doi:10.1016/j.ejphar.2005.09.022 
Copyright © 2005 Elsevier B.V. All rights reserved.
Hemodynamic effects of combined sildenafil and l-arginine during acute pulmonary embolism-induced pulmonary hypertension
Allethea R. Souza-Silvaa, Carlos A. Dias-Juniora, Juliana A.Uzuellia, Heitor Moreno, Jr.b, Paulo R. Evorac and Jose E. Tanus-Santosa, 
, 
aDepartment of Pharmacology, Faculty of Medicine of Ribeirao Preto, University of Sao Paulo, Av. Bandeirantes, 3900, Ribeirao Preto, SP, 14049-900, Brazil
bDepartment of Pharmacology, State University of Campinas, University of Sao Paulo, Av. Bandeirantes, 3900, Ribeirao Preto, SP, 14049-900, Brazil
cDivision of Experimental Surgery, Faculty of Medicine of Ribeirao Preto, University of Sao Paulo, Av. Bandeirantes, 3900, Ribeirao Preto, SP, 14049-900, Brazil
Received 9 May 2005;
revised 12 September 2005;
accepted 21 September 2005.
Available online 25 October 2005.
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Abstract
Sildenafil attenuates acute pulmonary embolism-induced pulmonary hypertension. However, the hemodynamic effects of sildenafil in combination with other vasodilators during acute pulmonary embolism have not been examined yet. In the present study, we examined the hemodynamic effects of combined sildenafil (0.25 mg/kg, i.v.) and l-arginine (100, 200, 500, and 1000 mg/kg/h, i.v.) in an anesthetized dog model of acute pulmonary embolism. Plasma nitrite/nitrate (NOx) and cGMP concentrations were determined using an ozone-based chemiluminescence assay and a commercial enzyme immunoassay, respectively. We found that l-arginine alone did not attenuate acute pulmonary embolism-induced pulmonary hypertension. However, significant decreases in mean pulmonary artery pressure were observed 30, 45, 60, and 75 min after the administration of sildenafil alone or after the combined administration of sildenafil and l-arginine (all P < 0.05). No significant differences among groups were observed in the respiratory parameters. While l-arginine significantly increased NOx concentrations, cGMP concentrations increased only when sildenafil was administered (all P < 0.05). These results suggest that while sildenafil attenuates acute pulmonary embolism-induced pulmonary hypertension, l-arginine does not enhance the beneficial hemodynamic effects of sildenafil. In addition, these findings suggest that stimulation of NO synthesis with l-arginine during acute pulmonary embolism does not produce beneficial effects.
Keywords: Acute pulmonary embolism; l-arginine; Nitric oxide; Phosphodiesterase-5 inhibitor; Pulmonary hypertension; Sildenafil
Fig. 1. Pulmonary vascular resistance index (PVRI) and mean pulmonary arterial pressure (MPAP) at baseline (BL), after 15 min (15E) and 30 min (30E) of acute pulmonary embolism, and after 15 min (15), 30 min (30), 45 min (45), 60 min (60) and 75 min (75) of l-arginine and sildenafil infusion in the Sild + Arg group (
), or only l-arginine infusion in the Arg group (●), or only sildenafil infusion in the Sild group (■), or saline infusion in the Control group (○). Values are the mean ± S.E.M. *P < 0.05 for Sild and Sild + Arg groups versus the control group.
Fig. 2. Systemic vascular resistance index (SVRI) and mean arterial pressure (MAP) at baseline (BL), after 15 min (15E) and 30 min (30E) of acute pulmonary embolism, and after 15 min (15), 30 min (30), 45 min (45), 60 min (60) and 75 min (75) of l-arginine and sildenafil infusion in the Sild + Arg group (), or only l-arginine infusion in the Arg group (●), or only sildenafil infusion in the Sild group (■), or saline infusion in the Control group (○). Values are the mean ± S.E.M. *P < 0.05 for Sild + Arg group versus the Control group.
Fig. 3. Cardiac index (CI) and heart rate (HR) at baseline (BL), after 15 min (15E) and 30 min (30E) of acute pulmonary embolism, and after 15 min (15), 30 min (30), 45 min (45), 60 min (60) and 75 min (75) of l-arginine and sildenafil infusion in the Sild + Arg group (), or only l-arginine infusion in the Arg group (●), or only sildenafil infusion in the Sild group (■), or and saline infusion in the Control group (○). Values are the mean ± S.E.M.
Fig. 4. Concentrations of nitrite/nitrate in plasma at baseline (open bars) and after 60 min (diagonal bars) of saline infusion in the Control group, or only sildenafil infusion in the Sild group, or only l-arginine infusion in the Arg group, or l-arginine and sildenafil infusion in the Sild + Arg group. Values are the mean ± S.E.M. *P < 0.05 versus baseline.
Fig. 5. Concentrations of cyclic GMP in plasma at baseline (open bars) and after 60 min (diagonal bars) of saline infusion in the Control group, or only sildenafil infusion in the Sild group, or only l-arginine infusion in the Arg group, or l-arginine and sildenafil infusion in the Sild + Arg group. Values are the mean ± S.E.M. *P < 0.05 versus baseline.
Table 1.
Respiratory responses at baseline, after 15 min (15 E) and 30 min (30 E) of acute pulmonary embolism, and after 15 min (15), 30 min (30), 45 min (45), 60 min (60) and 75 min (75) after l-arginine and/or sildenafil infusion in the Control (n = 8), Arg (N = 7), Sild (N = 8), and Sild + Arg (N = 8) groups
Values are mean ± S.E.M.
pH = arterial pH; PaCO2 = arterial CO2 tension; PaO2 = arterial O2 tension; SaO2 = arterial O2 saturation.
a P < 0.05 vs. 30E.
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