Antiparasitic Shows Potential as PAH Treatment in Preclinical Study
Diminazene aceturate (DIZE), an approved antiparasitic medication, lessened the development of pulmonary arterial hypertension (PAH) in a rat model, a study has demonstrated.
These findings support further investigation of DIZE as a potential treatment for PAH, scientists said.
The study, “Angiotensin-Converting Enzyme 2 Activator Ameliorates Severe Pulmonary Hypertension in a Rat Model of Left Pneumonectomy Combined With VEGF Inhibition,” was published in the journal Frontiers in Medicine.
PAH is characterized by narrowing of the pulmonary arteries, the blood vessels that supply the lungs, leading to high blood pressure or hypertension.
Recently, DIZE, an agent used to treat parasitic infections, demonstrated off-target effects by activating angiotensin-converting enzyme 2 (ACE2), known to regulate dilation of pulmonary arteries.
To investigate potential PAH medicines such as DIZE, the SU5416 hypoxia animal model was developed to mimic PAH by exposing animals to a combination of low oxygen (hypoxia) and SU5416, an experimental cancer therapy (semaxanib) that blocks the growth of new blood vessels.
Recently, a newer rodent PAH model has been created that combines this approach with the surgical removal of a lung (pneumonectomy). Unlike the original SU5416 hypoxia model, which can be partially reversed upon exposure to normal oxygen levels, this new model is not reversible and right ventricular systolic pressure (RVSP) — a measure of blood pressure inside the artery that supplies the lung — increases over time. This may favor the assessment of new therapies, the researchers wrote.
Although DIZE has been successfully investigated in other rodent models of pulmonary hypertension, it has not been tested in this more recent model.
Investigators at the Kaohsiung Medical University Hospital in Taiwan have now designed a study to test DIZE in rats after left lung removal and injection of a single dose of SU5416 the following day (day 1).
“Herein we hypothesized diminazene aceturate (DIZE), an ACE2 activator, could ameliorate the development of PAH and pulmonary vascular remodeling,” the team wrote.
Rats were randomly assigned to undergo either a sham operation (surgical control) or left pneumonectomy with SU5416 injection (SuPNx). SuPNx rats were further divided for subcutaneous (under-the-skin) saline injection as a treatment control, or DIZE from day 1 to day 42 as an early treatment group or from day 29 to day 42 as a late treatment group.
As expected, compared to surgical controls, SuPNx rats showed a significant increase in RVSP. In contrast, both early and late DIZE treatment groups showed decreased RVSP compared to treatment controls.
The Fulton index, a measure of enlargement of the heart’s right ventricle, was significantly increased in SuPNx rats. However, the Fulton index in early and late groups was unaffected by DIZE treatment. There was no change in lung or body weight among all four groups.
Elevated brain natriuretic peptide levels (BNP) in blood, a marker for heart failure, were observed in the SuPNx group but were significantly reduced in the early DIZE treatment group. The team found no changes in the late treatment group.
BNP from the right ventricle was also elevated in SuPNx rats and significantly decreased in both early and late treatment groups compared to treatment controls.
Thickness in the wall of the pulmonary arterioles, which are blood vessels that branch from an artery to smaller capillaries, increased significantly in SuPNx rats and was significantly attenuated by early DIZE but not by later treatment.
The growth of vascular smooth muscle cells resulting in the thickening of arterial walls (vascular remodeling) was severe in SuPNx rats. In the early DIZE treatment group, these effects were significantly decreased, while in the late treatment group there was a non-significant trend of improvement.
An analysis of protein production in response to DIZE exposure found significantly elevated levels of eNOS in the early treatment group, an enzyme responsible for generating nitric oxide, which dilates blood vessels. This effect was not seen in the late treatment group.
“The increased expression of eNOS could contribute to the lowering of pulmonary artery pressure,” the researchers wrote.
Compared to surgical control rats, pulmonary levels of ACE — an enzyme usually targeted by blood pressure-lowering therapies — was elevated in the SuPNx group. In both early and late treatment rats, ACE protein levels significantly decreased in comparison with treatment controls.
While the pulmonary expression of ACE2 was increased in the early treatment group, no differences were noted among the sham, SuPNx, and late treatment groups.
Finally, Ang-(1-7), a blood vessel widener generated by ACE2, did not change in the SuPNx group compared to the surgical control group. However, right ventricle Ang-(1-7) increased significantly in both the early and late treatment groups compared to treatment controls. In addition, early DIZE treatment also increased pulmonary Ang levels-(1-7) in comparison.
“The efficacy of DIZE in the early and late treatment group suggests its ability to rescue animals from established hypertensive pulmonary vascular disease,” the investigators wrote. “However, the exact mechanisms by which DIZE exerts its beneficial effects remain to be investigated.”
“Our study showed that DIZE may be a potential agent for the treatment of PAH,” they added.