Procedures using cardiopulmonary bypass (CPB) and aortic cross-clamping are associated with a variable degree of ischemia/reperfusion of the lungs, leading to acute pulmonary hypertension (PHT). The purpose of this study was to compare the effects of the sildenafil analog (UK343-664), a phosphodiesterase type V(PDEV) inhibitor, with milrinone, a PDE type III inhibitor, in a porcine model of acute PHT following CPB. After the pigs were anesthetized, pressure-tipped catheters were placed in the right ventricle and carotid and pulmonary arteries. Cardiac output was measured with an ultrasound probe on the ascending aorta. After heparinization and placement of aortic and right atrial cannulae, non-pulsatile CPB was instituted and cardioplegia administered following aortic cross-clamping. After 30 minutes, the clamp was removed and the animals re-warmed and separated from CPB in sinus rhythm. The animals were randomized to 3 groups, and 16 animals were studied to completion: milrinone (n=5) 50 μg/kg; sildenafil-analog (n=5) 500 μg/kg; and normal saline (NS) (n=6). Hemodynamic data were collected at baseline pre-CPB and, following termination of CPB, at baseline, 5, 10 and 30 minutes after administration of the drug. Pulmonary hypertension was present in all groups following CPB. After administration of the drugs, mean pulmonary artery pressure decreased in all 3 groups; however, only in the sildenafil-analog group did pulmonary vascular resistance(PVR) decrease by 35%, from 820 to 433 dynes · cm · sec-5 at 5 minutes (p<0.05), and continued to be decreased at 10 minutes by 26% (P<0.05). Pulmonary selectivity was demonstrated with sildenafil-analog, because there were no similar changes in systemic vascular resistance(SVR) and no significant changes in systemic hemodynamics. Sildenafil-analog, a PDEV inhibitor, shows a promising role for managing the PVR increases that occur following CPB.
1 Tilney NL Hester WJ . Physiologic and histologic changes in the lungs of patients dying after prolonged cardiopulmonary bypass: an inquiry into the nature of post-perfusion lung. Ann Surg.1967; 166: 759–766.
2.
2 Wessel DL Adatia I Giglia TM Thompson JE Kulic TJ . Use of inhaled nitric oxide and acetylcholine in the evaluation of pulmonary artery hypertension and endothelial function after cardiopulmonary bypass. Circulation1993; 88: 447–453.
3.
3 Hopkins RA Bull C Haworth SG Leval MR Stark J . Pulmonary hypertensive crises following surgery for congenital heart defects in young children. Eur J Cardio-thorac Surg1991; 5: 628–634.
4.
4 Wahlers TH Beer C Fieguth HG . Right heart failure following orthotopic cardiac transplantation. Clin Transplant1988; 2: 252–256.
5.
5 Kaye MP . The registry of the International Society for Heart and Lung Transplantation: 10th official report—1993. J Heart Lung Transplant1993; 12: 541–548.
6.
6 Reich DL Bodian CA Krol M Kuroda M Osinski T Thys DM . Intraoperative hemodynamic predictors of mortality, stroke, and myocardial infarction after coronary artery bypass surgery. Anesth Analg.1999; 89: 814–822.
7.
7 Ocal A Kiris I Erdinc M Peker O Yavuz T Ibrisim E . Efficiency of prostacyclin in the treatment of protamine-mediated right ventricular failure and acute pulmonary hypertension. Tohoku J Exp Med2005; 207: 51–58.
8.
8 Fattouch K Sbraga F Sampognaro R . Treatment of pulmonary hypertension in patients undergoing cardiac surgery with cardiopulmonary bypass: a randomized, prospective, double-blind study. J Cardiovasc Med (Hagerstown)2006; 7: 119–123.
9.
9 Ibrahim M Hendry P Masters R . Management of acute severe perioperative failure of cardiac allografts: a single-centre experience with a review of the literature. Can J Cardiol2007; 23: 363–367.
10.
10 Oztekin I Yazici S Oztekin DS Goksel O Issever H Canik S . Effects of low-dose milrinone on weaning from cardiopulmonary bypass and after in patients with mitral stenosis and pulmonary hypertension. Yakugaku Zasshi2007; 127: 375–383.
11.
11 Lowson SM Doctor A Walsh BK Doorley PA . Inhaled prostacyclin for the treatment of pulmonary hypertension after cardiac surgery. Crit Care Med2002; 30: 2762–2764.
12.
12 Ichinose F Roberts JD Zapol W . Inhaled nitric oxide: a selective pulmonary vasodilator: current uses and therapeutic potentials. Circulation2004; 109: 3106–3111.
13.
13 Fullerton DC Mc Intyre RC . Inhaled nitric oxide: therapeutic applications in cardiothoracic surgery. Ann Thorac Surg1996; 61: 1856–1864.
14.
14 Schmid ER Burki C Engel MH Schmidlin D Tornic M Seifert B . Inhaled nitric oxide versus intravenous vasodilators in severe pulmonary hypertension after cardiac surgery. Anesth Analg1999; 89: 1108–1115.
15.
15 McMullan DM Bekker JM Johengen MJ . Inhaled nitric oxide-induced rebound pulmonary hypertension: role for endothelin-1. Am J Physiol Heart Circ Physiol2001; 280: H777–H785.
16.
16 Bradford KK Deb B Pearl RG . Combination therapy with inhaled nitric oxide and intravenous dobutamine during pulmonary hypertension in the rabbit. J Cardiovasc Pharmacol2000; 36: 146–151.
17.
17 Pascual JM Fiorelli AI Bellotti GM Stolf NA Jatene AD . Prostacyclin in the management of pulmonary hypertension after heart transplantation. J Heart Transplant1990; 9: 644–651.
18.
18 Van Obbergh LJ Charbonneau M Blaise G . Combination of inhaled nitric oxide with IV nitroglycerin or with a prostacyclin analogue in the treatment of experimental pulmonary hypertension. Br J Anaesth1996; 77: 227–231.
19.
19 Tonz M von Segesser LK Schilling J . Treatment of acute pulmonary hypertension with inhaled nitric oxide. Ann Thorac Surg1994; 58: 1031–1035.
20.
20 Dent G Magnussen H Rabe KF . Cyclic nucleotide phosphodiesterases in the human lung. Lung1994; 172: 129–146.
21.
21 Chen EP Bittner HB Davis RD Van Trigt P . Hemodynamic and inotropic effects of milrinone after heart transplantation in the setting of recipient pulmonary hypertension. J Heart Lung Transplant1998; 17: 669–678.
22.
22 Bhatia S Frantz RP Severson CJ Durst LA McGoon MD . Immediate and long-term hemodynamic and clinical effects of sildenafil in patients with pulmonary arterial hypertension receiving vasodilator therapy. Mayo Clin Proc2003; 78: 1207–1213.
23.
23 Schulze-Neick I Hartenstein P Li J . Intravenous sildenafil is a potent pulmonary vasodilator in children with congenital heart disease. Circulation2003; 108(Suppl 1): II167–II173.
24.
24 Bonnell M Urdaneta F Kirby DS Valdez N Beaver TM Lobato EB . Effects of a sildenafil analog UK343-664 on a porcine model of acute pulmonary hypertension. Ann Thorac Surg2004; 77: 238–242.
25.
25 Atz AM Wessel DL . Sildenafil ameliorates effect of inhaled nitric oxide withdrawal. Anesthesiology1999; 91: 307–310.
26.
26 Mychaskiw G Sachdev V Heath BJ . Sildenafil (Viagra) facilitates weaning of inhaled nitric oxide following placement of a biventricular device. J Clin Anesth2001; 13: 218–220.
27.
27 Weimann J Ullrich R Hromi J . Sildenafil is a pulmonary vasodilator in awake lambs with acute pulmonary hypertension. Anesthesiology2000; 92: 1702–1712.
28.
28 Tanaka H Tajimi K Moritsune O Kobayashi K Okada K . Effects of milrinone on pulmonary vasculature in normal dogs and in dogs with pulmonary hypertension. Crit Care Med1991; 19: 68–74.
29.
29 Tanaka H Tajimi K Matsumoto A Kobayashi K . Vasodilatory effects of milrinone on pulmonary vasculature in dogs with pulmonary hypertension due to pulmonary embolism: a comparison with those of dopamine and dobutamine. Clin Exp Pharmacol Physiol1990; 17: 681–690.
30.
30 Tsai BM Wang M Pitcher JM Kher A Crisostomo P Meldrum DR . Zaprinast attenuates hypoxic pulmonary artery injury and causes less aortic relaxation than milrinone. Shock2005; 24: 417–420.
31.
31 Schermuly RT Krupnik E Tenor H . Coaerosolization of phosphodiesterase inhibitors markedly enhances the pulmonary vasodilatory response to inhaled iloprost in experimental pulmonary hypertension. Maintenance of lung selectivity. Am J Respir Crit Care Med2001; 164: 1694–1700.
32.
32 Matot I Gozal Y . Pulmonary responses to selective phosphodiesterase-5 and phosphodiesterase-3 inhibitors. Chest2004; 125: 644–651.
33.
33 Carteaux JP Roux S Siaghy M . Acute pulmonary hypertension after cardiopulmonary bypass in pig: the role of endogenous endothelin. Eur J Cardiothorac Surg1999; 15: 346–352.
34.
34 Trachte AL Lobato EB Urdaneta F . Oral sildenafil reduces pulmonary hypertension after cardiac surgery. Ann Thorac Surg2005; 79: 194–197.
35.
35 Ghofrani HA Voswinckel R Reichenberger F . Differences in hemodynamic and oxygenation responses to three different phosphodiesterase-5 inhibitors in patients with pulmonary arterial hypertension: a randomized prospective study. J Am Coll Cardiol2004; 44: 1488–1496.
36.
36 Lobato EB Beaver T Muehlschlegel J Kirby DS Klodell C Sidi A . Treatment with phosphodiesterase inhibitors type III and V: milrinone and sildenafil is an effective combination during thromboxane-induced acute pulmonary hypertension. Br J Anaesth2006; 96: 317–322.
37.
37 Steiner MK Preston IR Klinger JR Hill NS . Pulmonary hypertension: inhaled nitric oxide, sildenafil and natriuretic peptides. Curr Opin Pharmacol2005; 5: 245–250.
38.
38 Russell PC Emery CJ Cai YN Barer GR Howard P . Enhanced reactivity to bradykinin, angiotensin I and the effect of captopril in the pulmonary vasculature of chronically hypoxic rats. Eur Respir J1990; 3: 779–785.
39.
39 Madden BP Sheth A Ho TB Park JE Kanagasabay RR . Potential role for sildenafil in the management of perioperative pulmonary hypertension and right ventricular dysfunction after cardiac surgery. Br J Anaesth2004; 93: 155–156.
40.
40 Mikhail GW Prasad SK Li W . Clinical and haemodynamic effects of sildenafil in pulmonary hypertension: acute and mid-term effects. Eur Heart J2004; 25: 431–436.
41.
41 Rybalkin SD Yan C Bornfeldt KE Beavo JA . Cyclic GMP phosphodiesterases and regulation of smooth muscle function. Circ Res2003; 93: 280–291.
42.
42 Ockaili R Salloum F Hawkins J Kukreja RC . Sildenafil (Viagra) induces powerful cardioprotective effect via opening of mitochondrial K (ATP) channels in rabbits. Am J Physiol Heart Circ Physiol2002; 283: H1263–H1269.
43.
43 Kieler-Jensen N Milocco I Ricksten SE . Pulmonary vasodilation after heart transplantation. A comparison among prostacyclin, sodium nitroprusside, and nitroglycerin on right ventricular function and pulmonary selectivity. J Heart Lung Transplant1993; 12: 179–184.
44.
44 Lowson SM . Inhaled alternatives to nitric oxide. Anesthesiology2002; 96: 1504–1513.
