Sildenafil Preserves Lung Endothelial Function and Prevents Pulmonary Vascular Remodeling in a Rat Model of Diastolic Heart Failure

Abstract

Background-Pulmonary hypertension as a frequent complication of left heart disease (PH-LHD) is characterized by lung endothelial dysfunction and vascular remodeling. Although PH-LHD contributes to morbidity and mortality in heart failure, established therapies for PH-LHD are lacking. We tested the effect of chronic sildenafil treatment in an experimental model of PH-LHD. Methods and Results-In Sprague-Dawley rats, PH-LHD was induced by supracoronary aortic banding. Oral sildenafil treatment (60 mg/kg daily) was initiated after 7 days, and lung endothelial function (nϭ5), vascular remodeling, and right ventricular function (nϭ11 each) were analyzed 9 weeks after banding. As compared with sham-operated controls, aortic banding induced pulmonary hypertension and lung endothelial dysfunction evident as lack of endothelial nitric oxide production and endothelium-dependent vasodilation. These changes were associated with an increased pulmonary vascular resistance, medial thickening, and biventricular cardiac hypertrophy. Sildenafil treatment largely attenuated these pathological changes and was not associated with detectable adverse effects pertinent to lung vascular barrier function, edema formation, or systemic hemodynamics. Conclusions-Our data identify sildenafil as a promising therapy for PH-LHD. In light of its documented protective effects at the myocardial level in heart failure, sildenafil presents a particularly attractive strategy in that it simultaneously targets cardiac remodeling and secondary PH-LHD. (Circ Heart Fail. 2011;4:198-206.)Key Words: congestive heart failure Ⅲ pulmonary hypertension Ⅲ vascular remodeling Ⅲ endothelial dysfunction I n 60% to 80% of patients, congestive heart failure (CHF) is complicated by pulmonary hypertension (PH). 1,2 Accordingly, PH owing to left heart disease (PH-LHD) constitutes one of the most common forms of PH. PH-LHD is not solely caused by a "passive" increase in pulmonary vascular pressures but is frequently aggravated by a concomitant rise in pulmonary vascular resistance (PVR). 2 This "reactive" increment in PVR further increases right ventricular (RV) afterload, promoting RV dysfunction and ultimately failure. Clinical Perspective on p 206Although underlying causes differ, PH-LHD shares the common pathophysiological characteristics of pulmonary arterial hypertension (PAH): Lung vascular remodeling is manifest in experimental heart failure 3 and in lungs from patients with CHF. 4 Lung endothelial dysfunction is evident in animal models of CHF as impaired endothelium-dependent vasodilation 5 and was similarly observed in patients with CHF caused by severe mitral stenosis. 6 The resulting imbalance between endothelium-derived vasoconstrictive and vasodilatory mediators is considered to constitute the major driving force for the increase in lung vascular tone and pulmonary vascular remodeling. 7 Although the past decade has witnessed the introduction of a series of innovative strategies for the treatment of PAH, approved therapeutic options for non-PAH forms of P...

Pulmonary Hypertension in Heart Failure Preserved Ejection Fraction

“…Interestingly, associated with severe LV diastolic dysfunction, there was a significant increase of lung weight that was not merely the result of an increase of lung water, but rather the consequence of intrinsic tissue and vascular changes. 8 Additional findings obtained in a similar experimental model were a clear stress failure of small capillaries and alveoli 29 The significance of these findings in humans is still under scrutiny, and a severity-related definition of molecular and cellular pathways implicated in the capillary lung disease seems to be a missing step for knowledge advancement on left-sided PH consequences and their role in the progression of the disease.…”

Endothelial Dysfunction and Lung Capillary Injury in Cardiovascular Diseases

“…PDE-5 activity is increased in various experimental models of PH 61 . In remarkable experiments by Yin et al, sildenafil given to a rat model of PH secondary to massive left ventricular hypertrophy was capable of reversing endothelial dysfunction and alveolar capillary remodeling, including capillary and small artery thickness that reversed their structural changes to normal after active drug therapy 62 .…”

Pulmonary veins in the normal lung and pulmonary hypertension due to left heart disease

“…The model based on AOB-induced PH-LHD has been used to describe the pulmonary venous and arterial remodeling and to identify mechanisms involved in the pathogenesis of PH following left ventricular dysfunction in rats (13,14,35). We therefore performed AOB or sham operations in rats, followed, 9 wk later, by invasive hemodynamic measurements and morphometric/morphological studies.…”

“…PH-LHD was induced in juvenile rats (92 Ϯ 9.7 g in weight) by supracoronary aortic banding (AOB) as previously described (35). Isoflurane was used as the anesthetic for all procedures.…”