a-192621 and Hypertension--Pulmonary

The functional roles of endothelin ETA and ETB receptors in the development of monocrotaline (MCT)-induced pulmonary hypertension were investigated using MCT-treated rats in the absence or presence of a daily administration of A-192621, a selective ETB receptor antagonist, ABT-627, a selective ETA receptor antagonist, or a combination of both drugs. Four weeks after the injection of saline or MCT (60 mg/kg, s.c.), cardiac hypertrophy, right ventricular systolic pressure and morphologic changes of pulmonary arteries were evaluated. Compared with the control animals, MCT produced marked pulmonary hypertension associated with increases in right ventricular pressure and hypertrophy, and pulmonary arterial medial thickening. These MCT-induced alterations were markedly suppressed by daily treatment with ABT-627 for 4 weeks (10 mg/kg/d, twice daily), whereas treatment with A-192621 significantly aggravated the above MCT-induced pathologic changes. The blockade of both receptor subtypes by a combination of A-192621 and ABT-627 also significantly improved the MCT-induced pathologic changes, to the same extent as with ABT-627 administration. Thus, an exaggerated response to MCT during ETB receptor blockade also seems to be mediated by ETA receptor activation, thereby suggesting that ETA receptor-mediated action is exclusively contributive to the pathogenesis of MCT-induced pulmonary hypertension, although we cannot rule out a protective role of ETB receptor-mediated action.

Topics: Administration, Oral; Animals; Atrasentan; Blood Pressure; Body Mass Index; Body Weight; Cardiomegaly; Drug Administration Schedule; Drug Therapy, Combination; Heart; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Injections, Subcutaneous; Intubation, Gastrointestinal; Lung; Male; Monocrotaline; Organ Size; Pulmonary Artery; Pyrrolidines; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Receptor, Endothelin B; Time Factors; Tunica Media; Ventricular Pressure

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 >or= 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 >or= 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 ETARa, 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.

Topics: Acute Disease; Animals; Aspartic Acid Endopeptidases; Atrasentan; Benzofurans; Cardiovascular Agents; Disease Models, Animal; Embolism, Air; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-Converting Enzymes; Endothelins; Hemodynamics; Hypertension, Pulmonary; Male; Metalloendopeptidases; Organophosphonates; Protease Inhibitors; Pyrrolidines; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Receptor, Endothelin B; Sulfonamides; Time Factors; Ventricular Dysfunction, Right

The effects of SB 217242, a non-peptide endothelin (ET) receptor antagonist, were investigated against hypoxia-induced cardiopulmonary changes in high altitude-sensitive rats. In isolated pulmonary artery rings, SB 217242 (30 n m) antagonized ET-1-induced contractions with a p KB of 8.0. There was no difference in the sensitivity to ET-1 or the potency of SB 217242 in pulmonary artery from normoxic rats vs. rats exposed to hypoxia (9% O2) for 14 days. However, there was a marked reduction in the maximum response to ET-1, but not to KCl or phenylephrine, in pulmonary artery from hypoxic rats; this phenomenon was inhibited by treatment of animals with SB 217242 (10.8 mg/day, ip by osmotic pump) for the 14-day hypoxic period. Furthermore, there was a significant reduction in carbachol-induced, endothelium-dependent relaxation of precontracted pulmonary artery from hypoxic animals; SB 217242 treatment during the hypoxic period did not influence this difference. Vehicle-treated rats exposed to 14-day hypoxia had 173% higher pulmonary artery pressures and 75% higher right/left+septum ventricular mass ratios compared to normoxic animals. SB 217242 (3.6 or 10.8 mg/day, ip) markedly reduced (80 and 95%, respectively) hypoxia-induced increases in pulmonary artery pressure. Right ventricular hypertrophy was inhibited by 40% at the 10.8 mg/day dose. Marked medial thickening and luminal stenosis of small and medium-sized pulmonary arteries was observed in hypoxic rats. The SB 217242-treated, hypoxia-exposed rats had comparable small and medium-sized arteries to normoxic rats. Rats treated with SB 217242 (10.8 mg/day) for the last 14 days of a 28-day hypoxic exposure had significantly lower pulmonary artery pressures than those of vehicle-treated rats. In addition, the effects of the selective ETA receptor antagonist, SB 247083, and the selective ETB receptor antagonist, A-192621 (3.6 or 10.8 mg/day, ip), were compared against hypoxia-induced increases in pulmonary artery pressure and plasma ET concentrations. SB 247083, but not A-192621, inhibited hypoxia-induced pulmonary hypertension, whereas A-192621, but not SB 247083, significantly exacerbated hypoxia-induced increases in ET concentrations, suggesting that hypoxia-induced pulmonary pressor responses are mediated via ETA receptor activation, while ETB receptor blockade may alter clearance of hypoxia-induced elevated plasma ET. The inhibitory effects of SB 217242 on the functional and remodeling changes induced by

Topics: Altitude; Animals; Benzofurans; Carboxylic Acids; Endothelin Receptor Antagonists; Endothelin-1; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Hypoxia; Indans; Male; Propionates; Pulmonary Artery; Pyrrolidines; Random Allocation; Rats; Receptors, Endothelin