Hemodynamic effects of vasorelaxant compounds in mice lacking one, two or all three angiotensin II receptors.
The renin-angiotensin system (RAS) has a vital role in regulating the cardiovascular system. The primary effector of the RAS is the octapeptide angiotensin (Ang) II, a potent regulator of blood pressure and water homeostasis. Ang II mediates its functions through the stimulation of two distinct receptors, AT(1) (two subtypes in rodents (AT(1a) and AT(1b))) and AT(2). It was shown that in addition to Ang II, shorter fragments of Ang are also biologically active. Ang-(1-7) came into focus because it opposes many of the detrimental effects of Ang II. However, it is still controversial whether Ang II receptors are involved in Ang-(1-7)-mediated signaling. To characterize the impacts of Ang II receptors on Ang-(1-7)-stimulated vascular relaxation, the effects of acute infusion of the three vasorelaxant compounds, that is, Ang-(1-7), bradykinin (BK) and acetylcholine (ACh), on heart rate (HR) and mean arterial pressure (MAP) were investigated in mice deficient for one, two or all three Ang II receptors. Ang-(1-7) and BK reduced MAP in wild-type, AT(1a)/AT(1b)-deficient and AT(2)-deficient mice. Although the change in absolute MAP values in the hypotensive triple knockouts (KO) could not be further reduced by both peptides, the percent change in MAP was comparable between the triple KO and wild-type mice. Both peptides did not alter the HR in all four genotypes. ACh significantly reduced absolute MAP values in all four genotypes with a similar percentage of reduction. In contrast to Ang-(1-7) and BK, ACh significantly reduced HR without genotypic differences. Our results generate proof that Ang-(1-7)-induced effects on MAP are mediated by a receptor that is independent of AT(1) and AT(2).
Gembardt, F; van Veghel, R; Coffman, TM; Schultheiss, H-P; Danser, AHJ; Walther, T
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