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 im plicated in the pathogenesis of pulmonary hypertension (PH). Therefore , we examined NO-related relaxation and ET-1 levels in rat hilar pulmo nary arteries (PA) during the progression of monocrotaline (MCT)-induc ed PH. Methods: Rats were studied 1 and 2 weeks after a single subcuta neous injection of MCT (80 mg/kg). Pulmonary artery pressure (PAP), ri ght 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 a denosine 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 di d not develop PH or RVH. Two weeks post-MCT, E-dependent relaxation wa s 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 we re elevated (1925 +/- 244 pg/g wwt vs. C, 469 +/- 59 pg/g wwt, P < 0.0 5). In addition, significant PH and RVH were present (PAP 33 +/- 4 mmH g vs. C 18 +/- 0.8 mmHg, P < 0.05; RVH index 0.40 +/- 0.006 vs. C, 0.2 5 +/- 0.01, P < 0.05). Incubation with 10 mu M indomethacin, 150 U/ml superoxide dismutase or 300 mu M 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, 8 7 +/- 3%, P < 0.05) with further inhibition at 2 weeks (39 +/- 4%). Re sponse 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 d ysfunction 1 week post-MCT, NO-related relaxation and ET-1 levels are normal. At 2 weeks post-MCT, inhibition of E-dependent NO-related rela xation and elevation of ET-1 levels are associated with PH and RVH. Th us, inhibition of NO production associated with elevated ET-1 levels m ay play an important role in the pathophysiology of MCT-induced PH.