Daniela Ravizzoni Dartora

An orally active angiotensin-(1–7) inclusion compound and exercise training produce similar cardiovascular effects in spontaneously hypertensive rats

Low angiotensin-(1-7) (Ang-(1-7)) concentration is observed in some cardiovascular diseases and exercise training seems to restore its concentration in the heart. Recently, a novel formulation of an orally active Ang-(1-7) included in hydroxy-propyl-beta-cyclodextrin (HPB-CD) was developed and chronically administered in experimental models of cardiovascular diseases. The present study examined whether chronic administration of HPB-CD/Ang-(1-7) produces beneficial cardiovascular effects in spontaneously hypertensive rats (SHR), as well as to compare the results obtained with those produced by exercise training. Male SHR (15-week old) were divided in control (tap water) or treated with HPB-CD/Ang-(1-7) (corresponding to 30μgkg(-1)day(-1) of Ang-(1-7)) by gavage, concomitantly or not to exercise training (treadmill, 10 weeks). After chronic treatment, hemodynamic, morphometric and molecular analysis in the heart were performed. Chronic HPB-CD/Ang-(1-7) decreased arterial blood pressure (BP) and heart rate in SHR. The inclusion compound significantly improved left ventricular (LV) end-diastolic pressure, restored the maximum and minimum derivatives (dP/dT) and decreased cardiac hypertrophy index in SHR. Chronic treatment improved autonomic control by attenuating sympathetic modulation on heart and vessels and the SAP variability, as well as increasing parasympathetic modulation and HR variability. Overall results were similar to those obtained with exercise training. These results show that chronic treatment with the HPB-CD/Ang-(1-7) inclusion compound produced beneficial effects in SHR resembling the ones produced by exercise training. This observation reinforces the potential cardiovascular therapeutic effect of this novel peptide formulation.

Hypertension, Blood Pressure Variability, and Target Organ Lesion.

Hypertensive patients have a higher risk of developing health complications, particularly cardiovascular (CV) events, than individuals with normal blood pressure (BP). Severity of complications depends on the magnitude of BP elevation and other CV risk factors associated with the target organ damage. Therefore, BP control and management of organ damage may contribute to reduce this risk. BP variability (BPV) has been considered a physiological marker of autonomic nervous system control and may be implicated in increased CV risk in hypertension. This review will present some evidence relating BPV and target organ damage in hypertension in clinical and experimental settings.

Increased vascular sympathetic modulation in mice with Mas receptor deficiency

Introduction: The angiotensin-converting enzyme 2 (ACE2)/angiotensin (Ang)-(1–7)/Mas axis could modulate the heart rate (HR) and blood pressure variabilities (BPV) which are important predictors of cardiovascular risk and provide information about the autonomic modulation of the cardiovascular system. Therefore we investigated the effect of Mas deficiency on autonomic modulation in wild type and Mas-knockout (KO) mice. Methods: Blood pressure was recorded at high sample rate (4000 Hz). Stationary sequences of 200–250 beats were randomly chosen. Frequency domain analysis of HR and BPV was performed with an autoregressive algorithm on the pulse interval sequences and on respective systolic sequences. Results: The KO group presented an increase of systolic arterial pressure (SAP; 127.26±11.20 vs 135.07±6.98 mmHg), BPV (3.54±1.54 vs 5.87±2.12 mmHg2), and low-frequency component of systolic BPV (0.12±0.11 vs 0.47±0.34 mmHg2). Conclusions: The deletion of Mas receptor is associated with an increase of SAP and with an increased BPV, indicating alterations in autonomic control. Increase of sympathetic vascular modulation in absence of Mas evidences the important role of Ang-(1–7)/Mas on cardiovascular regulation. Moreover, the absence of significant changes in HR and HRV can indicate an adaptation of autonomic cardiac balance. Our results suggest that the Ang-(1–7)/Mas axis seems more important in autonomic modulation of arterial pressure than HR.

Improved cardiovascular autonomic modulation in transgenic rats expressing an Ang-(1-7)-producing fusion protein

Angiotensin-(1-7) counterbalances angiotensin II cardiovascular effects. However, it has yet to be determined how cardiovascular autonomic modulation may be affected by chronic and acute elevation of Ang-(1-7). Hemodynamics and cardiovascular autonomic profile were evaluated in male Sprague-Dawley (SD) rats and transgenic rats (TGR) overexpressing Ang-(1-7) [TGR(A1-7)3292]. Blood pressure (BP) was directly measured while cardiovascular autonomic modulation was evaluated by spectral analysis. TGR received A-779 or vehicle and SD rats received Ang-(1-7) or vehicle and were monitored for 5 h after i.v. administration. In another set of experiments with TGR, A-779 was infused for 7 days using osmotic mini pumps. Although at baseline no differences were observed, acute administration of A-779 in TGR produced a marked long-lasting increase in BP accompanied by increased BP variability (BPV) and sympathetic modulation to the vessels. Likewise, chronic administration of A-779 with osmotic mini pumps in TGR increased heart rate, sympathovagal balance, BPV, and sympathetic modulation to the vessels. Administration of Ang-(1-7) to SD rats increased heart rate variability values in 88% accompanied by 8% of vagal modulation increase and 18% of mean BP reduction. These results show that both acute and chronic alteration in the Ang-(1-7)-Mas receptor axis may lead to important changes in the autonomic control of circulation, impacting either sympathetic and (or) parasympathetic systems.

Optimization of Vagal Stimulation Protocol Based on Spontaneous Breathing Rate

Controlled breathing maneuver is being widely applied for cardiovascular autonomic control evaluation and cardiac vagal activation through reduction of breathing rate (BR). However, this maneuver presented contradictory results depending on the protocol and the chosen BR. These variations may be related to the individual intrinsic profile baseline sympathetic tonus, as described before by others. In this study, we evaluated the effect of controlled breathing maneuver on cardiovascular autonomic control in 26 healthy subjects allocated into two protocols: (1) controlled breathing in three different rates (10, 15, and 20 breaths/min) and (2) controlled breathing in rates normalized by the individual spontaneous breathing rate (SBR) at 100, 80, 70, and 50%. Our results showed autonomic responses favorable to vagal modulation with the lower BR maneuvers. Nevertheless, while this activation was variable using the standard protocol, all participants of the normalized protocol demonstrated an increase of vagal modulation at 80% BR (HFnu 80 = 67.5% vs. 48.2%, p < 0.0001). These results suggest that controlled breathing protocols to induce vagal activation should consider the SBR, being limited to values moderately lower than the baseline.

Glucagon-producing cells are increased in Mas-deficient mice

It has been shown that angiotensin(1–7) (Ang(1–7)) produces several effects related to glucose homeostasis. In this study, we aimed to investigate the effects of genetic deletion of Ang(1–7), the GPCR Mas, on the glucagon-producing cells. C57BL6/N Mas−/− mice presented a significant and marked increase in pancreatic α-cells (number of cells: 146 ± 21 vs 67 ± 8 in WT; P < 0.001) and the percentage per islet (17.9 ± 0.91 vs 12.3 ± 0.9% in WT; P < 0.0001) with subsequent reduction of β-cells percentage (82.1 ± 0.91 vs 87.7 ± 0.9% in WT; P < 0.0001). Accordingly, glucagon plasma levels were increased (516.7 ± 36.35 vs 390.8 ± 56.45 pg/mL in WT; P < 0.05) and insulin plasma levels were decreased in C57BL6/N Mas−/− mice (0.25 ± 0.01 vs 0.31 ± 56.45 pg/mL in WT; P = 0.02). In order to eliminate the possibility of a background-related phenotype, we determined the number of glucagon-producing cells in FVB/N Mas−/− mice. In keeping with the observations in C57BL6/N Mas−/− mice, the number and percentage of pancreatic α-cells were also significantly increased in these mice (number of α-cells: 260 ± 22 vs 156 ± 12 in WT, P < 0.001; percentage per islet: 16 ± 0.8 vs 10 ± 0.5% in WT, P < 0.0001). These results suggest that Mas has a previously unexpected role on the pancreatic glucagon production.

1031 ROLE OF ANG-(1-7)/MAS AXIS ON AUTONOMIC CARDIOVASCULAR CONTROL IN DIFFERENT GENETICALLY ALTERED MODELS

Background: Angiotensin-(1–7)/Mas axis seems to have an important role in cardiovascular regulation once that in cardiovascular diseases Ang-(1-7) concentrations are altered as well the autonomic control of cardiovascular function. Heart rate (HRV) and blood pressure variability (BPV) are predictors of cardiovascular risk and provide information about cardiac and vascular autonomic modulation. Objectives: Investigate the effect of Mas receptor deletion in mice and the effect of the Ang-(1-7) overexpression in a rat transgenic model on sympathetic and parasympathetic modulation. Methods: Mice was divided in two groups: receptor Mas knockout (KO) (n = 8); wild type (WT) (n = 6). Transgenic rats were divided in three groups: transgenic rats with increased plasmatic Ang-(1-7) concentration (TGR) (n = 5), Sprangue-Dawley (SD) (n = 5) and transgenic rats with osmotic pump containing A779 during 7 days (TGRb) (n = 5). BP was recorded and stationary sequences of 300 beats were randomly chosen. Frequency domain analysis of HRV and BPV was performed with an autoregressive model. Results: SBP, BPV and vascular sympathetic modulation were higher in the KO animals compared to WT. There were no significant differences between TGR and SD rats. TGRb showed higher HR, SAP, DAP and sympathetic-vagal balance compared to TGR. Conclusions: Ang-(1-7)/Mas axis is important in autonomic modulation of BP and sympathetic-vagal balance in regard of KO animals. Although the TGR are similar to SD animals on basal conditions the Ang-(1-7)/Mas blockage demonstrates an expressive dependence for this axis in the autonomic control of cardiovascular function. This data reinforce the possibility of a novel pharmacological intervention in hypertension therapy.