Pulmonary hemodynamic response to acute combination and monotherapy with sildenafil and brain natriuretic peptide in rats with monocrotaline-induced pulmonary hypertension

Carl Carlino, Joseph D. Tobias, Rebecca I. Schneider, Randall L. Heller, Martin A. Alpert, Ryan E. Grueber, Kevin C Dellsperger, Vincent G. Demarco

Research output: Contribution to journalArticle

8 Citations (Scopus)

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 μg/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 μg/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 BNP 50 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.

Original languageEnglish (US)
Pages (from-to)55-59
Number of pages5
JournalAmerican Journal of the Medical Sciences
Volume339
Issue number1
DOIs
StatePublished - Jan 2010

Fingerprint

Monocrotaline
Ventricular Pressure
Pulmonary Hypertension
Hemodynamics
Arterial Pressure
Blood Pressure
Lung
Brain Natriuretic Peptide
Cyclic GMP
Therapeutics
Phosphodiesterase 5 Inhibitors
Guanosine
Vasodilation
Intravenous Administration
Biological Availability
Sprague Dawley Rats
Sildenafil Citrate
rat natriuretic peptide precursor type B
Nitric Oxide
Heart Rate

Keywords

  • Cyclic guanosine monophosphate
  • Natriuretic peptides
  • Phosphodiesterase inhibitors
  • Pulmonary arterial hypertension
  • Sildenafil

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Pulmonary hemodynamic response to acute combination and monotherapy with sildenafil and brain natriuretic peptide in rats with monocrotaline-induced pulmonary hypertension. / Carlino, Carl; Tobias, Joseph D.; Schneider, Rebecca I.; Heller, Randall L.; Alpert, Martin A.; Grueber, Ryan E.; Dellsperger, Kevin C; Demarco, Vincent G.

In: American Journal of the Medical Sciences, Vol. 339, No. 1, 01.2010, p. 55-59.

Research output: Contribution to journalArticle

Carlino, Carl ; Tobias, Joseph D. ; Schneider, Rebecca I. ; Heller, Randall L. ; Alpert, Martin A. ; Grueber, Ryan E. ; Dellsperger, Kevin C ; Demarco, Vincent G. / Pulmonary hemodynamic response to acute combination and monotherapy with sildenafil and brain natriuretic peptide in rats with monocrotaline-induced pulmonary hypertension. In: American Journal of the Medical Sciences. 2010 ; Vol. 339, No. 1. pp. 55-59.
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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 μg/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 μg/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 BNP 50 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.",
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T1 - Pulmonary hemodynamic response to acute combination and monotherapy with sildenafil and brain natriuretic peptide in rats with monocrotaline-induced pulmonary hypertension

AU - Carlino, Carl

AU - Tobias, Joseph D.

AU - Schneider, Rebecca I.

AU - Heller, Randall L.

AU - Alpert, Martin A.

AU - Grueber, Ryan E.

AU - Dellsperger, Kevin C

AU - Demarco, Vincent G.

PY - 2010/1

Y1 - 2010/1

N2 - 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 μg/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 μg/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 BNP 50 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.

AB - 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 μg/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 μg/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 BNP 50 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.

KW - Cyclic guanosine monophosphate

KW - Natriuretic peptides

KW - Phosphodiesterase inhibitors

KW - Pulmonary arterial hypertension

KW - Sildenafil

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