Acute vasodilator testing in idiopathic pulmonary arterial hypertension: must we take NO for the answer?

he earliest clinical descriptions of primary pulmonary hypertension, now known as idiopathic pulmonary arterial hypertension (IPAH), were accompanied by the hypothesis that pulmonary vasoconstriction was one of its key pathophysiological elements [1] and that vasodilators could, therefore, be therapeutically useful. In support of this concept, DRESDALE et al. [2] first reported attenuation of pulmonary hypertension with the systemic vasodilator tolazo-line, while HARRIS [3] and WOOD et al. [4] achieved more preferential pulmonary vasodilation with acetylcholine infused directly in the pulmonary artery. Only years later, when FURCHGOTT and ZAWADZKI [5] demonstrated that acetylcholine-induced vasodilation was mediated by nitric oxide (NO), an observation for which R.F. Furchgott shared the Nobel Prize in Medicine in 1998, was the importance of endothelial dysfunction in the pathogenesis of IPAH appreciated , and the rationale for testing acute vasoreactivity in IPAH using inhaled NO (iNO) or other endothelial-derived vasodi-lator substances established. When RICH and BRUNDAGE [6] treated patients with high-dose calcium channel blockers (CCBs) in an attempt to reverse pulmonary vasoconstriction it became clear, however, that only a subgroup of IPAH patients responded with haemo-dynamic and clinical improvement. Furthermore, since it was impossible to identify a priori any clinical or haemodynamic predictors for a positive responder status, nonresponders were subjected both acutely and chronically to the risks of potent systemic vasodilator agents without any chance of benefit. Additionally, the criteria for ''acute response'' that was predictive of at least a reasonable chance of achieving a favourable long-term response to treatment with CCB was not clear until SITBON et al. [7] retrospectively analysed their experience with acute vasodilator testing and long-term treatment with CCBs and suggested that a near normalisation of pulmonary haemodynamics in response to acute testing is needed in order to warrant consideration of long-term CCB therapy. This response, a fall in mean pulmonary artery pressure of o10 mmHg to a level ,40 mmHg with an unchanged or increased cardiac output and unchanged systemic blood pressure [8, 9], while fairly uncommon in IPAH (,10% of patients) and almost unheard of in other forms of pulmonary arterial hypertension (PAH), is the criteria suggested in published guidelines for ''positive'' acute vasoreactivity testing, and should be met before CCBs are prescribed to treat PAH. The ideal drug to assess acute vasoreactivity should be potent, titratable, short acting and convenient to administer. It should also be widely available, making cost an important criterion, as well. Intravenous epoprostenol and adenosine, …