The NO donor molsidomine reduces endothelin-1 gene expression in chronic hypoxic rat lungs.
We investigated the effects of the nitric oxide (NO) donor molsidomine and the nitric oxide synthase inhibitor N-nitro-L-arginine methyl ester (L-NAME) on pulmonary endothelin (ET)-1 gene expression and ET-1 plasma levels in chronic hypoxic rats. Two and four weeks of hypoxia (10% O2) significantly increased right ventricular systolic pressure, the medial cross-sectional vascular wall area of the pulmonary arteries, and pulmonary ET-1 mRNA expression (2-fold and 3.2-fold, respectively). ET-1 plasma levels were elevated after 4 wk of hypoxia. In rats exposed to 4 wk of hypoxia, molsidomine (15 mg x kg(-1) x day(-1)) given either from the beginning or after 2 wk of hypoxia significantly reduced pulmonary hypertension, pulmonary vascular remodeling, pulmonary ET-1 gene expression, and ET-1 plasma levels. L-NAME administration (45 mg x kg(-1) x day(-1)) in rats subjected to 2 wk of hypoxia did not modify these parameters. Our findings suggest that in chronic hypoxic rats, exogenously administered NO acts in part by suppressing the formation of ET-1. In contrast, inhibition of endogenous NO production exerts only minor effects on the pulmonary circulation and pulmonary ET-1 synthesis in these animals.
Blumberg
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FC
Department of Internal Medicine II, University of Regensburg, 93042 Regensburg, Germany. friedrich.blumberg@klinik.uni-regensburg.de
Wolf
K
K
Sandner
P
P
Lorenz
C
C
Riegger
G A
GA
Pfeifer
M
M
D000818:Animals; D002908:Chronic Disease; D004195:Disease Models, Animal; D019332:Endothelin-1 / Q000235:genetics / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000235:genetics / Q000378:metabolism; D006400:Hematocrit; D006439:Hemodynamics / Q000187:drug effects; D006976:Hypertension, Pulmonary / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology; D000860:Hypoxia / Q000188:drug therapy / Q000378:metabolism*; D008168:Lung / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008981:Molsidomine / Q000008:administration & dosage / Q000494:pharmacology*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D011651:Pulmonary Artery / Q000187:drug effects / Q000473:pathology; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D014665:Vasodilator Agents / Q000494:pharmacology
D019332:Endothelin-1; D004791:Enzyme Inhibitors; D020030:Nitric Oxide Donors; D012333:RNA, Messenger; D014665:Vasodilator Agents; D008981:Molsidomine; D019001:Nitric Oxide Synthase; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D019331:NG-Nitroarginine Methyl Ester