Randomized, prospective, placebo-controlled trial of bosentan in interstitial lung disease secondary to systemic sclerosis.

OBJECTIVE: Endothelin is implicated as a participatory pathway in systemic sclerosis (SSc). We tested this hypothesis in a 12-month trial of bosentan, a nonselective endothelin receptor antagonist, as a therapy for SSc-related interstitial lung disease (ILD). METHOD: Patients with SSc and significant ILD were recruited to this prospective, double-blind, randomized, placebo-controlled, parallel group study. The inclusion criteria were designed to select a cohort enriched for patients with active and progressive disease. Exclusion factors included significant pulmonary hypertension. Patients with a diffusing capacity for carbon monoxide of <80% predicted and a 6-minute walk distance of 150-500 meters or a 6-minute walk distance of > or = 500 meters with a decrease in oxygen saturation received bosentan or placebo. The primary efficacy end point was a change in the 6-minute walk distance from baseline up to month 12. Secondary end points included time to death or worsening results of pulmonary function tests (PFTs). The safety and tolerability of bosentan were also assessed. RESULTS: Among the 163 patients, 77 were randomized to receive bosentan, and 86 were randomized to receive placebo. No significant difference between treatment groups was observed for change in the 6-minute walk distance up to month 12. No deaths occurred in this study group. Forced vital capacity and diffusing capacity for carbon monoxide remained stable in the majority of patients in both groups. Significant worsening of PFT results occurred in 25.6% of patients receiving placebo and 22.5% of those receiving bosentan (P not significant). CONCLUSION: No improvement in exercise capacity was observed in the bosentan-treated group compared with the placebo group, and no significant treatment effect was observed for the other end points. Although many outcome variables were stable, bosentan did not reduce the frequency of clinically important worsening. These data do not support the use of endothelin receptor antagonists as therapy for ILD secondary to SSc.

Echocardiographic assessment of hemodynamic changes produced by two methods of inducing fluid deficit in dogs.

BACKGROUND: Hydration status is important to the cardiovascular system because of its effects on preload. Decreased preload can alter echocardiographic measurements of systolic and diastolic function, potentially confounding interpretation of results. HYPOTHESIS/OBJECTIVES: Mild fluid deficits are associated with measurable echocardiographic changes that are validated by physical and biochemical markers of decreased intravascular volume. ANIMALS: Twenty-five healthy staff/student-owned dogs with no evidence of cardiac or renal disease. METHODS: Prospective, interventional laboratory study. Dogs were randomly assigned to water deprivation (WD) alone for 8 hours (n = 13) or to furosemide treatment (FTx, 2.5mg/kg IV) followed by WD for 8 hours (n = 12). Echocardiograms, biochemical sampling, and physical parameters were measured at baseline, and after 4 and 8 hours. RESULTS: Both protocols induced fluid deficit as indicated by significant (P < .00001) decreases in weight at 4 hours (WD, 1.1%; FTx, 3.7%) and 8 hours (WD, 2.7%; FTx, 4.5%). Furosemide significantly decreased left ventricular end-diastolic volume (54.3 +/- 19.3-42.1 +/- 17.3 mL, P < .0001), cardiac index (4.2 +/- 1.1-2.9 +/- 0.9 L/min/M2, P < .0001), and mitral valve E wave velocity (0.79 +/- 0.2-0.66 +/- 0.2 m/s, P = .0004). These changes were accompanied by significant increases in blood urea nitrogen concentration (13.8 +/- 2.6-14.8 +/- 2.7 mg/dL, P = .04), vasopressin concentration (1.4 +/- 1.2-3.3 +/- 1.9 pg/mL, P = .045), and PCV (49.8 +/- 4.5-53.2 +/- 6.5%, P = .006). Effects of water deprivation alone were similar, but less pronounced. CONCLUSIONS AND CLINICAL IMPORTANCE: Mild fluid deficits have measurable hemodynamic effects in dogs. Hydration status should be considered when evaluating cardiac function by echocardiogram.

Nonadrenergic effects of isoproterenol in dogs with hypoxic pulmonary vasoconstriction. Possible role of prostaglandins.

To determine whether the pulmonary vasodilation produced by isoproterenol is mediated solely by its beta adrenergic effects, we studied the hemodynamic responses to isoproterenol in three groups of dogs with pulmonary vasoconstriction produced by continuous ventilation with 10% oxygen: (a) hypoxia alone, (b) hypoxia and propranolol 0.3 mg/kg i.v. bolus followed by an infusion of 5 micrograms/kg per min, and (c) hypoxia after pretreatment with an inhibitor of cyclooxygenase, either indomethacin or meclofenamate 5 mg/kg s.c. twice daily for 2 d prior to study. All groups had similar values for mean pulmonary artery pressure (PAPm) and pulmonary vascular resistance (PVR) during room air and hypoxic ventilation. Isoproterenol in doses of 0.0025, 0.005, and 0.05 micrograms/kg per min produced a dose-related decline in PAPm and PVR during hypoxia in group 1. Despite beta-blockade with propranolol (group 2), isoproterenol at all three doses significantly reduced PAPm and PVR. The responses to isoproterenol were comparable in the presence or absence of propranolol; at 0.05 micrograms/kg per min the effects of isoproterenol were blunted, but not abolished, by propranolol. Similar results were observed even when five times the dose of propranolol was given. Isoproterenol at all three doses had no effect, however, on PAPm and PVR in the cyclooxygenase inhibitor-pretreated group. These data suggest that the pulmonary vasodilator effects of isoproterenol are not mediated solely by pulmonary vascular beta adrenergic receptors, and that vasodilator prostaglandins may play a role in the responses to this drug.

Influence of prostaglandin synthesis inhibitors on pulmonary vasodilatory effects of hydralazine in dogs with hypoxic pulmonary vasoconstriction.

TO DETERMINE WHETHER HYDRALAZINE, A SYSTEMIC VASODILATOR, EXERTED A SIMILAR EFFECT ON THE PULMONARY CIRCULATION, WE STUDIED THE CIRCULATORY CHANGES IN DOGS DURING THREE INTERVENTIONS: (a) the control state during room air ventilation; (b) during continuous hypoxic ventilation with 10% oxygen, and maintaining continuous hypoxic ventilation; and (c) after 1 mg/kg hydralazine intravenously. Ventilation with 10% oxygen caused the mean pulmonary artery pressure to increase from 10+/-1.2 to 23+/-2.4 mm Hg (P < 0.01) and the pulmonary arteriolar resistance to increase from 1.51+/-0.19 to 5.87+/-1.10 U (P < 0.01). Hydralazine significantly lowered the pulmonary artery pressure (23.0+/-2.4 to 14.3+/-1.5 mm Hg, P < 0.01) and the pulmonary arteriolar resistance (5.87+/-1.10 to 2.87+/-0.52 U, P < 0.01). Femoral artery pressure, pulmonary artery wedge pressure, heart rate, and cardiac output remained unchanged throughout. To ascertain the contribution of the prostaglandin system to the pulmonary vasodilator effects of hydralazine, we pretreated a group of dogs with the prostaglandin synthetase inhibitor, indomethacin, 5 mg/kg s.c., twice daily for 2 d. These animals then underwent identical studies.The pretreated dogs had comparable base-line and hypoxia hemodynamic data. However, hydralazine had no effect on pulmonary artery pressure (23.3+/-1.6 vs. 21.7+/-2.3 mm Hg, NS) or pulmonary arteriolar resistance (8.03+/-1.09 vs. 7.14+/-1.42, NS) during continuous hypoxic ventilation in the indomethacin-pretreated group. Pretreatment with indomethacin did not, however, block the pulmonary vasodilator effects of intravenous prostacyclin (PGI(2)). Pretreatment with meclofenamate, a cyclo-oxygenase inhibitor structurally unrelated to indomethacin, also blocked the effects of hydralazine during hypoxic ventilation. These data suggest that hydralazine exerts a pulmonary vasodilatory effect during hypoxia-induced pulmonary vasoconstriction, and that this vasodilator effect may be mediated by prostaglandins.

Hypoxia inhibits gene expression of voltage-gated K+ channel alpha subunits in pulmonary artery smooth muscle cells.

Activity of voltage-gated K+ channels (KV) in pulmonary arterial smooth muscle cells (PASMC) is pivotal in controlling membrane potential, cytoplasmic free Ca2+ concentration ([Ca2+]cyt, and pulmonary vasomotor tone. Acute hypoxia selectively inhibits KV channels, depolarizes PASMC, raises [Ca2+]cyt, and causes pulmonary vasoconstriction and vascular remodeling. Prolonged hypoxia (24-60 h) decreased significantly the mRNA levels of KV channel alpha subunits, KV1.2 and KV1.5. Consistently, the protein levels of KV1.2 and KV1.5 were also decreased significantly by hypoxia (48-72 h). Nevertheless, hypoxia affected negligibly the mRNA levels of KV channel beta subunits (KVbeta1, KVbeta2, and KVbeta3). The native K+ channels are composed of pore-forming alpha and auxiliary beta subunits. Assembly of KV beta subunits with alpha subunits confers rapid inactivation on the slowly or non-inactivating delayed rectifier KV channels. KV beta subunits also function as an open-channel blocker of KV channels. Thus, the diminished transcription and expression of KV alpha subunits may reduce the number of KV channels and decrease KC currents. Unchanged transcription of KV beta subunits may increase the fraction of the KV channel alpha subunits that are associated with beta subunits and further reduce the total KV currents. These data demonstrate a novel mechanism by which chronic hypoxia may cause pulmonary vasoconstriction and hypertension.

c-Jun decreases voltage-gated K(+) channel activity in pulmonary artery smooth muscle cells.

BACKGROUND: Activity of voltage-gated K(+) (K(v)) channels controls membrane potential (E(m)) that regulates cytosolic free Ca(2+) concentration ([Ca(2+)](cyt)) by regulating voltage-dependent Ca(2+) channel function. A rise in [Ca(2+)](cyt) in pulmonary artery smooth muscle cells (PASMCs) triggers vasoconstriction and stimulates PASMC proliferation. Whether c-Jun, a transcription factor that stimulates cell proliferation, affects K(v) channel activity in PASMCs was investigated. METHODS AND RESULTS: Infection of primary cultured PASMCs with an adenoviral vector expressing c-jun increased the protein level of c-Jun and reduced K(v) currents (I(K(V))) compared with control cells (infected with an empty adenovirus). Using single-cell reverse transcription-polymerase chain reaction, we observed that the mRNA level of Kv1.5 and the current density of I(K(V)) were both attenuated in c-jun-infected PASMCs compared with control cells and cells infected with antisense c-jun. Overexpression of c-Jun also upregulated protein expression of Kvbeta(2) and accelerated I(K(V)) inactivation. Furthermore, E(m) was more depolarized and [(3)H]thymidine incorporation was greater in PASMCs infected with c-jun than in control cells and cells infected with antisense c-jun. CONCLUSIONS: These results suggest that c-Jun-mediated PASMC proliferation is associated with a decrease in I(K(V)). The resultant membrane depolarization increases [Ca(2+)](cyt) and enhances PASMC growth.

Metabolic activation of AMP kinase in vascular smooth muscle.

AMP-activated kinase (AMPK) is a highly conserved heterotrimeric kinase that functions as a metabolic master switch to coordinate cellular enzymes involved in carbohydrate and fat metabolism that regulate ATP conservation and synthesis. AMPK is activated by conditions that increase AMP-to-ATP ratio, such as exercise and metabolic stress. In the present study, we probed whether AMPK was expressed in vascular smooth muscle and would be activated by metabolic stress. Endothelium-denuded porcine carotid artery segments were metabolically challenged with 2-deoxyglucose (10 mM) plus N(2) (N(2)-2DG). These vessels exhibited a rapid increase in AMPK activity by 1 min that was near maximal by 20 min. AMPK inactivation on return to normal physiological saline was approximately 50% in 1 min and fully recovered by 5 min. Immunoprecipitation of the alpha(1)- and alpha(2)-catalytic subunit followed by immunoblot analysis for [P]Thr(172)-AMPK indicates that alpha(1)-AMPK accounts for all activity. Little if any alpha(2)-AMPK was detected in carotid smooth muscle. AMPK activity was not increased by contractile agonist (endothelin-1) or by the reported AMPK activators 5-aminoimidazole-4-carboxamide ribofuranoside (2 mM), metformin (2 mM), or phenformin (0.2 mM). AMPK activation by N(2)-2DG was associated with a rapid and pronounced reduction in endothelin-induced force and reduced phosphorylation of Akt and Erk 1/2. These data demonstrate that AMPK expression differs in vascular smooth muscle compared with striated muscles and that activation and inactivation after metabolic stress occur rapidly and are associated with signaling pathways that may regulate smooth-muscle contraction.

Cardiovascular effects of pulmonary hypertension.

Right ventricular dysfuction is the most significant cardiovascular effect of pulmonary hypertension. A variety of techniques to evaluate right ventricular dysfuction have been examined. but, due to the complex geometry of the right ventricle, the optimal method has yet to be established. Vasodilator therapy has been shown to be beneficial in improving cardiovascular function in some patients. Echocardiography holds promise in evaluating response to therapy nonivasively.

Primary pulmonary hypertension. An analysis of 28 cases and a review of the literature.

The diverse potential etiologies and varying degrees of severity at the time of presentation suggest that primary pulmonary hypertension is a spectrum of disease states, all of which share the hemodynamic and pathologic correlates of pulmonary hypertension without a demonstrable cause. The course is variable, but manifestations of a low cardiac output or right ventricular failure imply a poor prognosis; the median survival is 2 to 3 years from the time of diagnosis. Although several systemic vasodilators have been demonstrated to improve pulmonary hemodynamics and ameliorate symptoms in some cases, these drugs may produce undesirable adverse effects, including death, in unresponsive patients. Additionally, the impact of vasodilator therapy on mortality from PPH has not been assessed. Combined heart-lung transplantation should be considered in patients who are unresponsive to vasodilators and who manifest the indicators of a poor prognosis.

Effects of oral hydralazine on gas exchange in patients with cor pulmonale.

Vasodilators lower total pulmonary vascular resistance in some patients with pulmonary hypertension, but if vasodilators worsen arterial oxygenation in cor pulmonale, as they do in some patients with left ventricular failure, the benefits of a decrease in vascular resistance would be offset by a lack of change or a deterioration in systemic oxygen delivery. Measurement was made of arterial and mixed venous blood gases, minute ventilation, shunt fraction, alveolar-arterial oxygen difference, pulmonary arterial pressures, and cardiac output before and four hours after a single dose of hydralazine, 75 mg orally, in six patients (Group I) and before and after 48 hours of hydralazine, 50 to 75 mg orally, every six hours in 10 patients (Group II). Cardiac output increased 36 percent in Group I and 48 percent in Group II. In both groups total pulmonary vascular resistance decreased (8.0 +/- 2.8 to 6.1 +/- 2.6 units in Group I, p less than 0.01; 9.7 +/- 3.7 to 5.6 +/- 2.1 units in Group II, p less than 0.01). Arterial PO2 increased significantly both in Group I (61 +/- 8 to 67 +/- 10 torr, p less than 0.05) and Group II (50 +/- 13 to 54 +/- 13, p less than 0.05); however shunt fraction and alveolar-arterial oxygen difference were unchanged. The ratio of dead space to tidal volume decreased slightly in both groups, and minute ventilation increased significantly. Systemic oxygen delivery was increased by 39 and 51 percent in Groups I and II, respectively. Thus, gas exchange may be preserved or improved when hydralazine is used in the treatment of cor pulmonale.

Gas exchange during dialysis. Contrasting mechanisms contributing to comparable alterations with acetate and bicarbonate buffers.

Although arterial hypoxemia during hemodialysis is common and may contribute to dialysis morbidity, the mechanisms responsible remain uncertain. Additionally, controversy exists as to whether bicarbonate dialysate produces less hypoxemia than acetate dialysate. The short- and long-term effects of acetate dialysate and bicarbonate dialysate on gas exchange were compared in eight stable patients undergoing dialysis using a closed, proportioning system and a double-blind, crossover study design. Dialysate was sampled immediately proximal and distal to the dialyzer to determine its contribution to total carbon dioxide elimination. Ventilatory parameters and blood gas values were measured before dialysis, at one hour, and after dialysis. Arterial oxygen tension fell significantly and comparably at one hour with both dialysates, whereas the alveolar-arterial oxygen gradient increased only slightly. Despite hypoxemia, minute ventilation decreased by 4 to 18 percent, and arterial carbon dioxide tension was unchanged. Although total carbon dioxide elimination was unchanged in all groups, there was a significant decrease in lung total carbon dioxide elimination with acetate dialysate of 9.23 +/- 2.69 to 7.74 +/- 1.57 mmol per minute on Day 1 (mean +/- SD, p less than 0.025) concomitant with a loss of total carbon dioxide into the bath of 2.04 +/- 0.20 mmol per minute, resulting in a significant reduction in respiratory quotient (0.92 +/- 0.07 to 0.75 +/- 0.05, p less than 0.01). In contrast, there was a gain of total carbon dioxide into the blood of 1.64 +/- 0.45 mmol per minute with bicarbonate dialysate, which resulted in an increased pH at one hour compared with acetate dialysate (7.39 +/- 0.04 versus 7.35 +/- 0.03, p less than 0.05). Hypoxemia persisted after dialysis in all groups and was associated with an increased alveolar-arterial oxygen gradient in three of the four groups. It is concluded that transitory hypoventilation contributes to comparable hypoxemia with both acetate and bicarbonate dialysates by different mechanisms. With acetate dialysate, there is a decrease in carbon dioxide load to the lungs, whereas with bicarbonate dialysate, the mechanism responsible appears to be a suppression of respiratory drive resulting from a gain of bicarbonate from the dialysate. Additionally, neither dialysate prevents post-dialysis hypoxemia, which is associated with an increased alveolar-arterial oxygen gradient resulting from a mechanism that remains to be elucidated.

Continuous intravenous infusion of epoprostenol for the treatment of portopulmonary hypertension.

The association of pulmonary hypertension with portal hypertension, also called portopulmonary hypertension (PPHTN), is a known complication of chronic liver disease. Previously, the presence of PPHTN was considered to be a contraindication to orthotopic liver transplantation (OLT). Although there are selected case reports of successful OLT in the setting of PPHTN, an excessive mortality rate is associated with OLT and PPHTN. Heretofore, therapy for chronic management of PPHTN was lacking. Recently, continuous intravenous infusion of epoprostenol has been demonstrated to improve symptomatology and survival in the general population of patients with primary pulmonary hypertension. We now report the use of epoprostenol in the more specific instance of PPHTN. Over a period of 6-14 months, epoprostenol (10-28 ng/kg/min) therapy was associated with a 29-46% decrease in mean pulmonary artery pressure, a 22-71% decrease in pulmonary vascular resistance, and a 25-75% increase in cardiac output in a group of four patients. These results suggest that effective chronic therapy for PPHTN is available. In conjunction with inhaled nitric oxide as acute intraoperative therapy, epoprostenol infusion represents an additional therapeutic option for treatment of PPHTN in the liver transplant candidate.

Successful use of chronic epoprostenol as a bridge to liver transplantation in severe portopulmonary hypertension.

BACKGROUND: Portopulmonary hypertension, defined as mean pulmonary artery pressure >25 mmHg in the presence of a normal pulmonary capillary wedge pressure and portal hypertension, is a known complication of end-stage liver disease that has been associated with high morbidity and mortality at the time of liver transplantation. We have recently reported the successful treatment of portopulmonary hypertension with chronic intravenous epoprostenol and now report the first patient with severe portopulmonary hypertension successfully treated with epoprostenol who subsequently underwent successful liver transplantation. METHODS: A patient with severe portopulmonary hypertension was treated with intravenous epoprostenol, 23 ng/kg/min, for a 4-month period, after which the portopulmonary hypertension resolved and the patient underwent successful liver transplantation. RESULTS: The patient was discharged, continues to do well, and at 3 months is off epoprostenol with near normal pulmonary artery pressures. CONCLUSIONS: Chronic epoprostenol, in conjunction with a multidisciplinary, well-planned perioperative evaluation and treatment plan, may be the answer to a heretofore untreatable disease.

Portopulmonary hypertension and the liver transplant candidate.

The management of the liver transplant (OLT) candidate with portopulmonary hypertension (PPHTN) has dramatically changed in the past 3 years. Careful preoperative evaluation with functional characterization of right ventricular function plays a critical role. The pulmonary vascular response to epoprostenol infusion serves as a deciding factor for OLT candidacy. Careful perioperative attention to avoid right ventricular failure from acutely elevated pulmonary artery pressures or sudden increases in right ventricular preload is a key physiologic tenet of management. With increased surgical expertise, anesthetic sophistication, and availability of epoprostenol, PPHTN is no longer considered an absolute contraindication for OLT.

Pathology and pathophysiology of primary pulmonary hypertension.

Primary pulmonary hypertension (PPH) is at present little understood. It is characterized by extensive remodeling of the pulmonary vasculature, with consequent deleterious hypertrophic changes in the right ventricle. Median survival is 2.6 years, although this varies with the severity of right heart failure. Although PPH can occur at any age and in either sex, it primarily affects young to middle-aged women. A genetic predisposition appears to be a component of this disease, triggered by presentation of a stimulus (e.g., drugs or HIV infection). Symptomatic presentation includes exertional dyspnea, chest pain, and syncope. At present, therapy consists principally of anticoagulation, calcium antagonists, nitric oxide inhalation, or continuous intravenous prostacyclin.

Hemodynamics at rest and during exercise after oral hydralazine in patients with cor pulmonale.

Oral hydralazine has been shown to be effective in decreasing pulmonary arteriolar resistance and increasing cardiac output in some patients with primary pulmonary hypertension. To determine whether a similar response could be observed in patients with chronic cor pulmonale, the hemodynamic status before and after the oral administration of hydralazine (25 mg, then 50 mg every 6 hours for 48 hours) were evaluated in 12 patients at rest and in 8 during upright exercise. After hydralazine, there was an increase in cardiac output at rest, from 4.3 to 6.3 liters/min (p < 0.001), and reductions in arteriovenous oxygen difference, from 8.1 to 6.1 volume percent (p < 0.001), mean pulmonary arterial pressure, from 52 to 44 mm Hg (p < 0.01), and pulmonary arteriolar resistance, from 11.2 to 6.2 units (p < 0.0005). Similar hemodynamic changes occurred during exercise, including an increase in pulmonary arterial saturation from 27 to 39 percent (p < 0.001) and a decrease in total pulmonary resistance from 12.7 to 8.9 units (p < 0.01). Results of pulmonary function tests performed before and after hydralazine did not change with drug administration. These findings indicate that the lung vascular bed in some patients with cor pulmonale is capable of responding to hydralazine with a reduction in pulmonary resistance and an increase in cardiac output both at rest and during exercise.

Relation between mixed venous oxygen tension and pulmonary vascular tone during normoxic, hyperoxic and hypoxic ventilation in dogs.

To evaluate the relation between the oxygen tension of pulmonary arterial blood (PvO2) and pulmonary vascular resistance (PVR), an extracorporeal circuit was used to vary the PvO2 of blood perfusing the left lung in 3 groups of open-chest dogs mechanically ventilated with an inspired fraction of oxygen of 0.35 (group I), 0.21 (group II), or 0.10 (group III). Left lung pulmonary blood flow, left atrial pressure and perfusate, and systemic pH and PCO2 did not change significantly as PvO2 was varied over a range of 11 to 52 mm Hg in groups I and II. There was no correlation between decreases in PvO2 and the percent change in left lung PVR compared with baseline (PvO2 approximately 40 mm Hg) in group I (r = 0.12, difference not significant). In contrast, there was a significant correlation between decreases in PvO2 and the percent change from baseline in PVR in group II (r = -0.50, p less than 0.02). Left lung alveolar oxygen tension (PAO2) decreased significantly when PvO2 was at its lowest in group II (p less than PAO2 0.05). Both groups I and II had a significant pulmonary vasoconstrictor response to hypoxic ventilation, indicating that vasoreactivity was preserved in this model. The increase in PVR with hypoxia was significantly blunted in dogs perfused with blood that had a high PvO2 (41 +/- 12.4 mm Hg, group IIIa) compared with dogs perfused with blood that had a low PvO2 (25 +/- 6 mm Hg, group IIIb), despite comparable values for PAO2.(ABSTRACT TRUNCATED AT 250 WORDS)

Primary pulmonary hypertension. Practical therapeutic recommendations.

Primary pulmonary hypertension (PPH) is a rare disease of unknown aetiology which typically results in right heart failure and death within several years of the onset of symptoms. While there is no cure for PPH, several pharmacological and surgical approaches to treatment have been developed over the past decade which proved useful in a significant proportion of patients. In particular, vasodilator therapy may produce sustained haemodynamic and symptomatic improvement in up to approximately two-thirds of patients; in the remaining patients, vasodilators may either produce no benefit or result in deterioration. The calcium channel blocking agents are the most widely used oral vasodilators; continuous intravenous infusions of epoprostenol (prostacyclin; prostaglandin I2) have been used in some patients who are refractory to oral therapy, particularly as a bridge to transplantation. While combined heart-lung transplantation has been considered the surgical procedure of choice for severe pulmonary hypertension, single lung transplantation has been performed successfully in a small number of patients, and may be the preferred approach in patients with reasonably preserved right heart function.

Cytosolic Ca2+ concentration and contraction-relaxation properties of ventricular myocytes from Escherichia coli endotoxemic guinea pigs: effect of fluid resuscitation.

Hearts isolated from a guinea pig model of Escherichia coli endotoxemia exhibit decreased systolic contractile function and reduced diastolic compliance of the left ventricle within 4 h after injection of endotoxin. Fluid resuscitation prevented the endotoxin-induced decrease in diastolic compliance without affecting systolic contractile depression. Because intrinsic myocardial dysfunction after endotoxemia may result from alterations in intracellular Ca2+ handling, we tested the hypothesis that in vivo fluid resuscitation improved diastolic function by altering Ca2+ handling of the myocardium. We tested this hypothesis by measuring cell shortening and intracellular Ca2+ of ventricular myocytes isolated from endotoxemic guinea pigs. E. coli endotoxin (LPS, 1 mg/kg)-injected guinea pigs were divided into resuscitated and nonresuscitated groups. Fluid resuscitated animals received a Ringer's infusion (8 mL.kg-1.h-1) intravenously (i.v.) beginning immediately after endotoxin injection. Four hours later, ventricular myocytes were isolated enzymatically and loaded with fura-2/AM. When myocytes were field stimulated at .8 Hz, peak systolic Ca2+ transients of LPS-resuscitated (619 +/- 75 nM) and LPS-nonresuscitated (599 +/- 60 nM) myocytes were not significantly different from each other, but both were significantly less than values from control myocytes (1187 +/- 118 nM, p < .05). The percentage of cell shortening of LPS-resuscitated (6.2 +/- .9%) and LPS-nonresuscitated (6.2 +/- .3%) myocytes were also less than control (11.8 +/- .5%, p < .05). In contrast to improved diastolic compliance of fluid-resuscitated hearts, diastolic [Ca2+]i of myocytes (at .8 Hz) from LPS-resuscitated animals (138 +/- 47 nM) was not statistically different from LPS-nonresuscitated animals (129 +/- 19 nM). Diastolic values of both LPS groups were consistently lower than control value (251 +/- 38 nM, p < .05). These data suggest that improved diastolic compliance of LPS hearts following fluid resuscitation is not associated with improved myocyte contractility or myoplasmic Ca2+ handling.