Am Thereapy In Pulmonary Hypertension

Primary pulmonary hypertension (PPH) is a rare but life-threatening disease characterized by progressive pulmonary hypertension, ultimately producing right ventricular failure and death (Rich et al., 1987). Median survival is considered to be 2.8 years from the time of diagnosis. Because the presence of endothelial injury in the pulmonary vascular bed develops pulmonary vasoconstriction, smooth muscle cell proliferation, and in situ thrombosis (Archer et al., 2000), a variety of vasodilators, anti-proliferative agents, and anticoagulants have been proposed as therapeutic agents of PPH. Despite therapeutic medical advances including prostacyclin therapy (Barst et al., 1996; McLaughlin et al., 1998), some patients ultimately require heart-lung or lung transplantation (Pasque et al., 1991). Therefore, a novel therapeutic strategy is desirable for the treatment of pulmonary hypertension including PPH. Experimental studies have shown that AM plays an important role in the regulation of pulmonary vascular tone and vascular remodeling. Thus, we investigated the therapeutic potential of AM administration for the treatment of pulmonary hypertension in humans. This review will summarize the effects of two types of AM delivery systems: intravenous administration and inhalation of AM peptide.

(1) Intravenous Administration

Intralobar arterial infusion of AM causes dose-related decreases in pulmonary vascular resistance under conditions of high pulmonary vascular tone (Heaton et al. 1995; Lippton et al., 1994). The vasodilatory effect is mediated by cAMP-dependent and nitric oxide-dependent mechanisms. Thus, AM is known to be one of the most potent endogenous vasodilators in the pulmonary vascular bed. However, little information is available regarding the hemodynamic effects of intravenously administered AM in patients with pulmonary hypertension. Accordingly, we examined the hemodynamic and hormonal responses to intravenous infusion of AM (0.05 //g/kg/min) or placebo were examined in 13 patients with pulmonary arterial hypertension including PPH (Nagaya et al. 2000b). Because AM-induced hypotension may cause adverse effects in patients with pulmonary hypertension, we used a relatively low dose of AM. Intravenous infusion of AM increased plasma AM level in patients with pulmonary hypertension (15 ± 1 to 48 ± 8 fmol/ml). Infusion of AM significantly decreased pulmonary vascular resistance by 32% without inducing a marked hypotension. The hemodynamic effects of AM lasted at least 15 min after the end of infusion. These results suggest that AM has potent, relatively long-lasting pulmonary vasodilator activities in patients with pulmonary hypertension. We have shown that administered AM increases plasma cAMP, but not cGMP, in patients with pulmonary hypertension, in association with its hemodynamic effects. The increase in cAMP in smooth muscle cells by AM activates protein kinase A, resulting in the decrease in calcium content in smooth muscle cells. It is therefore possible that AM may relax vascular smooth muscle through a cAMP/protein kinase A-dependent mechanism. On the other hand, Nossaman et al have shown that AM regulates pulmonary vascular tone in rats through an endothelium-derived nitric oxide-dependent mechanism (Nossaman et al. 1996). Because the vascular effects of AM are known to vary with species and vascular regions, further studies are necessary to elucidate the mechanisms responsible for pulmonary vasodilator activity of AM in humans.

Intravenous infusion of AM markedly increased cardiac index in patients with pulmonary hypertension (Nagaya et al. 2000b), consistent with our previous results from left sided heart failure. Considering the strong vasodilator activity of AM in the systemic and pulmonary vasculature, the significant decrease in cardiac afterload may be responsible for increased cardiac index with AM. On the other hand, AM produces a positive inotropic action through cAMP-independent mechanisms. These findings suggest that the increase in cardiac index may be attributable not only to a fall in cardiac afterload but also to the direct positive inotropic action of AM. It appears that a number of similarities in pharmacological actions, i.e. vasodilatation, cardiac effect, and cAMP production, exist between AM and prostacyclin that is used for reducing pulmonary resistance in PPH. Unlike prostacyclin, however, AM has diuretic and natriuretic activities. AM inhibits inflammation and aldosterone production (Clementi et al., 1999; Yamaguchi et al. 1995). Thus, these biological effects may be the advantages of AM over prostacyclin in respect of therapeutic effectiveness. Exogenously administered AM at a pharmacological level increased plasma cAMP in association with hemodynamic effects. Thus, additional administration of AM may be effective in patients with pulmonary hypertension.

(2) Inhalation Therapy

The goal of vasodilator therapy for patients with PPH is to reduce pulmonary vascular resistance without producing systemic hypotension, and improve quality of life and survival. We have shown that intravenous administration of AM markedly decreases pulmonary vascular resistance in patients with pulmonary hypertension (Nagaya et al. 2000b). Nevertheless, systemically administered AM decreases systemic arterial pressure, which may be harmful in treating patients with PPH. Recently, inhalation of aerosolized prostacyclin and its analogue, iloprost, has been shown to cause pulmonary vasodilation without systemic hypotension in patients with PPH (Hoeper et al.

2000). In addition, inhalant application of vasodilators does not impair gas exchange because the ventilation-matched deposition of drug in the alveoli causes pulmonary vasodilation matched to ventilated areas. In clinical settings, inhalation therapy may be more simple, noninvasive, and comfortable than continuous intravenous infusion therapy. Thus, the purpose of this study was to investigate the effects of AM inhalation on hemodynamics and exercise capacity in patients with PPH.

Interestingly, Champion et al have shown that intratracheal gene transfer of calcitonin gene-related peptide (CGRP), a member of the same peptide family as AM, to bronchial epithelial cells attenuates chronic hypoxia-induced pulmonary hypertension in the mouse (Champion et al., 2000). These results raise the possibility that intratracheal delivery of a vasodilator peptide may be sufficient to alter pulmonary vascular function. In fact, inhalation of AM significantly decreased pulmonary vascular resistance in patients with pulmonary hypertension, whereas it did not alter systemic arterial pressure or systemic vascular resistance (Nagaya et al., 2004). The ratio of pulmonary vascular resistance to systemic vascular resistance was significantly reduced by AM inhalation. These results suggest that inhaled AM improves hemodynamics with pulmonary selectivity. This is consistent with earlier findings that inhaled prostacyclin or its analogue, iloprost, acts transepithelially with pulmonary selectivity and improves pulmonary hypertension.

We examined the long-term effects of inhaled AM in monocrotaline (MCT)-induced pulmonary hypertension rats (Nagaya et al., 2003). AM or saline was inhaled as an aerosol using an ultrasonic nebulizer, for 30 min, 4 times a day. Repeated inhalation of AM for three weeks markedly decreased mean pulmonary arterial pressure and pulmonary vascular resistance in MCT rats without systemic hypotension. The potent, long-lasting pulmonary vasodilator effect of inhaled AM may contribute to the strong inhibition of the development of pulmonary hypertension. In addition, considering intermittent delivery of AM to the lungs, the chronic effects of inhaled AM appear to go beyond acute pulmonary vasodilation. Inhalation of AM inhibited an increase in the medial wall thickness of peripheral pulmonary arteries of MCT rats. In vitro studies have shown that AM inhibits the migration and proliferation of vascular smooth muscle cells (Horio et al., 1995; Kano et al., 1996). Given the known potent vasoprotective effects of AM such as vasodilation and inhibition of smooth muscle cell migration and proliferation, it is interesting to speculate that AM trapped in the bronchial epithelium or alveoli leaks to the pulmonary arteries to maintain pulmonary vascular integrity in MCT rats. Importantly, Kaplan-Meier analysis demonstrated that the 6-week survival rate for MCT rats treated with aerosolized AM was significantly high (70%) as compared with 10% in those given saline (Nagaya et al., 2003). Thus, treatment with aerosolized AM may be an alternative approach for severe pulmonary hypertension that is refractory to conventional therapy. Although further studies are necessary to maximize the efficiency and reproducibility of pulmonary AM delivery, combining AM inhalation therapy with other modalities that have a different mode of action may have beneficial effects in patients with PPH.

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