A study in a rat model of pulmonary arterial hypertension (PAH) found that vitamin D deficiency causes a reduced response to sildenafil, but not to riociguat. Lower levels of vitamin D are also associated with an insufficient response to phosphodiesterase type 5 (PDE5) inhibitors such as sildenafil and tadalafil in patients with PAH, according to the study published in the European Respiratory Journal.

According to the authors, restoring optimal vitamin D levels may, therefore, help improve patients’ responsiveness to PDE5 inhibitors.

A team of researchers led by Francisco Perez-Vizcaino from the Department of Pharmacology and Toxicology, School of Medicine, Complutense University of Madrid in Spain used a rat model of the disease to investigate the effect of vitamin D on the response to different PAH treatments.

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The researchers isolated the pulmonary arteries of rats that were fed a vitamin D-free diet for 8 weeks and rats in which the vitamin D status was restored in the last 3 weeks. They then treated the arteries with sildenafil and riociguat.

They found that there was a poor vasodilator response to sildenafil in the arteries of rats that were given a vitamin D-free diet for the entire 8 weeks. This response was reverted in the arteries of rats in which vitamin D levels were restored. Interestingly, there was no difference between the groups in terms of response to riociguat.

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The researchers then wanted to assess whether reduced vitamin D levels would also account for the limited efficacy of sildenafil in some patients with PAH.

They collected serum samples from the Spanish National Pulmonary Hypertension Biobank and clinical data from the Spanish Registry of Pulmonary Arterial Hypertension (REHAP). The researchers then compared vitamin D levels in the serum samples of patients with PAH who responded to PDE inhibitor therapy with those of patients who did not.

They found that responders to sildenafil had significantly higher serum vitamin D levels than nonresponders.

This, the researchers concluded, suggests that vitamin D deficiency may cause an insufficient response to PDE5 inhibitors in some patients with PAH. 

PDE5 inhibitors are often used to treat PAH. However, some patients with the disease do not respond well to these drugs, and combined therapy with other drugs such as riociguat is recommended.


Callejo M, Blanco I, Barberá JA, Perez-Vizcaino F. Vitamin D deficiency, a potential cause for insufficient response to sildenafil in pulmonary arterial hypertension. Eur Respir J. Published online August 12, 2021. doi:10.1183/13993003.01204-2021