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Background and Purpose Bradykinin (BK‐(1–9)) is an endogenous nonapeptide involved in multiple physiological and pathological processes. Peptide fragments of bradykinin are believed to be biologically inactive. We have now tested the two major peptide fragments of bradykinin in human and animals. Experimental Approach BK peptides were quantified by MS in male rats. NO release was quantified from human, mouse and rat cells loaded with DAF‐FM. Rat aortic rings were used to measure vascular reactivity. Changes in BP and HR were measured in conscious male rats. To evaluate pro‐inflammatory effects both vascular permeability and nociception were measured in adult mice. Key Results BK‐(1–7) and BK‐(1–5) are produced in vivo from BK‐(1–9). Both peptides induced NO production in all cell types tested. However, unlike BK‐(1–9), NO production elicited by BK‐(1–7) or BK‐(1–5) was not inhibited by B1 or B2 receptor antagonists. BK‐(1–7) and BK‐(1–5) induced concentration‐dependent vasorelaxation of aortic rings, without involvement of B1 or B2 receptors. Intravenous or intra‐arterial administration of BK‐(1–7) or BK‐(1–5) induced similar hypotensive response in vivo. Nociceptive responses of BK‐(1–7) and BK‐(1–5) were reduced compared to BK‐(1–9), and no increase in vascular permeability was observed for BK‐(1–9) fragments. Conclusions and Implications BK‐(1–7) and BK‐(1–5) are endogenous peptides present in plasma. BK‐related peptide fragments show biological activity, not mediated by B1 or B2 receptors. These BK fragments could constitute new, active components of the kallikrein–kinin system.

Background and purpose: Bradykinin [BK-(1-9)] is an endogenous peptide involved in many physiological and pathological processes, such as cardiovascular homeostasis and inflammation. The central dogma of the kallikrein-kinin system is that BK-(1-9) fragments are biologically inactive. In this manuscript, we proposed to test whether these fragments were indeed inactive. Experimental Approach: Nitric oxide (NO) was quantified in human, mouse and rat cells loaded with DAF-FM after stimulation with BK-(1-9), BK-(1-7), BK-(1-5) and BK-(1-3). We used adult male rat aortic ring preparation to test vascular reactivity mediated by BK-(1-9) fragments. Changes in blood pressure and heart rate was measured in conscious adult male rats by intraarterial catheter method. Key results: BK-(1-9) induced NO production in all cell types tested by B2 receptor activation. BK-(1-7), BK-(1-5) and BK-(1-3) also induced NO production in all tested cell types but this response was independent of the activation of B1 receptor and/or B2 receptor. BK-(1-7), BK-(1-5) or BK-(1-3) induced only vasorelaxant effect and in a concentration-dependent fashion. Vasorelaxant effects for BK-(1-7), BK-(1-5) or BK-(1-3) were independent of the kinin receptors. Different administration routes (i.e., intravenous or intra-arterial) did not affect the observed hypotension induced by BK-(1-7), BK-(1-5) or BK-(1-3). Importantly, these observations diverged from the BK-(1-9) results, highlighting that indeed the BK-(1-9) fragments do not seem to act via the classical kinin receptors. Conclusions and implications: In conclusion, BK-(1-7), BK-(1-5) and BK-(1-3) are biologically active components of the kallikrein-kinin system. Importantly, observed pathophysiological outcomes of these peptides are independent of B1R and/or B2R activation.

Purpose of Review The response to natural stressors involves both cardiac stimulation and vascular changes, primarily triggered by increases in sympathetic activity. These effects lead to immediate flow redistribution that provides metabolic support to priority target organs combined with other key physiological responses and cognitive strategies, against stressor challenges. This extremely well-orchestrated response that was developed over millions of years of evolution is presently being challenged, over a short period of time. In this short review, we discuss the neurogenic background for the origin of emotional stress-induced hypertension, focusing on sympathetic pathways from related findings in humans and animals. Recent Findings The urban environment offers a variety of psychological stressors. Real or anticipatory, emotional stressors may increase baseline sympathetic activity. From routine day-to-day traffic stress to job-related anxiety, chronic or abnormal increases in sympathetic activity caused by emotional stressors can lead to cardiovascular events, including cardiac arrhythmias, increases in blood pressure and even sudden death. Among the various alterations proposed, chronic stress could modify neuroglial circuits or compromise antioxidant systems that may alter the responsiveness of neurons to stressful stimuli. These phenomena lead to increases in sympathetic activity, hypertension and consequent cardiovascular diseases. Summary The link between anxiety, emotional stress, and hypertension may result from an altered neuronal firing rate in central pathways controlling sympathetic activity. The participation of neuroglial and oxidative mechanisms in altered neuronal function is primarily involved in enhanced sympathetic outflow. The significance of the insular cortex-dorsomedial hypothalamic pathway in the evolution of enhanced overall sympathetic outflow is discussed.

Evidence indicates that the dorsomedial hypothalamic region (DMH) plays a key role in the organization of the cardiovascular (CV) response to acute emotional stress. Inhibition of DMH and/or blockade of excitatory amino acid (EAA) receptors in this region attenuate the physiological responses evoked by stress. However, all these effects have been explored in a single stress model (air‐stress). We evaluate the contribution of NMDA receptors in the DMH on the CV response evoked by cage switch stress (CS stress). Under anesthesia (tribromoethanol, 250 mg/kg), Wistar rats received guide cannulas into DMH. Seven days after, a cannula was inserted into femoral artery for HR and BP recording. After 24 hs, bilateral nanoinjections (100nL) of vehicle (saline 0.9%, n=7), the GABAA agonist muscimol (100pmol, n=8) or the NMDA antagonist AP‐5 (100pmol, n=6) were performed into DMH; ten min later, rats were submitted to CS stress. An additional control group was also tested (no injection, intact group, n=9). In the intact group and in the vehicle group CS stress evoked a tachycardic response (Δ 119±12 bpm and 121±11 bpm) accompanied by large increases in BP (Δ 60±2 mmHg and Δ 60±3 bpm, respectively). The tachycardic and pressor responses were markedly reduced by muscimol and AP‐5 (musc: ΔHR: 62±7 bpm and Δ MAP: 37±4 mmHg; AP‐5: Δ HR: 31±7 bpm and Δ MAP: 39±3 mmHg, P<0.05 vs. vehicle). Corticosterone and glucose levels were unaffected by CS or any treatment. Data suggest that the DMH is also important for controlling CV responses in other forms of acute emotional stress. Part of this response involves activation of NMDA EAA receptors. Support: Fapemig, Capes, CNPq