Angiotensin II and monocrotaline-induced pulmonary hypertension: effect of losartan (DuP 753), a nonpeptide angiotensin type 1 receptor antagonist.
Administration of the pyrrolizidine alkaloid monocrotaline (MCT) to rats results in hypertensive pulmonary vascular disease characterized by a structurally based increase in pulmonary vascular resistance and right ventricular hypertrophy. Alterations in lung angiotensin converting enzyme activity in MCT-treated rats have suggested a role for angiotensin II (AII) in the pathogenesis of this model of hypertensive pulmonary vascular disease. To determine if increases in AII contribute to the development of pulmonary hypertension in MCT-treated rats, we examined the effect of chronic administration of the nonpeptide AII receptor antagonist Losartan on indices of pulmonary hypertension, Losartan (DuP 753; 10 mg/kg s.c.) administration for 21 days did not prevent the development of hypertensive pulmonary vascular disease in MCT-treated rats. However, 18 hr after the last dose of Losartan, AII (0.1 micrograms/kg i.v.)-induced pressor responses were inhibited by 63% in Losartan-treated rats. Losartan administration in MCT-treated rats did not prevent increases in pulmonary artery pressure or development of right ventricular hypertrophy. Additionally, increases in medial arterial thickness in pulmonary artery vessels (less than 50 microns and 50-100 microns external diameter) from MCT-treated rats were still evident in Losartan-treated rats. However, Losartan administration decreased medial pulmonary artery thickness of 50 to 100 microns external diameter vessels in control rats. These results demonstrate that AII. acting at the AT1 receptor subtype, does not contribute to pulmonary hypertension in this animal model.
Cassis
L A
LA
Division of Pharmacology and Experimental Therapeutics, College of Pharmacy, University of Kentucky, Lexington.
Rippetoe
P E
PE
Soltis
E E
EE
Painter
D J
DJ
Fitz
R
R
Gillespie
M N
MN
D000804:Angiotensin II / Q000037:antagonists & inhibitors; D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology*; D001835:Body Weight / Q000187:drug effects; D006976:Hypertension, Pulmonary / Q000139:chemically induced* / Q000517:prevention & control; D007093:Imidazoles / Q000494:pharmacology*; D019808:Losartan; D008297:Male; D016686:Monocrotaline / Q000037:antagonists & inhibitors / Q000633:toxicity*; D011311:Pressoreceptors / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D012083:Renin / Q000097:blood; D013777:Tetrazoles / Q000494:pharmacology*
D001713:Biphenyl Compounds; D007093:Imidazoles; D013777:Tetrazoles; D000804:Angiotensin II; D016686:Monocrotaline; D012083:Renin; D019808:Losartan