Biomedical subjects

S Roux

Publications and source records attributed to S Roux.

At least 55 records · Page 3Linked to original sources

PubMed2000

A new model of chronic cardiac ischemia in rabbits.

Chronic cardiac ischemia has mainly been studied in large species such as pigs or dogs. Little research has been performed using small species such as rabbits. In the present study, 1-3 wk after implantation of a novel device (ameroid) on the circumflex coronary artery of New Zealand White rabbits, vessel patency was evaluated by coronary angiography, corrosion cast, and radiolabeled microspheres. Coronary angiograms showed, after 21 days, either total occlusion or severe stenosis in seven of eight arteries, which was confirmed by corrosion casts. The ameroid group had less blood flow in the epicardial (-62%) and endocardial (-54%) layers of the ischemic area compared with sham-operated rabbits (P < 0.05). Blood flow increased in the ischemic area compared with day 0 during acute occlusion, suggesting that progressive coronary occlusion initiated the growth of de novo collateral vessels. Thus we have developed a new model of chronic cardiac ischemia in rabbits with documented progressive coronary stenosis and occlusion that is suitable to test various therapeutic angiogenesis strategies.

Animals↗

PubMed2000

The family history of patients with primary or secondary antiphospholipid syndrome (APS).

OBJECTIVE: To evaluate familial history for evidence of antiphospholipid syndrome (APS) and autoimmune disease in rheumatology department patients with primary or secondary APS. METHODS: We retrospectively studied patients with APS and systemic lupus erythematosus (SLE) managed at the Rheumatology Department of the Bichat University Hospital, Paris, between 1987 and 1996. Data were collected by chart review and by a 1997 standardized telephone interview. RESULTS: We identified 108 patients with APS managed during the ten-year study period. According to classical classification criteria, 39 patients had primary antiphospholipid syndrome (PAPS) and 69 secondary antiphospholipid syndrome (SAPS). Family history data were obtained for 29 (74%) and 55 (80%) PAPS and SAPS patients. respectively (78% of the 108 patients). Twelve PAPS (41% and 19 SAPS (35%) patients had one or more relatives with evidence of at least one clinical feature of APS such as thrombosis or recurrent fetal loss; of these patients, seven in the PAPS (24%) and 11 in the SAPS (20%) group had two or more relatives with evidence of a clinical feature of APS. Three PAPS (10%) and 14 SAPS (25%) patients had one or more family members with an autoimmune disease. CONCLUSION: A positive family history for autoimmune disease and/or antiphospholipid syndrome is common in patients with PAPS or SAPS. This finding supports a genetic contribution to APS. The percentage of a positive family history for autoimmune disease tend to be higher in patients with SAPS than in those with PAPS.

Abortion, Habitual↗

PubMed2000

Private practice interdisciplinary breast centers: their rationale and impact on patients, physicians, and the health care industry: a bicoastal perspective.

This article reports on the experience of two private practice breast centers in New York and California. It demonstrates that comprehensive breast centers directed by full-time breast imagers have a significant impact on medical care from the perspective of the patient, her physicians, and the health care system. These two centers, separated by a continent, disparate in their formation and founding philosophies, yield very similar results in breast cancer diagnosis, reduction of the benign biopsies, and improving the cost of breast biopsies.

Biopsy↗

PubMed2000

[The pharmacology of endothelin and its antagonist bosentan].

Endothelin is one of the most potent vasoconstrictors known, but it also plays a role in inflammation, fibrosis and cellular hypertrophy. Endothelin is a key pathogenic factor in congestive heart failure, essential hypertension and pulmonary hypertension. Bosentan is a specific mixed antagonist of endothelin receptors. Preclinical and clinical data suggest that bosentan might become a new approach for the chronic treatment of these cadiovascular and pulmonary diseases.

Animals↗

PubMed2000

IgG anti-beta2-glycoprotein I antibodies in adult patients with systemic lupus erythematosus: prevalence and diagnostic value for the antiphospholipid syndrome.

OBJECTIVE: To investigate the prevalence of serum anti-beta2-glycoprotein I (anti-beta2-GPI) antibodies and other antiphospholipid antibodies (aPL) in patients with systemic lupus erythematosus (SLE). To study their diagnostic value for the antiphospholipid syndrome (APS). METHODS: Anti-beta2-GPI and IgG anticardiolipin (aCL) were determined in sera from 102 consecutive patients with SLE using ELISA. Serum and plasma tests were also done for lupus anticoagulant (LAC), syphilis, and antibodies to dsDNA. Clinical and laboratory features of APS were observed. RESULTS: Prevalences were 23.5% for aCL and 18.6% for anti-beta2-GPI. Correlations between the presence of aCL and anti-beta2-GPI and between their titers were statistically significant (p<0.0001). No associations were found between anti-beta2-GPI and disease activity criteria (SLEDAI, ECLAM, dsDNA). Anti-beta2-GPI were significantly associated with LAC (p = 0.005), APS (p = 0.005), and a high aCL titer (aCL > 5 SD; p< or =0.001). LAC was the best diagnostic criterion for APS. CONCLUSION: These data suggest that determination of anti-beta2-GPI in addition to aCL and LAC is unlikely to improve the diagnosis of APS in patients with SLE.

Adolescent↗

PubMed2000

Hematological malignancies and the bone (myeloma excluded).

Bone involvement is a rare event in lymphomas, except in patients with adult T-cell leukemia/lymphoma associated with HTLVI. It is usually characterised by lytic bone lesions located in the metaphysis of long bones or in the axial skeleton. The occurrence of bone lesions reflects a progression of the disease affecting the prognosis that is related to lymphoma histologic features and staging. Bone lesions may occur in some lymphoproliferative disorders such as LLC or Waldenstrom's disease, or in myeloproliferative disorders. They may reflect a progression to a more aggressive disorder with a worse prognosis. The treatment of hematologic malignancies presenting with bone lesions and/or hypercalcemia is similar to the treatment of the systemic disease. In primary lymphomas of bone presenting with an isolated bone lesion, local treatment with radiation therapy and/or surgical ablation is required, and adjuvant chemotherapy may improve the prognosis of these located lymphomas. Glucocorticoid therapy and bisphosphonates are effective in treating associated hypercalcemia. Except for myeloma and ATL, the underlying mechanisms responsible for bone involvement in hematologic malignancies remain poorly understood. The unusual occurrence of bone lesions in these diseases probably implies distinct pathogenic mechanisms, but one can speculate that an increased expression of RANK/RANKL, the common final pathway in bone resorption, may be involved.

Bone Neoplasms↗

PubMed2000

Anxiolytic-like effects of the prototypical metabotropic glutamate receptor 5 antagonist 2-methyl-6-(phenylethynyl)pyridine in rodents.

Recently, selective and systemically active antagonists for the metabotropic glutamate 5 receptor (mGlu(5)) were discovered, and the most potent derivative was found to be MPEP (2-methyl-6-(phenylethynyl)pyridine). Given the high expression of mGlu(5) receptors in limbic forebrain regions, it was decided to evaluate the anxiolytic potential of MPEP. After an acute oral administration, MPEP attenuated the anxiety-dependent variable in a variety of well established anxiety test paradigms. In rats, MPEP (10, 30, and 100 mg/kg) increased punished responses in the Geller-Seifter test, but none of these effects reached statistical significance. MPEP significantly increased the ratio (open/total arm entries; 0.1, 1, and 10 mg/kg), the number of open arm entries (0.1, 1, and 10 mg/kg), as well as time spent on open arm (0.1 and 1 mg/kg) in the elevated plus maze test. Furthermore, MPEP (0.3 and 1 mg/kg) significantly increased the time spent in social contact in the social exploration test. In mice, MPEP attenuated stress-induced hyperthermia (15 and 30 mg/kg) and decreased the number of buried marbles in the marble burying test (7.5 and 30 mg/kg). Finally, MPEP (0.01, 0.1, 1, 10, and 100 mg/kg) was tested on spontaneous locomotor activity in mice, and only a dose of 100 mg/kg significantly reduced vertical activity; no effect was seen on horizontal activity. MPEP (7.5, 15, and 30 mg/kg) was ineffective on d-amphetamine-induced (2.5 mg/kg) locomotor activity in mice and prepulse inhibition in rats (1, 3, or 10 mg/kg). Thus, these findings indicate that MPEP exhibits anxiolytic-like effects and low risks for sedation and psychotomimetic side-effects in rodents.

Animals↗

PubMed1999

Conformational change in the human glucocorticoid receptor induced by ligand binding is altered by mutation of isoleucine 747 by a threonine.

Limited proteolysis experiments were performed to study conformation changes induced by ligand binding on in vitro produced wild-type and I747T mutant glucocorticoid receptors. Dexamethasone-induced conformational changes were characterized by two resistant proteolysis fragments of 30 and 27 kDa. Although dexamethasone binding affinity was only slightly altered by the I747T substitution (Roux, S., Térouanne, B., Balaguer, P., Loffreda-Jausons, N., Pons, M., Chambon, P., Gronemeyer, H., and Nicolas, J.-C. (1996) Mol. Endocrinol. 10, 1214-1226), higher dexamethasone concentrations were required to obtain the same proteolysis pattern. This difference was less marked when proteolysis experiments were conducted at 0 degrees C, indicating that a step of the conformational change after ligand binding was affected by the mutation. In contrast, RU486 binding to the wild-type receptor induced a different conformational change that was not affected by the mutation. Analysis of proteolysis fragments obtained in the presence of dexamethasone or RU486 indicated that the RU486-induced conformational change affected the C-terminal part of the ligand binding domain differently. These data suggest that the ligand-induced conformational change occurs via a multistep process. In the first step, characterized by compaction of the ligand binding domain, the mutation has no effect. The second step, which stabilizes the activated conformation and does not occur at 4 degrees C, seems to be a key element in the activation process that can be altered by the mutation. This step could involve modification of the helix H12 position, explaining why the conformation induced by RU486 is not affected by the mutation.

Amino Acid Substitution↗

PubMed1999

Endothelin antagonism with bosentan: a review of potential applications.

Endothelin receptor antagonists have been proposed for the treatment of a variety of disorders in which the endothelins may act as pathogenic mediators, such as congestive heart failure, systemic and pulmonary hypertension, and cerebral vasospasm. Bosentan (Ro 47-0203) is a nonpeptide competitive antagonist, which can be a good tool for studying the endothelin system because it may be administered either acutely or chronically. It is specific for the endothelin system and blocks the actions of endothelin at both mammalian receptors (A and B). In experimental models of heart failure bosentan acts as a vasodilator and neurohormonal blocker that improves overall left ventricular performance and reduces renal dysfunction. Furthermore, in chronic studies, bosentan attenuates cardiac remodeling and significantly improves survival. In patients with chronic heart failure bosentan produces pulmonary and systemic vasodilation and may enhance conventional treatment with angiotensin-converting enzyme inhibitors. Long-term studies are being conducted to characterize the full therapeutic potential of bosentan in chronic heart failure. In experimental models bosentan reverses established pulmonary hypertension. Preclinical efficacy has also been demonstrated in essential hypertension, where bosentan can reduce blood pressure and end-organ damage. Clinical trials in hypertensive patients indicate that bosentan reduces blood pressure without heart rate increase or neurohumoral stimulation. Finally, bosentan is being considered for the treatment of cerebral vasospasm following subarachnoid hemorrhage. Bosentan reverses experimentally induced vasospasm of the basilar artery, and preliminary trials indicate that it can increase cerebral blood flow after aneurysmal subarachnoid hemorrhage.

Animals↗

PubMed1999

SAPHO syndrome: a long-term follow-up study of 120 cases.

OBJECTIVE: To assess the long-term outcome of the synovitis, acne, pustulosis, hyperostosis, osteitis (SAPHO) syndrome. METHODS: All patients with the SAPHO syndrome seen at our unit between 1974 and 1997 were identified. Follow-up was prospective from 1992 to 1997. Data before 1992 were analyzed retrospectively. Clinical symptoms, treatments and biological data, including erythrocyte sedimentation rate and C-reactive protein, were recorded at least yearly. When available, radiological data, HLA B27 status, and findings from bone or skin biopsy specimens were recorded. For each drug, an efficacy index (El) was determined as follows: "0" for less than 30% improvement, as judged by the patient, on horizontal visual analog scale, "0.5" for partial efficacy, and "1" for more than 60% improvement. RESULTS: We identified 120 patients with the SAPHO syndrome (50 men, 70 women), of whom 102 patients were followed-up prospectively after 1992; 3 of these 102 patients were lost to follow-up. Six patients also had Crohn's disease, and three had ulcerative colitis. Except for a significant association of palmoplantar pustulosis (PPP) or psoriasis vulgaris (PV) with axial osteitis (P = .007), the dermatologic presentation had no significant influence on rheumatic symptoms (ie, osteitis or arthritis, peripheral or axial). The HLA B27 antigen was not significantly associated with a particular pattern of distribution of arthritis or osteitis. No severe or disabling complications were noted. In the 47 patients followed-up for more than 5 years (mean, 9.5; range, 5 to 23), the mean number of osteitis or arthritis foci increased during follow-up from 1.57 to 1.91 and from 2.68 to 3.11, respectively. Nonsteroidal antiinflammatory drugs (NSAIDs) were prescribed in 113 of 120 (94%) patients, with a mean El of 0.67 (+/-0.39). Corticosteroid (CS) therapy was used in 23 patients, with a mean El of 0.67 (+/-0.42). Colchicine and sulfasalazine had a mean El of 0.36 (+/-0.44) and 0.16 (+/-0.30), in 28 and 18 patients, respectively. Methotrexate was given to 10 patients (6 with peripheral arthritis), with a mean El of 0.64 (+/-0.48). Doxycyclin (100 mg twice daily) was used in 20 patients, usually to treat osteitis, with a mean El of 0.26 (+/-0.42). Intraarticular injections of a CS or osmic acid were used in 27 patients, with a mean El of 0.77 (+/-0.35). CONCLUSIONS: SAPHO syndrome is a relevant and stable entity, with a good long-term prognosis. NSAIDs and intraarticular injections (CS or osmic acid) most often alleviate rheumatic symptoms, but prednisone or methotrexate are sometimes necessary and appear globally helpful.

Acquired Hyperostosis Syndrome↗

PubMed1999

Acute pulmonary hypertension after cardiopulmonary bypass in pig: the role of endogenous endothelin.

BACKGROUND: Acute pulmonary hypertension occurring after cardiopulmonary bypass can be a cause of post-operative morbidity and mortality. The purpose of this study was to investigate whether bosentan, a non-peptidic mixed endothelin antagonist affected the pulmonary hypertension induced by experimental cardiopulmonary bypass. METHODS: Pigs were anesthetized and instrumented to determine hemodynamic measurements. Pigs were randomized to receive either 3 mg/kg bolus + 7 mg/kg per h bosentan (n = 8) or saline (n = 7). All pigs underwent 90 min of cardiopulmonary bypass and were further observed for a 120-min period. RESULTS: In the control group, cardiopulmonary bypass induced a dramatic pulmonary hypertension (+78 +/- 13%, P < 0.005) and accompanied an increase of pulmonary vascular resistance (+228 +/- 50%, P < 0.005), whereas, in the treated group, bosentan completely prevented these deleterious effects of cardiopulmonary bypass with only a moderate decrease of systemic vascular resistance (-19 +/- 14.6%, P < 0.05). CONCLUSIONS: The present findings support the hypothesis that endogenous endothelin is a mediator of acute pulmonary hypertension occurring after cardiopulmonary bypass. Bosentan, a mixed endothelin antagonist completely prevented pulmonary hypertension after cardiopulmonary bypass and may, therefore, have therapeutic applications in the management of patients following cardiac surgery.

Acute Disease↗

PubMed1999

Auditory associative cortex dysfunction in children with autism: evidence from late auditory evoked potentials (N1 wave-T complex).

OBJECTIVES: Auditory processing at the cortical level was investigated with late auditory evoked potentials (N1 wave-T complex) in 4-8-year-old autistic children with mental retardation and compared to both age-matched normal and mentally retarded children (16 children in each group). METHODS: Two negative peaks which occurred in the 80-200 ms latency range were analyzed according to stimulus intensity level (50 to 80 dB SPL): the first culminated at fronto-central sites (N1b) and the second at bitemporal sites (N1c, equivalent to Tb of the T complex). The latter wave was the most prominent and reliable response in normal children at this age. RESULTS: Our results in autistic children indicated abnormalities of this wave with markedly smaller amplitude at bitemporal sites and pronounced peak latency delay (around 20 ms). Moreover, in both reference groups the intensity effect was found on both sides whereas in autistic children it was absent on the left side but present on the right. CONCLUSION: These findings in autistic children showing very disturbed verbal communication argue for dysfunction in brain areas involved in N1c generation i.e., the auditory associative cortex in the lateral part of the superior temporal gyrus, with more specific left side defects when auditory stimulus have to be processed.

Acoustic Stimulation↗

PubMed1999

Observation and execution of movement: similarities demonstrated by quantified electroencephalography.

Quantified electroencephalography (qEEG) was used to compare cerebral electrical variations while human subjects (10 males and 10 females) were observing and executing finger movements and while they were resting. Video recording enabled elimination of subjects performing involuntary movements. EEGs were recorded from 14 sites in seven frequency bands: theta 1, theta 2, alpha 1, alpha, beta 1, beta 2 and beta 3. Analyses were performed on logarithmically transformed absolute spectral power values. Both observation and execution of finger movements involved a decrease in spectral power compared with resting. This decrease was significant only for the alpha 1 frequency band (7.5-10.5 Hz) and it involved nine of the 14 electrode locations (F7, F8, F4, T6, T5, C3, C4, P3 and P4). This indicates that the motor cortex and the frontal cortex are specifically activated by both observation and execution of finger movements. These results provide evidence that observation and execution of movement share the same cortical network.

Adult↗

PubMed1999

Mibefradil prevents L-NAME-exacerbated nephrosclerosis in spontaneously hypertensive rats.

OBJECTIVE: To determine the potential renal protective effects of a novel calcium channel blocker mibefradil in chronic renal failure. METHOD: We compared the long-term effects of mibefradil with an angiotensin-converting enzyme inhibitor cilazapril on blood pressure, proteinuria, renal function and histological alterations in N-nitro-L-arginine methylester (L-NAME)-treated spontaneously hypertensive rats (SHR). Three groups of SHR were studied for 45 days: group 1 (n = 14), treated with L-NAME only (50 mg/l in the drinking water); group 2 (n = 15) L-NAME plus co-treatment with mibefradil (30 mg/kg per day); group 3 (n = 15), L-NAME plus co-treatment with cilazapril (10 mg/kg per day). RESULTS: Both mibefradil and cilazapril attenuated the increased systolic blood pressure, and prevented the development of proteinuria and the decreased creatinine clearance (Ccr) seen at day 42 in the group treated with L-NAME alone. Notably, mibefradil had similar effects to cilazapril on proteinuria and Ccr, despite a reduced antihypertensive effect All animals receiving mibefradil co-treatment remained alive throughout the experiment, whereas the mortality rate was 43% in SHR treated with L-NAME alone. Both mibefradil and cilazapril completely prevented renal structural damage as assessed by scoring glomerular, tubulo-interstitial and vascular lesions. CONCLUSIONS: Our data show that mibefradil prevented the development of hypertension and proteinuria, renal functional impairment and nephrosclerosis, and also improved animal survival. The renal protective effects of mibefradil were at least equivalent to those of an ACE inhibitor in this animal model of chronic renal failure.

Animals↗

PubMed1999

Protective effects of endothelin receptor antagonists in dogs with aortic cross-clamping.

Endothelin (ET) may play an important role in the pathogenesis of vasoconstriction and acute renal failure after aortic cross-clamping (ACC). However, the relative contribution of the ET(A) and ET(B) receptors to the physiopathology of ischemic acute renal failure is poorly understood. This study was carried out to evaluate the potential protective effect of a selective ET(A) antagonist versus combined ET(A)/ET(B) antagonist on altered systemic, pulmonary, and renal hemodynamics induced by cross-clamping the suprarenal aorta for 1 h, followed by 2-h reperfusion. Studies were performed in three groups of anesthetized mongrel dogs. After baseline measurements, treatment (3 mg/kg i.v. bolus + 3 mg/kg/h infusion) with either a selective ET(A) antagonist, Ro 61-1790 (n = 5), or a combined ET(A)/ET(B) antagonist, bosentan (n = 5) or vehicle (n = 8) was initiated 5 min before ACC. There were marked increases in total peripheral (TPR), pulmonary (PVR), and renal (RVR) vascular resistances, and significant decreases in cardiac output (CO) and glomerular filtration rate (GFR) and tubular sodium reabsorption after ACC in the vehicle group. Both Ro 61-1790 and bosentan prevented the marked increases in TPR, PRV, and RVR, and attenuated the declines in CO, GFR, and tubular sodium reabsorption. We concluded that the profound systemic, pulmonary, and renal vasoconstriction, as well as the impairments in glomerular and tubular functions associated with ACC, is mostly ET mediated and that the ET(A) receptor activation makes a major contribution to the ET-mediated impairments of hemodynamics and renal function after ACC.

Acute Kidney Injury↗

PubMed1999

Apyrase functions in plant phosphate nutrition and mobilizes phosphate from extracellular ATP.

ATP, which is present in the extracellular matrix of multicellular organisms and in the extracellular fluid of unicellular organisms, has been shown to function as a signaling molecule in animals. The concentration of extracellular ATP (xATP) is known to be functionally modulated in part by ectoapyrases, membrane-associated proteins that cleave the gamma- and beta-phosphates on xATP. We present data showing a previously unreported (to our knowledge) linkage between apyrase and phosphate transport. An apyrase from pea (Pisum sativum) complements a yeast (Saccharomyces cerevisiae) phosphate-transport mutant and significantly increases the amount of phosphate taken up by transgenic plants overexpressing the gene. The transgenic plants show enhanced growth and augmented phosphate transport when the additional phosphate is supplied as inorganic phosphate or as ATP. When scavenging phosphate from xATP, apyrase mobilizes the gamma-phosphate without promoting the transport of the purine or the ribose.

Adenosine Triphosphate↗

PubMed1999

Anti-heat shock protein 70 kDa and 90 kDa antibodies in serum of patients with rheumatoid arthritis.

OBJECTIVES: Stress proteins (HSPs) are highly conserved immunodominant antigens found in various species. The purpose of this study was to assess the prevalence and prognostic significance of antibodies to HSC 70 kDa and HSP 90 kDa in three groups of patients with longstanding rheumatoid arthritis (RA) defined based on the severity of articular erosions. METHODS: 73 patients with longstanding (> 6 years) RA whose HLA-DR genotype was known were divided in three groups according to Larsen's score and compared with 47 recent onset (<1 year) RA patients and with control groups composed of patients with other inflammatory diseases (n=137) or of normal controls (n=48). IgGs and IgMs to HSC 70 kDa and HSP 90 kDa were determined using an ELISA with purified bovine HSC 70kDa or HSP 90 kDa. RESULTS: Concentrations of IgGs and IgMs to HSC 70 were significantly increased in 41.1% and 42.5% of longstanding RA patients, respectively. Corresponding figures for IgGs and IgMs to HSP 90 were 39.7% and 56%. IgMs to HSC 70 and HSP 90 were less frequent in recent onset RA (19% and 13% respectively). Among the groups with other inflammatory diseases, only the MCTD group exhibited high frequencies of IgGs to HSC 70 (80%) and HSP 90 (85%). DRB1*0401 positive RA patients (n=23) were not more likely to have increased concentrations of antibodies to HSC 70 kDa or HSP 90 kDa than other RA patients (DR4 positive but DRB1*0401 negative, or DR1 positive, n=31; or negative for both DR4 and DR1, n=14). IgGs to HSP 90 kDa were significantly more frequent (p<0.05) in longstanding RA patients whose Larsen's score was 4 or more (57%) than in those whose Larsen's score was 2 or 3 (39.4%) or less than 2 (16%). No associations were found between Larsen's score and IgGs or IgMs to HSC 70 kDa or IgMs to HSP 90 kDa. A significant correlation was demonstrated between IgGs to HSP 90 kDa and two other serological markers for RA, rheumatoid factor, and anti-Sa antibody; there were no correlations with antikeratin antibody, antiperinuclear factor, or anti-RA 33. CONCLUSION: IgGs to HSP 90 kDa are most common in longstanding RA patients with articular erosions, suggesting that they may be related to the articular prognosis in RA

Adolescent↗

PubMed1999

Pharmacology of tezosentan, new endothelin receptor antagonist designed for parenteral use.

Tezosentan (Ro 61-0612) [5-isopropyl-pyridine-2-sulfonic acid 6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(2-1H-tetrazol-5-yl-+ ++pyri din-4-yl)-pyrimidin-4-ylamide] is a new endothelin (ET) receptor antagonist specifically designed for parenteral use. Tezosentan competitively antagonizes the specific binding of (125)I-labeled ET-1 and of the selective ET(B) receptor ligands (125)I-labeled ET-3 and (125)I-labeled sarafotoxin S6c on cells and tissues carrying ET(A) and ET(B) receptors, with inhibitory constants in the nanomolar range, and has high water solubility. Tezosentan exhibits high functional inhibitory potency for inhibiting contraction induced by ET-1 on isolated rat aorta (ET(A) receptors; pA(2) = 9.5) and by sarafotoxin S6c on rat trachea (ET(B) receptors; pA(2) = 7.7). In vivo, tezosentan inhibits the pressor effect of big ET-1 in pithed rats and increases ET-1 plasma concentrations in conscious rats in a dose-dependent fashion. In spontaneously hypertensive rats, i.v. injection of tezosentan has acute hemodynamic effects and decreases blood pressure. Tezosentan is also able to prevent the acute renal failure that complicates rhabdomyolysis in a rat model of myoglobinuric nephropathy. Finally, tezosentan exhibits an apparent elimination half-life of less than 1 h in rabbits and primates and of 2 h in rats. In conclusion, tezosentan, a potent mixed ET receptor antagonist with a short half-life, may offer a novel medical approach for the i.v. treatment of acute pathological conditions.

Acute Kidney Injury↗