Sildenafil in a cigarette smoke-induced model of COPD in the guinea-pig

Abstract

Sildenafil, a phosphodiesterase-5 inhibitor used to treat pulmonary hypertension, may have effects on pulmonary vessel structure and function. We evaluated the effects of sildenafil in a cigarette smoke (CS)-exposed model of chronic obstructive pulmonary disease (COPD).42 guinea-pigs were exposed to cigarette smoke or sham-exposed and treated with sildenafil or vehicle for 12 weeks, divided into four groups. Assessments included respiratory resistance, pulmonary artery pressure (PAP), right ventricle (RV) hypertrophy, endothelial function of the pulmonary artery and lung vessel and parenchymal morphometry. CS-exposed animals showed increased PAP, RV hypertrophy, raised respiratory resistance, airspace enlargement and intrapulmonary vessel remodelling. CS exposure also produced wall thickening, increased contractility and endothelial dysfunction in the main pulmonary artery. CS-exposed animals treated with sildenafil showed lower PAP and a trend to less RV hypertrophy than CS-exposed only animals. Furthermore, sildenafil preserved the intrapulmonary vessel density and attenuated the airspace enlargement induced by CS. No differences in gas exchange, respiratory resistance, endothelial function and vessel remodelling were observed.We conclude that in this experimental model of COPD, sildenafil prevents the development of pulmonary hypertension and contributes to preserve the parenchymal and vascular integrity, reinforcing the notion that the nitric oxide-cyclic guanosine monophosphate axis is perturbed by CS exposure.

Pulmonary vascular endothelium: the orchestra conductor in respiratory diseases

“…The pulmonary endothelium represents an interesting therapeutic target in COPD. Studies conducted in experimental models show that targeting the NO-cGMP signalling pathway with sGC stimulators [16] or phosphodiesterase-5 (PDE5) inhibitors [94,95] prevents the development of PH, pulmonary vascular remodelling and right-ventricle hypertrophy. Interestingly, sGC stimulators and PDE5 inhibitors also attenuated the development of pulmonary emphysema [16,95], an effect that was associated with a reduction in the number of neutrophils and alveolar macrophages in lung tissue, as well as a reduction in leukocyte adhesion [16].…”

Animal Models of Chronic Obstructive Pulmonary Disease

“…Other animal models include the guinea pig model, which has been shown to be susceptible to whole-body CS-exposures. CS exposure in guinea pigs induces several pulmonary and cardiovascular changes, such as pulmonary artery pressure, right ventricle hypertrophy, raised respiratory resistance, airspace enlargement, intrapulmonary vessel remodeling, loss of elastin and type III collagen in the alveolar walls, immune cell infiltration, protease and kinase activity [97][98][99]. Measurable emphysematous changes are also detected in rats following 2-months of whole body CS exposure [100].…”

“…Mice and rats exposed to CS have reduced body weight, fat mass, hind-limb skeletal muscles mass, grip strength and aerobic endurance [82,205]. CS exposure also enhances pulmonary artery wall thickening, increased contractility and endothelial dysfunction in guinea pigs [99]. Chronic CS exposure was recently shown to alter several cardiovascular parameters, such as enlarging ventricular end systolic and diastolic diameters, reducing myocardial and cardiomyocyte contractile function, and disrupting intracellular Ca 2+ homoeostasis, regulating fibrosis, apoptosis and mitochondrial damage [206].…”

“…Chronic CS exposure was recently shown to alter several cardiovascular parameters, such as enlarging ventricular end systolic and diastolic diameters, reducing myocardial and cardiomyocyte contractile function, and disrupting intracellular Ca 2+ homoeostasis, regulating fibrosis, apoptosis and mitochondrial damage [206]. Mice and guinea pig exposed to CS, displaying lung inflammation and emphysema, have pulmonary hypertension and significant impairments to right ventricular diastolic and systolic function and contractility [99,207]. CS in mice also causes hypertension, endothelial dysfunction and cardiac remodeling [208].…”

Hypoxic pulmonary vasoconstriction in COPD-associated pulmonary hypertension: been there, done that?

“…In fact, most clinical studies on the use of vasodilators in COPD have already shown that pulmonary vascular resistance can be lowered in the condition, but with very little benefit to the patient [18][19][20]. Even if some pulmonary hypertension drugs ultimately show benefit in COPD, it is probably not because they lower pulmonary artery pressure but rather because they improve maintenance of the pulmonary endothelium [21]. Unfortunately, the double-edged sword of HPV (improving oxygenation while at the same time raising pulmonary pressures) implicates that any intervention to alter p22phox levels in COPD is unlikely to benefit COPD patients.…”