Efeitos da Angiotensina-(1-7) e Angiotensina II no inotropismo cardíaco e vasomotricidade coronariana: um complexo envolvimento entre os receptores angiotensinérgicos
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2018-04-26
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Universidade Federal de Goiás
Resumo
Despite Angiotensin-(1-7) [Ang-(1-7)] and Angiotensin II (Ang II) be
considered important regulators of the cardiovascular system, its direct effects
on cardiac contractility remain unclear and even controversial. Several studies,
using different preparations, have showed that Ang-(1-7) or Ang II produce
positive, negative or no inotropic effects. Thus, the aim of this study was to
increase the knowledge about the effect of the low concentration of Ang-(1-7)
and Ang II on cardiac contractility, coronary vascular function and the possible
receptors and mechanisms of action involved in these effects. The in vivo
effects of Ang-(1-7) and Ang II on cardiac contractility were evaluated in
anesthetized rats. The Ang-(1-7) 4 nmol/L and Ang II 40 nmol/L caused
negative inotropism in anesthetized rats. None of the peptides were able to
change heart rate or arterial blood pressure in anesthetized rats. The direct
effects of the Ang-(1-7) and Ang II on cardiac contractility were evaluated in
isolated perfused rat hearts. After a basal period (30-40 minutes), the hearts
were perfused for an additional 15 min with Ang-(1-7) and Ang II (20 pmol/L) in
presence or absence of Mas receptor antagonist A-779 (2 nmol/L), AT2
receptor antagonist PD1233190 (2 nmol/L), AT1 receptor antagonist Losartan
(1μmol/L), MrgD receptor antagonist D-PRO (2 nmol/L), ACE2 inhibitor DX600
(2nmol/L), Nitric Oxide synthase (NOS) inhibitor L-Name (10 nmol/L), Guanylyl
cyclase (GC) inhibitor ODQ (200 nmol/L) and Adenylyl cyclase (AC) inhibitor
MDL 12,330A (1μmol/L). Low concentrations of Ang-(1-7) and Ang II reduced
the left ventricular end-systolic pressure (LVESP). The A-779 did not blocked
the effect of Ang-(1-7) or Ang II. PD123319 and Losartan inhibited the Ang-(1-7)
but not Ang II-induced negative inotropic effects. On the other hand, D-PRO
was able to block the negative inotropic effect of the Ang II and Ang-(1-7).
Furthermore, L-Name, ODQ and MDL 12,330A inhibited the Ang-(1-7) but not
Ang II-induced negative inotropic effects. Similarly, low concentrations of Ang-
(1-7) and Ang II-induced coronary vasodilatation. The A-779, D-PRO, L-Name,
MDL 12,330A blocked the effect of Ang-(1-7) or Ang II. The DX600 blocked the
vasodilatation induced by Ang II. PD123319, Losartan and ODQ inhibited the
Ang-(1-7) but not Ang II-induced coronary vasodilatation. In addiction, the
pharmacological blocked and gene silencing of AT1 receptor in endothelial
human cells stimulated with Ang-(1-7) decreased AKT phosphorilation induced
by Ang-(1-7). These data demonstrate that Ang-(1-7) and Ang II, at picomolar
concentrations, induce significant and similar negative inotropic and coronary
vasodilatation effects involving complex interaction mechanisms between many
different receptors, altering intracellular signaling and their constitutive activity.
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Citação
NUNES, A. D. C. Efeitos da Angiotensina-(1-7) e Angiotensina II no inotropismo cardíaco e vasomotricidade coronariana: um complexo envolvimento entre os receptores angiotensinérgicos. 2018. 148 f. Tese (Doutorado em Ciências Biológicas) - Universidade Federal de Goiás, Goiânia, 2018.