Postoperative Stroke after Spinal Anesthesia and Responses of Carotid or Cerebral Blood Flow and Baroreflex Functionality to Spinal Bupivacaine in Rats.

Spinal anesthesia is generally accepted as an effective and safe practice. Three rare incidents of postoperative cerebral infarction after surgery under spinal anesthesia prompted us to assess whether spinal bupivacaine may compromise carotid or cerebral blood flow. Postoperative examination after the stroke incident revealed that all three patients shared a common pathology of stenosis or atheromatosis in the carotid or middle cerebral artery. In a companion study using 69 Sprague-Dawley rats, subarachnoid application of bupivacaine elicited an initial (Phase I) reduction in the mean arterial pressure, carotid blood flow (CBF) and baroreflex-mediated sympathetic vasomotor tone, all of which subsequently returned to baseline (Phase II). Whereas heart rate (HR) exhibited sustained reduction, cardiac vagal baroreflex, baroreflex efficiency index (BEI) and tissue perfusion and oxygen in the cerebral cortex remained unaltered. However, in one-third of the rats studied, Phase II gave way to Phase III characterized by secondary hypotension and depressed baroreflex-mediated sympathetic vasomotor tone, along with declined HR, sustained cardiac vagal baroreflex, decreased BEI, reduced CBF and waning tissue perfusion or oxygen in the cerebral cortex. We concluded that carotid and cerebral blood flow can indeed be compromised after spinal anesthesia, and an impaired baroreflex-mediated sympathetic vasomotor tone, which leads to hypotension, plays a contributory role.

Differential impacts of brain stem oxidative stress and nitrosative stress on sympathetic vasomotor tone.

Based on work-done in the rostral ventrolateral medulla (RVLM), this review presents four lessons learnt from studying the differential impacts of oxidative stress and nitrosative stress on sympathetic vasomotor tone and their clinical and therapeutic implications. The first lesson is that an increase in sympathetic vasomotor tone because of augmented oxidative stress in the RVLM is responsible for the generation of neurogenic hypertension. On the other hand, a shift from oxidative stress to nitrosative stress in the RVLM underpins the succession of increase to decrease in sympathetic vasomotor tone during the progression towards brain stem death. The second lesson is that, by having different cellular sources, regulatory mechanisms on synthesis and degradation, kinetics of chemical reactions, and downstream signaling pathways, reactive oxygen species and reactive nitrogen species should not be regarded as a singular moiety. The third lesson is that well-defined differential roles of oxidative stress and nitrosative stress with distinct regulatory mechanisms in the RVLM during neurogenic hypertension and brain stem death clearly denote that they are not interchangeable phenomena with unified cellular actions. Special attention must be paid to their beneficial or detrimental roles under a specific disease or a particular time-window of that disease. The fourth lesson is that, to be successful, future antioxidant therapies against neurogenic hypertension must take into consideration the much more complicated picture than that presented in this review on the generation, maintenance, regulation or modulation of the sympathetic vasomotor tone. The identification that the progression towards brain stem death entails a shift from oxidative stress to nitrosative stress in the RVLM may open a new vista for therapeutic intervention to slow down this transition.

Activation of spinal nociceptin receptors induces cardiovascular depression and antinociception in an independent manner in mice.

PURPOSE: The nociceptin receptor (NOP) was discovered in 1994 and was designated opioid-like receptor; activation of NOP leads to reduced neuronal excitability. Although suggested by the anatomical localization of NOP in brain or spinal cord, the cardiovascular or nociceptive effects of its endogenous ligand, nociceptin, are equivocal. Taking advantage from intrathecal application of nociceptin to simultaneously activate NOP on sympathetic preganglionic neurons in the intermediolateral column (IML) and superficial laminae of dorsal horn, we investigated whether the nociceptin-induced cardiovascular effects engage the participation of baroreflex, and whether the concurrently elicited changes in blood pressure and pain responses are interrelated. METHODS: NOPs in the thoracic spinal cord of ICR or C57BL/6 mice were identified with immunofluorescence staining and were activated through intrathecal administration of nocicetpin. The elicited changes in cardiovascular parameters and tail-flick nociceptive responses were measured. RESULTS: Positive immunoreactivity against NOP colocalized with neurons in the IML and superficial dorsal horn layers of thoracic spinal cord. Intrathecal administration of nociceptin (1, 2, or 5 nmol) elicited a significant and dose-dependent decrease in blood pressure or heart rate that was paralleled by reduced baroreflex-mediated sympathetic vasomotor tone and mirrored by augmented cardiac vagal baroreflex, alongside prolonged tail-flick latency with an efficacy of hypotension <<< antinociception. Coadministration of the specific NOP antagonist, UFP101 (10 nmol), blunted all nociceptin-elicited responses. However, restoring blood pressure to baseline level failed to affect the antinociceptive actions of nociceptin. CONCLUSION: Activation of thoracic spinal NOP in ICR and C57BL/6 mice induces blood pressure and heart rate by decreasing the sympathetic outflow of both arms of the baroreflex arc to the blood vessels and the heart, and the antinociceptive responses to nociceptin are independent of and disproportional to its cardiovascular actions.

Anomalous baroreflex functionality inherent in floxed and Cre-Lox mice: an overlooked physiological phenotype.

The last two decades have seen the emergence of Cre-Lox recombination as one of the most powerful and versatile technologies for cell-specific genetic engineering of mammalian cells. Understandably, the primary concerns in the practice of Cre-Lox recombination are whether the predicted genome has been correctly modified and the targeted phenotypes expressed. Rarely are the physiological conditions of the animals routinely examined because the general assumption is that they are normal. Based on corroborative results from radiotelemetric recording, power spectral analysis, and magnetic resonance imaging/diffusion tensor imaging in brain-derived neurotrophic factor-floxed mice, the present study revealed that this assumption requires amendment. We found that despite comparable blood pressure and heart rate with C57BL/6 or Cre mice under the conscious state, floxed and Cre-Lox mice exhibited diminished baroreflex-mediated sympathetic vasomotor tone and cardiac vagal baroreflex. We further found that the capacity and plasticity of baroreflex of these two strains of mice under isoflurane anesthesia were retarded, as reflected by reduced connectivity between the nucleus tractus solitarii and rostral ventrolateral medulla or nucleus ambiguus. The identification of anomalous baroreflex functionality inherent in floxed and Cre-Lox mice points to the importance of incorporating physiological phenotypes into studies that engage gene manipulations such as Cre-Lox recombination.NEW & NOTEWORTHY We established that anomalous baroreflex functionality is inherent in floxed and Cre-Lox mice. These two mouse strains exhibited diminished baroreflex-mediated sympathetic vasomotor tone and cardiac vagal baroreflex under the conscious state, retarded capacity and plasticity of baroreflex under isoflurane anesthesia, and reduced connectivity between key nuclei in the baroreflex neural circuits.

Impact of a motivated performance task on autonomic and hemodynamic cardiovascular reactivity.

Motivated performance (MP) tasks include mental stressors characterized by a high degree of motivation, individual engagement, and sympathetic overstimulation. It is therefore important to document the independent influence of motivation apart from engagement on markers of cardiovascular autonomic modulation, including vasomotor tone (low-frequency systolic blood pressure, LFSBP), blood pressure homeostasis (baroreflex sensitivity, BRS), and myocardial oxygen consumption (rate pressure product, RPP). Accordingly, an arithmetic task (AT) was used to manipulate motivation to evaluate its impact on cardiovascular reactivity. Forty-two young adults (Mage = 20.21 years, SD = 2.09) qualified for the study. After a 10-min resting period, electrocardiogram and finger beat-to-beat blood pressure were recorded at three distinct 5-min stages: baseline (BASE), AT, and recovery (REC). Prior to AT initiation, participants were randomized into two groups based on directions stating that the AT task was either designed to be entertaining and fun (low MP, LMP) or a test diagnostic of one's intelligence (high MP, HMP). Independent of task engagement ratings, motivation to complete the AT task as well as solution success was significantly greater in the HMP than the LMP condition. Regarding physiological parameters, two (LMP vs. HMP) × three (BASE, AT, REC) repeated measures ANOVAs revealed no significant baseline differences but a significant higher order interaction indicating that in comparison to LMP, individuals in the HMP condition had significantly higher vasomotor tone and myocardial oxygen consumption but not BRS. Greater motivation during a performance task may provide the substrate for the development of adverse cardiovascular events by increasing sympathetic activity and ultimately increasing myocardial oxygen demand which could lead to acute coronary syndromes.

Digitoxin improves cardiovascular autonomic control in rats with heart failure.

The effects of chronic treatment with digitoxin on arterial baroreceptor sensitivity for heart rate (HR) and renal sympathetic nerve activity (rSNA) control, cardiopulmonary reflex, and autonomic HR control in an animal model of heart failure (HF) were evaluated. Wistar rats were treated with digitoxin, which was administered in their daily feed (1 mg/kg per day) for 60 days. The following 3 experimental groups were evaluated: sham, HF, and HF treated with digitoxin (HF + DIG). We observed an increase in rSNA in the HF group (190 ± 29 pps, n = 5) compared with the sham group (98 ± 14 pps, n = 5). Digitoxin treatment prevented an increase in rSNA (98 ± 14 pps, n = 7). Therefore, arterial baroreceptor sensitivity was decreased in the HF group (-1.24 ± 0.07 bpm/mm Hg, n = 8) compared with the sham group (-2.27 ± 0.23 bpm/mm Hg, n = 6). Digitoxin did not alter arterial baroreceptor sensitivity in the HF + DIG group. Finally, the HF group showed an increased low frequency band (LFb: 23 ± 5 ms(2), n = 8) and a decreased high frequency band (HFb: 77 ± 5 ms(2), n = 8) compared with the sham group (LFb: 14 ± 3 ms(2); HFb: 86 ± 3 ms(2), n = 9); the HF+DIG group exhibited normalized parameters (LFb: 15 ± 3 ms(2); HFb: 85 ± 3 ms(2), n = 9). In conclusion, the benefits of decreasing rSNA are not directly related to improvements in peripheral cardiovascular reflexes; such occurrences are due in part to changes in the central nuclei of the brain responsible for autonomic cardiovascular control.

School burnout: increased sympathetic vasomotor tone and attenuated ambulatory diurnal blood pressure variability in young adult women.

Two studies examined autonomic and cardiovascular functioning that may link school burnout to cardiovascular risk factors in young healthy adult females. Study 1 (N = 136) investigated whether school burnout was related to resting values of blood pressure (BP) and blood pressure variability (BPV) through laboratory beat-to-beat BP assessment. Study 2 (N = 94) examined the link between school burnout and diurnal BPV through ambulatory BP monitoring. Controlling for anxiety and depressive symptomatology, school burnout demonstrated strong positive relationships with indices of cardiac sympathovagal tone, sympathetic vasomotor tone, inefficient myocardial oxygen consumption, increased 24-h ambulatory heart rate and BP, blunted BP diurnal variability, and increased arterial stiffness. These studies establish cardiovascular biomarkers of school burnout and suggest that even in a seemingly healthy sample school burnout may predispose females to increased cardiovascular risk. Several future lines of research are outlined.

Role of the caudal pressor area in the regulation of sympathetic vasomotor tone

It is well known that the ventrolateral medulla contains neurons involved in the tonic and reflex control of the cardiovascular system. Two regions within the ventrolateral medulla were initially identified: the rostral ventrolateral medulla (RVLM) and the caudal ventrolateral medulla (CVLM). Activation of the RVLM raises arterial blood pressure and sympathetic nerve activity, and activation of the CVLM causes opposite effects. The RVLM premotor neurons project directly to sympathetic preganglionic neurons and are involved in the maintenance of resting sympathetic vasomotor tone. A significant proportion of tonic activity in the RVLM sympathetic premotor neurons is driven by neurons located in a third region of the ventrolateral medulla denominated caudal pressor area (CPA). The CPA is a pressor region located at the extreme caudal part of the ventrolateral medulla that appears to have an important role controlling the activity of RVLM neurons. In this brief review, we will address the importance of the ventrolateral medulla neurons for the generation of resting sympathetic tone related to arterial blood pressure control focusing on two regions, the RVLM and the CPA.