Sildenafil Improves the Beneficial Haemodynamic Effects of Intravenous Nitrite Infusion during Acute Pulmonary Embolism

Abstract

Acute pulmonary embolism produces acute pulmonary hypertension, which can be counteracted by activating the nitric oxide-cyclic guanosine 3 ′ ,5 ′ -monophosphate (cGMP) pathway. While previous studies have shown that sildenafil (an inhibitor of cGMP-specific phosphodiesterase type 5) or nitrite (a storage molecule for nitric oxide) produces beneficial effects during acute pulmonary embolism, no previous study has examined whether the combination of these drugs can produce additive effects. Here, we expand previous findings and examine whether sildenafil enhances the beneficial haemodynamic effects produced by a low-dose infusion of nitrite in a dog model of acute pulmonary embolism. Haemodynamic and arterial blood gas evaluations were performed in non-embolized dogs treated with saline (n = 4), and in embolized dogs (intravenous injections of microspheres) that received nitrite (6.75 μ mol/kg intravenously over 15 min. followed by 0.28 μ mol/kg/min.) and sildenafil (0.25 mg/kg over 30 min.; n = 8), or nitrite followed by saline (n = 8), or saline followed by sildenafil (n = 7), or only saline (n = 8). Plasma thiobarbituric acid-reactive substances (TBARS) concentrations were determined using a fluorometric method. Acute pulmonary embolism increased pulmonary artery pressure by ∼ 24 mmHg. While the infusion of nitrite or sildenafil infusions reversed this increase by ∼ 42% (both P < 0.05), the combined infusion of both drugs reversed this increase by ∼ 58% (P < 0.05). Similar effects were seen on the pulmonary vascular resistance index. Nitrite or sildenafil alone produced no significant hypotension. However, the combined infusion of both drugs caused transient hypotension (P < 0.05). Both dugs, either alone or combined, blunted the increase in TBARS concentrations caused by acute pulmonary embolism (all P < 0.05). These results suggest that sildenafil improves the beneficial haemodynamic effects of nitrite during acute pulmonary embolism.Acute pulmonary embolism is a serious complication resulting from the migration of embolus to the lungs and obstruction of pulmonary vessels. This critical condition is a leading cause of death [1], which results from acute right heart failure and circulatory shock [2]. The understanding that acute pulmonary embolism-induced pulmonary hypertension results from interactions of multiple mechanisms, including active pulmonary vasoconstriction, has motivated some investigators to study new pharmacological interventions that could attenuate the haemodynamic changes associated with this condition [3,4]. Particularly, reversing the pulmonary vasoconstrictor response by activating the nitric oxide-cyclic guanosine 3 ′ ,5 ′ -monophosphate (cGMP) pathway has been shown to improve haemodynamics in different animal models of pulmonary embolism [5][6][7][8][9][10][11][12][13][14]. However, few studies have addressed the hypothesis that the combination of drugs that produce beneficial effects can increase the effects produced by each drug alone.We were first to show that sildenafil ...

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