Subarachnoid Hemorrhage, Spreading Depolarizations and Impaired Neurovascular Coupling

Aneurysmal subarachnoid hemorrhage (SAH) has devastating consequences on brain function including profound effects on communication between neurons and the vasculature leading to cerebral ischemia. Physiologically, neurovascular coupling represents a focal increase in cerebral blood flow to meet increased metabolic demand of neurons within active regions of the brain. Neurovascular coupling is an ongoing process involving coordinated activity of the neurovascular unit—neurons, astrocytes, and parenchymal arterioles. Neuronal activity can also influence cerebral blood flow on a larger scale. Spreading depolarizations (SD) are self-propagating waves of neuronal depolarization and are observed during migraine, traumatic brain injury, and stroke. Typically, SD is associated with increased cerebral blood flow. Emerging evidence indicates that SAH causes inversion of neurovascular communication on both the local and global level. In contrast to other events causing SD, SAH-induced SD decreases rather than increases cerebral blood flow. Further, at the level of the neurovascular unit, SAH causes an inversion of neurovascular coupling from vasodilation to vasoconstriction. Global ischemia can also adversely affect the neurovascular response. Here, we summarize current knowledge regarding the impact of SAH and global ischemia on neurovascular communication. A mechanistic understanding of these events should provide novel strategies to treat these neurovascular disorders

Capsaicin-Induced Ca2+ Influx and Constriction of the Middle Meningeal Artery

Research in the past on transient receptor potential cation channel subfamily V member 1 (TRPV1) has been limited to mainly nervous tissue TRPV1 because of the channel’s role in pain perception. Here, we studied the potential role of TRPV1 in vascular smooth muscle. We have observed that capsaicin, a TRPV1 agonist, induced constriction of the middle meningeal artery (MMA). Our goal was to decipher the mechanism of capsaicin-induced constriction of the MMA. Arterial diameter measurements showed that constriction due to 100 nM capsaicin (65.4% ± 3.7, n=7) was significantly diminished in the presence of the voltage-dependent calcium channel (VDCC) blocker 100 µM diltiazem (43.1% ± 8.1, n=7). Capsaicin-induced constriction was not significantly altered in the presence of the sarco/endoplasmic reticulum calcium transport ATPase (SERCA) inhibitor 30 µM cyclopiazonic acid (63.7 ± 9.0%, n=5) compared to control arteries (58.4 ± 8.6%, n=5). The unaltered capsaicin-induced constriction of the MMA in the presence of a SERCA inhibitor suggests that calcium-induced calcium release does not contribute to the overall calcium influx mechanism within the smooth muscle cells of the MMA. The diminished capsaicin-induced constriction of the MMA in the presence of a VDCC blocker suggests that sodium entry through TRPV1 channels can possibly lead to the membrane potential depolarization and increased activity of VDCCs causing further calcium influx. Furthermore, since the capsaicin effect was not abolished by the blockage of VDCCs, our data suggest that calcium entry through TRPV1 is sufficient to cause approximately 65% of the total constriction of the MMA in response to activation of TRPV1

Inversion of neurovascular coupling after subarachnoid hemorrhage in vivo

Subarachnoid hemorrhage (SAH) induces acute changes in the cerebral microcirculation. Recent findings ex vivo suggest neurovascular coupling (NVC), the process that increases cerebral blood flow upon neuronal activity, is also impaired after SAH. The aim of the current study was to investigate whether this occurs also invivo. C57BL/6 mice were subjected to either sham surgery or SAH by filament perforation. Twenty-four hours later NVC was tested by forepaw stimulation and CO2 reactivity by inhalation of 10% CO2. Vessel diameter was assessed invivo by two-photon microscopy. NVC was also investigated ex vivo using brain slices. Cerebral arterioles of sham-operated mice dilated to 130% of baseline upon CO2 inhalation or forepaw stimulation and cerebral blood flow (CBF) increased. Following SAH, however, CO2 reactivity was completely lost and the majority of cerebral arterioles showed paradoxical constriction invivo and ex vivo resulting in a reduced CBF response. As previous results showed intact NVC 3h after SAH, the current findings indicate that impairment of NVC after cerebral hemorrhage occurs secondarily and is progressive. Since neuronal activity-induced vasoconstriction (inverse NVC) is likely to further aggravate SAH-induced cerebral ischemia and subsequent brain damage, inverse NVC may represent a novel therapeutic target after SAH

Design and baseline characteristics of the finerenone in reducing cardiovascular mortality and morbidity in diabetic kidney disease trial

Background: Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. Patients and Methods: The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate >= 25 mL/min/1.73 m(2) and albuminuria (urinary albumin-to-creatinine ratio >= 30 to <= 5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level alpha = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Conclusions: FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049

Inversion of neurovascular coupling by subarachnoid blood depends on large-conductance Ca2+-activated K+(BK) channels

The cellular events that cause ischemic neurological damage following aneurysmal subarachnoid hemorrhage (SAH) have remained elusive. We report that subarachnoid blood profoundly impacts communication within the neurovascular unit - neurons, astrocytes, and arterioles - causing inversion of neurovascular coupling. Elevation of astrocytic endfoot Ca2+ to ∼400 nM by neuronal stimulation or to ∼300 nM by Ca2+ uncaging dilated parenchymal arterioles in control brain slices but caused vasoconstriction in post-SAH brain slices. Inhibition of K+ efflux via astrocytic endfoot large-conductance Ca2+-activated K+ (BK) channels prevented both neurally evoked vasodilation (control) and vasoconstriction (SAH). Consistent with the dual vasodilator/vasoconstrictor action of extracellular K+ ([K+]o), [K+] o 20 mM constricted isolated brain cortex parenchymal arterioles with or without SAH. Notably, elevation of external K+ to 10 mM caused vasodilation in brain slices from control animals but caused a modest constriction in brain slices from SAH model rats; this latter effect was reversed by BK channel inhibition, which restored K+-induced dilations. Importantly, the amplitude of spontaneous astrocytic Ca2+ oscillations was increased after SAH, with peak Ca2+reaching ∼490 nM. Our data support a model in which SAH increases the amplitude of spontaneous astrocytic Ca 2+ oscillations sufficiently to activate endfoot BK channels and elevate [K+]o in the restricted perivascular space. Abnormally elevated basal [K+]ocombined with further K+ efflux stimulated by neuronal activity elevates [K +]o above the dilation/constriction threshold, switching the polarity of arteriolar responses to vasoconstriction. Inversion of neurovascular coupling may contribute to the decreased cerebral blood flow and development of neurological deficits that commonly follow SAH