Inhalation of the phosphodiesterase-3 inhibitor milrinone attenuates pulmonary hypertension in a rat model of congestive heart failure.
BACKGROUND
Most patients with congestive heart failure (CHF) develop pulmonary venous hypertension, but right ventricular afterload is frequently further elevated by increased pulmonary vascular resistance. To investigate whether inhalation of a vasodilatory phosphodiesterase-3 inhibitor may reverse this potentially detrimental process, the authors studied the effects of inhaled or intravenous milrinone on pulmonary and systemic hemodynamics in a rat model of CHF.


METHODS
In male Sprague-Dawley rats, CHF was induced by supracoronary aortic banding, whereas sham-operated rats served as controls. Milrinone was administered as an intravenous infusion (0.2-1 microg.kg body weight.min) or by inhalation (0.2-5 mg/ml), and effects on pulmonary and systemic hemodynamics and lung water content were measured.


RESULTS
In CHF rats, intravenous infusion of milrinone reduced both pulmonary and systemic arterial blood pressure. In contrast, inhalation of milrinone predominantly dilated pulmonary blood vessels, resulting in a reduced pulmonary-to-systemic vascular resistance ratio. Repeated milrinone inhalations in 20-min intervals caused a stable reduction of pulmonary artery pressure. No hemodynamic effects were detected when 0.9% NaCl was administered instead of milrinone or when milrinone was inhaled in sham-operated rats. No indications of potentially adverse effects of milrinone inhalation in CHF, such as left ventricular volume overload, were detected. Moreover, lung edema was significantly reduced by repeated milrinone inhalation.


CONCLUSIONS
If these results can be confirmed in humans, inhalation of nebulized milrinone may present a novel, effective, safe, and pulmonary selective strategy for the treatment of pulmonary venous hypertension in CHF.
Hentschel
Thomas
T
Department of Anesthesiology, German Heart Institute Berlin, Institute of Physiology, Charité-Universitaetsmedizin Berlin, Campus Benjamin Franklin, Germany.
Yin
Ning
N
Riad
Alexander
A
Habbazettl
Helmut
H
Weimann
Jörg
J
Koster
Andreas
A
Tschope
Carsten
C
Kuppe
Hermann
H
Kuebler
Wolfgang M
WM
D000280:Administration, Inhalation; D000818:Animals; D000242:Cyclic AMP / Q000097:blood; D006152:Cyclic GMP / Q000097:blood; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography; D006333:Heart Failure / Q000150:complications*; D006976:Hypertension, Pulmonary / Q000188:drug therapy*; D008297:Male; D020105:Milrinone / Q000008:administration & dosage* / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage*; D011654:Pulmonary Edema / Q000517:prevention & control; D051381:Rats; D017207:Rats, Sprague-Dawley
D010726:Phosphodiesterase Inhibitors; D000242:Cyclic AMP; D006152:Cyclic GMP; D020105:Milrinone