Diminazene aceturate improves autonomic modulation in pulmonary hypertension

Abstract

We have previously demonstrated that diminazene aceturate (DIZE), a putative angiotensin 1–7 converting enzyme activator, protects rats from monocrotaline (MCT)-induced pulmonary hypertension (PH). The present study was conducted to determine if the beneficial effects of DIZE are associated with improvements in autonomic nervous system (ANS) modulation. PH was induced in male rats by a single subcutaneous injection of MCT (50mg/kg). A subset of MCT rats were treated with DIZE (15mg/kg/day) for a period of 21 days, after which the ANS modulation was evaluated by spectral and symbolic analysis of heart rate variability (HRV). MCT administration resulted in a significant (P<0.001) increase in the right ventricular systolic pressure (62±14mmHg) when compared with other experimental groups (Control: 26±6; MCT+DIZE: 31±7mmHg), while DIZE treatment was able to decrease this pressure. Furthermore MCT-treated rats had significantly reduced total power of HRV than the controls. On the other hand, although not significant, a trend towards increased HRV was observed in the MCT+DIZE group (Control: 108±47; MCT: 12±8.86 and MCT+DIZE: 40±14), suggesting an improvement of the cardiac autonomic modulation. This observation was further confirmed by the low-frequency/high-frequency index of spectral analysis (Control: 0.74±0.62; MCT: 1.45±0.78 and MCT+DIZE: 0.34±0.49) which showed that DIZE treatment was able to recover the ANS imbalance observed in the MCT-induced pulmonary hypertensive rats. Collectively, our results demonstrate that MCT-induced PH is associated with a significant increase in sympathetic modulation and a decrease in HRV, which are markedly improved by DIZE treatment.

Heart rate variability parameters and ventricular arrhythmia correlate with pulmonary arterial pressure in adult patients with idiopathic pulmonary arterial hypertension

“…Furthermore, frequency-domain measurements (HF, LF, and TP) were all decreased compared to those in control patients. Our study findings were consistent with those of previous reports showing that HRV measurements were decreased in animal models 27,28 and clinical subjects 11,29,30 with PAH. Since RMSSD is used to evaluate short-term heart rate variation modulated by parasympathetic activity, it is possible that the parasympathetic modulation activity was impaired, leading to a reduced RMSSD in patients with IPAH.…”

“…3 Recently, some animal studies showed that interventions that improve HRV might also reduce the risk of sudden cardiac death. 27,28,40 Further understanding of the causality and mechanisms between low HRV and mortality will be useful in developing treatments that could increase HRV and hopefully improve survival. The current study might be helpful in delineating the supplemental prognostic information contained in HRV and provide a research guide for prospective studies in future.…”

The vasoprotective axes of the renin-angiotensin system: Physiological relevance and therapeutic implications in cardiovascular, hypertensive and kidney diseases

“…However, despite of its impressive antihypertensive and cardiovascular protective effects, there are very few follow-up studies to confirm these findings by this and other groups. Additionally, a chemical compound, diminazene aceturate (DIZE), has been promoted as a potential ACE2 activator to treat ischemia-induced cardiac pathophysiology, pulmonary hypertension, and ischemic stroke [160–163]. DIZE is a widely used antiprotozoal agent to treat trypanosomiasis in domestic livestock, but rarely used in humans [164].…”

“…This was interpreted as that DIZE may have cerebroprotective properties against endothelin 1-induced ischemic stroke [162]. Subsequent studies by the same group of investigators have demonstrated that DIZE significantly protected rats from monocrotaline (MCT)-induced pulmonary hypertension (PH) [163,165], and decreased myocardial infarction (MI)-induced infarct area, LV remodeling post-MI, and restored normal balance of the cardiac renin-angiotensin system [160]. Recently, the cardiovascular, hypertensive, and renal effects of targeting ACE2 with DIZE in various animal models have been comprehensively reviewed elsewhere often with mixed or conflicting results [161].…”

Angiotensin-Converting Enzyme 2–Independent Action of Presumed Angiotensin-Converting Enzyme 2 Activators

“…22 Three years later, diminazene (DIZE), 23 an agent already established in veterinary medicine, for example, as a treatment option against trypanosomiasis, 24 was identified via virtual screening as an ACE2 activator. In the following years, XNT and DIZE have been used successfully to treat a vast array of conditions, such as hypertension, 22,25 pulmonary hypertension, [26][27][28] cardiac and renal fibrosis, 22 and glaucoma, 29 in experimental rat or mice models. The premise of the therapeutic benefit has been attributed to ACE2 activation and the conversion of Ang II to Ang (1-7).…”