Intravenous Tezosentan and Vardenafil Attenuate Acute Hypoxic Pulmonary Hypertension

Abstract

Excessive hypoxic pulmonary hypertension imposes right ventricular strain by increasing afterload that may lead to right heart failure and death. Increased phosphodiesterase activity, as well as increased levels of endothelin-1, has been discussed as molecular mechanisms. We investigated the hemodynamic and intrapulmonary effects of the intravenous dual endothelin A and B receptor blocker tezosentan, and of the phosphodiesterase-5 (PDE-5) antagonist vardenafil in a pig model of acute normobaric hypoxic pulmonary hypertension. Eighteen 4-week-old ventilated white farm pigs were exposed to normobaric hypoxia (FiO2 12%) and randomly assigned to three groups (n = 6) in order to receive either intravenous tezosentan or vardenafil or to serve as control. Arterial alveolar oxygen differences were the same with both drugs. After 90 min of treatment, pulmonary artery pressure and vascular resistance were significantly lower in both treatment groups when compared to controls (p < 0.001). Cardiac index increased significantly with vardenafil alone (2.8 l x min(-1) x m2 +/- 0.7 to 4.2 l x min x m2 +/- 0.7, p = 0.0003). Intravenous tezosentan, as well as vardenafil equipotently attenuate acute hypoxic pulmonary hypertension without afflicting pulmonary gas exchange. However, cardiac index increases with vardenafil only.

Cyclooxygenase‐2 inhibition and thromboxane A2 receptor antagonism attenuate hypoxic pulmonary vasoconstriction in a porcine model

“…Our study was furthermore performed in an in vivo pig model, and hence one must consider a redundancy, where for instance endothelin‐1, a potent pulmonary vasoconstrictor that modulates HPV (Geiger et al . , Hedelin et al . ), potentially may compensate when inhibiting COX‐2 or blocking the TXA 2 receptor.…”

“…Our study was furthermore performed in an in vivo pig model, and hence one must consider a redundancy, where for instance endothelin-1, a potent pulmonary vasoconstrictor that modulates HPV (Geiger et al 2008, Hedelin et al 2012), potentially may compensate when inhibiting COX-2 or blocking the TXA 2 receptor. Using an in vivo model, though, the qualitative significance of selective COX-2 inhibition with nimesulide and TXA 2 receptor blockade with daltroban in acute hypoxia-induced PH was revealed.…”

The principal pathways involved in the in vivo modulation of hypoxic pulmonary vasoconstriction, pulmonary arterial remodelling and pulmonary hypertension

“…) and fully reversed the sustained phase of the HPV response in pigs (Geiger et al . ). A stimulator of sGC also reversed HPV in pigs (Lundgren et al .…”

“…) and pigs (Geiger et al . , Hedelin et al . ) as well as during 60‐min exposure to normobaric hypoxia or 3 days of hypobaric hypoxia at 4559 m, respectively, in humans (Modesti et al .…”

Dual endothelin receptor blockade with tezosentan markedly attenuates hypoxia‐induced pulmonary vasoconstriction in a porcine model

“…Tezosentan (Actelion, Allschwil, Switzerland), at a dose of 5 mg kg −1 body weight, was dissolved in 10 mL of sterile water and delivered as a manual bolus injection in the right atrium, through the catheter in the internal jugular vein. In a pilot dose titration, a 7.5 mg kg −1 test dose was applied, which induced a potent and rapid initial blood pressure drop; 5 mg kg −1 body weight was therefore chosen for the main experiments, as it previously also had been found to induce a potent effect (Geiger et al. 2008b).…”