Reflexos cardiovasculares em camundongos com alteração na expressão do receptor da Angiotensina-(1-7), MAS

Abstract

Several substances may modulate reflex cardiovascular activity, such reninangiotensin system peptides. The tecidual renin-angiotensin system is involved in regulation of cardiovascular structures and functions and, consequently in long-term blood pressure control, contributing in a significant way to maintenance and development of highperipheral resistance and vascular hypereactivity found in the essential and experimental hypertension. Studies about the renin-angiotensin influences on neural control of BP show that Ang II reduces baroreflex sensitivity, reduces the Bezold-Jarisch reflex sensitivity and increases the chemoreflex responses. Because known that several Ang-(1-7) actions are opposite to Ang II actions, mainly about cardiac and vascular control, as well baroreflex sensibility, it is reasonable to suppose that the heptapeptide Ang-(1-7) acting on Ang-(1-7)s Mas receptor, also to take part of the Bezold-Jarisch reflex and the chemoreflex. To have the opportunity to use genetic change animals as for Mas receptor expression, we asses the hypothesis that Ang-(1-7), via Mas receptor, to contribute for the reflex cardiovascular modulation, in mice with Mas receptor deletion ou Mas receptor overexpression at brain. In sequence, considering the evidences of counter-regulatory actions between Ang II/Ang-(1-7), and the possibility to interaction between Mas/AT1receptors, we also to asses the hypothesis that Mas receptor deletion to change the Ang II effects, because the absence to counter-regulatory effects to Ang-(1-7), via Mas receptor.We use control (Wild-Type) and Mas receptor expression changes mice, Knockout Mas receptor mice (KO-Mas) and overexpression in brain Mas receptor (NSE-Mas), with background C57BL6J and FVBN. We showed in this study, through genetic manipulation of the Mas receptor expression, the effective participation of Angiotensin-(1-7) in the xiii cardiovascular control. Mas knockout mice (FVBN background) awake show highbasal MAP values in comparison with control mice (118 ± 1 vs. 109 ± 2 mmHg, p<0.01), but not show significant changes in basal HR values (615 ± 30 vs. 648 ± 13 bpm). The deletion of Mas receptor decreases baroreflex bradycardia (0.78 ± 0.44 vs. 1.3 ± 0.14 ms/mmHg, p<0.05), increases baroreflex tachycardia (1.63 ± 0.4 vs. 0.80 ± 0.13ms/mmHg, p<0.05), decreases the bradycardic and hypotensive response of Bezold-Jarisch reflex (-17 ± 5 vs. -45 ± 6 mmHg e -212 ± 36 vs. -391 ± 29 bpm, FB 0.5Ng/5Nl, p<0.01) and increases the reflex responses observed by chemoreflex stimulation (20 ± 3vs. 12 ± 0.8 mmHg e -250 ± 74 vs. -52 ± 26 bpm, KCN 2.5Ng/5Nl, p<0.05) in awake FVBN background mice. In accordance with changes describe, we showed that Mas knockoutreceptor mice had reduce tachycardic effect produce by methilatropine administration (23 ±4 vs. 70 ± 19 bpm, p<0.05) and increase bradycardic effect induced by atenolol administration (-181 ± 10 vs. -115 ± 23 bpm, p<0.05). When we measure transgenic mice with overexpression of Mas receptor in brain (NSE-Mas), demonstrate that Ang-(1-7), acting in CNS, participate of basal and reflex cardiovascular variables control. The Masreceptor overexpression in brain mice induces increases of basal MAP (116 ± 3 vs. 109 ± 2 mmHg, p<0.05) and not change basal HR values (641 ± 18 vs. 648 ± 13 bpm). About bradycardic barorefelx response, we showed that Mas receptor overexpression in brain promoves increase this response (2.03 ± 0.33 vs. 1.3 ± 0.14 ms/mmHg, p<0.05). After A-779, Ang-(1-7) antagonist, ICV administration, despite did not show significant changes in MAP and HR basal values in NSE-Mas and control mice, we show that bradycardic (1.17 ± 0.14 vs. 1.92 ± 0.37 ms/mmHg, p<0.05), and tachycardic (0.49 ± 0.11 vs. 0.94 ± 0.32 ms/mmHg, p<0.01), baroreflex responses were significantly decrease only in control FVBNbackground awake mice. In this study, we highlight the important interaction Ang-(1-7)/Mas couter-balancing the classic actions of Ang II/AT1 in the cardiac autonomic activity maintenance, as reflexes and basal cardiovascular responses control. These results join with literature reports, contribute to physiologic relevancy of Ang-(1-7), acting on the Masreceptor, in the cardiovascular function control.