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Repeated inhalation of adrenomedullin ameliorates pulmonary hypertension and survival in monocrotaline rats

¹Department of Internal Medicine, National Cardiovascular Center, Osaka 565-8565; ²Department of Biochemistry, National Cardiovascular Center Research Institute, Osaka 565-8565; ³Cardiovascular Division, Kansai Rosai Hospital, Hyogo 660-0064, Japan; and ⁴Department of Cardiac Physiology, National Cardiovascular Center Research Institute, Osaka, Japan 565-8565

Submitted 1 July 2002 ; accepted in final form 31 December 2002

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 µg/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.

vasodilator; hemodynamics; aerosol; survival

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