Sepsis is the leading cause of acute kidney injury (AKI) and leads to increased morbidity and mortality in intensive care units. Current treatments for septic AKI are largely supportive and are not targeted towards its pathophysiology. Sepsis is commonly characterized by systemic inflammation and increased production of reactive oxygen species (ROS), particularly superoxide. Concomitantly released nitric oxide (NO) then reacts with superoxide, leading to the formation of reactive nitrogen species (RNS), predominantly peroxynitrite. Sepsis-induced ROS and RNS can reduce the bioavailability of NO, mediating renal microcirculatory abnormalities, localized tissue hypoxia and mitochondrial dysfunction, thereby initiating a propagating cycle of cellular injury culminating in AKI. In this review, we discuss the various sources of ROS during sepsis and their pathophysiological interactions with the immune system, microcirculation and mitochondria that can lead to the development of AKI. We also discuss the therapeutic utility of N-acetylcysteine and potential reasons for its efficacy in animal models of sepsis, and its inefficacy in ameliorating oxidative stress-induced organ dysfunction in human sepsis. Finally, we review the pre-clinical studies examining the antioxidant and pleiotropic actions of vitamin C that may be of benefit for mitigating septic AKI, including future implications for clinical sepsis.

Zinc, an abundant transition metal, serves as a signalling molecule in several biological systems. Zinc transporters are genetically associated with cardiovascular diseases but the function of zinc in vascular tone regulation is unknown. We found that elevating cytoplasmic zinc using ionophores relaxed rat and human isolated blood vessels and caused hyperpolarization of smooth muscle membrane. Furthermore, zinc ionophores lowered blood pressure in anaesthetized rats and increased blood flow without affecting heart rate. Conversely, intracellular zinc chelation induced contraction of selected vessels from rats and humans and depolarized vascular smooth muscle membrane potential. We demonstrate three mechanisms for zinc-induced vasorelaxation: (1) activation of transient receptor potential ankyrin 1 to increase calcitonin gene-related peptide signalling from perivascular sensory nerves; (2) enhancement of cyclooxygenase-sensitive vasodilatory prostanoid signalling in the endothelium; and (3) inhibition of voltage-gated calcium channels in the smooth muscle. These data introduce zinc as a new target for vascular therapeutics.

Aggregation of tau protein into intracellular deposits is a pathognomonic feature of tauopathies such as Alzheimer’s disease (AD) and lowering tau is a prominent therapeutic strategy under development. However, the physiological function of tau protein is not well known, particularly in the periphery. Lowering tau protein risks disrupting its physiological role leading to unwanted effects. In this study, the presence of tau protein in cardiac tissue is confirmed and the functional role in the cardiovascular system and the consequences of its loss were explored. Isolated right and left atria and small mesenteric arteries from wild type and tau deficient (KO) mice of two age groups (13 and 23 months old) were used to assess cardiovascular phenotypes. Tau KO mice showed an increased systolic blood pressure and cardiac hypertrophy at 13 months, which was accompanied by a significantly lower right atrial rate and a subtle decrease in the maximum contractility to calcium, isoprenaline, and electrical sympathetic nerve stimulation. Aging tau KO mice to 23 months resulted in cardiac hypertrophy with significantly attenuated left atrial contractility, increased blood pressure, and sensitivity of isolated mesenteric arteries to angiotensin II contraction and isoprenaline relaxation compared to their younger counterparts. This study supports a functional role of tau in the heart and loss of this protein leads to a deterioration in cardiovascular performance which worsens with age. Taken together, these results provide insight into the peripheral function of tau protein, and give caution to the therapeutic strategy of lowering tau protein.

α_1A-, α_1B-, and α_1D-adrenoceptors (α₁-ARs) are members of the adrenoceptor G protein-coupled receptor family that are activated by adrenaline (epinephrine) and noradrenaline. α₁-ARs are clinically targeted using antagonists that have minimal subtype selectivity, such as prazosin and tamsulosin, to treat hypertension and benign prostatic hyperplasia, respectively. Abundant expression of α₁-ARs in the heart and central nervous system (CNS) makes these receptors potential targets for the treatment of cardiovascular and CNS disorders, such as heart failure, epilepsy, and Alzheimer's disease. Our understanding of the precise physiological roles of α₁-ARs, however, and their involvement in disease has been hindered by the lack of sufficiently subtype-selective tool compounds, especially for α_1B-AR. Here, we report the discovery of 4-[(2-hydroxyethyl)amino]-6-methyl-2H-chromen-2-one (Cpd1), as an α_1B-AR antagonist that has 10-15-fold selectivity over α_1A-AR and α_1D-AR. Through computational and site-directed mutagenesis studies, we have identified the binding site of Cpd1 in α_1B-AR and propose the molecular basis of α_1B-AR selectivity, where the nonconserved V197^45.52 residue plays a major role, with contributions from L314^6.55 within the α_1B-AR pocket. By exploring the structure-activity relationships of Cpd1 at α_1B-AR, we have also identified 3-[(cyclohexylamino)methyl]-6-methylquinolin-2(1H)-one (Cpd24), which has a stronger binding affinity than Cpd1, albeit with reduced selectivity for α_1B-AR. Cpd1 and Cpd24 represent potential leads for α_1B-AR-selective drug discovery and novel tool molecules to further study the physiology of α₁-ARs.

Summary: Introduction: Acute kidney injury is common after cardiac surgery requiring cardiopulmonary bypass, yet preventive strategies are limited. Progress has been hindered by a lack of clinically relevant experimental models incorporating pre‐existing heart disease. This study aimed to evaluate the impact of heart failure on renal oxygenation and histopathological injury during and after cardiopulmonary bypass in a large animal model. Methods: Heart failure was induced in 10 sheep (study group) via progressive coronary artery ligation; 10 healthy sheep served as controls (control group). We measured renal blood flow, renal function and renal cortical and medullary oxygenation before and after induction of anaesthesia, during 2 h of cardiopulmonary bypass and for 48 h postoperatively. Kidneys were collected at 48 h for histopathology. Results: Cardiopulmonary bypass reduced renal blood flow (55%) and medullary oxygen tension (50%) in both groups (both p < 0.001). During the 48‐h recovery period, medullary oxygen tension remained low in the study group but normalised in the control group (mean (SD) 11 (11) vs. 31 (10) mmHg at 48 h, p = 0.01). Urine output was lower in the study group than in the control group over the 48‐h recovery period (mean (SD) 0.90 (0.54) vs. 2.24 (1.84) ml.kg ^‐1 .h ^‐1 at 48 h, p = 0.03). Histopathologically, the study group had a higher incidence of neutrophil infiltration (89% vs. 30%, p = 0.04), although the incidence of acute tubular necrosis, fibrosis and tubular casts did not differ significantly between groups. Discussion: In this ovine model of heart failure, cardiopulmonary bypass led to persistent renal medullary hypoxia, oliguria and increased renal inflammation. These findings suggest that impaired renal medullary oxygenation and inflammation may drive cardiac surgery‐associated acute kidney injury and represent a key target for renoprotective strategies.