Bradykinin increases blood pressure in endotoxemic rats
Authors: Anton Elaine , Corrêa Thiago , Fernandes Daniel , Assreuy Jamil , da Silva Santos José Eduardo 
Published: June 2021

Despite the knowledge about the mechanisms triggered by bradykinin (BK), mainly its hypotensive effect, several aspects of biological effects of this peptide remain unclear, such as its release and action in endotoxemia. The main hypothesis of this study was that blood pressure responses to BK are impaired in experimental models of sepsis. Female Wistar rats (200–280 g) received intraperitoneal (i.p.) injections of sterile saline (1 ml/kg), or lipopolysaccharide (LPS; 1 mg/kg), and were anesthetized at 6, 24, 48, or 72 h after for direct measurement of the mean arterial pressure (MAP). The hypotensive effect of intravenous (i.v.) BK (6, 20 and 60 nmol/kg), and acetylcholine (ACh; 60 nmol/kg) were assessed before and after the treatment with prazosin (0.5 mg/kg i.v.), HOE 140 (20 nmol/kg s.c.), [Leu8]des‐Arg9‐BK (100 nmol/kg, i.v.), losartan (15 mg/kg, i.v.), Y‐27632 (0.1 mg/kg, i.v.), or indomethacin (10 mg/kg i.v.). We also evaluated the influence of endotoxemia on BK‐ and ACh‐induced vasodilation in the in vitro perfused mesenteric vascular bed obtained from both control and LPS 24 h groups. Moreover, the expression of bradykinin B2 and angiotensin II AT1 receptors, and the phosphorylated MYPT‐1 subunit of myosin phosphatase (pMYPT‐1) was detected by Western blotting in homogenates of resistance mesenteric arteries. In spite of the lack of changes in the MAP, and the hypotensive effects induced by BK and ACh remained unaltered in the LPS groups, LPS‐treated animals presented hematological evidence of systemic inflammation (i.e. leukocytosis, high levels of nitrate + nitrite), compared with the control group. Although endotoxemia have not changed the hypotensive effects induced by BK and ACh, BK‐induced hypotension in LPS treated animals (both 24 h and 48 h groups) was followed by an immediate and sustained pressor effect. For instance, the MAP increased by 9 ± 2, 18 ± 5, and 24 ± 3 mm Hg in the control group, and by 29 ± 4, 42 ± 3, and 56 ± 4 mm Hg in the LPS 24 h group, after administration of 6, 20, and 60 nmol/kg BK, respectively. This hypertensive response to BK was not reduced by the selective antagonist of the alpha‐1 adrenergic receptor prazosin, nor by the antagonist of the BK B1 receptor [Leu8]des‐Arg9‐BK, but it was vanished by HOE‐140, a selective BK B2 receptor antagonist, and losartan, an angiotensin II AT1 receptor antagonist. We also found that the hypertensive effect of angiotensin II (60 nmol/kg) was enhanced from 52 ± 5 mm Hg in control animals to 75 ± 3 mm Hg in the LPS 24 h group, an event that was fully prevented by HOE‐140. Although the cyclooxygenase inhibitor indomethacin has not had any influence on BK effects, the Rho‐associated kinase (ROCK) inhibitor Y‐27632 avoided the enhanced hypertensive effect of BK in LPS‐treated animals. Western blotting analysis revealed that B2 and AT1 receptors, and pMYPT‐1, were significantly increased in resistance arteries at 24 h after LPS, compared with samples from control animals. Notably, perfused mesenteric vascular bed obtained from the LPS 24 h group also displayed pressor responses to BK. These results disclose that in spite of the typical hypotension produced by BK in healthy animals, administration of BK in endotoxemic rats produces a biphasic effect, which is characterized by a hypotension followed by a sustained rise in blood pressure. The pressor effect of BK, induced by endotoxemia, appears to be mediated by both bradykinin B2 and angiotensin II AT1 receptors and is fully dependent on activation of ROCK.

Support or Funding Information

CNPq (448738/2014‐7). This study was approved by CEUA/UFSC (PP00566).

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.