Repeated inhalation of adrenomedullin ameliorates pulmonary hypertension and survival in monocrotaline rats.
Adrenomedullin (AM) is a potent vasodilator peptide. We investigated whether inhalation of aerosolized AM ameliorates monocrotaline (MCT)-induced pulmonary hypertension in rats. Male Wistar rats given MCT (MCT rats) were assigned to receive repeated inhalation of AM (n = 8) or 0.9% saline (n = 8). AM (5 mug/kg) or saline was inhaled as an aerosol using an ultrasonic nebulizer for 30 min four times a day. After 3 wk of inhalation therapy, mean pulmonary arterial pressure and total pulmonary resistance were markedly lower in rats treated with AM than in those given saline [mean pulmonary arterial pressure: 22 +/- 2 vs. 35 +/- 1 mmHg (-37%); total pulmonary resistance: 0.048 +/- 0.004 vs. 0.104 +/- 0.006 mmHg.ml(-1).min(-1).kg(-1) (-54%), both P < 0.01]. Neither systemic arterial pressure nor heart rate was altered. Inhalation of AM significantly attenuated the increase in medial wall thickness of peripheral pulmonary arteries in MCT rats. Kaplan-Meier survival curves demonstrated that MCT rats treated with aerosolized AM had a significantly higher survival rate than those given saline (70% vs. 10% 6-wk survival, log-rank test, P < 0.01). In conclusion, repeated inhalation of AM inhibited MCT-induced pulmonary hypertension without systemic hypotension and thereby improved survival in MCT rats.
Nagaya
Noritoshi
N
Dept. of Internal Medicine, National Cardiovascular Center, 5-7-1 Fujishirodai, Suita, Osaka 565-8565, Japan. nagayann@hsp.ncvc.go.jp
Okumura
Hiroyuki
H
Uematsu
Masaaki
M
Shimizu
Wataru
W
Ono
Fumiaki
F
Shirai
Mikiyasu
M
Mori
Hidezo
H
Miyatake
Kunio
K
Kangawa
Kenji
K
D000280:Administration, Inhalation; D053607:Adrenomedullin; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000188:drug therapy* / Q000401:mortality; D008297:Male; D016686:Monocrotaline; D010455:Peptides / Q000494:pharmacology*; D011379:Prognosis; D011651:Pulmonary Artery / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D015996:Survival Rate; D014655:Vascular Resistance / Q000187:drug effects
D000959:Antihypertensive Agents; D010455:Peptides; D053607:Adrenomedullin; D016686:Monocrotaline