Search PubMed⌕ Search

Biomedical subjects

D J Stewart

Publications and source records attributed to D J Stewart.

At least 19 recordsLinked to original sources
PubMed1999

Concurrent chemotherapy with hyperfractionated accelerated thoracic irradiation in stage III non-small cell lung cancer.

OBJECTIVES: We evaluated the effect of hyperfractionated accelerated radiotherapy combined with low dose radiosensitisers followed by standard dose chemotherapy in the treatment of unresectable stage III non small cell lung cancer (NSCLC). METHODS: Forty-seven patients received thoracic radiotherapy (1.5 bid x 5 days x 4 weeks) in combination with low dose daily (3-6 mg/m2) cisplatin +/- weekly vinblastine chemotherapy (step I), followed by three cycles of standard dose chemotherapy alone consisting of cisplatin (75-80 mg/m2) and vinblastine (8-16 mg/m2) given at 3-4 week intervals (step II). RESULTS: The overall response rate was 70% (21% CR). The progression free interval and the median survival duration were 10.4 months and 17.3 months, respectively. The 3 year survival rate was 21%. The site of first progression was local in 44%, distant in 41%, and simultaneous in 15% of patients. Levels of esophageal toxicity were significant but acceptable with the use of prophylactic therapy. Grade 3 or 4 esophageal toxicity was observed in 28 and 19% of patients during step I and II of the study, respectively. There were three deaths associated with esophageal toxicity. All occurred prior to the implementation of the prophylactic therapy for esophagitis. Acute pulmonary symptoms were reported in 25% of patients in step I, and pulmonary fibrosis, primarily asymptomatic, was observed in 51% of patients. Hematological toxicity was moderate. Two patients died of neutropenic sepsis/pneumonia. CONCLUSION: Concurrent chemotherapy and hyperfractionated accelerated radiotherapy followed by chemotherapy appears moderately effective in controlling tumour growth as measured by response rates and survival estimates. Toxicity is considerable but manageable and compatible with results from other combined modality studies.

Adult↗
PubMed1999

Obesity is associated with increased myocardial oxidative stress.

OBJECTIVE: To determine: 1) whether obesity predisposes the myocardium to oxidative stress as evidenced by higher tissue levels of myocardial lipid peroxidation, and 2) what cellular mechanisms are responsible for this predisposition. DESIGN: Comparative, descriptive study of the myocardial tissue of lean and obese Fatty Zucker animals. ANIMALS: 12 month old lean (-/fa; n = 6; mean body weight = 590 g) and obese (fa/fa; na = 7; mean body weight= 882 g) male Fatty Zucker rats. MEASUREMENTS: Basal lipid peroxidation (assessed using thiobarbituric reactive acid substances (TBARS) and cumene hydroperoxide equivalents), oxidative and antioxidant enzyme activities (citrate synthase (CS), superoxide dismutase (SOD), glutathione peroxidase (GPX) and catalase (CAT), thiol content, heat shock protein expression (HSP72/73) and TBARS concentrations following an iron-mediated challenge in vitro. RESULTS: Compared to lean, lipid peroxidation was greater (P < 0.05) in the left ventricle (LV) from obese rats as indicated by higher levels of lipid hydroperoxides (mean = 11.48 vs 13.7 cumene hydroperoxide equivalents (CHPE)/mg lipid) and TBARS (mean = 11.1 vs 13.9 nMol/mg lipid.). The activity of the manganese isoform of superoxide dismutase in the LV was higher (P < 0.05) in obese animals, compared to controls (mean = 135 vs 117 U/mg protein). In contrast, LV catalase and glutathione peroxidase activities did not differ (P > 0.05) between groups. Also, LV levels of HSP 72 (inducible) and 73 (constitutive) did not differ (P > 0.05)( between lean and obese animals. Following an iron-stimulated oxidative challenge in vitro, TBARS concentration was significantly greater (P < 0.05) in LV of obese rats compared to the lean (mean = 12.7 vs 16.7 nMol/mg lipid). CONCLUSIONS: These results support the notion that obesity predisposes the myocardium to oxidative stress. However, the postulate that obesity is associated with elevated myocardial antioxidant enzyme activities and HSPs was only partially supported by these findings.

Animals↗
PubMed1999

Topotecan versus cyclophosphamide, doxorubicin, and vincristine for the treatment of recurrent small-cell lung cancer.

PURPOSE: Topotecan and cyclophosphamide, doxorubicin, and vincristine (CAV) were evaluated in a randomized, multicenter study of patients with small-cell lung cancer (SCLC) who had relapsed at least 60 days after completion of first-line therapy. PATIENTS AND METHODS: Patients received either topotecan (1.5 mg/m2) as a 30-minute infusion daily for 5 days every 21 days (n = 107) or CAV (cyclophosphamide 1,000 mg/m2, doxorubicin 45 mg/m2, and vincristine 2 mg) infused on day 1 every 21 days (n = 104). Eligibility included the following: bidimensionally measurable disease, Eastern Cooperative Oncology Group performance status of less than or equal to 2, and adequate marrow, liver, and renal function. Response was confirmed by blinded independent radiologic review. RESULTS: Response rate was 26 of 107 patients (24.3%) treated with topotecan and 19 of 104 patients (18.3%) treated with CAV (P = .285). Median times to progression were 13.3 weeks (topotecan) and 12.3 weeks (CAV) (P = .552). Median survival was 25.0 weeks for topotecan and 24.7 weeks for CAV (P = .795). The proportion of patients who experienced symptom improvement was greater in the topotecan group than in the CAV group for four of eight symptoms evaluated, including dyspnea, anorexia, hoarseness, and fatigue, as well as interference with daily activity (P< or =.043). Grade 4 neutropenia occurred in 37.8% of topotecan courses versus 51.4% of CAV courses (P<.001). Grade 4 thrombocytopenia and grade 3/4 anemia occurred more frequently with topotecan, occurring in 9.8% and 17.7% of topotecan courses versus 1.4% and 7.2% of CAV courses, respectively (P<.001 for both). Nonhematologic toxicities were generally grade 1 to 2 for both regimens. CONCLUSION: Topotecan was at least as effective as CAV in the treatment of patients with recurrent SCLC and resulted in improved control of several symptoms.

Antineoplastic Agents↗
PubMed1999

Human endothelin-1 clearance kinetics revealed by a radiotracer technique.

Levels of endothelin-1 (ET-1) are elevated in many disease states, although its total body kinetics of elimination are poorly understood. Therefore, it remains uncertain whether the presence of elevated levels of ET-1 in the setting of disease are secondary to changes in production or clearance or some combination thereof. Using a 125I-labeled ET-1 infusion technique, the volume of distribution and kinetics of clearance of endothelin were described in five normal volunteers. Heart rate, blood pressure, right atrial pressure, and arterial blood samples for the counting of 125I and the measurement of ET-1 were obtained at multiple time points before and up to 45 h after the start of the infusion. The radiotracer infusion had no effect on heart rate, blood pressure, right atrial pressure, or endogenous ET-1 levels. ET-1 clearance was best described by a three-compartment model, which revealed that ET-1 has a much longer terminal half-life and volume of distribution than was previously reported. This suggests extensive uptake of ET-1 in various organ systems and slow clearance. These new findings have important implications for the understanding of the pathophysiology of ET-1 in disease states as well as for the understanding and development of ET-1 receptor blockers and endothelin-converting enzyme inhibitors.

Adult↗
PubMed1998

Endothelin A receptor blockade causes adverse left ventricular remodeling but improves pulmonary artery pressure after infarction in the rat.

BACKGROUND: Endothelin A (ETA) receptor antagonists have been shown to improve ventricular remodeling and survival in rats when started 10 days after infarction. Whether starting them earlier would have a more or less beneficial effect is uncertain. METHODS AND RESULTS: Rats surviving an acute myocardial infarction (MI) for 24 hours (n=403) were assigned to saline or the ETA receptor antagonist LU 127043 or its active enantiomer LU 135252 for 4 weeks. Chronic LU treatment had no effect on survival, with 46% of LU rats and 47% of saline-treated rats with large MI surviving to the end of the study. LU treatment led to scar thinning, further left ventricular (LV) dilatation, an increase in LV end-diastolic pressure, and an increase in wet lung weight (P<0.05). Despite this detrimental effect on LV function, LU led to a significant decrease in RV systolic (50+/-2 to 44+/-2 mm Hg, P<0.05 vs saline) and right atrial pressures. LU treatment also prevented the increase in pulmonary ET-1 found in saline-treated rats with large MI but did not modify the increase in cardiac ET-1 in hearts with large MI. CONCLUSIONS: The early use of the ETA receptor antagonists LU 127043 or its active enantiomer LU 135252 after infarction in the rat leads to impaired scar healing and LV dilatation and dysfunction. This is accompanied by a decrease in RV systolic and right atrial pressures and a decrease in pulmonary but not cardiac ET-1 levels. It would thus appear that the early use of ETA receptor antagonists after infarction may be detrimental.

Animals↗
PubMed1998

EndothelinA receptor blockade improves nitric oxide-mediated vasodilation in monocrotaline-induced pulmonary hypertension.

BACKGROUND: Nitric oxide (NO) and endothelin (ET) have been implicated in the pathogenesis of pulmonary hypertension (PH). Chronic ETA antagonist therapy reduces PH in monocrotaline (MCT)-treated rats. Interactions between the L-arginine-NO pathway and the ET system have been described. We therefore studied the effect of long-term treatment with an oral ETA antagonist (LU 135252) on NO-related vasodilation in isolated lungs from control rats and rats with MCT-induced PH. METHODS AND RESULTS: Three weeks after MCT injection, PH was associated with an increase in right ventricular pressure (from 27.4 +/- 0.9 to 66.6 +/- 4.1 mm Hg) and a decrease in endothelium-independent vasodilation in response to sodium nitroprusside (10(-10) to 10(-5) mol/L; delta Emax, from 11.1 +/- 0.9 to 2.7 +/- 0.3 mm Hg). Endothelium-dependent vasodilation in response to acetylcholine (10(-9) to 10(-4) mol/L) and the calcium ionophore A23187 (10(-9) to 10(-7) mol/L) remained unaffected. Treatment with LU 135252 did not significantly affect the endothelium-dependent and -independent vasodilations in control rats. However, in MCT-treated rats, LU 135252 therapy significantly reduced right ventricular pressure (39.7 +/- 2.1 mm Hg), potentiated acetylcholine-induced vasodilatation (delta Emax, from 1.6 +/- 0.2 to 3.7 +/- 0.4 mm Hg), and improved the responses to sodium nitroprusside (delta Emax, from 2.7 +/- 0.3 to 5.6 +/- 0.6 mm Hg). LU 135252 did not significantly alter the non-receptor-mediated endothelium-dependent vasodilation to A23187 or pulmonary constitutive NO synthase activity. CONCLUSIONS: MCT PH is associated with a reduced smooth muscle responsiveness to NO but a maintained endothelium-dependent vasodilatory potency. Long-term ETA antagonist therapy not only restores smooth muscle responsiveness to NO but also increases endothelium-dependent dilation in response to acetylcholine. This mechanism may contribute to the therapeutic benefit of ETA antagonists in PH.

Animals↗
PubMed1998

Role of nitric oxide in the angiogenic response in vitro to basic fibroblast growth factor.

Angiogenesis is a complex process that involves the activation of quiescent endothelial cells (ECs) to a proliferative and migratory phenotype and, subsequently, their redifferentiation to form vascular tubes. We hypothesized that NO contributes to angiogenesis by terminating the proliferative action of angiogenic growth factors and initiating a genetic program of EC differentiation. Human umbilical vein ECs (HUVECs) and calf pulmonary artery ECs (CPAECs) were grown directly on plastic dishes or on three-dimensional fibrin matrices. In the absence of fibrin, treatment with NO-donor compounds, such as S-nitroso-N-acetylpenicillamine (SNAP, 0.1 and 0.4 mmol/L), produced a dose-dependent inhibition of proliferation in both cell lines, whereas the inhibition of endogenous NO production using NG-nitro-L-arginine methyl ester (L-NAME, 1 mmol/L) or NG-monomethyl-L-arginine (L-NMMA, 1 mmol/L) significantly increased proliferation of the CPAECs. The addition of basic fibroblast growth factor (bFGF, 30 ng/mL) increased the expression of endothelial NO synthase mRNA and the production of NO in both cell types when cultured on three-dimensional fibrin gels and produced profound morphological changes characterized by the appearance of extensive capillary-like vascular structures and the loss of EC monolayers. These changes were quantified by measuring total tube length per low-power field (x100), and a differentiation index was derived using the ratio of tube length over area covered by residual EC monolayer. In the absence of additional angiogenic factors, the differentiation index was low for both HUVECs and CPAECs (control, 1.16+/-0.19 and 2.07+/-0.87, respectively). Treatment with bFGF increased the differentiation index significantly in both cell types (10.59+/-2.03 and 20.02+/-5.01 for HUVECs and CPAECs, respectively; P<.05 versus control), and the addition of SNAP (0.4 mmol/L) mimicked the angiogenic response to bFGF (8.57+/-1.34 and 12.20+/-3.49 for HUVECs and CPAECs, respectively; P<.05 versus control). Moreover, L-NAME inhibited EC tube formation in response to bFGF in a dose-response manner, consistent with a role of endogenous NO production in EC differentiation in this angiogenic model. These findings suggest that NO may act as a crucial signal in the angiogenic response to bFGF, terminating the proliferative actions of angiogenic growth factors and promoting EC differentiation into vascular tubes.

Animals↗
PubMed1998

Reduced pulmonary clearance of endothelin-1 in pulmonary hypertension.

OBJECTIVE: Pulmonary hypertension (PHT) is associated with increased endothelin-1 (ET-1) levels that correlate with the severity of the disease. The pulmonary circulation is an important site for ET-1 metabolism and may modulate plasma ET-1 through an increase in production, a reduction in removal, or a combination of both. We measured and compared pulmonary metabolism of circulating ET-1 in controls and in patients with PHT. METHODS AND RESULTS: The indicator-dilution technique was combined with measurements of ET-1 levels to quantify pulmonary metabolism of ET-1 in controls (n = 13) and in patients with PHT (n = 17). ET-1 levels doubled in PHT (p < 0.05) and, although there was no difference between aortic and pulmonary artery levels in controls (0.68+/-0.09 and 0.61+/-0.08 pg/ml, respectively, p = 0.22), they tended to be higher in PHT (1.23+/-0.26 vs 1.07+/-0.19 pg/ml, p = 0.08). Pulmonary extraction of tracer iodine-125-ET-1 was reduced from 47%+/-2.0% in the controls to 34%+/-3.6% in PHT (p = 0.005) and inversely correlated with the severity of pulmonary hypertension (r = -0.524, p = 0.03). Consequently, circulating ET-1 clearance was reduced by PHT from 1424+/-77 ml/min to 892+/-119 ml/min (p < 0.001). Pulmonary production of circulating ET-1 (in picograms per minute) was not different but the quantity of ET-1 that survives passage through the lungs was increased by PHT (1860+/-359 pg/min vs 992+/-152 pg/min, p = 0.037). CONCLUSION: PHT is associated with a reduced pulmonary clearance of ET-1 that contributes to the increase in circulating levels.

Aorta, Thoracic↗
PubMed1998

Beneficial effects of long-term selective endothelin type A receptor blockade in canine experimental heart failure.

OBJECTIVES: We examined the effects of chronic type A endothelin receptor (ETA) blockade in a dog model of pacing-induced cardiomyopathy. METHODS: Eight dogs received an ETA antagonist, LU 135252 (50 mg/kg orally daily) and nine dogs received a matching placebo starting at day three of pacing and continued for the remainder of the three weeks of pacing. RESULTS: In the placebo group, the mean pulmonary artery pressure and left ventricular end diastolic pressure increased from 16 +/- 3 and 8 +/- 2 mmHg, respectively, at baseline to 40 +/- 11 and 34 +/- 7 mmHg, respectively, at two weeks (both p < 0.001 versus baseline). Cardiac output declined from 3.5 +/- 0.7 to 1.9 +/- 0.6 l/min (p < 0.001). In the treatment group, LU 135252 attenuated the increase in mean pulmonary artery and left ventricular end diastolic pressure (16 +/- 3 and 9 +/- 1 mmHg at baseline to 29 +/- 3 and 27 +/- 3 mmHg, respectively, at two weeks (p < 0.001), and the decline in cardiac output (3.2 +/- 0.3 to 2.6 +/- 0.8 l/min, p < 0.01; p < 0.05 versus placebo for the three parameters). Systemic and pulmonary vascular resistance increased only in the placebo group. Left ventricular end-diastolic volume increased to a similar degree. However, LU 135252 attenuated the increase in plasma norepinephrine level (placebo, 1.2 +/- 0.5 to 3.7 +/- 1.9 pmol/l; treatment, 0.8 +/- 0.3 to 2.4 +/- 0.6 pmol/l; both p < 0.001 versus baseline; p < 0.05 versus placebo). CONCLUSION: Our results suggest that endothelin-1 plays a role in the hemodynamic perturbations in canine pacing-induced cardiomyopathy. The favourable hemodynamic effects without concomitant aggravation of neurohormonal activation suggests that ETA receptor blockade may be beneficial in the treatment of heart failure.

Administration, Oral↗
PubMed1998

A phase I study of gemcitabine/cisplatin/etoposide in the treatment of small-cell lung cancer.

PURPOSE: To define the maximum tolerated dose and toxicity of combined cisplatin, etoposide, and gemcitabine in patients with small-cell lung cancer. METHODS: We undertook a phase I study in patients with either extensive small-cell lung cancer with or without prior chemotherapy, or limited disease who had progressed or recurred despite prior treatment. Patients received cisplatin 75 mg/m2 i.v. day 1, etoposide 50-100 mg/m2 i.v. day 1 followed by oral administration of 50-100 mg/m2 days 2 5, and gemcitabine at either 800 or 1000 mg/m2 i.v. days 1 and 8, on a 3 weekly cycle. RESULTS: We treated 20 patients, 14 at the 800 mg/m2 gemcitabine dose level, and six at the 1000 mg/m2 dose level. The protocol initially used an etoposide dose of 100 mg/m2 etoposide daily (i.v. day 1 and orally days 2-5), but the first two patients died of septic complications. With reduction of the etoposide dose to 50 mg/m2 daily x 5, the regimen was well tolerated. At this etoposide dose, neutropenia, mucositis, and gastrointestinal toxicity occurred in one patient at each of the two gemcitabine dose levels. In addition, one patient receiving gemcitabine at the 1000 mg/m2 level experienced a possible allergic reaction. The overall response rate was 54%. Patients on gemcitabine at the 800 mg/m2 level who had not received prior chemotherapy had the highest response rate, at 75%. CONCLUSION: The recommended phase II doses for this regimen are cisplatin 75 mg/m2 i.v. day 1, etoposide 50 mg/m2 i.v. day 1 and orally days 2-5, and gemcitabine 800 mg/m2 i.v. days 1 and 8. Future trials should further examine the optimal relative doses and schedule of gemcitabine and etoposide.

Adult↗
PubMed1998

A rapid reversed phase high performance liquid chromatographic method for the determination of docetaxel (Taxotere) in human plasma using a column switching technique.

A rapid, simple and sensitive isocratic high performance liquid chromatography (HPLC) method was developed to measure the concentration of docetaxel in plasma samples with UV detection at 227 nm. The method uses a column switching technique with an Ultrasphere C18 column (75 x 4.6 mm ID, 3 mu, Altex, USA) as clean-up column and a CSC-nucleosil C8 column (150 x 4.6 mm ID, 5 mu, CSC, Montreal, Canada) as the analytical column. The mobile phase consisted of Phosphate buffer (30 mM, pH = 3)-acetonitrile (47:53, v/v) with the flow rates of 1.1 and 1.3 ml min-1 for clean-up and analytical columns, respectively. Paclitaxel was used as an internal standard. The plasma samples were extracted using a solid phase extraction method with Ammonium acetate (30 mM, pH = 5)-acetonitrile (50:50, v/v) as final eluent. The extraction method showed a recovery of 92% for docetaxel. In this system, the retention times of docetaxel and Paclitaxel were 7.2 and 8.5 min, respectively. The detection limit of docetaxel in plasma is 2.5 ng ml-1. This analytical method has a very good reproducibility (7.2% between-day variability at a concentration of 10 ng ml-1). It is applicable in clinical and pharmacokinetic studies.

Antineoplastic Agents, Phytogenic↗
PubMed1998

Design, synthesis, and application of a protein A mimetic.

Low-molecular-weight synthetic molecules that mimic the activity of native biological macromolecules have therapeutic potential, utility in large-scale production of biopharmaceuticals, and the capacity to act as probes to study molecular recognition events. We have developed a nonpeptidyl mimic for Staphylococcus aureus Protein A (SpA). The specific recognition and complexation elements between the B domain (Fb) of SpA and the Fc fragment of IgG were identified from the x-ray crystallographic structure. Computer-aided molecular modeling was used to design a series of biomimetic molecules around the Phe132-Tyr133 dipeptide involved in its binding to IgG. One of the ligands binds IgG competitively with SpA in solution and when immobilized on agarose beads, with an affinity constant of 10(5)-10(6) M-1. The immobilized artificial Protein A was used to purify IgG from human plasma and murine IgG from ascites fluid, and to remove bovine IgG from fetal calf serum.

Animals↗
PubMed1998

Regulation of endothelin-B receptor mRNA expression in human endothelial cells by cytokines and growth factors.

The regulation of endothelin-B receptor (ETB) mRNA expression in human endothelial cells (ECs) by cytokines and growth factors may play an important role in the response of the endothelium to inflammatory and angiogenic stimuli. Using quantitative RT-PCR, we studied ETB expression in human umbilical vein ECs (HUVECs) grown in culture on either plastic or fibrin matrix for 24 h in the presence or absence of tumor necrosis factor-alpha (TNF-alpha, 100 U/ml) or basic fibroblast growth factor (bFGF, 30 ng/ml). In addition, the effect of the nitric oxide (NO) donor S-nitrosyl-acetylpenicillamine (SNAP, 0.4 mM) was examined directly on ETB expression or on the response to bFGF. Under control conditions, ETB mRNA was detected after 35 cycles of amplification as a band of the expected size (553 bp). In the absence of fibrin matrix, ETB was downregulated by bFGF and TNF-alpha and could barely be detected by PCR. Southern analysis of the RT-PCR products after 25 cycles revealed that bFGF reduced ETB mRNA expression by 2.7 +/- 0.4-fold (p < 0.01) and TNF-alpha tended to reduce its expression by 1.8 +/- 0.9-fold of control, although this did not reach statistical significance (p < 0.20). In contrast, on fibrin matrix both bFGF and TNF-alpha increased ETB mRNA expression by 25 +/- 9-fold (p < 0.05) and 68 +/- 19-fold (p < 0.05) of control, respectively, suggesting a role for ETB in the vascular tube formation that occurs under these conditions. Pharmacologic addition of NO mimicked the effect of fibrin, converting the response to bFGF from down- to upregulation of ETB, raising the possibility that NO acts as a molecular switch modulating the response to angiogenic factors.

Blotting, Northern↗
PubMed1998

Coordinated upregulation of the cardiac endothelin system in a rat model of heart failure.

The potent vascular, cardiac, and renal actions of endothelin-1 (ET-1) suggest a role for this vasoconstrictor peptide in the pathophysiology of heart failure (HF). Recent studies have shown increased levels of ET-1 peptide accompanied by increased ETB receptor binding in the left ventricle during experimental HF. However, much less is known about the regulation of mRNA expression of these genes in HF. We compared the levels of mRNA expression for ET-1 and ET receptors (ETA and ETB) in the left ventricle of rats with HF induced by coronary artery ligation (n = 6) vs. sham-operated animals (n = 6). Levels of mRNA for ET-1 were determined by ribonuclease protection assay (RPA) using beta-actin as the internal control, whereas ET receptors were quantified by quantitative-competitive RT-PCR. Compared with sham animals, ET-1, ETA, and ETB receptor mRNA levels were markedly upregulated in the left ventricle by 6.6 +/- 1.8-fold (p < 0.01), 3.2 +/- 0.6-fold (p < 0.05), and 3.5 +/- 1.0-fold (p < 0.05), respectively. ET-1 mRNA levels were measured in two additional groups of rats (HF and sham; n = 6 each) treated for 4 weeks with the selective ETA receptor antagonist LU135252. This treatment had no significant effect on ET-1 mRNA expression in sham animals but reduced the upregulation of ET-1 expression in the HF group by 41 +/- 19% (p < 0.05). This study confirms the potential importance of ET-1 in HF and suggests that increased expression of ET-1 and ET receptors in the failing ventricle may contribute to alteration in basal cardiac contractility and myocardial remodeling.

Animals↗
PubMed1998

Chronic endothelin-1 blockade preserves myocardial contractility in dilated cardiomyopathy.

Endothelin-1 (ET-1) is known to have positive inotropic effects in isolated cardiac muscle strips. ET-1 levels are elevated in congestive heart failure (CHF). We investigated the effects of ET-1 on contractility and cardiac relaxation (lusitropy) of the intact healthy murine heart and myocarditic/cardiomyopathic heart by chronic oral treatment with a mixed ETA/ETB blocker SB217242. Chronic ET-1 blockade of normal hearts resulted in depression of contractility and lusitropy of the normal heart but preservation and enhancement of contractility and lusitropy in myocarditic animals, in which ET-1 cardiac content is elevated. This suggests that ET-1 is important in the basal contractility and relaxation of the normal heart but that its chronic elevation in CHF causes impairment of cardiac systolic and diastolic performance.

Animals↗
PubMed1998

Expression of endothelial factors after arterial injury in the rat.

Endothelin-1 (ET-1) and nitric oxide (NO) are potent vasoactive factors known to play a role in vascular remodeling. This study assessed the temporal expression of endothelial NO synthase (eNOS), preproET-1, and ETA and ETB receptor mRNAs in the rat carotid artery after balloon injury using quantitative competitive reverse transcription-polymerase chain reaction (qcRT-PCR) and the ribonuclease protection assay (RPA). Levels of ET-1 increased sharply after arterial injury, peaking (5.1-fold) at 2 days. This was associated with a dramatic increase in the expression of ETB (63-fold) and ETA (158-fold) receptor mRNA, peaking at days 1 and 2, respectively. Expression of eNOS was not detectable immediately after balloon injury, consistent with complete denudation, but reappeared after day 2 and increased to preinjury levels by day 14. The recovery of eNOS expression mirrored the return of ET-1 and ET receptor expression to baseline levels. The results confirm profound upregulation of the ET system in this model of arterial injury and suggest a critical role for eNOS expression and re-endothelialization in the normalization of ET-1 and ET receptor expression during the recovery phase, events that may be important in long-term arterial patency.

Animals↗