Pulmonary arterial hypertension (PAH) is characterized by vasoconstriction and by obstructive changes of the pulmonary vasculature including smooth muscle cell proliferation which leads to medial hypertrophy and subsequent luminal narrowing. Sildenafil, an orally active inhibitor of cGMP phosphodiesterase-type-5, exerts pulmonary vasodilator activity in PAH patients. We evaluated the effects of sildenafil on growth of cultured human pulmonary artery smooth muscle cells (PASMC). The results indicate that sildenafil reduced DNA synthesis stimulated by PDGF and dose dependently inhibited PASMC proliferation. These effects were paralleled by a progressive increase in cGMP content, followed by an accumulation of cAMP. The treatment with 8-bromo-cGMP or dibutyryl-cAMP mimicked all the effects of sildenafil. On the other hand, treatment of PASMC with inhibitors of cGMP-dependent protein kinase (PKG) or cAMP-dependent protein kinase (PKA) reversed the antiproliferative effect of sildenafil. In addition, sildenafil inhibited the phosphorylation of ERK, a converging point for several pathways leading to cell proliferation. This effect was partially reduced by PKG inhibition and completely abolished by PKA inhibition.We conclude that sildenafil exerts an antiproliferative effect on human PASMC that is mediated by an interaction between the cGMP-PKG and the cAMP-PKA activated pathways, leading to inhibition of PDGF-mediated activation of the ERK.

Twenty-four-hour home esophageal pH monitoring is proposed in order to study gastroesophageal reflux (GER) so that prolonged use of costly hospital equipment and staff can be curtailed and the diagnostic accuracy of the examination improved. Eighty-six patients affected by GER symptoms and 20 healthy volunteers underwent 24-hr home esophageal pH monitoring, x-rays, and endoscopy of the upper gastrointestinal tract to investigate reliability of outpatient recording. Fifteen more patients consecutively underwent out- and inpatient recording to detect possible differences between these methods in the two daily periods. Outpatient monitoring was well tolerated in 94.7% of the patients; 14.3% of them markedly reduced their routine activities. The range of normality of outpatient recording does not differ from that of inpatients. In the 15 patients who consecutively underwent out- and inpatient monitoring, no significant differences were reported. The sensitivity of 24-hr home esophageal pH recording is 0.85, the specificity 1, the accuracy for negative prediction 0.68, and the accuracy for positive prediction 1. The reliability of 24-hr home esophageal pH monitoring is comparable to inpatient recording. It allows hospital cost reduction and is also better tolerated by patients but has not greatly improved the diagnostic accuracy of the gastroesophageal reflux pH monitoring.

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