title: Synergistic effects of ANP and sildenafil on cGMP levels and amelioration of acute hypoxic pulmonary hypertension.
abstract: We hypothesized that the phosphodiesterase 5 inhibitor, sildenafil, and the guanosine cyclase stimulator, atrial natriuretic peptide (ANP), would act synergistically to increase cGMP levels and blunt hypoxic pulmonary hypertension in rats, because these compounds act via different mechanisms to increase the intracellular second messenger. Acute hypoxia: Adult Sprague-Dawley rats were gavaged with sildenafil (1 mg/ kg) or vehicle and exposed to acute hypoxia with and without ANP (10(-8)-10(-5) M ). Sildenafil decreased systemic blood pressure (103 +/- 10 vs. 87 +/- 6 mm Hg, P < 0.001) and blunted the hypoxia-induced increase in right ventricular systolic pressure (RVSP; percent increase 73.7% +/- 9.4% in sildenafil-treated rats vs. 117.2% +/- 21.1% in vehicle-treated rats, P = 0.03). Also, ANP and sildenafil had synergistic effects on blunting the hypoxia-induced increase in RVSP (P < 0.001) and on rising plasma cGMP levels (P < 0.05). Chronic hypoxia: Other rats were exposed to prolonged hypoxia (3 weeks, 0.5 atm) after subcutaneous implantation of a sustained-release pellet containing lower (2.5 mg), or higher (25 mg) doses of sildenafil, or placebo. Higher-dose, but not lower-dose sildenafil blunted the chronic hypoxia-induced increase in RVSP (P = 0.006). RVSP and plasma sildenafil levels were inversely correlated in hypoxic rats (r(2) = 0.68, P = 0.044). Lung cGMP levels were increased by both chronic hypoxia and sildenafil, with the greatest increase achieved by the combination. Plasma and right ventricular (RV) cGMP levels were increased by hypoxia, but sildenafil had no effect. RV hypertrophy and pulmonary artery muscularization were also unaffected by sildenafil. In conclusion, sildenafil and ANP have synergistic effects on the blunting of hypoxia-induced pulmonary vasoconstriction. During chronic hypoxia, sildenafil normalizes RVSP, but in the doses used, sildenafil has no effect on RV hypertrophy or pulmonary vascular remodeling.
authors.affiliation: Department of Pulmonary, Critical Care and Sleep Medicine, Tufts-New England Medical Center, 750 Washington Street, Box #257, Boston, MA 02111, USA.
authors.forename: Ioana R
authors.initials: IR
authors.lastname: Preston
authors.forename: Nicholas S
authors.initials: NS
authors.lastname: Hill
authors.forename: Lee S
authors.initials: LS
authors.lastname: Gambardella
authors.forename: Rod R
authors.initials: RR
authors.lastname: Warburton
authors.forename: James R
authors.initials: JR
authors.lastname: Klinger
mesh_terms: D000208:Acute Disease; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000008:administration & dosage / Q000627:therapeutic use*; D006152:Cyclic GMP / Q000378:metabolism*; D004357:Drug Synergism; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy*; D000860:Hypoxia / Q000188:drug therapy*; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D010879:Piperazines / Q000008:administration & dosage / Q000627:therapeutic use*; D011687:Purines; D051381:Rats; D017207:Rats, Sprague-Dawley; D000068677:Sildenafil Citrate; D013450:Sulfones
chemical_list: D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D009320:Atrial Natriuretic Factor; D000068677:Sildenafil Citrate; D006152:Cyclic GMP