Role of inhibition of nitric oxide production in monocrotaline-induced pulmonary hypertension.
Monocrotaline (MCT)-induced pulmonary hypertension (PH) is associated with impaired endothelium-dependent nitric oxide (NO)-mediated relaxation. To examine the role of NO in PH, Sprague-Dawley rats were given a single subcutaneous injection of normal saline [control (C)], 80 mg/kg MCT, or the same dose of MCT and a continuous subcutaneous infusion of 2 mg.kg-1.day-1 of molsidomine, a NO prodrug (MCT+MD). Two weeks later, plasma NO3- levels, pulmonary arterial pressure (Ppa), ratio of right-to-left ventricular weights (RV/LV) to assess right ventricular hypertrophy, and pulmonary histology were evaluated. The plasma NO3- level in the MCT group was reduced to 9.2 +/- 1.5 microM (n = 12) vs. C level of 17.7 +/- 1.8 microM (n = 8; P < 0.02). In the MCT+MD group, plasma NO3- level was 12.3 +/- 2.0 microM (n = 8). Ppa and RV/LV in the MCT group were increased compared with C [Ppa, 34 +/- 3.4 mmHg (n = 6) vs. 19 +/- 0.8 mmHg (n = 8) and 0.41 +/- 0.01 (n = 9) vs. 0.25 +/- 0.008 (n = 8), respectively; P < 0.001]. In the MCT+MD group, Ppa and RV/LV were not different when compared with C [19 +/- 0.5 mmHg (n = 5) and 0.27 +/- 0.01 (n = 9), respectively; P < 0.001 vs. MCT]. Medial wall thickness of lung vessels in the MCT group was increased compared with C [31 +/- 1.5% (n = 9) vs. 13 +/- 0.66% (n = 9); P < 0.001], and MD partially prevented MCT-induced pulmonary vascular remodeling [22 +/- 1.2% (n = 11); P < 0.001 vs. MCT and C]. These results indicate that a defect in the availability of bioactive NO may play an important role in the pathogenesis of MCT-induced PH.
Mathew
R
R
Department of Pediatrics, New York Medical College, Valhalla 10595, USA.
Gloster
E S
ES
Sundararajan
T
T
Thompson
C I
CI
Zeballos
G A
GA
Gewitz
M H
MH
D000818:Animals; D001160:Arterioles / Q000473:pathology; D001794:Blood Pressure; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000378:metabolism*; D017380:Hypertrophy, Right Ventricular / Q000378:metabolism; D007279:Injections, Subcutaneous; D008297:Male; D008981:Molsidomine / Q000494:pharmacology; D016686:Monocrotaline; D009566:Nitrates / Q000097:blood; D009569:Nitric Oxide / Q000096:biosynthesis* / Q000378:metabolism; D011042:Poisons; D011651:Pulmonary Artery / Q000473:pathology; D011652:Pulmonary Circulation / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014665:Vasodilator Agents / Q000494:pharmacology; D015430:Weight Gain
D009566:Nitrates; D011042:Poisons; D014665:Vasodilator Agents; D009569:Nitric Oxide; D016686:Monocrotaline; D008981:Molsidomine