Zaprinast attenuates hypoxic pulmonary artery injury and causes less aortic relaxation than milrinone.
Hypoxic pulmonary vasoconstriction is a challenging clinical problem with limited therapeutic options. Milrinone, a phosphodiesterase (PDE)-3 inhibitor, is frequently used to treat perioperative pulmonary hypertension. However, recent evidence suggests that the PDE-5 isoform may be more specific for lung tissue. We hypothesized that the PDE-5 inhibitor zaprinast has greater efficacy for pulmonary vasorelaxation, attenuation of hypoxic pulmonary vasoconstriction, and inhibition of hypoxia-induced pulmonary artery cytokine expression when compared with milrinone. To study this, isolated rat pulmonary artery and thoracic aorta rings suspended in physiologic organ baths for measurement of isometric force transduction were treated with vehicle (dimethyl sulfoxide), milrinone, or zaprinast to assess pulmonary artery relaxation, thoracic aorta relaxation, inhibition of hypoxic (pO2 = 30-35 mmHg) pulmonary vasoconstriction, and hypoxia-induced pulmonary artery TNF-alpha and IL-1beta expression (reverse transcriptase-PCR). Milrinone and zaprinast resulted in dose-dependent pulmonary artery and aortic relaxation, but zaprinast caused significantly less aortic relaxation compared with milrinone (50.12% +/- 3.36% versus 91.03% +/- 2.97%, P < 0.001). Zaprinast, but not milrinone, significantly inhibited hypoxic pulmonary vasoconstriction (zaprinast, 58.42% +/- 5.37%; milrinone, 77.65% +/- 4.42% versus vehicle: 74.42% +/- 7.54%). Hypoxia-induced upregulation of TNF-alpha and IL-1beta mRNA in pulmonary artery was decreased by zaprinast, but not milrinone, pretreatment. These results suggest that zaprinast, but not milrinone, preferentially vasodilates pulmonary artery over aorta, attenuates hypoxic pulmonary vasoconstriction, and inhibits hypoxia-induced pulmonary artery TNF-alpha and IL-1beta expression. Therefore, PDE-5 inhibition may be advantageous in the treatment of pulmonary hypertension.
Tsai
Ben M
BM
Department of Surgery, Indiana University Medical Center, Indiana 46202, USA. btsai@iupui.edu
Wang
Meijing
M
Pitcher
Jeffrey M
JM
Kher
Ajay
A
Crisostomo
Paul
P
Meldrum
Daniel R
DR
D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000473:pathology*; D001013:Aorta, Thoracic / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006976:Hypertension, Pulmonary / Q000188:drug therapy*; D000860:Hypoxia; D007249:Inflammation; D007375:Interleukin-1 / Q000096:biosynthesis; D008168:Lung / Q000473:pathology; D008171:Lung Diseases / Q000188:drug therapy*; D008297:Male; D020105:Milrinone / Q000494:pharmacology*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D016133:Polymerase Chain Reaction; D011651:Pulmonary Artery / Q000293:injuries*; D011688:Purinones / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D014661:Vasoconstriction; D014665:Vasodilator Agents / Q000494:pharmacology*
D007375:Interleukin-1; D010726:Phosphodiesterase Inhibitors; D011688:Purinones; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D014665:Vasodilator Agents; C011145:zaprinast; D020105:Milrinone