Role of nitric oxide and endothelin-1 in monocrotaline-induced pulmonary hypertension in rats.
OBJECTIVE
Nitric oxide (NO) and endothelin-1 (ET-1) have both been implicated in the pathogenesis of pulmonary hypertension (PH). Therefore, we examined NO-related relaxation and ET-1 levels in rat hilar pulmonary arteries (PA) during the progression of monocrotaline (MCT)-induced PH.


METHODS
Rats were studied 1 and 2 weeks after a single subcutaneous injection of MCT (80 mg/kg). Pulmonary artery pressure (PAP), right ventricular hypertrophy (RVH), NO-related relaxation and tissue ET-1 levels in PA were evaluated and compared with control (C).


RESULTS
One week post-MCT, endothelium (E)-dependent relaxation to 10(-5) M adenosine diphosphate (ADP), 10(-5) M A23187 and 10(-5) M acetylcholine (ACh) and tissue ET-1 levels in PA were normal. Rats in this group did not develop PH or RVH. Two weeks post-MCT, E-dependent relaxation was impaired (ADP, 7 +/- 3% VS. c, 62 +/- 5%; A23187, 2 +/- 7% vs. C, 58 +/- 2%; ACh, 33 +/- 7% vs. C, 86 +/- 2%; P < 0.05) and ET-1 levels were elevated (1925 +/- 244 pg/g wwt vs. C, 469 +/- 59 pg/g wwt, P < 0.05), In addition, significant PH and RVH were present (PAP 33 +/- 4 mmHg vs. C 18 +/- 0.8 mmHg, P < 0.05; RVH index 0.40 +/- 0.006 vs. C, 0.25 +/- 0.01, P < 0.05). Incubation with 10 microM indomethacin, 150 U/ml superoxide dismutase or 300 microM L-arginine failed to restore impaired relaxation to ACh. In E-intact rings, relaxation to 10(-6) M glyceryl trinitrate (GTN) was inhibited at 1 week post-MCT (72 +/- 2% vs. C, 87 +/- 3%, P < 0.05) with further inhibition at 2 weeks (39 +/- 4%). Response to GTN in E-denuded rings was normal in MCT groups.


CONCLUSIONS
These results indicate that MCT injection in rats results in delayed but progressive endothelial injury and PH. Despite mild endothelial dysfunction 1 week post-MCT, NO-related relaxation and ET-1 levels are normal. At 2 weeks post-MCT, inhibition of E-dependent NO-related relaxation and elevation of ET-1 levels are associated with PH and RVH. Thus inhibition of NO production associated with elevated ET-1 levels may play an important role in the pathophysiology of MCT-induced PH.
Mathew
R
R
Section of Pediatric Cardiology, New York Medical College, Valhalla 10595, USA.
Zeballos
G A
GA
Tun
H
H
Gewitz
M H
MH
D000109:Acetylcholine / Q000494:pharmacology; D000244:Adenosine Diphosphate / Q000494:pharmacology; D000818:Animals; D001120:Arginine / Q000494:pharmacology; D000001:Calcimycin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D016232:Endothelins / Q000032:analysis / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000187:drug effects; D006976:Hypertension, Pulmonary / Q000209:etiology* / Q000378:metabolism; D017380:Hypertrophy, Right Ventricular / Q000378:metabolism; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D016686:Monocrotaline; D009569:Nitric Oxide / Q000378:metabolism*; D005996:Nitroglycerin / Q000494:pharmacology; D011651:Pulmonary Artery / Q000737:chemistry / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013482:Superoxide Dismutase / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects
D016232:Endothelins; D009569:Nitric Oxide; D000001:Calcimycin; D000244:Adenosine Diphosphate; D016686:Monocrotaline; D001120:Arginine; D013482:Superoxide Dismutase; D005996:Nitroglycerin; D000109:Acetylcholine; D007213:Indomethacin