Search

Phosphodiesterases are a class of proteins that primarily modulate intracellular levels of cyclic nucleotides such as cGMP and cAMP. Phosphodiesterase-5 (PDE5) is mainly involved in the smooth muscle cell cGMP inactivation. Chemical inhibition of PDE5 has recently become a valid therapeutic option of nitric oxide pathway potentiation via cell cGMP availability. More specifically, PDE5 inhibition appears successful for the treatment of idiopathic pulmonary arterial hypertension. Additional intriguing therapeutic properties are a protective effect on the myocardium through antihypertrophic and antiapoptotic mechanisms and on vascular function by improving endothelial responsiveness and tolerance to myocardial ischemia-reperfusion injury. These effects imply a potential usefulness in the treatment of coronary artery disease and heart failure. Evidence currently available for considering PDE5 inhibition an additional therapeutic opportunity in cardiovascular disorders is provided.

Insulin is a hormone that possesses several therapeutic properties, some of which are only partially known and not definitely appreciated. Insulin appears to be an attractive therapeutic tool in several cardiovascular diseases and particularly in chronic heart failure (CHF). Insulin, in fact, exerts a direct effect on biological properties of myocytes by increasing the transmembrane glucose transport through glucose-specific insulin-regulated receptors, whose gene expression is down-regulated since the initial stages of myocyte hypertrophy. In addition, a hormonal antiapoptotic molecular effect has also been reported. These effects explain, at least in part, the observed improvement in ejection fraction and cardiac output in CHF patients when given insulin. Vasodilation is the most remarkable peripheral effect of insulin that seems to be due to a direct activity on vascular smooth muscle cells and, more remarkably, on an increased release of endothelium-derived relaxing factors, such as nitric oxide and vasodilator prostaglandins. In accordance with most recent clinical observations, this endothelial modulatory activity is not limited to the systemic circulation but involves also the pulmonary one and the alveolar-capillary interface, resulting in a facilitation of the alveolar gas diffusion. Such an effect on alveolar gas diffusion appears to play a major role in CHF patients. The present review focuses on the pathophysiological mechanisms underlying the insulin benefits, and emphasizes the hormone therapeutic applicability in a CHF setting.

Heart failure increases the resistance to gas transfer across the alveolar-capillary interface. In different experimental conditions of vascular capillary injury, peculiar anatomical and functional abnormalities of the alveolar unit have been reported and consist of a disruption of its anatomical configuration and of a loss of fluid-flux regulation and gas exchange efficiency (i.e. "stress failure" of the alveolar-capillary membrane). In heart failure, the pathophysiological relevance of these changes has been only recently appreciated. Alveolar-capillary membrane conductance and capillary blood volume are subcomponents of lung diffusion capacity. A reduction of the former with an increase of the latter and consequent impairment of gas exchange are typical of heart failure syndrome. Alveolar-capillary membrane conductance abnormalities have been shown to be a sensitive index of the underlying lung tissue damage, bring an independent prognostic information and play a significant role in the pathogenesis of exercise limitation and ventilatory abnormalities. This review examines the current knowledge on this topic.