Dilutional and modified ultrafiltration reduces pulmonary hypertension after operations for congenital heart disease: a prospective randomized study

OBJECTIVE: A prospective randomized study was performed to test whether removal of endothelin-1, by ultrafiltration techniques, will reduce pulmonary hypertension after operations for congenital heart disease. METHODS: Twenty-four patients with pulmonary hypertension (systolic pulmonary/systemic arterial pressure ratio > 60%) undergoing cardiac operations were randomized into a control group (n = 12) having conventional ultrafiltration and an experimental group (n = 12) undergoing dilutional ultrafiltration during and modified ultrafiltration after cardiopulmonary bypass. Plasma endothelin-1, nitric oxide metabolites, and cyclic guanosine monophosphate were assayed before bypass, 10 minutes into bypass, after bypass, and 0, 3, 6, and 12 hours after the operation in both groups, as well as in the ultrafiltrates and after modified ultrafiltration in the experimental group. Both groups received alpha-blockers (chlorpromazine and/or prazosin) postoperatively using the same guidelines. RESULTS: The ultrafiltrates contained significant amounts of endothelin-1 (1.81 +/- 0.86 pg/ml, dilutional, and 6.44 +/- 1.82 pg/ml, modified ultrafiltrate). Endothelin-1 and the pulmonary/systemic pressure ratio were significantly lower in experimental compared with control patients. Nitric oxide metabolites and cyclic guanosine monophosphate increased similarly in both groups for 12 hours after the operation (p = not significant). Three of 12 control patients (25%) but no experimental patients had pulmonary hypertensive crises (p = 0.07). The experimental patients required significantly less ventilatory support (67 +/- 47 hours vs 178 +/- 139 hours for control patients, p = 0.048). CONCLUSIONS: Dilutional and modified ultrafiltration reduce endothelin-1 and the pulmonary/systemic pressure ratio postoperatively and may become an important adjunct for preventing pulmonary hypertension after operations for congenital heart disease in high-risk patients.     

Endothelin plasma levels during heart surgery: influence on pulmonary artery pressure?

OBJECTIVE: Some studies found endothelin-1 to be a trigger for pulmonary hypertension. Endothelin-1 is an endothelial derived substance with generally vasoconstrictive properties, but probably vasodilatory effects on pulmonary arteries. The aim of the present study was to look for influences of endothelin-1 plasma values on pulmonary artery pressure. METHODS: Endothelin-1 levels during and after cardiac surgery and correlations to pulmonary artery pressure were tested in 10 control patients and 21 patients with pulmonary hypertension (mean pulmonary arterial pressure > 20 mmHg, systolic pulmonary arterial pressure > 30 mmHg). RESULTS: According to endothelin-1 values before anaesthesia (normal value below 4 pg/ml) patients with pulmonary hypertension could be divided into a "high endothelin-1" (10 patients, mean 8.25 +/- 2.06 pg/ml) and a "normal endothelin-1" (11 patients, mean 2.13 +/- 0.86 pg/ml) subgroup (p < 0.01). Values of the "high endothelin-1" group decreased until end of operation (from 7.58 +/- 2.35 to 2.95 +/- 1.44 pg/ml, n = 6) when pulmonary artery pressure returned to normal. Otherwise they slightly increased (from 9.43 +/- 2.24 to 11.07 +/- 1.96 pg/ml, n = 4). Levels of the "normal endothelin-1" group increased (to 2.55 pg/ml). Endothelin-1 values peaked on the intensive care unit (ICU) in all patients. Baseline endothelin-1 and systolic pulmonary artery pressure values correlated well with each other (r = 0.73, p < 0.001). Endothelin-1 decreased after extracorporeal circulation in all patients in whom pulmonary artery pressure tended to normalise, whereas no rise in pulmonary artery pressure paralleled the marked increase in endothelin-1 on the ICU. Vasodilatory effects of endothelin on pulmonary arteries can attribute to this course. CONCLUSIONS: Endothelin-1 seems not to trigger pulmonary hypertension but rather to vasodilate pulmonary vasculature.     

Time course of endothelin-1 and nitrate anion levels after cardiopulmonary bypass in congenital heart defects

BACKGROUND: The endothelium-derived vasoconstrictor endothelin-1 (ET-1) may be involved in pulmonary hypertension (PH), but production of the endothelium-derived vasodilator nitric oxide (NO) after cardiopulmonary bypass (CPB) in congenital heart disease is unclear. METHODS: Twenty patients (age, 4 months to 12 years) were divided into three groups: severe PH (mean pulmonary-to-systemic arterial pressure ratio > 0.5) and high pulmonary flow (n = 8), mild PH (mean pulmonary-to-systemic arterial pressure ratio < 0.35) and high pulmonary flow (n = 6), and no PH and low pulmonary flow (n = 6). The mean pulmonary-to-systemic arterial pressure ratio was calculated and blood samples were taken, and NO3-, an NO metabolite, was measured. RESULTS: Levels of ET-1 in the group with severe PH and high pulmonary flow were higher than in the other groups until 6 hours after CPB, and NO3- was not changed significantly in the group with severe PH and high pulmonary flow and or the group with mild PH and high pulmonary flow during CPB. Endothelin-1 in the group with no PH and low pulmonary flow was higher than in the group with mild PH and high pulmonary flow after CPB, and NO3- in the group with no PH and low pulmonary flow significantly decreased after CPB. A positive correlation was obtained between mean pulmonary-to-systemic arterial pressure ratio and ET-1 (r = 0.742 before CPB; r = 0.689 after CPB). CONCLUSIONS: Imbalance between increased ET-1 and constant NO after CPB in the group with severe PH and high pulmonary flow could contribute to dominant effects of ET-1, which may injure the lung. The increased ET-1 and the decreased NO after CPB in the group with no PH and low pulmonary flow may induce a mechanism of protective vasoconstriction against an acute increase in pulmonary flow.     

Screening for congenital hypothyroidism in cognitively delayed children

BACKGROUND: Estrogen replacement therapy (ERT) in postmenopausal women decreases cardiac mortality and improves endothelial function. The endothelium regulates vascular tone and growth by releasing such factors as nitric oxide and endothelin-1. OBJECTIVE: To determine whether ERT alters the balance between the total oxidized products of nitric oxide and endothelin-1. DESIGN: Single-arm, before-after clinical trial. SETTING: Outpatient clinical research center of an academic medical center. PATIENTS: 15 postmenopausal women. INTERVENTION: Treatment with 17 beta-estradiol for 6 months and a 10-day course of methoxyprogesterone every 3 months. MEASUREMENTS: Plasma nitric oxide and endothelin-1 levels were measured at baseline and after 6 months of ERT. RESULTS: The mean baseline nitric oxide level was 27.5 nmol/mL (range, 20.3 to 34.8 nmol/mL) and increased by a mean of 7.2 nmol/mL (range, 0.2 to 14.1 nmol/mL) (P = 0.04). The mean baseline plasma endothelin-1 level was 16.4 pg/mL (range, 12.0 to 20.8 pg/mL) and decreased by a mean of 3.9 pg/mL (range, 0.4 to 7.8 pg/mL) (P = 0.04). The mean baseline ratio of nitric oxide to endothelin-1 was 2.0 (range, 1.3 to 2.8) and increased by 1.2 (range, 0.1 to 2.2) (P = 0.03). CONCLUSION: ERT results in an increased ratio of nitric oxide to endothelin-1. This may be one mechanism by which ERT provides cardiovascular benefit.     

The role of endothelial nitric oxide synthase expression in the development of pulmonary hypertension in chronically hypoxic infant swine

OBJECTIVE: Our goal was to determine the role of pulmonary endothelial nitric oxide synthase expression in the development of pulmonary hypertension in infants with congenital cyanotic heart disease. METHODS: Two groups of 4-week-old piglets were studied. In one group, the piglets were raised in an environment of 10% oxygen from 2 days of age (cyanotic, n = 6), and in the other group the piglets were raised at room air (control, n = 5). Pulmonary hemodynamics were measured in vivo for each animal, and peripheral lung biopsy specimens were obtained for Western blot analysis with the use of antiendothelial nitric oxide synthase antibody and for activity analysis with the use of the tritiated L-arginine assay. RESULTS: The piglets in the chronically hypoxic group had significant increases in mean pulmonary arterial pressure (44.0 +/- 3.8 mm Hg vs 14.8 +/- 1.2 mm Hg in controls, p = 0.0007) and pulmonary vascular resistance (7272.0 +/- 871.1 dyne x cm x sec(-5) vs 1844.5 +/- 271.2 dyne x cm x sec(-5) in controls, p = 0.002). These changes in the pulmonary hemodynamics of the hypoxic piglets were accompanied by a twofold increase in the expression of pulmonary endothelial nitric oxide synthase (p = 0.0043) but no corresponding increase in nitric oxide synthase activity. CONCLUSIONS: Raising infant piglets in an environment of 10% oxygen for 4 weeks results in significant pulmonary arterial hypertension accompanied by increased expression of nitric oxide synthase within the lung endothelium. Furthermore, the increased levels of nitric oxide synthase within the lungs of the hypoxic swine were not accompanied by a proportional increase in enzyme activity. These findings suggest that the development of pulmonary hypertension in infants with congenital cyanotic disease is not due to decreased expression of endothelial nitric oxide synthase, but instead may be related to a decreased ability of the enzyme to produce sufficient nitric oxide.     

Reduced pulmonary clearance of endothelin-1 contributes to the increase of circulating levels in heart failure secondary to myocardial infarction

BACKGROUND: The pulmonary vascular bed is a major site for endothelin-1 (ET-1) clearance. A reduced clearance could contribute to the increase in circulating ET-1 levels found in heart failure (HF). We therefore evaluated the effect of HF on pulmonary ET-1 clearance and on plasma ET-1 concentrations. METHODS AND RESULTS: Rats with myocardial infarction (n=24) were compared with sham-operated rats (n=22). The lungs were isolated and perfused at a constant flow rate of 10 mL/min. Pulmonary ET-1 clearance was measured by the single-bolus indicator-dilution technique with 125I-labeled ET-1. Infarct rats developed HF with mild pulmonary hypertension. ET-1 extraction was reduced by HF from 63+/-1.5% to 41+/-4.5% (mean+/-SEM, P<0.001). Mixed venous (MV) and aortic ET-1 levels doubled with HF. There was a plasma ET-1 gradient across the lungs of sham rats (MV-aortic levels, 0.21+/-0.12 pg/mL) but not in lungs of HF rats (0.01+/-0.17 pg/mL). Plasma ET-1 levels correlated closely and inversely with ET-1 extraction (P<0.001). CONCLUSIONS: HF is associated with reduced pulmonary ET-1 clearance that contributes to the increase in circulating levels.     

Plasma adrenomedullin during acute changes in intravascular volume in hemodialysis patients

BACKGROUND: Adrenomedullin, is a potent vasorelaxant that is highly expressed in the adrenal medulla, kidney, heart and lung. Since there is indirect evidence that hypervolemia enhances the release of this peptide, we measured plasma adrenomedullin in 9 uremic patients on chronic dialysis treatment and in 10 healthy subjects matched for age and gender. METHODS: Measurements were performed in baseline conditions, after isotonic fluid subtraction (by isolated ultrafiltration) and during a 70 degrees tilt. Tilt was performed in volume-depleted state, that is, after isolated ultrafiltration (UF). In the control experiment patients underwent sham UF (UF = 0) followed by a period of supine resting identical to the one they had spent in tilted position in the active experiment. Adrenomedullin was measured on pre-extracted plasma samples (Sep-Pak C-18 cartridges) by a specific RIA for human adrenomedullin 1-52. RESULTS: The average plasma adrenomedullin was 2.6 times higher (P < 0.01) in uremic patients (103 +/- 8 pg/ml) than in healthy subjects (39 +/- 7 pg/ml). After fluid subtraction (-2.6 +/- 0.2 liter) adrenomedullin fell to 79. +/- 8 pg/ml (P = 0.02) but remained well above the upper limit of the 95% CI in normal subjects (52 pg/ml). There was no relationship between adrenomedullin and ANF changes. In the control experiment sham UF did not modify plasma adrenomedullin. Tilt did not significantly change plasma adrenomedullin either in dialysis patients or healthy subjects. CONCLUSIONS: Plasma adrenomedullin is markedly raised in uremic patients on dialysis, which confirms that the kidney has a major role in the clearance of this peptide. However, the fall in plasma adrenomedullin after isolated UF indicates that the plasma concentration of this peptide is influenced by the body fluid volume status. Whether or not adrenomedullin participates in the counter-regulatory response to fluid subtraction in uremic patients remains to be explored by specific antagonists of this substance.     

Autocrine role for the endothelin-B receptor in the secretion of adrenomedullin

Adrenomedullin, originally discovered in human pheochromocytoma, is a vasodilating and natriuretic peptide of vascular endothelial and smooth muscle cell origin. Although endothelin-1 (ET-1) has been implicated as a vasoconstricting and growth-promoting peptide of endothelial origin, it may more importantly function as an autocrine factor and release vasodilatory substances such as nitric oxide by mechanisms linked to the endothelin-B (ETB) receptor subtype. The present study was designed to establish that the ETB receptor stimulates the secretion of adrenomedullin from cultured canine aortic endothelial cells. We first sought to determine the presence and production of adrenomedullin in canine aortic endothelial cells using immunohistochemistry and Northern blot analysis, which revealed that adrenomedullin immunoreactivity and adrenomedullin mRNA were present in canine aortic endothelial cells. Second, adrenomedullin was time-dependently secreted from canine aortic endothelial cells, with a secretion rate of 15.7+/-1.5 pg/10(5) cells per 24 hours. Furthermore, immunohistochemistry revealed the presence of the ETB receptor in canine aortic endothelial cells, and ETB receptor stimulation by sarafotoxin S6c increased adrenomedullin production and secretion from canine aortic endothelial cells. Such actions were blocked with the ETB receptor antagonist IRL-2500 but not with ETA receptor antagonist FR-139317. These studies are the first to report an additional autocrine role of the ETB receptor in the release of vasodilating and natriuretic peptide adrenomedullin, and they suggest another important vasoactive system regulated by the ET receptor subtype.     

Endothelin-1 and thromboxane A2 increase pulmonary vascular resistance in granulocyte-mediated lung injury

OBJECTIVE: To examine the pathophysiologic role of vasoactive eicosanoids and endothelin-1 in granulocyte-mediated effects in the pulmonary vasculature. DESIGN: Prospective experimental study in rabbits. SETTING: Experimental laboratory in a university teaching hospital. SUBJECTS: Thirty adult rabbits. INTERVENTIONS: The experiments were performed on 30 isolated and ventilated rabbit lungs that were perfused with a cell- and plasma-free buffer solution. MEASUREMENTS AND MAIN RESULTS: The pulmonary arterial pressure and the lung weight gain were continuously registered. Intermittently perfused samples were taken to determine endothelin-1 and thromboxane A2 concentrations. Six experiments without intervention served as the sham group. The granulocytes in the pulmonary circulation were stimulated with N-formyl-L-leucin-methionyl-L-phenylalanine (FMLP; 10(-6) M; control, n = 6). To investigate whether activated granulocytes influence the pulmonary vasculature via endothelin-1, the endothelin-A receptor antagonist LU135252 (10(-6) M) was added to the perfusate before FMLP injection (n = 6). The potential involvement of thromboxane A2 in granulocyte-endothelial interaction was investigated by pretreatment with the cyclooxygenase inhibitor diclofenac (10 microg/mL; n = 6). Activation of granulocytes resulted in an acute increase in pulmonary arterial pressure (>9 mm Hg), which was followed by a second delayed pressure increase after 60 mins (>14 mm Hg) and was paralleled by a massive generation of thromboxane A2 (>250 pg/ mL). Fifteen minutes after FMLP-injection, endothelin-1 was detectable in the perfusate. Pretreatment with the selective endothelin-A antagonist LU135252 significantly (p< .01) reduced the initial pressure response after FMLP stimulation, while diclofenac significantly reduced (p < .05) the delayed pressure increase. Using diclofenac (10 microg/mL) in conjunction with LU135252 (10(-6) M; n = 6) before FMLP injection significantly reduced the early and the delayed pressure increase. CONCLUSIONS: Activated granulocytes seem to enhance pulmonary vascular resistance via endothelin-1 and thromboxane A2. The endothelin-1 effects are probably mediated via endothelin-A receptors since the endothelin-A receptor antagonist LU135252 was able to suppress the early pressure reaction after FMLP injection, whereas the cyclooxygenase inhibitor diclofenac was able to reduce the second pressure increase.     

Selective pulmonary vasodilation by inhaled nitric oxide is due to hemoglobin inactivation

BACKGROUND: Inhaled nitric oxide gas selectively decreases pulmonary artery pressure without affecting systemic arterial pressure. To determine if the selective pulmonary vasodilating effect of inhaled nitric oxide gas is due to inactivation by hemoglobin, we studied the ability of whole blood to inhibit the vasodilator activity of effluent from isolated lungs exposed to inhaled nitric oxide. METHODS AND RESULTS: The effluent from ventilated, Krebs-perfused rabbit lungs was passed directly over 3- to 4-mm rabbit aortic rings. Inhaled nitric oxide (150 ppm for 3 minutes) reduced pulmonary perfusion pressure, elevated by a continuous infusion of U46619, by 35 +/- 7% (mean +/- SEM, n = 5). Lung effluent from this series of experiments caused 40 +/- 13% relaxation of phenylephrine-preconstricted aortic rings. When blood was added to the combined lung/ring perfusion cascade (final hemoglobin concentration, 1 g/dL), inhaled nitric oxide again significantly reduced pulmonary perfusion pressure, but the effluent now failed to relax the aortic rings (30 +/- 6% [control] versus 1.5 +/- 1% [blood]). Both reduction in pulmonary perfusion pressure and relaxation of the rings during nitric oxide exposure were unchanged from control values after discontinuing the blood infusion. CONCLUSIONS: The presence of hemoglobin, even in extremely small amounts, restricts the vasodilating effect of inhaled nitric oxide gas to the pulmonary circulation.     

Adrenomedullin, a new vasoactive peptide, is increased in preeclampsia

Adrenomedullin is a novel peptide that elicits a long-lasting vasorelaxant activity. Recently, we found high concentrations of adrenomedullin in maternal and umbilical cord plasma and in amniotic fluid in full-term human pregnancy, indicating a role of this peptide during gestation. To investigate the possibility that adrenomedullin is involved in the pathophysiology of preeclampsia, we measured its concentration in maternal and fetoplacental compartments. We studied 12 normotensive nonpregnant women, 13 hypertensive nonpregnant subjects, 29 patients with preeclampsia, and 30 normotensive pregnant women. In all patients, plasma was collected from the cubital vein, and amniotic fluid samples were obtained by transabdominal amniocentesis or at elective cesarean section. Plasma samples from umbilical vein and placental tissues were collected at delivery. Adrenomedullin was assayed on plasma and amniotic fluid samples using a specific radioimmunoassay, and its localization and distribution on placental sections was determined by immunohistochemistry. Adrenomedullin concentrations were higher in hypertensive than in normotensive nonpregnant patients. Pregnant women had higher adrenomedullin levels than nonpregnant subjects, although maternal plasma adrenomedullin concentrations did not differ between normal pregnant and preeclamptic women. Preeclamptic patients showed higher concentrations (P<0.01) than normotensive pregnant women of adrenomedullin in amniotic fluid (252+/-29 versus 112+/-10 fmol/ micromol creatinine) and umbilical vein plasma (18.1+/-2.1 versus 8. 5+/-1.1 fmol/mL). Increased local production of adrenomedullin is associated with preeclampsia. The fetus seems to be responsible for the higher levels of this hormone. Increased adrenomedullin concentrations may be necessary to maintain placental vascular resistance and/or fetal circulation at a physiological level.     

Elevated plasma adrenomedullin level in hyperthyroidism

Adrenomedullin is a recently discovered peptide that was first purified from phaeochromocytoma tissue and has marked vasodilatory activity, causing hypotension. In thyrotoxicosis, various haemodynamic changes are observed, including an increase in cardiac output and heart rate with a concomitant decrease in peripheral vascular resistance. To evaluate the mechanism underlying these haemodynamic changes in thyrotoxicosis, we measured the plasma adrenomedullin concentration in thyrotoxic patients with Graves' disease. The plasma concentration of adrenomedullin was elevated in hyperthyroid patients (14.7 +/- 5.7 pmol L-1) compared with euthyroid control subjects (5.6 +/- 1.3 pmol L-1) (P < 0.001). The correlation between the plasma adrenomedullin concentration and serum free thyroid hormone levels was marginally significant. The mean blood pressure was relatively low in the face of an elevated plasma adrenomedullin level. Adrenomedullin may therefore be responsible for the vasodilatation observed in thyrotoxicosis.     

Low-dose sodium nitroprusside reduces pulmonary reperfusion injury

BACKGROUND: Reperfusion injury is a significant cause of early allograft dysfunction after lung transplantation. We hypothesized that direct pulmonary arterial infusion of an intravascular nitric oxide donor, sodium nitroprusside (SNP), would ameliorate pulmonary reperfusion injury more effectively than inhaled nitric oxide without causing profound systemic hypotension. METHODS: Using an isolated, ventilated, whole-blood-perfused rabbit lung model, we studied the effects of both inhaled and intravascular nitric oxide during lung reperfusion. Group I (control) lungs (New Zealand White rabbits, 3 to 3.5 kg) were harvested en bloc, flushed with Euro-Collins solution, and then stored inflated for 18 hours at 4 degrees C. Lungs were then reperfused with whole blood and ventilated with 60% oxygen for 30 minutes. Groups II, III, and IV received pulmonary arterial infusions of SNP at 0.2, 1.0, and 5.0 micrograms.kg-1.min-1, respectively, whereas group V was ventilated with 60% oxygen and nitric oxide at 80 ppm during reperfusion. RESULTS: Pulmonary arterial infusions of SNP even at 0.2 microgram.kg-1.min-1 (group II) showed significant improvements in pulmonary artery pressure (31.35 +/- 0.8 versus 40.37 +/- 3.3 mm Hg; p < 0.05) and pulmonary vascular resistance (38,946 +/- 1,269 versus 52,727 +/- 3,421 dynes.s/cm-5; p < 0.05) when compared with control (group I) lungs after 30 minutes of reperfusion. Infusions of SNP at 1.0 microgram.kg-1.min-1 (group III) showed additional significant improvements in dynamic airway compliance (1.98 +/- 0.10 versus 1.46 +/- 0.02 mL/mm Hg; p < 0.05), venous-arterial oxygenation gradient (116.00 +/- 24.4 versus 34.43 +/- 2.5 mm Hg; p < 0.05), and wet-to-dry ratio (6.9 +/- 0.9 versus 9.1 +/- 2.2; p < 0.05) when compared with control (group I) lungs. Lungs that received inhaled nitric oxide at 80 ppm (group V) were significantly more compliant (1.82 +/- 0.13 versus 1.46 +/- 0.02 mL/mm Hg; p < 0.05) than control (group I) lungs. CONCLUSIONS: Pulmonary arterial infusion of low-dose SNP during lung reperfusion significantly improves pulmonary hemodynamics, oxygenation, compliance, and edema formation. These effects were achieved at doses of SNP that did not cause profound systemic hypotension. Direct intravascular infusion of SNP via pulmonary arterial catheters could potentially abate reperfusion injury immediately after allograft implantation.     

Estrogen receptor alpha and beta expression in upper gastrointestinal tract with regulation of trefoil factor family 2 mRNA levels in ovariectomized rats

STUDY OBJECTIVE: To investigate the effect of short-term inhalation of nitric oxide (NO) on transpulmonary angiotensin II formation in patients with severe ARDS. DESIGN: Prospective, clinical study. SETTING: Anesthesiology ICU of a university hospital. PATIENTS: Ten ARDS patients who responded to inhalation of 100 ppm NO by decreasing their pulmonary vascular resistance (PVR) by at least 20 dyne x s x cm(-5) were included in the study. INTERVENTIONS AND MEASUREMENTS: In addition to standard treatment, the patients inhaled 0, 1, and 100 ppm NO in 20-min intervals. Fraction of inspired oxygen was 1.0. Hemodynamics were measured and recorded online. Mixed venous (pulmonary arterial catheter) and arterial (arterial catheter) blood samples were taken simultaneously for hormonal analyses at the end of each inhalation period. RESULTS: Pulmonary arterial pressure decreased from 33+/-2 mm Hg (0 ppm NO, mean+/-SEM) to 29+/-2 mm Hg (1 ppm NO, p<0.05), and to 27+/-2 mm Hg (100 ppm NO, p<0.05, vs 0 ppm). PVR decreased from 298+/-56 (0 ppm NO) to 243+/-45 dyne x s x cm(-5) (1 ppm NO, not significant [NS]), and to 197+/-34 dyne x s x cm(-5) (100 ppm NO, p<0.05, vs 0 ppm). Arterial oxygen pressure increased from 174+/-23 mm Hg (0 ppm NO) to 205+/-26 mm Hg (1 ppm NO, NS), and to 245+/-25 mm Hg (100 ppm NO, p <0.05, vs 0 ppm). Mean plasma angiotensin II concentrations were 85+/-20 (arterial) and 57+/-13 pg/mL (mixed venous) during 0 ppm NO and did not change during inhalation of 1 and 100 ppm NO. Mean transpulmonary plasma angiotensin II concentration gradient (=difference between arterial and mixed venous blood values) was 28+/-8 pg/mL (range, 0 to 69) during 0 ppm NO and did not change during inhalation of 1 and 100 ppm NO. Mean transpulmonary angiotensin II formation (transpulmonary angiotensin II gradient multiplied with the cardiac index) was 117+/-39 ng/min/m2 (range, 0 to 414) during 0 ppm NO and did not change during inhalation of 1 and 100 ppm NO. Mean arterial plasma cyclic guanosine monophosphate concentration was 11+/-2 pmol/mL (0 ppm NO), did not change during 1 ppm NO, and increased to 58+/-8 pmol/mL (100 ppm NO, p<0.05). Arterial plasma concentrations of aldosterone (142+/-47 pg/mL), atrial natriuretic peptide (114+/-34 pg/mL), angiotensin-converting enzyme (30+/-5 U/L), and plasma renin activity (94+/-26 ng/mL/h of angiotensin I) did not change. CONCLUSION: The decrease of PVR by short-term NO inhalation in ARDS patients was not accompanied by changes in transpulmonary angiotensin II formation. Our results do not support any relationship between transpulmonary angiotensin II formation and the decrease in PVR induced by inhaled NO.     

Hemodynamic, hormonal, and renal effects of intracerebroventricular adrenomedullin in conscious sheep

Adrenomedullin, the recently described vasodilator that exhibits potent hypotensive actions when administered systemically, is also found in the central nervous system, suggesting a role for adrenomedullin as a neurohormone. However, only a limited number of studies have examined the central effects of adrenomedullin. Therefore, we have examined the integrative hemodynamic, renal, and hormonal effects of intracerebroventricular (I.C.V.) adrenomedullin in conscious sheep. Eight surgically prepared sheep received I.C.V. infusions of adrenomedullin at two doses (2 ng/kg x min followed immediately by 20 ng/kg x min each for 90 min) in a vehicle-controlled study. Water deprivation for 48 h before control infusion resulted in sheep drinking 2617 +/- 583 ml in the 90-min period following reintroduction of water. On the adrenomedullin day, drinking was halved to 1392 +/- 361 ml (P < 0.05). Adrenomedullin had no significant effect on urinary volume and sodium excretion. Plasma adrenomedullin levels remained unchanged during control infusions but were elevated by the end of I.C.V. adrenomedullin infusions (P < 0.001). Plasma ANP levels were also increased approximately 50% (P < 0.05). Plasma levels of both ACTH and cortisol were also increased 3- to 4-fold in response to I.C.V. adrenomedullin (P < 0.05). There was no significant difference in arterial pressure, heart rate, or cardiac output between study days. In conclusion, adrenomedullin within the central nervous system may have at least two roles: modulation of the hypothalamo-pituitary-adrenal axis and protection against fluid overload.     

A study of cis-diamminedichloroplatinum(II) suppositories for the treatment of rabbit uterine endometrial carcinoma

OBJECTIVE: To determine the effects of continuous ambulatory peritoneal dialysis (CAPD) and hemodialysis (HD) on endothelin-1 (ET-1) levels in patients with end-stage renal disease (ESRD) and to assess the relationship between plasma ET-1 levels and selected patient parameters. DESIGN: Prospective, nonrandomized comparison study. SETTING: Outpatient CAPD and HD units of a university medical center. PARTICIPANTS: Twelve ESRD patients (6 on CAPD and 6 on HD) and 5 healthy normotensive subjects. INTERVENTIONS: CAPD patients had blood and peritoneal dialysate samples collected and measurements made following an overnight exchange. HD patients had blood collected and measurements made at 0 hours (basal) and again at 3 hours during a midweek HD session. Blood samples were also collected from normal subjects and served as ET-1 controls. MEASUREMENTS: ET-1 and patient parameters (creatinine, peritoneal dialysate volume, blood pressure, body weight, age, and treatment duration) were determined. Data are reported as the mean +/- one standard deviation. RESULTS: Plasma and dialysate ET-1 levels in the CAPD group were 19.5 +/- 4.2 pg/mL and 9.2 +/- 4.2 pg/mL, respectively. The control group plasma and unused dialysate contained no detectable ET-1 (< 3.0 pg/mL, the limit of detection). The peritoneal clearance of ET-1 was less than that of creatinine (2.29 +/- 0.69 mL/minute vs 4.22 +/- 0.66 mL/minute, p = 0.005). The basal (0 hour) plasma ET-1 level in the HD group (16.5 +/- 7.8 pg/mL) did not differ from that of the CAPD group, p = 0.423. Furthermore, no differences in patient parameters were detected between the CAPD and basal HD groups. Although the mean arterial pressure (MAP) decreased during HD, the plasma ET-1 level at 3 hours (13.5 +/- 5.4 pg/mL) remained unchanged from the basal level, p = 0.307. An analysis of pooled data from the CAPD and HD groups revealed no significant correlation between plasma ET-1 and MAP, body weight, creatinine, or treatment duration. There was, however, a positive correlation between plasma ET-1 and age (r = 0.643, p = 0.024).     

The BAX gene, the promoter of apoptosis, is mutated in genetically unstable cancers of the colorectum, stomach, and endometrium

OBJECTIVE: The study's objective was to determine whether there is a difference in the plasma concentration of adrenomedullin, a hypotensive peptide, between arterial and venous umbilical cord blood of uncomplicated gestations with vaginal delivery. STUDY DESIGN: Arterial and venous umbilical cord blood was obtained immediately after vaginal delivery of 44 term infants with uncomplicated antepartum and intrapartum courses. Radioimmunoassay was performed to assess adrenomedullin concentrations in the plasma. The paired t test was used to compare arterial and venous concentrations. Significance was set at P < .05. RESULTS: Mean +/- SE adrenomedullin concentrations were 178.7 +/- 4.7 pg/mL and 190.6 +/- 6.3 pg/mL for arterial and venous cord plasma, respectively. The difference between the 2 concentrations was not significant (11.8 pg/mL, P = .09). CONCLUSION: Arterial and venous umbilical plasma concentrations of adrenomedullin do not differ significantly in uncomplicated gestations terminating with uncomplicated vaginal deliveries. This suggests that in the normal state there is neither net production nor net clearance of adrenomedullin in the placenta.     

Urodynamic risk factors for renal dysfunction in men with obstructive and nonobstructive voiding dysfunction

BACKGROUND AND PURPOSE: Adrenomedullin is a recently discovered vasoactive peptide that is structurally related to calcitonin gene-related peptide (CGRP). Adrenomedullin is produced by vascular endothelium and smooth muscle and is present in the brain. The goals of this study were to determine (1) whether adrenomedullin produces dilatation of cerebral arterioles and whether this effect is mediated by activation of CGRP receptors and (2) whether vasodilatation to adrenomedullin was mediated by K+ channels. METHODS: Diameter of cerebral arterioles (mean +/- SE baseline, 46 +/- 1 microns) was measured using a closed cranial window in anesthetized rats. RESULTS: Application of rat adrenomedullin (10(-7) and 10(-6) mol/L) increased vessel diameter by 16 +/- 3% and 45 +/- 8% (n = 5), respectively. Vasodilator responses to repeated application of adrenomedullin were reproducible. Pretreatment of cerebral arterioles with the specific CGRP1 receptor antagonist CGRP-(8-37) (5 x 10(-7) mol/L) selectively inhibited the vasodilator responses to adrenomedullin without inhibiting responses to ADP (10(-5) to 10(-3) mol/L). Responses to adrenomedullin (10(-7) and 10(-6) mol/L) were 14 +/- 1% and 40 +/- 3% before and 2 +/- 2% and 6 +/- 1% after CGRP-(8-37), respectively (P < .01). Glibenclamide (10(-6) mol/L), an inhibitor of ATP-sensitive K+ channels, reduced the responses to adrenomedullin without attenuating responses to ADP. Responses to adrenomedullin were 19 +/- 4% and 35 +/- 6% before and 6 +/- 3% and 19 +/- 5% after glibenclamide, respectively (P < .05). Iberiotoxin (10(-7) mol/L), an inhibitor of calcium-dependent K+ channels, also significantly attenuated responses to adrenomedullin and did not inhibit vasodilatation to papaverine. Responses to adrenomedullin were 16 +/- 2% and 55 +/- 8% before and 12 +/- 4% and 26 +/- 3% after iberiotoxin, respectively (P < .01 for 10(-6) mol/L adrenomedullin). CONCLUSIONS: Adrenomedullin produces substantial dilatation of cerebral arterioles in vivo, and the response is mediated in large part by activation of CGRP1 receptors. Cerebral vasodilatation to adrenomedullin appears to be dependent on activation of K+ channels.     

Inhaled nitric oxide reduction in systolic pulmonary artery pressure is less in patients with decreased left ventricular ejection fraction

OBJECTIVE: To assess whether inhaled nitric oxide decreases pulmonary artery pressure in patients with depressed left ventricular ejection fraction. DESIGN: Randomized, blinded, crossover clinical trial. SETTING: Tertiary care university referral hospital. PATIENTS: Thirty-three patients with pulmonary hypertension and left ventricular dysfunction or valvular heart disease were recruited by convenience. INTERVENTIONS: Systolic pulmonary artery pressure was measured by Doppler echocardiography during randomized inhalation of either 20 ppm or 40 ppm nitric oxide in 30% oxygen as well as during control periods without nitric oxide. MAIN RESULTS: Systolic pulmonary artery pressure was significantly (P < 0.05) decreased with 20 ppm nitric oxide (53.4 +/- 13.9 mmHg) and 40 ppm nitric oxide (53.1 +/- 14.4 mmHg) compared with either initial control (55.8 +/- 15.3 mmHg) or terminal control (56.3 +/- 15.2 mmHg) values. The regression equation for the change in systolic pulmonary artery pressure (y) as predicted by the left ventricular ejection fraction (x) alone for 20 ppm nitric oxide was y = 13.8x-2.9; R2adj = 0.30, P < 0.0001. For 40 ppm nitric oxide alone, the regression equation was y = 16.3x-3.3; R2adj = 0.25, P < 0.0001. Left ventricular ejection fraction was the most explanatory independent variable in the multivariate equation for nitric oxide-induced change in systolic pulmonary artery pressure (R2 = 0.61, P = 0.0000). The change in systolic pulmonary artery pressure was -5.1 +/- 5.2 versus 0.8 +/- 4.9 mmHg (P < 0.0000) in patients with left ventricular ejection fractions greater than 0.25, and 0.25 or less, respectively. CONCLUSIONS: These data imply that in patients with left ventricular ejection fraction of 0.25 or less, nitric oxide may not decrease systolic pulmonary artery pressure. Nitric oxide inhalation may result in a paradoxical increase in systolic pulmonary artery pressure in patients with severely depressed left ventricular ejection fraction. This effect would significantly limit the therapeutic role of nitric oxide in patients with severe heart failure.     

Solitary pulmonary nodule due to Leishmania in a patient with AIDS

BACKGROUND: Nitric oxide is an endothelium-derived vasodilator. Cardiopulmonary bypass may induce transient pulmonary endothelial dysfunction with decreased nitric oxide release that contributes to postoperative pulmonary hypertension and lung injury. Exhaled nitric oxide levels may reflect, in part, endogenous production from the pulmonary vascular endothelium. METHODS: We measured exhaled nitric oxide levels before and 30 minutes after cardiopulmonary bypass in 30 children with acyanotic congenital heart disease and left-to-right intracardiac shunts undergoing repair. RESULTS: Exhaled nitric oxide levels decreased by 27.6%+/-5.6% from 7+/-0.8 to 4.4+/-0.5 ppb (p < 0.05) 30 minutes after cardiopulmonary bypass despite a reduction in hemoglobin concentration. CONCLUSIONS: The decrease in exhaled nitric oxide levels suggests reduced nitric oxide synthesis as a result of pulmonary vascular endothelial or lung epithelial injury. This may explain the efficacy of inhaled nitric oxide in the treatment of postoperative pulmonary hypertension. Furthermore, strategies aimed at minimizing endothelial dysfunction and augmenting nitric oxide production during cardiopulmonary bypass may decrease the incidence of postoperative pulmonary hypertension. Exhaled nitric oxide levels may be useful to monitor both cardiopulmonary bypass-induced endothelial injury and the effect of strategies aimed at minimizing such injury.