Role of the endothelin system in secondary pulmonary hypertension related to air embolism: Lessons learned from testing four classes of endothelin blockers in a rat model

被引:5
作者
Battistini, B
Verreault, M
Ayach, B
Blouin, A
Cernacek, P
Jeng, AY
Wessale, J
Opgenorth, T
Tsang, J
机构
[1] Univ Laval, Hop Laval, Res Ctr, Quebec Heart & Lung Inst,Dept Med, Ste Foy, PQ G1V 4G5, Canada
[2] McGill Univ, Royal Victoria Hosp, Montreal, PQ H3A 1A1, Canada
[3] Novartis Inst BioMed Res, E Hanover, NJ USA
[4] Abbott Labs Inc, Pharmaceut Prod Div, Abbott Pk, IL USA
[5] Univ British Columbia, Dept Med, Vancouver, BC, Canada
关键词
pulmonary air embolism; pulmonary hypertension; blood gas; endothelin; endothelin-converting enzyme; endothelin receptor; antagonists; inhibitors;
D O I
10.1097/01.fjc.0000166295.18066.f8
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
A rat model of acute pulmonary air embolism (APAE) was developed. These animals had a higher right ventricular systolic pressure (RVSP) (+ 69% at 15-minute peak, and 21-34% at 30-180 minutes), as well as a reduced mean arterial blood pressure (10-20% at 60-180 minutes), heart rate (20-26% at 60-180 minutes) and PaO2 (9-11 % at 30-180 minutes) compared with control rats. The role of the endothelin (ET) system, known to be involved in pulmonary hypertension of various etiologies, was investigated by evaluating the effect of the four classes of ET blockers: ET-converting enzyme inhibitor (ECEi) (CGS 35066), selective endothelin-A receptor antagonist (ETA-Ra) (Atrasentan, ABT-627), endothelin-B receptor antagonist (ETB-Ra) (A-192621) or mixed endothelin-A/endothelin-B receptor antagonist (ETA/B-Ra) (A-182086) in this animal model. All four were effective, to various degrees, at reducing the APAE-induced rise in RVSP. The relative efficacy of those compounds in reducing the acute elevation (15 minutes) of RVSP was ECEi greater than or equal to ETA/B-Ra >> ETA-Ra = ETB-Ra. The sustained elevation (30-180 minutes) of RVSP was totally abolished by ECEi and attenuated by other ET blockers with a relative efficacy of ETA-Ra > ETA/B-Ra greater than or equal to ETB-Ra. ET receptor antagonists did not affect right ventricular basal tone (control rats) whereas ECEi reduced it by up to 12% after 2 hours. The APAE reduction in mean arterial blood pressure was unaffected by ETA Ra, was completely normalized by ETB-Ra, but was further reduced by either ETA/B-Ra or ECEi. The basal mean arterial blood pressure in control rats was unaffected by ETA-Ra, was elevated by ETB-Ra, but was depressed by ETA/B-Ra and ECEi. All ET blockers maintained normal oxygen saturation in APAE. These results support a role for ETs in rat APAE, since ET blockers can attenuate the cardiopulmonary deterioration and blood gas exchange. However, modulation of the central hemodynamic profile is more complex and may limit the usefulness of some ET blockers.
引用
收藏
页码:S386 / S389
页数:4
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