The Pressor Effects of Angiotensin II are Sensitive to Bradykinin B2 Receptor Modulation in Septic Rats

Background: Septic shock, responsible for high mortality rates in intensive care units, is characterized by severe hypotension, which is unresponsive to vasopressor agents commonly used in clinical practice. Bradykinin, a potent endogenous vasodilator, was previously suggested as one of the mediators involved in the installation of this condition. In this study, we aimed to examine the hypothesis that blockade of bradykinin B2 receptors by icatibant can improve the vasopressor effects of norepinephrine (NOR) and angiotensin II (AII) in sepsis. Methods: We randomly separated male and female Wistar rats (3-4 months) into control (CT; naïve animals) or septic groups. Sepsis was induced throughout cecal ligation puncture (CLP) surgery following a non-obstructive ligation and four non-transfixing holes using an 18G needle. All CLP surgeries were performed under isoflurane-induced general anesthesia in animals previously treated with tramadol (5 mg/kg). Control and septic animals received two s.c. injections of 60 nmol/kg of icatibant given at 2 and 5 h after CLP. Separated groups of CT and CLP-subjected animals treated only with sterile saline (100 μL, s.c.) were used for comparisons. At 6 h (CLP6h group) and 14 h (CLP14h group) after CLP, the animals were anesthetized (ketamine/xylazine, 100/10 mg/kg, i.m.) and prepared for intravenous injections and direct measurement of blood pressure. After 20 min of stabilization, basal cardiovascular parameters (systolic, diastolic, and mean arterial pressures – SAP, DAP, and MAP, respectively, in mmHg; and heart rate, HR, in bpm) were recorded. Then, the animals received subsequent i.v. injection of BK (30 nmol/kg) and continuous infusion of NOR (10-100 nmol/kg) or AII (0.3-3 nmol/kg). The results (n = 6/group) were described as mean ± SEM and evaluated using ANOVA followed by Tukey. A p-value < 0.05 was adopted for significant differences. Results: Male and female animals from both CLP6h and CLP14h groups presented reduced systemic arterial pressure and augmented HR, compared with values from the CT group. For instance, in male rats, MAP and HR were 93.8 ± 2.5 mmHg and 235 ± 6 bpm in CT, 60.3 ± 3.8 mmHg and 304 ± 10 bpm in CLP6h, 62.5 ± 3.7 mmHg and 281 ± 12 bpm in CLP24h groups. The double administration of icatibant fully blocked the hypotensive effect of BK in CT and CLP6h groups but not in the CLP14h group. However, blockage of B2 receptors by icatibant did not alter sepsis-associated hypotension and tachycardia neither in CLP6h nor in CLP14h groups. Male and female animals subjected to CLP displayed reduced responses to both NOR and AII. For instance, in female rats, the continuous infusion of AII increased the SAP to 194.4 ± 4.4, 129.6 ± 7.2, and 113.9 ± 3.9 mmHg in CT, CLP6h and CLP14h groups, respectively. The treatment with icatibant did not improve the hypertensive effects of NOR, regardless of the sex of the animals. On the other hand, although the administration of icatibant for female rats had increased the pressor responses to AII in both CLP6h and CLP14h groups, it was effective for male rats only in the CLP14h group. Notably, the treatment with icatibant did not change the pressor effects of AII in male and female animals from CT groups. Conclusions: Our results indicate that even though icatibant had failed to prevent the development of hypotension, the early blockage of B2 receptors can be a helpful strategy to improve the systemic pressor response to AII even in the late stages of sepsis. Understanding how the modulation of B2 bradykinin receptors impacts the pressor effects of angiotensin II, as well the existence of sex-related differences, can open new strategies for managing sepsis and other cardiovascular conditions. CAPES, 001; CNPq 405538/2021-9 and 403615/2023-2. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.