Chronic hypoxia-induced cardiopulmonary changes in three rat strains: inhibition by the endothelin receptor antagonist SB 217242.
The cardiopulmonary profile of three different rat strains was compared after exposure to hypoxia (9% O2) for 0, 7, or 14 days. In Sprague-Dawley (SD), Wistar (W), and high altitude-sensitive (HAS) rats, pulmonary arterial pressure (PAP) rose 30, 58, and 85% respectively, after 7 days of hypoxia, and by 108, 116, and 167%, respectively, at 14 days compared to strain- and age-matched normoxic controls. Right ventricular hypertrophy (RVH), expressed as the ratio of right free wall/left wall + septum weight, in SD, W, and HAS was increased by 24, 53, and 48%, respectively, at 7 days, and by 51, 93, and 55% at 14 days compared to normoxic littermates. Histologically, marked medial thickening and luminal stenosis of small and medium-sized arteries were observed in all hypoxic rats, being most pronounced in the HAS rats at 14 days. Treatment of HAS rats with the ET receptor antagonist SB 217242 (3.6 or 10.8 mg/day i.p. by osmotic pump) significantly inhibited the hypoxia-induced increases in PAP (70-75% decrease). RVH was inhibited by 40% at the dose of 10.8 mg/day. Histologically, the SB 217242-treated rats had almost "normal" small and medium-sized arteries, comparable to those of the normoxic HAS controls. This study demonstrates an exaggerated PAP response to chronic hypoxia in HAS compared to SD and W rats. The inhibitory influence of SB 217242 on the functional and morphologic changes induced by hypoxia provides further evidence for a role for ET and the potential utility of ET receptor antagonists in the treatment of pulmonary hypertension.
Underwood
D C
DC
Department of Pulmonary, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406-0939, USA.
Bochnowicz
S
S
Osborn
R R
RR
Louden
C S
CS
Hart
T K
TK
Ohlstein
E H
EH
Hay
D W
DW
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002264:Carboxylic Acids / Q000627:therapeutic use*; D002908:Chronic Disease; D065128:Endothelin Receptor Antagonists; D000860:Hypoxia / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D007189:Indans / Q000627:therapeutic use*; D008168:Lung / Q000473:pathology*; D008297:Male; D009206:Myocardium / Q000473:pathology*; D011651:Pulmonary Artery / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D017207:Rats, Sprague-Dawley; D013997:Time Factors
D002264:Carboxylic Acids; D065128:Endothelin Receptor Antagonists; D007189:Indans; C098288:enrasentan