Endothelin receptor blockade improves endothelial function in human internal mammary arteries.

OBJECTIVE: Endothelial dysfunction, specifically endothelium-derived contracting factors have been implicated in the development of arterial conduit vasospasm. The potent vasoconstrictor endothelin-1 (ET-1) has received much attention in this regard. The present study was designed to evaluate the role of ET-1 in the development of endothelial dysfunction in human internal mammary arteries (IMA). To this aim, we examined the effects of specific and non-specific ET-receptor antagonists on endothelial function (assessed using acetylcholine (ACh)-induced vasodilation) in segments of IMA obtained during coronary artery bypass graft (CABG) surgery. METHODS: Vascular segments of IMA were obtained from 51 patients undergoing elective coronary artery bypass graft (CABG) surgery and in vitro endothelium-dependent and -independent responses to ACh and sodium nitroprusside (SNP) were assessed. Isometric dose response curves (DRC) to ACh and SNP were constructed in pre-contracted rings in the presence and absence of bosentan (ET(A/B) receptor antagonist, 3 microM), BQ-123 (ET(A) antagonist, 1 microM) and BQ-788 (ET(B) antagonist, 1 microM) using the isolated organ bath apparatus. Percent maximum relaxation (%E(max)) and sensitivity (pEC(50)) were compared between interventions. RESULTS: ACh caused dose-dependent endothelium-mediated relaxation in IMA (%E(max) 43+/-4, pEC(50) 6. 74+/-0.12). In the presence of bosentan, BQ-123 and BQ-788 ACh-induced relaxation was significantly augmented (%E(max) bosentan 60+/-3, BQ-123 56+/-4, BQ-788 53+/-5 vs. control 43+/-4, P<0.05) without affecting sensitivity. The effects of these antagonists were endothelium-specific since endothelium-independent responses to SNP remained unaltered. Furthermore, the beneficial effects were independently and maximally mediated by ET(A) and ET(B) receptors (%E(max) BQ-123 56+/-4 vs. BQ-788 53+/-5 vs. bosentan 60+/-3, P>0. 05). CONCLUSIONS: These data uncover, for the first time, beneficial effects of ET receptor blockade on endothelial-dependent vasorelaxation in human IMA.

Raising tibet.

Thermochronologic, sedimentologic, oceanographic, and paleoclimatic studies suggest that rapid uplift and unroofing of southern Tibet began about 20 million years ago and that the present elevation of much of the Tibetan plateau was attained by about 8 million years ago. Hypotheses advanced to explain the tectonic evolution of the India-Asia collision, which began about 40 to 50 million years ago, predict the timing and rates of crustal thickening of the southern margin of Asia. However, these models do not predict the prominently enhanced early Miocene denudation and uplift that are manifested in a variety of geological records. A model involving continental extrusion, development of a crustal-scale thrust ramp of the Main Central Thrust beneath the Gangdese belt, and lithospheric delamination provides a history consistent with these observations.

The management of blunt splenic trauma.

Seventy cases of blunt splenic trauma were retrospectively reviewed for the period 1979-1984. There were 57 adults and 13 children. Motor vehicle accidents were implicated in 62%. Forty-five splenectomies and eight splenorrhaphies were performed. The patients fell into two groups. Group A, numbering 48 patients, were those operated upon within 24 hours of injury. The mortality rate was 16%, and no deaths were attributable to splenic injury. Indications for surgery were hemodynamic instability in 46% and positive peritoneal lavage in 40%. Group B included 22 patients, 17 of whom were managed nonoperatively with no deaths. Five patients eventually went to laparotomy. Fifty per cent of all patients had associated intra-abdominal injury but only 17% needed repair; 31% of patients were initially managed conservatively with a 77% success rate and no mortality. It is concluded that conservative management is safe in stable patients with blunt splenic trauma.

Serum levels of methotrexate by the ligand-binding assay after "high-dose" therapy for osteosarcoma.

The method of Arons et al. (Cancer Res. 35:2033-2038, 1975) for assaying methotrexate (MTX) was used to monitor serum levels of the drug attained in 18 patients with osteosarcomas. The patients received either 100 mg or 200 mg of MTX/kg via a 6-hour infusion. With one fatal exception, unacceptable toxicity to MTX was prevented by leucovorin. Serum levels of the drug were assayed routinely at 6, 12, and 18 hours after termination of the infusion. Although significantly higher serum levels of MTX were observed at 6 hours after the infusion of 200 mg MTX/kg than after 100 mg/kg, the variation in rate of clearance of individual patients masked any subsequent dosage-related differences. The mean half-time for clearance of MTX was similar irrespective of the dosage of MTX and was 2.91 +/- 1.51 hr for 53 treatments. The single incidence of toxicity, requiring hospitalization, was accompanied with markedly higher serum levels of MTX at 18 hours, but not at either 6 or 12 hours after termination of the drug infusion, and by a slightly slower rate of clearance, 6.2 hours. Certain minor adaptations were incorporated in the original assay to simplify the analysis of data.