This study investigated the effect of lisinopril (angiotensin-converting enzyme inhibitor) on potential behavioural alterations in spontaneously hypertensive rats (SHR). Three groups of 15-17-week-old rats were investigated for 2 weeks: Wistar control group, SHR group and SHR+lisinopril group. Systolic blood pressure (SBP) was normal in Wistar rats, SHR expressed hypertension and lisinopril normalized the SBP. We observed increased time spent in and increased frequency of entries to the central area of the open field in SHR, while lisinopril induced a trend to reduce the time spent in the central area of the open field and reduced the frequency of entries there. There was a positive correlation between SBP and reduced anxiety-like behaviour in normotensive rats; no correlations in the SHR or SHR+lisinopril groups were observed. We conclude that lisinopril normalized the increase in SBP and partly reversed the alterations of anxiety-like behaviour in SHR.

The objective of our study was to contribute to the characterization of monocrotaline-induced pulmonary arterial hypertension (PAH) in a rat model, with emphasis on the renin–angiotensin–aldosterone system, parameters of oxidative stress, the activity of matrix metalloproteinases, and erythrocyte parameters. Moreover, we aimed to analyze the effects of bosentan. Experiments were performed on 12-week-old male Wistar rats randomly assigned to 3 groups: control, monocrotaline-treated (60 mg/kg), and monocrotaline combined with bosentan (300 mg/kg/day). Our study confirmed the well-known effects of monocrotaline administration on lungs and the right ventricle, as well as pulmonary arterial pressure. In addition, we observed activation of the alternative pathway of the renin–angiotensin system, namely an increase in angiotensin (Ang) 1–7 and Ang 1-5 together with an increase in Ang I, but without any change in Ang II level, and downregulation of aldosterone 4 weeks after monocrotaline administration. For the first time, modifications of erythrocyte Na,K-ATPase enzyme kinetics were demonstrated as well. Our observations do not support data obtained in PAH patients showing an increase in Ang II levels, increase in oxidative stress, and deterioration in RBC deformability. Although bosentan primarily targets the vascular smooth muscle, our study confirmed its antioxidant effect. The obtained data suggest that besides the known action of bosentan, it decreases heart rate and increases erythrocyte deformability, and hence could have a beneficial hemodynamic effect in the PAH condition.

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Objective: Pulmonary arterial hypertension (PAH) is a rare, chronic and debilitating disease characterized by increased pulmonary arterial pressure leading to right heart failure and – eventually death. Several drugs are approved for the treatment of PAH, but due to ongoing disease progression only half of the patients survive more than 7 years after diagnosis. A novel therapeutic approach based on pharmacologic activation of the alternative RAS was investigated in monocrotaline induced PAH in rats. Design and method: PAH was induced in 12 week-old Wistar rats by an injection of monocrotaline (60 mg/kg). Immediately after PAH induction, the rats (n = 11-12 in each group) were treated for 4 weeks with either a) vehicle, b) the novel peptidase inhibitor ALT001, or c) the endothelin receptor antagonist bosentan – representing the standard of care. Vehicle-treated sham rats served as healthy controls. Analysis included tissue and plasma equilibrium levels of angiotensin metabolites, echocardiography determined right ventricular function and structure, pulmonary arterial pressure, systemic blood pressure and histomorphometrical evaluations. Results: Ang II was significantly increased in lungs of monocrotaline treated animals concomitant with a profound increase in pulmonary arterial pressure (mPAP), reduced fractional shortening, dilated pulmonary valve diameter and a thickened and enlarged right ventricle. ALT001 treatment resulted in increased Ang 1–7 levels while Ang II levels were normalized. Bosentan treatment did not affect angiotensin peptide levels. The PAH induced increase in mPAP was almost completely abolished by ALT001 treatment, while systemic blood pressure remained unaffected. Right ventricular structure and function was effectively preserved under ALT001 treatment and pathological changes in fractional shortening (FS) were significantly reduced. Conclusions: Small molecule based modulation of the RAS might represent a promising novel therapeutic approach in treating RAS-related diseases, including PAH. (Partly supported by VEGA 1/0127/17, FFG 872313)

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