Effects of monocrotaline on endothelial nitric oxide synthase expression and sulfhydryl levels in rat lungs.
The nitric oxide-cyclic guanosine monophosphate signal-transduction mechanism plays a key role in the regulation of vascular tone and structure. Monocrotaline-induced pulmonary hypertension is associated with low bioavailability of nitric oxide. To characterize the mechanism(s) involved in this dysfunction, rats received a single subcutaneous injection of monocrotaline, normal saline (control), or monocrotaline plus daily L-arginine, a precursor of nitric oxide, in drinking water. Pulmonary artery pressure and right ventricular hypertrophy were assessed 2 weeks later. In addition, the authors evaluated the expression of endothelial nitric oxide synthase messenger RNA, endothelial nitric oxide synthase protein, cyclic guanosine monophosphate, and sulfhydryl levels in the lungs. Sulfhydryls are needed for the dynamic modulation of soluble guanylate cyclase by nitric oxide, which results in cyclic guanosine monophosphate formation. L-arginine treatment did not attenuate monocrotaline-induced pulmonary hypertension or right ventricular hypertrophy. Monocrotaline did not alter the expression of endothelial nitric oxide synthase messenger RNA or endothelial nitric oxide synthase protein in the lungs. Protein-bound sulfhydryls (28 +/- 5 vs. 75 +/- 16 pmol/microg protein) and cyclic guanosine monophosphate (0.63 +/- 0.05 vs. 1.06 +/- 0.017 pmol/microg protein) levels in the monocrotaline group were significantly low compared with controls. The low sulfhydryl levels, an indicator of oxidant stress, may account for the impaired availability of bioactive nitric oxide and low cyclic guanosine monophosphate levels. These results suggest that oxidative stress may, in part, contribute to the pathogenesis of pulmonary hypertension in the monocrotaline model.
Mathew
Rajamma
R
Department of Pediatrics, New York Medical College, Valhalla, NY 10595, USA. rajamma_mathew@NYMC.edu
Yuan
Ning
N
Rosenfeld
Louis
L
Gewitz
Michael H
MH
Kumar
Ashok
A
D000818:Animals; D001483:Base Sequence; D001682:Biological Availability; D015153:Blotting, Western; D006152:Cyclic GMP / Q000378:metabolism; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000378:metabolism; D006976:Hypertension, Pulmonary / Q000378:metabolism* / Q000503:physiopathology; D008168:Lung / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D008969:Molecular Sequence Data; D016686:Monocrotaline / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000187:drug effects* / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011652:Pulmonary Circulation / Q000502:physiology; D012333:RNA, Messenger / Q000032:analysis; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012016:Reference Values; D012680:Sensitivity and Specificity; D013438:Sulfhydryl Compounds / Q000032:analysis / Q000378:metabolism*
D012333:RNA, Messenger; D013438:Sulfhydryl Compounds; D016686:Monocrotaline; D019001:Nitric Oxide Synthase; D006152:Cyclic GMP