for more/better educational experiences in thoracic oncology and esophageal surgery. CONCLUSIONS: Contemporary thoracic surgical education can be improved. A strong need for improvement exists in the teaching of "nonoperative" subjects. As graduates elect careers in thoracic subspecialties, a need exists to align thoracic surgery educational experiences with ultimate career goals of residents.

Differential inducible nitric oxide synthase expression in systemic and pulmonary vessels after endotoxin.

Inducible nitric oxide synthase (iNOS) is associated with vascular hypocontractility in systemic vessels after endotoxin lipopolysaccharide (LPS) administration. Although lung iNOS is increased after LPS, its role in the pulmonary circulation is unclear. We hypothesized that whereas iNOS upregulation is responsible for LPS-induced vascular dysfunction in systemic vessels, iNOS does not play a significant role in the pulmonary artery (PA). Using isolated aorta (AO) and PA rings, we examined the effect of nonselective NOS inhibition [N(G)-monomethyl-L-arginine (L-NMMA); 100 micromol/l] and selective iNOS inhibition (aminoguanidine, AG; 100 micromol/l) on alpha(1)-adrenergic-mediated vasoconstriction (phenylephrine; 10(-9) to 10(-3) M) after LPS (Salmonella typhimurium, 20 mg/kg ip). We also determined the presence of iNOS using Western blot and immunohistochemistry. LPS markedly impaired AO contractility (maximal control tension 1,076 +/- 33 mg vs. LPS 412 +/- 39 mg, P < 0.05), but PA contractility was unchanged (control 466 +/- 29 mg vs. LPS 455 +/- 27 mg, P > 0.05). Selective iNOS inhibition restored the AO's response to vasoconstriction (LPS + AG 1,135 +/- 54 mg, P > 0.05 vs. control and P < 0.05 vs. LPS), but had no effect on the PA (LPS + AG 422 +/- 38 mg, P > 0.05 vs. control and LPS). Western blot and immunohistochemistry revealed increased iNOS expression in the AO after LPS, but iNOS was not detected in the PA. Our results suggest that differential iNOS expression after LPS in systemic and pulmonary vessels contributes to the phenomenon of sepsis/endotoxemia-induced systemic hypotension and pulmonary hypertension.

Interleukin-11 attenuates pulmonary inflammation and vasomotor dysfunction in endotoxin-induced lung injury.

Interleukin (IL)-11, like other members of the gp130 receptor class, possesses anti-inflammatory properties. We hypothesized that IL-11 pretreatment would attenuate endotoxin [lipopolysaccharide (LPS)]-induced lung inflammation and diminish injury to endothelium-dependent and -independent mechanisms of pulmonary vasorelaxation that require cGMP in Sprague-Dawley rats. LPS (20 mg/kg ip) increased lung tumor necrosis factor (TNF)-alpha compared with the saline control (0.7 +/- 0.15 ng/g lung wet wt for control vs. 3.5 +/- 0.09 ng/g lung wet wt for LPS; P < 0.05). IL-11 (200 mg/kg ip) injected 10 min before LPS administration attenuated the LPS-induced lung TNF-alpha levels (1.6 +/- 0.91 ng/g lung wet wt; P < 0.05 vs. LPS). IL-11 also diminished LPS-induced lung neutrophil sequestration as assessed by myeloperoxidase units (2.1 +/- 0.25 U/g lung wet wt for saline and 15.6 +/- 2.02 U/g lung wet wt for LPS vs. 7.07 +/- 1.65 U/g lung wet wt for LPS plus IL-11; P < 0.05). Similarly, TNF-alpha binding protein (175 mg/kg) attenuated LPS-induced myeloperoxidase activity (6.04 +/- 0.14 U/g lung wet wt; P < 0.05). Both IL-11 and TNF-alpha binding protein similarly attenuated LPS-induced endothelium-dependent vasomotor dysfunction with improved relaxation responses to 10(-7) and 10(-6) M acetylcholine and A-23187 in phenylephrine-preconstricted isolated pulmonary artery rings (P < 0.05 vs. LPS). Endothelium-independent relaxation responses to sodium nitroprusside were also improved after LPS at 10(-6) M (P < 0.05 vs. LPS). Moreover, IL-11 decreased endotoxin-induced mortality in CF1 mice from 90 to 50% (P

Up-regulation of vascular endothelial growth factor mRNA and angiogenesis after transmyocardial laser revascularization.

BACKGROUND: Angiogenesis has been proposed as a potential mechanism whereby transmyocardial laser revascularization (TMLR) has provided clinical relief of angina. Experimental work has found histologic evidence supporting this, as well as an improved response when angiogenic growth factors have been added to TMLR. The purpose of this study was to demonstrate that the molecular response to TMLR was an increase in the production of endogenous vascular endothelial growth factor to promote angiogenesis. METHODS: Ameroid constrictors were placed on the proximal circumflex artery in 12 domestic pigs. After a chronic ischemic zone was established the animals were randomly divided into two groups. In the TMLR group the ischemic zone was treated with carbon dioxide laser. In the control group the ischemic zone was untreated. Six weeks later the animals were sacrificed, and sections from the ischemic zone and the nonischemic zone were submitted for immunohistochemical, histologic, and molecular analysis. Messenger RNA was obtained from northern blot analysis after being probed with vascular endothelial growth factor. RESULTS: There was a twofold increase in the vascular endothelial growth factor messenger RNA in the ischemic zone of the TMLR group compared with the control group. Additionally, there was a threefold increase in the number of new blood vessels in the ischemic zone of the TMLR group compared with the control group. CONCLUSIONS: Transmyocardial laser revascularization promotes angiogenesis by upregulation of vascular endothelial growth factor. The resulting angiogenesis could be the principle mechanism for the clinical efficacy of TMLR.

Cardiopulmonary bypass renders patients at risk for multiple organ failure via early neutrophil priming and late neutrophil disability.

BACKGROUND: Cardiopulmonary bypass (CPB) is associated with a systemic inflammatory response syndrome (SIRS) and these patients are recognized to be at increased risk for delayed infectious complications. We have documented that circulating neutrophils (PMNs) from patients manifesting SIRS have evidence of early postinjury priming for cytotoxicity. Consequently, we hypothesized that CPB would result in early postoperative PMN hyperresponsiveness (priming). MATERIALS AND METHODS: Six patients (mean age 50 +/- 2.9 years) who underwent CPB for CABG had sequential blood samples obtained perioperatively. PMNs were isolated and superoxide anion (O(-)(2)) generation (nmol O(-)(2)/3.75 x 10(5) PMNs/min) was measured by reduction of cytochrome c after exposure to fMLP, C5a, or PMA; elastase release (% total PMN elastase content) was measured by cleavage of AAPV-pNA after exposure to fMLP or C5a. RESULTS: PMNs were activated for increased elastase release 6 h after initiation of CPB. Significant PMN priming for O(-)(2) production was discovered at 3, 6, and 12 h following CPB and for elastase release at 3 and 6 h after CPB. At 2 to 3 days after CPB, O(-)(2) generation was significantly less than that of the preoperative control. Neutrophil primability with PAF was detected at 6 h after CPB. A similar defect in PAF-primable O(-)(2) production was seen 2 and 3 days post-CPB. Direct PMN interrogation with the receptor-independent activator PMA revealed loss of integrity of the NADPH oxidase at 2 and 3 days following CPB. CONCLUSIONS: A vulnerable window exists between 3 and 12 h after CPB when PMNs are primed for enhanced cytotoxicity via O(-)(2) production and elastase release. Paradoxically, PMN oxidase integrity becomes deficient 48 h post-CPB, while protease degranulation remains intact. These events render the bypass patient at risk for multiple organ failure via both early PMN-mediated tissue injury and delayed infectious complications.

L-arginine attenuates endothelial dysfunction in endotoxin-induced lung injury.

BACKGROUND: Pulmonary vasorelaxation to endothelium-dependent and independent agonists is dysfunctional in endotoxin-induced acute lung injury. L-arginine is the precursor to endothelial production of nitric oxide (NO), suggesting that arginine and NO are intimately linked. We hypothesized that L-arginine would attenuate endotoxin-induced dysfunction of guanosine 3',5'-cyclic monophosphate-mediated pulmonary vasorelaxation. METHODS: Concentration-response curves were generated for acetylcholine, calcium ionophore A23187, and sodium nitroprusside (SNP) in isolated phenylepherine-preconstricted pulmonary artery rings (10(-9) to 10(-6) mol/L) 4 hours after endotoxin (500 mg/kg intraperitoneal) or saline injection. The effect of L-arginine in vitro was determined with L- or D-arginine (50 mmol/L) 30 minutes before dose response. RESULTS: Endothelium-dependent pulmonary vasorelaxation was dysfunctional after endotoxin injection as demonstrated by impaired responses to acetylcholine and A23187 (P < .05 vs control). Endotoxin-induced dysfunction of these endothelium-dependent responses was attenuated by L-arginine (P < .05 vs endotoxin). Endothelium-independent vasorelaxation (SNP) was also dysfunctional after endotoxin treatment (P < .05 vs control). L-arginine failed to attenuate the endotoxin-induced dysfunction of the response to SNP. The concentration responses for endothelium-dependent and independent vasorelaxing agonists in endotoxin-treated rats were not influenced by D-arginine. CONCLUSION: L-arginine supplementation attenuates endotoxin-induced dysfunction of endothelium-dependent pulmonary vasorelaxation.

Endotoxin differentially impairs receptor-mediated relaxation in rat isolated pulmonary and thoracic aortic vessels.

PURPOSE: The purpose of this study was to determine the effect of endotoxin on vasorelaxation in the pulmonary and systemic circulations in response to the following agonists that require generation of cyclic adenosine monophosphate: (1) beta-adrenergic receptor stimulation with isoproterenol; (2) H2 receptor stimulation with dimaprit; and (3) adenylate cyclase stimulation with forskolin. METHODS: Male Sprague-Dawley rats weighing 250 to 350 g were injected with endotoxin (20 mg/kg intraperitoneal) or saline. Six hours later, the cumulative dose response to beta-adrenergic receptor stimulation (isoproterenol), H2 receptor stimulation (dimaprit), and adenylate cyclase stimulation (forskolin) was determined in isolated rat pulmonary artery and thoracic aortic rings preconstricted with phenylephrine. RESULTS: Endotoxin caused significant impairment of relaxation to isoproterenol in the pulmonary artery, but the response in the aorta was not different from the control response. In the pulmonary circulation, endotoxin converted the response to dimaprit from vasorelaxation to vasoconstriction. On the other hand, dimaprit resulted in vasorelaxation in the thoracic aorta after endotoxin; however, the response was impaired compared with the control response. Endotoxin did not affect the dose response to forskolin in either the pulmonary artery or the thoracic aorta. CONCLUSION: From these data, we conclude that endotoxin causes regional specific changes in vascular reactivity. These changes in vascular reactivity result in preserved vasorelaxation in the systemic circulation and impairment of vasorelaxation in the pulmonary circulation in response to endotoxin.

Left ventricular functional improvement after transmyocardial laser revascularization.

BACKGROUND: Transmyocardial laser revascularization has been used to treat patients with end-stage coronary artery disease that is not amenable to standard revascularization. Although there is evidence of angina relief and quality of life enhancement, there is little information concerning improvement in myocardial contractility. The purpose of this study was to determine whether transmyocardial laser revascularization improves myocardial function in chronically ischemic myocardium. METHODS: In a model of chronic ischemia by Ameroid occlusion of the circumflex artery, domestic pigs (n = 8) were treated with transmyocardial laser revascularization. Before laser treatment, segmental contraction was assessed at rest and with dobutamine stress echocardiography. Myocardium subtended by the occlusion was compared with that remote from the occlusion. Six weeks after transmyocardial laser revascularization, the animals were restudied at rest and with stress, and then sacrificed. Sham-treated control animals (n = 4) underwent the same procedures but were not treated with transmyocardial laser revascularization. Control animals did not demonstrate significant recovery of function. RESULTS: Transmyocardial laser revascularization improved resting function in chronically ischemic myocardium by 100%. CONCLUSIONS: Transmyocardial laser revascularization significantly improves the function of chronically ischemic myocardium. These data may help explain the mechanisms by which transmyocardial laser revascularization is clinically effective.

Nitric oxide downregulates lung macrophage inflammatory cytokine production.

BACKGROUND: Inflammatory cytokine production contributes to lung injury after lung ischemia reperfusion and during lung transplant rejection. Although nitric oxide has been demonstrated to reduce lung injury associated with the adult respiratory distress syndrome, it remains unknown whether the mechanism of nitric oxide's beneficial effects involves reducing lung macrophage inflammatory cytokine production. The purpose of this study was to determine whether nitric oxide downregulates lung macrophage inflammatory cytokine production. METHODS: Lung macrophages were harvested by bronchoalveolar lavage (10(6) macrophage per milliliter from normal Sprague-Dawley rats, 6 animals per group) and treated under ex vivo tissue culture conditions with the nitric oxide releasing compound S-nitoso-N-acetyl-D, L-penicillamine (0, 10(-5) 10(-4), 10(-3), 10(-2) mol/L) before induction of inflammatory cytokines with endotoxin, (50 ng/mL for 24 hours). Supernatants were assayed for inflammatory cytokine production (tumor necrosis factor alpha, interleukin-1beta) by enzyme-linked immunosorbent assay. RESULTS: Continuous nitric oxide release by S-nitoso-N-acetyl-D, L-penicillamine decreased lung macrophage tumor necrosis factor-alpha and interleukin-1beta production in a dose-dependent fashion (6 rats per group; data were analyzed for significance [p < 0.05] using two-way analysis of variance with Tukey's post-hoc correction). CONCLUSIONS: Nitric oxide decreases inflammatory cytokine production by lung macrophage. The mechanism of nitric oxide's beneficial effects may be partially attributable to decreased production of inflammatory cytokines. Nitric oxide may serve an expanded role for reducing inflammatory cytokine production during acute lung injury, ischemia-reperfusion-induced inflammation, or lung transplant rejection.

Infant heart transplantation: improved intermediate results.

OBJECTIVES: Our objectives were to (1) review our experience with heart transplants in infants (age < 6 months), (2) delineate risk factors for 30-day mortality, and (3) compare outcomes between our early and recent experience. METHODS: Records of all infants listed for transplantation in our center before September 1996 were analyzed. Early and recent comparisons were made between chronologic halves of the accrual period. Univariate analysis was used to analyze potential risk factors for 30-day mortality (categorical variables, Fisher's exact test; continuous variables, nonparametric Wilcoxon rank-sum test). Multivariable analysis included univariate variables with p values < or = 0.10. Actuarial survivals were estimated (Kaplan-Meier) and compared by the log-rank test. RESULTS: Fifty-one of the 60 infants listed for transplantation were operated on (waiting list mortality 15%). Thirty-day mortality was 18% overall, 30% in the first 3 years and 10% in the last 3 years (p = 0.07). Sepsis was the commonest cause of early death (4/9). Univariate analysis suggested four potential risk factors for early death: preoperative mechanical ventilation (p = 0.01), prior sternotomy (p = 0.002), preoperative inotropic drugs (p = 0.08), and warm ischemia time (p = 0.08). Multivariable analysis indicated that prior sternotomy (p = 0.01) was an independent risk factor for 30-day mortality. Actuarial survivals were 80%, 78%, and 70% at 1, 2, and 3 years, and these figures improved between early and recent groups (p = 0.05). Late deaths were most commonly due to acute rejection (3/5). CONCLUSIONS: Results of heart transplantation in infancy improve with experience. Prior sternotomy increases initial risk. Intermediate-term survival for infants with end-stage heart disease is excellent.

Early extubation following cardiac surgery in a veterans population.

BACKGROUND: Early tracheal extubation is an important component of the "fast track" cardiac surgery pathway. Factors associated with time to extubation in the Department of Veterans Affairs (DVA) population are unknown. The authors determined associations of preoperative risk and intraoperative clinical process variables with time to extubation in this population. METHODS: Three hundred four consecutive patients undergoing coronary artery bypass graft, valve surgery, or both on a fast track clinical pathway between October 1, 1993 and September 30, 1995 at a university-affiliated DVA medical center were studied retrospectively. After univariate screening of a battery of preoperative risk and intraoperative clinical process variables, stepwise logistic regression was used to determine associations with tracheal extubation < or = 10 h (early) or > 10 h (late) after surgery. Postoperative lengths of stay, complications, and 30-day and 6-month mortality rates were compared between the two groups. RESULTS: One hundred forty-six patients (48.3%) were extubated early; one patient required emergent reintubation (0.7%). Of the preoperative risk variables considered, only age (odds ratio, 1.80 per 10-yr increment) and preoperative intraaortic balloon pump (odds ratio, 7.88) were multivariately associated with time to extubation (model R) ("late" association is indicated by an odds ratio >1.00; "early" association is indicated by an odds ratio <1.00). Entry of these risk variables into a second regression model, followed by univariately significant intraoperative clinical process variables, yielded the following associations (model R-P): age (odds ratio, 1.86 per 10-yr increment), sufentanil dose (odds ratio, 1.54 per 1-microg/kg increment), major inotrope use (odds ratio, 5.73), platelet transfusion (odds ratio, 10.03), use of an arterial graft (odds ratio, 0.32), and fentanyl dose (odds ratio, 1.45 per 10-microg/kg increment). Time of arrival in the intensive care unit after surgery was also significant (odds ratio, 1.42 per 1-h increment). Intraoperative clinical process variables added significantly to model performance (P < 0.001 by the likelihood ratio test). CONCLUSIONS: In this population, early tracheal extubation was accomplished in 48% of patients. Intraoperative clinical process variables are important factors to be considered in the timing of postoperative extubation after fast track cardiac surgery.

L-arginine prevents lung neutrophil accumulation and preserves pulmonary endothelial function after endotoxin.

L-Arginine supplementation has been shown to restore endothelium-derived nitric oxide production in several pathological states. The purpose of this study was to examine the effect of administration of exogenous L-arginine on the endotoxin-induced lung neutrophil accumulation and impairment of endothelium-dependent guanosine 3',5'-cyclic monophosphate (cGMP)-mediated pulmonary vasorelaxation in rats. Endothelium-dependent relaxation was tested by receptor-dependent [acetylcholine (ACh)] and receptor-independent (A-23187) pathways. Endothelium-independent relaxation was tested with sodium nitroprusside (SNP). In isolated pulmonary arterial rings, concentration-response curves were generated with ACh, A-23187, and SNP (10(-9) to 10(-6) M) 4 h after endotoxin (500 micrograms/kg i.p.) with and without prior administration of L-arginine (300 mg/kg i.p.). Lung neutrophil accumulation was determined by myeloperoxidase (MPO) assay. After endotoxin, lung neutrophil accumulation was significantly increased (MPO activity, 3.8 +/- 0.4 vs. 0.8 +/- 0.1 units/g lung weight in control cells; P < 0.05), which was prevented by L-arginine treatment (MPO activity, 1.3 +/- 0.3 units/g lung weight; P < 0.05 vs. endotoxin). Endotoxin produced a significant impairment of endothelium-dependent cGMP-mediated pulmonary vasorelaxation by receptor-dependent (ACh) and -independent (A-23187) pathways as well as of endothelium-independent relaxation (SNP). Prior treatment with L-arginine, but not with D-arginine, preserved endothelium-dependent vasorelaxation. Neither L- nor D-arginine influenced endotoxin-induced impairment of endothelium-independent, cGMP-mediated pulmonary vasorelaxation. We conclude that administration of exogenous L-arginine prevents endotoxin-induced lung neutrophil accumulation and attenuates its associated impairment of endothelium-dependent, cGMP-mediated pulmonary vasorelaxation.

KATP channels contribute to beta- and adenosine receptor-mediated pulmonary vasorelaxation.

ATP-sensitive K+ (KATP) channels have been implicated in the regulation of vasomotor tone in aortic, mesenteric, and pulmonary vascular smooth muscle. Several investigators have described an association between KATP channels and isoproterenol (Iso)-stimulated relaxation responses. To study the relationship between receptor-dependent pulmonary vasorelaxation and KATP channels, we examined the response to agonists that generate adenosine 3',5'-cyclic monophosphate at two distinct levels of the signal transduction pathway after inhibition or activation of KATP channels in isolated rat pulmonary artery rings. Cumulative concentration responses to beta-adrenergic receptor stimulation (Iso), purinergic receptor stimulation [adenosine (Ado)], and direct stimulation of adenylate cyclase [forskolin (FSK)] were studied with and without concurrent inhibition of KATP channels (glibenclamide or tolbutamide). In addition, the effect of direct KATP channel activation (cromakalim) on the response to beta-adrenergic and purinergic receptor stimulation was determined. Last, we investigated the influence of KATP channel inhibition on endothelium-dependent and -independent mechanisms of pulmonary vasorelaxation linked to guanosine 3',5'-cyclic monophosphate production. KATP channel inhibition impaired the response to Iso and Ado. Activation of KATP channels caused a leftward shift in the dose responses of Iso and Ado, with a significant decrease in the 50% effective concentration for each agent. KATP channel inhibition did not impair the pulmonary arterial vasorelaxation response to FSK, acetylcholine, or sodium nitroprusside. KATP channels appear to contribute to beta-adrenergic and purinergic receptor-stimulated vasorelaxation in rat pulmonary arteries.

Lymphoepithelioma-like carcinoma of the lung.

Primary lymphoepithelioma-like carcinoma of the lung is rare; only 26 case reports have been identified in the literature. The present report presents a case of a 67-year-old white man with a T1 N1 M0 lymphoepithelioma-like carcinoma of the lung. He presented with severe arthritic complaints that resolved after resection of the tumor. The majority of these tumors have occurred in Asian patients who have shown evidence of previous exposure to the Epstein-Barr virus.

Endotoxin stuns cGMP-mediated pulmonary vasorelaxation.

Net pulmonary vascular tone is determined by the balance of pulmonary vasorelaxation and vasoconstriction. In endotoxemic rats, cGMP-mediated pulmonary vasorelaxation is impaired through neutrophil-dependent mechanisms, yet agonist stimulated vasoconstriction remains intact. Endotoxin-induced lung neutrophil accumulation is a transient response. In models of myocardial ischemia-reperfusion injury, "stunning" or reversible cardiac dysfunction is also associated with a reversible neutrophil presence. We hypothesized that lung neutrophil accumulation and dysfunction of cGMP-mediated pulmonary vasorelaxation is reversible after an endotoxin challenge. Our purpose was to examine lung neutrophil accumulation and endothelium-dependent and -independent mechanisms of cGMP-mediated pulmonary vasorelaxation 4 and 48 h after endotoxin challenge. Rats (n = 5 per group) were studied 4 and 48 h after injection of saline or endotoxin (500 micrograms/kg, intraperitoneal). Endothelium-dependent relaxation by receptor-dependent (acetylcholine) and -independent (A23187) mechanisms and endothelium-independent (sodium nitroprusside) relaxation were studied in isolated pulmonary artery rings preconstricted with phenylephrine. Lung neutrophil accumulation was examined by lung myeloperoxidase assay. Lung neutrophil accumulation was increased at 4 h (p < .05 vs. control) and was attenuated by 48 h (p < .05 vs. endotoxin x 4 h) following endotoxin challenge. Similarly, the endotoxin-induced dysfunction of endothelium-dependent and -independent cGMP-mediated pulmonary vasorelaxation at 4 h normalized by 48 h. Endotoxin appears to induce reversible dysfunction of pulmonary vasorelaxation through stunning of vascular endothelial and smooth muscle cells.

Phosphodiesterase inhibition overcomes pulmonary vasomotor dysfunction in acute lung injury.

Production of cGMP is impaired in endotoxin-induced acute lung injury. This results in dysfunction of endothelium-dependent and -independent cGMP-mediated pulmonary vasorelaxation and, therefore, pulmonary hypertension. We hypothesized that cyclic nucleotide phosphodiesterase (PDE) inhibition would attenuate endotoxin-induced impairment to cGMP-mediated mechanisms of pulmonary vasorelaxation. The purpose was to examine the effect of stimulating cGMP production with concurrent inhibition of cGMP catabolism by PDE inhibition following endotoxin-induced acute lung injury. Isolated pulmonary arterial rings from rats (n = 5) were studied 6 hrs after endotoxin (20 mg/kg ip) or saline. In a third group (n = 5), PDE inhibition was accomplished with in vitro 3-isobutyl-1-methylxanthine (IBMX, 1 microM for 30 min). Cyclic GMP-mediated relaxation was interrogated by stimulating (1) endothelium-dependent mechanisms with the receptor-dependent agonist acetylcholine and the receptor-independent agonist A23187, a calcium ionophore, and an (2) endothelium-independent mechanism with sodium nitroprusside. PDE inhibition attenuated endotoxin-induced vasomotor dysfunction. A two-pronged approach-stimulating cGMP production and preventing cGMP catabolism with PDE inhibition-may offer a therapeutically accessible mechanism to overcome vasomotor dysfunction in acute lung injury.