In patients with pulmonary arterial hypertension (PAH), β3 adrenergic receptor (β3 ARs) agonists may be effective therapies for the disorder, according to the results of a study conducted in Australia in 2 mouse models of PAH. Results of the analysis were published in the Physiological Reports journal.

Recognizing that mortality from PAH remains high despite treatment and that a considerable unmet need exists in the management of individuals with the disease, the researchers sought to examine the efficacy of β3 AR agonism as a novel pathway in experimental PAH.

It is well known that the efficacy of treatments that target the downstream nitric oxide (NO) pathway in patients with PAH is dependent on the availability of NO and that reduced NO levels in PAH are secondary to the “uncoupling” of endothelial nitric synthase (eNOS). The stimulation of β3 ARs may result in the “recoupling” of NOS and, in this way, prove beneficial in patients with PAH.


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The investigators used adult male FVB/N mice with a body weight of 20 to 25 grams to establish 2 models of PAH:
(1) a hypoxemia model, in which the mice were exposed to chronic hypoxemia (fraction of inspired oxygen [FiO2]=0.10) for 3 weeks in a hypoxemia chamber, and (2) a Sugen hypoxemia model, in which the mice were exposed to chronic hypoxemia (FiO2=0.10) for 3 weeks and received a weekly 20 mg/kg subcutaneous injection of the vascular endothelial growth factor receptor inhibitor SU5416, for a total of 3 injections.

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In both of the models, the mice were housed in the hypoxemia chamber for an additional 2 weeks, during which they were treated with (1) daily gavage with riociguat 10 mg/kg/day suspended in 1% dimethylcellulose, (2) sildenafil
50 mg/kg/day dissolved in distilled water, or (3) the selective β3 AR agonist CL316243, which was dissolved in saline via osmotic minipump at an infusion rate of 40 μg/kg/h. Control groups comprised 20 mice who received the vehicle for
2 weeks and were exposed to FiO2=0.10 or the ambient air for 5 weeks.

Echocardiographic indices and invasive right ventricular (RV)–­PA hemodynamics were measured. Comparisons were made of CL316243 combined with riociguat or with sildenafil. Treatment effects on RV-PA remodeling, oxidative stress, and eNOS glutathionylation—an oxidative modification that uncouples eNOS—were evaluated.

Results of the study revealed that compared with the normoxic mice, RV systolic pressure was increased significantly in the control hypoxic mice (P <.0001) and in the Sugen hypoxemic mice (P <.0001). Additionally, CL316243 decreased RV systolic pressure to a similar degree as riociguat and sildenafil, both in hypoxemia models (P <.0001) and in Sugen hypoxemia models (P =.03).

“CL316243 reversed pulmonary vascular remodeling, decreased RV afterload, improved RV-PA coupling efficiency, and reduced RV stiffness, hypertrophy, and fibrosis,” the authors wrote. Even though all therapies decreased oxidative stress, CL316243 was associated with significant reductions in glutathionylation as well.

The authors concluded that “β3 AR stimulation improved RV hemodynamics and led to beneficial RV-PA remodeling in experimental models of PAH. β3 AR agonists may [thus] be effective therapies in [patients with] PAH.”

Reference

Galougahi KK, Zhang Y, Kienzle V, et al. β3 adrenergic agonism: a novel pathway which improves right ventricular-pulmonary arterial hemodynamics in pulmonary arterial hypertension. Physiol Rep. 2023;11(1): e15549. doi:10.14814/phy2.15549