RESUMO
BACKGROUND: Hemolysis in sickle cell disease (SCD) releases cell free hemoglobin, which scavenges nitric oxide (NO), leading to pulmonary vascular vasoconstriction, increased pulmonary vascular resistance (PVR), and the development of PH. However, PVR is only one component of right ventricular (RV) afterload. Whether sickled red blood cells increase the total RV afterload, including compliance and wave reflections, is unclear. OBJECTIVE: Patients with SCD and pulmonary hypertension (PH) have a significantly increased risk of sudden death compared to patients with SCD alone. Sickled red blood cells (RBCs) are fragile and lyse easily. Here, we sought to determine the acute effects of SCD RBCs and increased cell free hemoglobin on RV afterload. METHODS: Main pulmonary artery pressures and flows were measured in C57BL6 mice before and after exchanges of whole blood (~200 uL, Hct=45%) with an equal volume of SCD RBCs in plasma (Hct=45%) or cell free hemoglobin (Hb+) in solution. After transfusions, animals were additionally stressed with acute hypoxia (AH; 10% O2). RESULTS: SCD RBCs increased PVR only compared to control RBCs; cell free hemoglobin increased PVR and wave reflections. These increases in RV afterload increased further with AH. CONCLUSIONS: The release of cell free hemoglobin from fragile SCD RBCs in vivo increases the total RV afterload and may impair RV function more than the SCD RBCs themselves.
RESUMO
The kinin-B2 receptor (B2BKR) activated by its endogenous ligand bradykinin participates in various metabolic processes including the control of arterial pressure and inflammation. Recently, functions for this receptor in brain development and protection against glutamate-provoked excitotoxicity have been proposed. Here, we report neuroprotective properties for bradykinin against organophosphate poisoning using acute hippocampal slices as an in vitro model. Following slice perfusion for 10min with diisopropylfluorophosphate (DFP) to initiate the noxious stimulus, responses of pyramidal neurons upon an electric impulse were reduced to less than 30% of control amplitudes. Effects on synaptic-elicited population spikes were reverted when preparations had been exposed to bradykinin 30min after challenging with DFP. Accordingly, bradykinin-induced population spike recovery was abolished by HOE-140, a B2BKR antagonist. However, the kinin-B1 receptor (B1BKR) agonist Lys-des-Arg(9)-bradykinin, inducing the phosphorylation of mitogen-activated protein kinase (MEK/MAPK) and cell death, abolished bradykinin-mediated neuroprotection, an effect, which was reverted by the ERK inhibitor PD98059. In agreement with pivotal B1BKR functions in this process, antagonism of endogenous B1BKR activity alone was enough for restoring population spike activity. On the other hand pralidoxime, an oxime, reactivating acetylcholinesterase (AChE) after organophosphate poisoning, induced population spike recovery after DFP exposure in the presence of bradykinin and Lys-des-Arg(9)-bradykinin. Lys-des-Arg(9)-bradykinin did not revert protection exerted by pralidoxime, however when instead bradykinin and Ly-des-Arg(9)-bradykinin were superfused together, recovery of population spikes diminished. These findings again confirm the neuroprotective feature of bradykinin, which is, diminished by its endogenous metabolites, stimulating the B1BKR, providing a novel understanding of the physiological roles of these receptors.