title: Pulmonary hemodynamic response to acute combination and monotherapy with sildenafil and brain natriuretic peptide in rats with monocrotaline-induced pulmonary hypertension.
abstract: BACKGROUND
  The lungs of patients with pulmonary arterial hypertension (PAH) exhibit decreased bioavailability of nitric oxide and downstream signaling through cyclic guanosine monophosphate (cGMP). Therapies that enhance cGMP-mediated vasodilation have shown efficacy in treating PAH. We tested the hypothesis that combination therapy with sildenafil, a cGMP phosphodiesterase type 5 inhibitor, and brain natriuretic peptide (BNP), a receptor-mediated guanosine cyclase stimulator, synergistically attenuates monocrotaline-induced PAH in rats compared with either monotherapy.
  
  
  METHODS
  Adult male Sprague-Dawley rats were subcutaneously injected with monocrotaline (n = 41, 50 mg/kg). After approximately 4 weeks, the rats were infused intravenously with vehicle solution, sildenafil (42 and 85 microg/kg/min), or BNP (50 and 100 ng/kg/min), alone and in varied combination. The primary endpoint was the relative change in right ventricular systolic pressure (RVSP) and mean arterial systemic pressure (MAP). Secondary endpoints included heart rate and dP/dt.
  
  
  RESULTS
  Vehicle infusions did not alter hemodynamic variables. Sildenafil85 (85 microg/kg/min) alone decreased RVSP (-16.6 +/- 5.6%) and decreased MAP (-4.0 +/- 4.7%). BNP50 (50 ng/kg/min) and BNP100 (100 ng/kg/min) decreased RVSP (-23.3 +/- 5.7% and -27.1 +/- 2.9%, respectively) and MAP (-6.4 +/- 5.8% and -14.3 +/- 4.1%, respectively). Combination therapy with sildenafil42 and BNP50 decreased RVSP (-20.7 +/- 5.6%) and showed a lessened systemic effect (MAP = -11.6 +/- 5.9%). Combination therapy with sildenafil85 and BNP100 decreased RVSP (-27.6 +/- 3.2%, P = NS) and showed increased systemic effect (MAP = -20.7 +/- 3.1%, P < 0.05) in comparison with sildenafil85.
  
  
  CONCLUSIONS
  This study suggests that intravenous administration of both sildenafil and BNP monotherapy produces significant improvement in RVSP, making them potentially viable options for the treatment of PAH, whereas combination therapy produces no additional improvement in pulmonary hemodynamics.
authors.affiliation: Department of Internal Medicine, University of Missouri School of Medicine, University of Missouri, Columbia, Missouri 65212, USA. carlinoc@health.missouri.edu
authors.forename: Carl
authors.initials: C
authors.lastname: Carlino
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Tobias
authors.forename: Rebecca I
authors.initials: RI
authors.lastname: Schneider
authors.forename: Randall L
authors.initials: RL
authors.lastname: Heller
authors.forename: Martin A
authors.initials: MA
authors.lastname: Alpert
authors.forename: Ryan E
authors.initials: RE
authors.lastname: Grueber
authors.forename: Kevin C
authors.initials: KC
authors.lastname: Dellsperger
authors.forename: Vincent G
authors.initials: VG
authors.lastname: Demarco
mesh_terms: D000818:Animals; D004359:Drug Therapy, Combination; D006439:Hemodynamics / Q000187:drug effects* / Q000502:physiology; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D016686:Monocrotaline / Q000633:toxicity*; D020097:Natriuretic Peptide, Brain / Q000008:administration & dosage*; D010879:Piperazines / Q000008:administration & dosage*; D011687:Purines / Q000008:administration & dosage; D051381:Rats; D017207:Rats, Sprague-Dawley; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000008:administration & dosage*; D013997:Time Factors
chemical_list: D010879:Piperazines; D011687:Purines; D013450:Sulfones; D020097:Natriuretic Peptide, Brain; D016686:Monocrotaline; D000068677:Sildenafil Citrate