The Effect of Sildenafil on Pulmonary Embolism-Induced Oxidative Stress and Pulmonary Hypertension

Abstract

Acute pulmonary embolism (APE) is a major cause of pulmonary hypertension and death. We examined the effects of sildenafil on the hemodynamic changes caused by APE in anesthetized dogs. Sham-operated dogs (n = 3) received only saline. APE was induced by stepwise IV injections of 300 mum microspheres in amounts adjusted to increase mean pulmonary artery pressures by 20 mm Hg. Hemodynamic evaluation was performed at baseline, after APE was induced, and then after sildenafil 0.25 mg/kg (n = 8), or sildenafil 1 mg/kg + 0.3 mg . kg(-1) . h(-1) (n = 8) or saline (n = 9) infusions were started. Similar experiments were conducted to examine the effects of sildenafil in rat isolated perfused lung preparation. Plasma thiobarbituric acid reactive species were also determined in both studies to measure oxidative stress. Both doses of sildenafil reduced mean pulmonary artery pressures in dogs by approximately 8 to 16 mm Hg (both P < 0.05) and attenuated the increase in oxidative stress after APE. Mean arterial blood pressure remained unaltered after both doses of sildenafil. Sildenafil produced similar effects after APE in rat isolated perfused lung preparation. These findings indicate that IV sildenafil can selectively attenuate the increases in mean pulmonary artery pressures after APE, possibly through antioxidant mechanisms.

Molecular pathogenesis of pulmonary arterial hypertension

“…Recent results from studies using the dual endothelin receptor antagonist bosentan (27), as well as studies of a more selective ET A receptor antagonist (28), show alleviation of symptoms and slowing in the progression of disease in some patients. The reduced expression of NO synthase, the enzyme that generates NO (29), suggests that treatment with phosphodiesterase V inhibitors such as sildenafil to prolong the NO-mediated increase in cGMP would be effective in dilating PAs (30) as well as in therapies for IPAH and APAH associated with collagen vascular disease (31), congenital cardiac left-to-right shunts (30), persistent PH of the newborn (32), PAH associated with hemoglobinopathies such as sickle cell disease (33), and PH related to thrombotic and embolic disorders (34). While one study reported that sildenafil can improve PAH in patients refractory to i.v.…”

Pharmacological Activation of Soluble Guanylate Cyclase Protects the Heart Against Ischemic Injury

“…In conditions associated with increased free radical release and oxidative stress, intracellular cGMP accumulation has been shown to reduce tissue injury. 35 …”

Importance of Oxidative Stress in Pathogenesis and its Value in Diagnosis of Pulmonary Embolism Patients

“…Reactive arterial vasoconstriction leads to pulmonary hypertension. Acute pulmonary hypertension may cause right ventricular failure (acute cor pulmonale) and finally cardiogenic shock (14,16). In addition to all these events, the existence of oxidative stress in the pathophysiology of PE was shown by previous studies (6,(17)(18)(19).…”