Intermittent Hypoxia-Induced Activation of Endothelial Cells Is Mediated via Sympathetic Activation-Dependent Catecholamine Release

Obstructive sleep apnea (OSA) is a common breathing disorder affecting a significant percentage of the adult population. OSA is an independent risk factor for cardiovascular disease (CVD); however, the underlying mechanisms are not completely understood. Since the severity of hypoxia correlates with some of the cardiovascular effects, intermittent hypoxia (IH) is thought to be one of the mechanisms by which OSA may cause CVD. Here, we investigated the effect of IH on endothelial cell (EC) activation, characterized by the expression of inflammatory genes, that is known to play an important role in the pathogenesis of CVD. Exposure of C57BL/6 mice to IH led to aortic EC activation, while in vitro exposure of ECs to IH failed to do so, suggesting that IH does not induce EC activation directly, but indirectly. One of the consequences of IH is activation of the sympathetic nervous system and catecholamine release. We found that exposure of mice to IH caused elevation of circulating levels of catecholamines. Inhibition of the IH-induced increase in catecholamines by pharmacologic inhibition or by adrenalectomy or carotid body ablation prevented the IH-induced EC activation in mice. Supporting a key role for catecholamines, epinephrine alone was sufficient to cause EC activation in vivo and in vitro. Together, these results suggested that IH does not directly induce EC activation, but does so indirectly via release of catecholamines. These results suggest that targeting IH-induced sympathetic nerve activity and catecholamine release may be a potential therapeutic target to attenuate the CV effects of OSA.

Innervated adrenomedullary microphysiological system to model prenatal nicotine and opioid exposure

The transition to extrauterine life results in a critical surge of catecholamines necessary for increased cardiovascular, respiratory, and metabolic activity. The mechanisms mediating adrenomedullary catecholamine release are poorly understood, given the sympathetic adrenomedullary control systems’ functional immaturity. Important mechanistic insight is provided by newborns delivered by cesarean section or subjected to prenatal nicotine or opioid exposure, demonstrating the impaired release of adrenomedullary catecholamines. To investigate mechanisms regulating adrenomedullary innervation, we developed compartmentalized 3D microphysiological systems (MPS) by exploiting the meniscus pinning effect via GelPins, capillary pressure barriers between cell-laden hydrogels. The MPS comprises discrete 3D cultures of adrenal chromaffin cells and preganglionic sympathetic neurons within a contiguous bioengineered microtissue. Using this model, we demonstrate that adrenal chromaffin innervation plays a critical role in hypoxia-medicated catecholamine release. Furthermore, opioids and nicotine were shown to affect adrenal chromaffin cell response to a reduced oxygen environment, but neurogenic control mechanisms remained intact. GelPin containing MPS represent an inexpensive and highly adaptable approach to study innervated organ systems and improve drug screening platforms by providing innervated microenvironments.

Carbidopa for Afferent Baroreflex Failure in Familial Dysautonomia

Afferent lesions of the arterial baroreflex occur in familial dysautonomia. This leads to excessive blood pressure variability with falls and frequent surges that damage the organs. These hypertensive surges are the result of excess peripheral catecholamine release and have no adequate treatment. Carbidopa is a selective DOPA-decarboxylase inhibitor that suppresses catecholamines production outside the brain. To learn whether carbidopa can inhibit catecholamine-induced hypertensive surges in patients with severe afferent baroreflex failure, we conducted a double-blind randomized crossover trial in which patients with familial dysautonomia received high dose carbidopa (600 mg/day), low-dose carbidopa (300 mg/day), or matching placebo in 3 4-week treatment periods. Among the 22 patients enrolled (13 females/8 males), the median age was 26 (range, 12–59 years). At enrollment, patients had hypertensive peaks to 164/116 (range, 144/92 to 213/150 mm Hg). Twenty-four hour urinary norepinephrine excretion, a marker of peripheral catecholamine release, was significantly suppressed on both high dose and low dose carbidopa, compared with placebo ( P =0.0075). The 2 co-primary end points of the trial were met. The SD of systolic BP variability was reduced at both carbidopa doses (low dose: 17±4; high dose: 18±5 mm Hg) compared with placebo (23±7 mm Hg; P =0.0013), and there was a significant reduction in the systolic BP peaks on active treatment ( P =0.0015). High- and low-dose carbidopa were similarly effective and well tolerated. This study provides class Ib evidence that carbidopa can reduce blood pressure variability in patients with congenital afferent baroreflex failure. Similar beneficial effects are observed in patients with acquired baroreflex lesions.

Computational Modeling of Catecholamines Dysfunction in Alzheimer’s Disease at Pre-Plaque Stage

Background: Alzheimer’s disease (AD) etiopathogenesis remains partially unexplained. The main conceptual framework used to study AD is the Amyloid Cascade Hypothesis, although the failure of recent clinical experimentation seems to reduce its potential in AD research. Objective: A possible explanation for the failure of clinical trials is that they are set too late in AD progression. Recent studies suggest that the ventral tegmental area (VTA) degeneration could be one of the first events occurring in AD progression (pre-plaque stage). Methods: Here we investigate this hypothesis through a computational model and computer simulations validated with behavioral and neural data from patients. Results: We show that VTA degeneration might lead to system-level adjustments of catecholamine release, triggering a sequence of events leading to relevant clinical and pathological signs of AD. These changes consist first in a midfrontal-driven compensatory hyperactivation of both VTA and locus coeruleus (norepinephrine) followed, with the progression of the VTA impairment, by a downregulation of catecholamine release. These processes could then trigger the neural degeneration at the cortical and hippocampal levels, due to the chronic loss of the neuroprotective role of norepinephrine. Conclusion: Our novel hypothesis might contribute to the formulation of a wider system-level view of AD which might help to devise early diagnostic and therapeutic interventions.

Fusion pore expansion and contraction during catecholamine release from endocrine cells

ABSTRACTAmperometry recording reveals the exocytosis of catecholamine from individual vesicles as a sequential process, typically beginning slowly with a pre-spike foot, accelerating sharply to initiate a spike, reaching a peak, and then decaying. This complex sequence reflects the interplay between diffusion, flux through a fusion pore, and possibly dissociation from a vesicle’s densecore. In an effort to evaluate the impacts of these factors, a model was developed that combines diffusion with flux through a static pore. This model recapitulated the rapid phases of a spike, but generated relations between spike shape parameters that differed from experimental results. To explore the possibility of fusion pore dynamics, a transformation of amperometry current was introduced that yields fusion pore permeability divided by vesicle volume (g/V). Applying this transform to individual fusion events yielded a highly characteristic time course. g/V initially tracks the pre-spike foot and the start of the spike, increasing ∼15-fold to the peak. However, after the spike peaks, g/V unexpectedly declines and settles to a constant value that indicates the presence of a stable post-spike pore. g/V of the post-spike pore varies greatly between events, and has an average that is ∼3.5-fold below the peak value and ∼4.5-fold above the pre-spike value. The post-spike pore persists and g/V remains flat for tens of milliseconds, as long as catecholamine flux can be detected. Applying the g/V transform to rare events with two peaks revealed a stepwise increase in g/V during the second peak. The g/V transform offers an interpretation of amperometric current in terms of fusion pore dynamics and provides a new framework for analyzing the actions of proteins that alter spike shape. The stable post-spike pore conforms with predictions from lipid bilayer elasticity, and offers an explanation for previous reports of prolonged hormone retention within fusing vesicles.STATEMENT OF SIGNIFICANCEAmperometry recordings of catecholamine release from single vesicles reveal a complex waveform with distinct phases. The role of the fusion pore in this waveform is poorly understood. A model based on a static fusion pore fails to recapitulate important aspects of the waveform. A new transform of amperometric current introduced here renders fusion pore permeability in real time. This transform reveals rich dynamic behavior of the fusion pore as catecholamine leaves a vesicle. This analysis shows that fusion pore permeability rapidly increases and then decreases before settling into a stable post-spike configuration.

Management of Supraventricular Tachycardia in Pregnancy

Supraventricular tachycardia is a common arrhythmia in pregnancy. During labor and delivery, neuraxial analgesia is important to prevent arrhythmia recurrence. We present the case of a 27-year-old gravida 2 para 1 woman at 35 weeks’ gestation presenting with supraventricular tachycardia that converted to normal sinus rhythm with adenosine. To prevent recurrence of the arrhythmia, an early epidural was provided during labor to minimize catecholamine release.

Multidisciplinary management of a large pheochromocytoma presenting with cardiogenic shock: a case report

Background Pheochromocytoma is well-known for sudden initial presentations, particularly in younger patients. Hemodynamic instability may cause serious complications and delay a patient’s ability to undergo surgical resection. Larger tumors present a further challenge because of the risk of catecholamine release during manipulations. In the case we present, increases in systemic vascular resistance caused cardiogenic shock, and the size of the lesion prompted surgeons to veer off from their usual approach. Case presentation A 38-year-old female patient was admitted to our intensive care unit with hypertension and later cardiogenic shock. Profound systolic dysfunction (left ventricular ejection fraction of 0.12) was noted together with severely increased systemic vascular resistance, and gradually responded to vasodilator infusion. A left-sided 11-cm adrenal mass was found with computed tomography and confirmed a pheochromocytoma with a meta-iodo-benzyl-guanidine scintigraphy. Surgical treatment was carefully planned by the endocrinologist, anesthesiologist and surgeon, and was ultimately successful. After prolonged hemodynamic stabilization, open adrenalectomy and nephrectomy were deemed safer because of lesion size and the apparent invasion of the kidney. Surgery was successful and the patient was discharged home 5 days after surgery. She is free from disease at almost 2 years from the initial event. Conclusions Large, invasive pheochromocytoma can be safely and effectively managed with open resection in experienced hands, provided all efforts are made to achieve hemodynamic stabilization and to minimize. Catecholamine release before and during surgery.