Searching the Ideal Inhaled Vasodilator: From Nitric Oxide to Prostacyclin

Abstract

Today, the technique to directly administer vasodilators via the airway to treat pulmonary hypertension and to improve pulmonary gas exchange is widely accepted among clinicians. The flood of scientific work focussing on this new therapeutic concept had been initiated by a fundamental new observation by Pepke-Zaba [1]and Frostell in 1991 [2]: Both scientists reported, that inhalation of exogenous nitric oxide (NO) gas selectively dilates pulmonary vessels without a concomittant systemic vasodilation. No more than another decade ago NO was identified as an important endogenous vasodilator [3]while having merely been regarded an environmental pollutant before that time. Although inhaled NO proved to be efficacious, alternatives were sought-after due to NO’s potential side-effects. In search for the ideal inhaled vasodilator another group of endogenous mediators – the prostanoids – came into the focus of interest. The evidence for safety and efficacy of inhaled prostanoids is – among a lot of other valuable work – based on a series of experimental and clinical investigations that have been performed or designed at the Institute for Surgical Research under the guidance and mentorship of Prof. Dr. med. Dr. h.c. mult. K. Messmer [4-19]. In the following, the current and newly emerging clinical applications of inhaled prostanoids and the experimental data which they are based on, will be reviewed.

Improved Ventricular Function during Inhalation of PGI₂ Aerosol Partly Relies on Enhanced Myocardial Contractility

“…Arterial and mixed-venous blood samples were taken simultaneously in air-free syringes, cooled and analyzed instantly in duplicate; pO 2 and pCO 2 were measured with a blood gas analyzer (Chiron Diagnostics, Fernwald, Germany). Hemoglobin concentration and hemoglobin O 2 saturation were measured by absorbance spectrophotometer (Instrumentation Laboratory, Lexington, Mass., USA).…”

“…Systemic effects after spill over of inhaled PGI 2 have been previously reported [6,19] . A direct action of EPO and ILO on the cardiomyocyte could result from activation of a PGI 2 cyclase of the sarcolemma in the myocytes. Since experimental administration of ß-blockers in isolated ventricles was shown to notably reduce the positive inotropic effects of PGI 2 [17] , PGI 2 might also exert part of its inotropic action via ß-receptors, which are also located on the surface of the myocytes.…”

“…The inhalation of short-acting vasodilator drugs is attractive to treat severe respiratory and cardiac disease: They may cause effective dilation of vessels within the lungs without affecting vascular tone in the systemic vasculature [1,2] . Prostacyclin (PGI 2 ) is ubiquitous in the human body.…”

“…Originally, it has been shown to safely, effectively and selectively dilate pulmonary vessels in experimental and clinical pulmonary hypertension of various origins [3][4][5][6] . Finally, PGI 2 and its analogs, epoprostenol (EPO) and the longer acting iloprost (ILO), have been shown to improve pulmonary hemodynamics, right heart function, and exercise capacity in patients with primary pulmonary hypertension [4,7] . So far, investigators have attributed the positive effects of inhaled PGI 2 -analogs mainly to the reduction in right ventricular afterload and -to some extent -of preload, as well.…”

“…Since PGI 2 exerts its effects on pulmonary vascular tone via elevation of intracellular levels of cyclic adenosine monophosphate in the vascular smooth muscle cells, an additional cyclic adenosine monophosphate-mediated positive inotropic effect of PGI 2 -analogs has been suggested [9,10] . In a recent experimental investigation, we have demonstrated that the intravenous administration of both EPO and ILO equally increases left ventricular myocardial contractility qualifying PGI 2 -analogs as inodilators [11] .…”