Inhaled Agonists of Soluble Guanylate Cyclase Induce Selective Pulmonary Vasodilation

Abstract

Rationale: Nitric oxide-independent agonists of soluble guanylate cyclase (sGC) have been developed. Objectives: We tested whether inhalation of novel dry-powder microparticle formulations containing sGC stimulators (BAY 41-2272, BAY 41-8543) or an sGC activator (BAY 58-2667) would produce selective pulmonary vasodilation in lambs with acute pulmonary hypertension. We also evaluated the combined administration of BAY 41-8543 microparticles and inhaled nitric oxide (iNO). Finally, we examined whether inhaling BAY 58-2667 microparticles would produce pulmonary vasodilation when the response to iNO is impaired. Methods: In awake, spontaneously breathing lambs instrumented with vascular catheters and a tracheostomy tube, U-46619 was infused intravenously to increase mean pulmonary arterial pressure to 35 mm Hg. Measurements and Main Results: Inhalation of microparticles composed of either BAY 41-2272, BAY 41-8543, or BAY 58-2667 and excipients (dipalmitoylphosphatidylcholine, albumin, lactose) produced dosedependent pulmonary vasodilation and increased transpulmonary cGMP release without significant effect on mean arterial pressure. Inhalation of microparticles containing BAY 41-8543 or BAY 58-2667 increased systemic arterial oxygenation. The magnitude and duration of pulmonary vasodilation induced by iNO were augmented after inhaling BAY 41-8543 microparticles. Intravenous administration of 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), which oxidizes the prosthetic heme group of sGC, markedly reduced the pulmonary vasodilator effect of iNO. In contrast, pulmonary vasodilation and transpulmonary cGMP release induced by inhaling BAY 58-2667 microparticles were greatly enhanced after treatment with ODQ. Conclusions: Inhalation of microparticles containing agonists of sGC may provide an effective novel treatment for patients with pulmonary hypertension, particularly when responsiveness to iNO is impaired by oxidation of sGC.

Inhalative and intravenous stimulation of soluble guanylate cyclase reduces pulmonary vascular resistance and increases cardiac output in experimental septic shock

“…The results of the present study indicate that additional pharmacological stimulation of sGC with BAY 41-8543 further increases vasodilation, particularly is more. A dose-dependent vasodilatory effect of BAY 41-8543 has been reported previously (25,26). In the current study, the positive effects of BAY 41-8543 (intravenous and inhaled) on PVR and CO were not significantly different when the dose was doubled.…”

“…In addition, there were no significant differences identified in the clinical effects of inhaled and intravenous administration routes. Previously, the inhalation of BAY 41-8543 has typically been performed using microparticles, for deep lung penetration and complete nebulisation (26). The results of the present study show that BAY 41-8543 can be nebulized in a solution and produce similar effects.…”

“…This may be due to sGC reaching maximum stimulation with one drug alone. However, the dose range of inhaled BAY 41-8543 chosen in the present study (from 6 to 12 mg dissolved in ethanol) has been reported to have only an intermediate effect on sGC and PVR (26), and the effect of BAY 41-8543 is dependent on the presence of NO (28). Evgenov et al (26) reported a synergistic effect of BAY 41-8543 and iNO on pulmonary vasodilation.…”

“…However, the dose range of inhaled BAY 41-8543 chosen in the present study (from 6 to 12 mg dissolved in ethanol) has been reported to have only an intermediate effect on sGC and PVR (26), and the effect of BAY 41-8543 is dependent on the presence of NO (28). Evgenov et al (26) reported a synergistic effect of BAY 41-8543 and iNO on pulmonary vasodilation. High endogenous NO levels in septic shock may explain why administration of exogenous NO together with BAY 41-8543 had no additional effect on PVR, whereas increasing the dosage of BAY 41-8543 did further decrease PVR.…”

Soluble guanylate cyclase stimulation: an emerging option in pulmonary hypertension therapy

“…BAY 41-8543 caused pulmonary vasodilation and improved systemic arterial oxygenation in a sheep model of pulmonary hypertension [42]. Although the preclinical data showed promise, further pharmacokinetic optimisation was required to yield a compound suitable for clinical development.…”