Brief adrenomedullin inhalation leads to sustained reduction of pulmonary artery pressure

Abstract

The effect of aerosolised adrenomedullin (ADM), a potent vasodilator peptide, on pulmonary artery pressure was studied for 24 h in a surfactant-depleted piglet model. Animals received either aerosolised ADM (50 ng?kg -1 ?min -1 , ADM, n=6), or aerosolised normal saline solution (control, n=6). Aerosol therapy was performed for a 2 h treatment period followed by a 22 h observation period. Ventilator settings were adapted to keep arterial oxygen tension and carbon dioxide arterial tension between 13.3-14.6 kPa and 4.9-5.7 kPa, respectively.Aerosolised ADM reduced mean pulmonary artery pressure (MPAP) compared with the control group (end-point median 24 h after therapy start: DMPAP -14.0 versus -8.0 mmHg; 23.5 h after therapy start). After therapy start, mean systemic arterial pressure (MAP) was not significantly different between the groups (end-point median: MAP ADM 70 (61/74) versus control 72 (54/81) mmHg). Endothelin-1, a potent pulmonary vasoconstrictor, is regulated by ADM via cAMP. Twenty two hours after inhalation of aerosolised ADM, endothelin-1 mRNA in lung tissue and endothelin-1 protein expression in pulmonary arteries was reduced compared with controls (median semi-quantitative immunhistochemical score: ADM 0.21, control 0.76).Aerosolised adrenomedullin significantly reduced mean pulmonary artery pressure independently of arterial oxygen tension. Pulmonary hypertension is often associated with an imbalance of vasoconstrictor and vasodilator peptides [1]. Endothelin-1 (ET-1) is the most potent constrictor and has been implicated in the pathogenesis of pulmonary hypertension [2]. Adrenomedullin (ADM), which consists of 52 amino acids, is actively produced and secreted by various cell types, particularly the vascular endothelial and smooth muscle cells [3], and has potent vasodilator properties. Transgenic mice overexpressing ADM in their vasculature have been shown to be resistant to lipopolysaccharide (LPS)-induced shock. LPS caused smaller drops in blood pressure and less severe organ damage than in the wild-type, despite lower basal blood pressure [4]. Moreover, ADM overexpression reduced reperfusion injury and superoxide production [5]. ADM -/-knock-out mice showed lethal cardiovascular pathology e.g. extreme hydrops foetalis [6], mice with ADM z/-mutation exhibited elevated blood pressures with diminished nitric oxide production and increased oxidative stress [7,8], suggesting a crucial role for ADM in the regulation of the cardiovascular system, particularly endothelial cell function. ADM plays an important role in vascular morphogenesis and the regulation of blood pressure by stimulating nitric oxide production [7].Intravenous infusion of ADM in patients with pulmonary hypertension significantly reduced pulmonary vascular resistance. However, systemic vascular resistance was simultaneously decreased [9]. Similar effects were seen with the application of ADM to the pulmonary artery [10]. To increase the pulmonary selectivity of ADM-induced vasodilation, the current authors examined the e...

Adrenomedullin: a smart road from pheochromocytoma to treatment of pulmonary hypertension

“…Interestingly, the adrenomedullin-linked amelioration in pulmonary hypertension was accompanied by a 30% reduction in interleukin (IL)-1b gene expression in lung tissue [13]. In agreement with VAN DER VARDT et al [13], other investigators have reported an anti-inflammatory property of adrenomedullin.…”

“…Another interesting and important finding by VON DER HARDT et al [13] is the observation that aerosolisation of adrenomedullin reduced endothelin (ET)-1 mRNA in lung tissue and ET-1 protein expression in endothelial cells of pulmonary arteries. Since ET-1 is a potent pulmonary vasoconstrictor, implicated in a broad spectrum of pulmonary disorders associated with pulmonary hypertension [18], adrenomedullin inhalation seems to be a goal-directed approach in this setting.…”

“…The major finding was that nebulisation of adrenomedullin (50 ng?kg -1 ?min -1 for 2 h) resulted in a sustained reduction in mean pulmonary arterial pressure (MPAP). While systemic blood pressure decreased only to a clinically insignificant extent, no changes occurred in systemic vascular resistance, heart rate and cardiac index [13]. The study by VON DER HARDT et al [13] is one of the first to have demonstrated that this route of adrenomedullin administration is a simple approach to effectively treat pulmonary hypertension while minimising the risk of systemic side-effects.…”

“…In the current issue of the European Respiratory Journal (ERJ), VON DER HARDT et al [13] report the results of a carefully conducted study on the effects of aerosolised adrenomedullin on pulmonary hypertension in a surfactantdepleted piglet model. The major finding was that nebulisation of adrenomedullin (50 ng?kg -1 ?min -1 for 2 h) resulted in a sustained reduction in mean pulmonary arterial pressure (MPAP).…”

Mediators and modulators of pulmonary arterial hypertension

“…For this reason, AM has recently been given by inhalation in tests of its potential benefit in PH. With this method of administration, AM led to sustained and selective reduction of pulmonary artery pressure in a surfactant-depleted piglet model (145) and in rats with monocrotaline-induced PH (88) and improved pulmonary hemodynamics and exercise tolerance in patients with IPAH (87).…”