Avaliação de efeitos cardiovasculares da combinação de um inibidor de renina com angiotensina-(1-7) em ratos TGR(mREN2)27

Abstract

The renin-angiotensin system (RAS) can be inhibited at various points, including the renin, which will lead to a reduction of the conversion of the angiotensinogen to Angiotensin I, decreasing Angiotensin II (Ang II) levels. However, this inhibition also causes reduction of Angiotensin-(1-7) [Ang-(1-7)] levels, whose actions are often opposite to those attributed to Ang II. Thus, in this study we investigated the efficacy of the combination of a renin inhibitor with Hydroxypropyl -cyclodextrin (HPCD) / Ang-(1-7) inclusion compound in reducing high blood pressure and end-organ damage. Hypertensive heterozygous TGR(mRen2)27 rats were treated during 15 days according to three different protocols: PEP group: treated with pepstatin A (renin inhibitor) through osmotic mini-pumps, 5g/Kg/day; A7 group: oral administration of HPCD-Ang-(1-7), 30g/Kg/day; and PEPA7 group: both treatments simultaneously, in the same doses. The mean arterial pressure (MAP), systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (HR) were measured by a radiotelemetry system in unanesthetized rats. After the treatment period, the animals were euthanized to remove blood, heart and kidney. The three treatments reduced MAP, SBP and DBP during light and dark periods, which were maximally reduced in 2nd and 1st treatment day, respectively. However, the arterial pressure progressively returned to baseline values, before the end of the treatment. The HR was not altered by any treatment in the light period, while in the dark period it was reduced from the 2nd to the 15th day of treatment by all three treatments. No statistical difference were detected between the treatments, indicating the absence of additive/synergic effects between them. At the 15th day of treatment, we investigated the cardiac sympathetic tonus, which was reduced in the PEP group, and the parasympathetic, which was increased in the PEPA7 group, both reducing sympathetic/parasympathetic ratio. Even though arterial pressure tends to return to baseline, there was a reversal of the perivascular collagen deposition in the left ventricle with all treatments, compared to control. There was a reduction of the cardiomyocytes diameter only in the animals of the A7 group. The plasma renin activity was reduced, as expected, in the pepstatin-treated groups. Strikingly, it was also reduced in the A7 group. These data suggest that absence of additive/synergic effects of pepstatin and Ang-(1-7) may be related to the inhibition of the renin release and/or synthesis by Ang-(1-7).