Differential Effects of Bradykinin B1 Antagonism in Heart and Kidney of Angiotensin IIInfused Rats
Authors: Siegel Matthew M , McCormick Brittney A , Nayek Tanvi , Hale Taben M 
Published: June 2021

Angiotensin II (AngII) is a potent vasoconstrictor and stimulator of pathologic cardiovascular remodeling. Bradykinin, has been shown to exert opposing effects when acting at its B2 receptor. However, the impact of B1 receptor stimulation on cardiovascular remodeling is less clear. In the kidney, B1 receptor antagonism has been shown to have reno‐protective effects in a model of obstructive nephropathy, while the impact on cardiac remodeling is equivocal. It has been shown to both induce and attenuate pathological cardiac remodeling. Activation of the B1 receptor and the Angiotensin II AT1 receptor have both been shown to increase oxidative stress and mitogen activated‐protein kinases (MAPK). Moreover, B1 receptor antagonism has been shown to offset AngII‐induced Erk phosphorylation and reactive oxygen species production. The goal of the present study was to determine the impact of B1 receptor antagonism in AngII‐infused rats on expression of reactive oxygen species (ROS) enzymes and MAPKs p38 and ERK1/2 in the left ventricle (LV) and kidney. Adult male Sprague Dawley Rats received a four‐week treatment of either saline or AngII (200ng/kg per min, s.c.), B1 receptor antagonist R‐954 (400 μg/kg per day, s.c.), or combined R‐954 + AngII. Mean arterial pressure (MAP) was measured via carotid catheter in anesthetized rats. Kidneys and hearts were excised and protein expression of the pro‐/anti‐oxidants (NOX2, SOD1, SOD2, and catalase) as well as phosphorylated and total p38 and p42/44 were measured by Western Blot. Relative to vehicle, MAP increased by 43% (p<0.05) in AngII treated rats, and by 64% (p<0.05) in AngII+R rats. LV/BW was significantly increased, relative to vehicle in AngII (30%) and AngII+R (31%) rats. In both the left ventricle and kidney, there were no notable effects on the expression of NOX2, SOD2, catalase, or pERK 1/2. In the heart, AngII decreased expression of SOD1 (−27% vs. vehicle, p=0.066) and this was offset by R‐954 (+7% vs. vehicle). In the kidney, AngII also decreased expression of SOD1 (−26% vs. vehicle, p=0.082) however this was not impacted by concomitant R‐954 (−44% vs. vehicle). In the heart, AngII treatment tended to increase p‐p38/p38 (+8.24%) and this was enhanced by combined treatment with R‐954 (+31%, p<0.05). There was no notable impact of treatment on p‐p38/ p38 in kidney. Taken together, the present findings demonstrate that while bradykinin B1 receptor antagonism did not impact AngII‐induced left ventricular remodeling, there appeared to be synergistic and antagonistic effects of this combination in the left ventricle. Namely, combination of angiotensin plus the B1R antagonist resulted in enhanced phosphorylation of p38, but attenuation of the AngII‐mediated reduction in SOD1 in the left ventricle. In contrast, there was no notable effect of B1R antagonism on these AngII‐mediated effects in the kidney. Future studies will investigate the apparent tissue‐specific cross‐talk between angiotensin and bradykinin receptor‐mediated signaling pathways.Support or Funding InformationAPS Undergraduate Summer Research Fellowship University of Arizona, College of Medicine ‐ Phoenix Springboard GrantThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.