Evidence that hemorrhagic hypotension is mediated by the ventrolateral periaqueductal gray region

Severe hemorrhage lowers arterial pressure by suppressing sympathetic activity. This study tested the hypothesis that the decompensatory phase of hemorrhage is mediated by the ventrolateral periaqueductal gray (vlPAG), a region importantly involved in the autonomic and behavioral responses to stress and trauma. Neuronal activity in the vlPAG was inhibited with either lidocaine or cobalt chloride 5 min before hemorrhage (2.5 ml/100 g body wt) was initiated in conscious, unrestrained rats. Bilateral injection of lidocaine (0.5 μl of a 2% or 1 μl of a 5% solution) into the caudal vlPAG delayed the onset and reduced the magnitude of the hypotension produced by hemorrhage significantly. In contrast, inactivation of the dorsolateral PAG with lidocaine was ineffective. Cobalt chloride (5 mM; 0.5 μl), which inhibits synaptic transmission but not axonal conductance, also attenuated hemorrhagic hypotension significantly. Microinjection of lidocaine or cobalt chloride into the vlPAG of normotensive, nonhemorrhaged rats did not influence cardiovascular function. These data indicate that the vlPAG plays an important role in the response to hemorrhage.

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Neuronal activity within the ventrolateral periaqueductal gray during simulated hemorrhage in conscious rabbits

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00374.2004 ◽

2006 ◽

Vol 290 (3) ◽

pp. R715-R725 ◽

Cited By ~ 4

Author(s):

James C. Schadt ◽

Heidi L. Shafford ◽

Michael D. McKown

Keyword(s):

Arterial Pressure ◽

Neuronal Activity ◽

Control Period ◽

Periaqueductal Gray ◽

Firing Frequency ◽

Time Interval ◽

Pulse Modulation ◽

Conscious Rabbits ◽

Simulated Hemorrhage ◽

A Site

The ventrolateral (vl) periaqueductal gray (PAG) has been proposed as a site responsible for the active process triggering the onset of hypotension (i.e., phase 2) during blood loss in conscious animals (Cavun S and Millington WR. Am J Physiol Regul Integr Comp Physiol 281: R747–R752, 2001). We recorded the extracellular activity of PAG neurons in conscious rabbits to test the hypothesis that vlPAG neurons change their firing frequency before the onset of hypotension during simulated hemorrhage. Arterial and venous catheters, an intrathoracic vena caval occluder, and midbrain microelectrodes on a microdrive were implanted in 10 rabbits. During simulated hemorrhage, the occluder was inflated until arterial pressure ≤40 mmHg. We compared changes in neuronal activity during simulated hemorrhage with those during a similar length control period for 64 vlPAG and 29 dorsolateral (dl) PAG neurons. Arterial pressure pulse modulation of neuronal activity was present in 45 and 76% of vlPAG and dlPAG neurons, respectively. When we evaluated the absolute change in activity, thus accounting for both increases and decreases, simulated hemorrhage had a significant effect on activity of vlPAG but not dlPAG neurons. The majority (56%) of vlPAG neurons did not appear to respond to simulated hemorrhage. Of the 28 responsive vlPAG neurons, 11 showed an abrupt change in firing frequency during the time interval preceding the onset of hypotension; 13 responded after the onset of hypotension; and 4 showed a consistent direction of change across the entire simulated hemorrhage. Thus 24 (38%) of the vlPAG neurons recorded responded at a time consistent with a contribution to the hypotension associated with simulated hemorrhage.

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New analytic framework for understanding sympathetic baroreflex control of arterial pressure

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1999.276.6.h2251 ◽

1999 ◽

Vol 276 (6) ◽

pp. H2251-H2261 ◽

Cited By ~ 44

Author(s):

Takayuki Sato ◽

Toru Kawada ◽

Masashi Inagaki ◽

Toshiaki Shishido ◽

Hiroshi Takaki ◽

...

Keyword(s):

Arterial Pressure ◽

Equilibrium Diagram ◽

Feedback System ◽

Systemic Arterial Pressure ◽

Equation Model ◽

Operating Point ◽

Baroreflex Control ◽

Efferent Nerve ◽

Severe Hemorrhage ◽

Mean Square Errors

The sympathetic baroreflex is an important feedback system in stabilization of arterial pressure. This system can be decomposed into the controlling element (mechanoneural arc) and the controlled element (neuromechanical arc). We hypothesized that the intersection of the two operational curves representing their respective functions on an equilibrium diagram should define the operating point of the arterial baroreflex. Both carotid sinuses were isolated in 16 halothane-anesthetized rats. The vagi and aortic depressor nerves were cut bilaterally. Carotid sinus pressure (CSP) was sequentially altered in 10-mmHg increments from 80 to 160 mmHg while sympathetic efferent nerve activity (SNA) and systemic arterial pressure (SAP) were recorded simultaneously under various hemorrhagic conditions. The mechanoneural arc was characterized by the response of SNA to CSP and the neuromechanical arc by the response of SAP to SNA. We parametrically analyzed the relationship between input and output for each arc using a four-parameter logistic equation model. In baseline states, the two arcs intersected each other at the point at which the instantaneous gain of each arc attained its maximum. Severe hemorrhage lowered the gain and offset of the neuromechanical arc and moved the operating point, whereas the mechanoneural arc remained unchanged. The operating points measured under the closed-loop conditions were indistinguishable from those estimated from the intersections of the two arc curves on the equilibrium diagram. The average root mean square errors of estimate for arterial pressure and SNA were 2 and 3%, respectively. Such an analytic approach could explain a mechanism for the determination of the operating point of the sympathetic baroreflex system and thus helps us integratively understand its function.

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Molecular and cellular adaptations in hippocampal parvalbumin neurons mediate behavioral responses to chronic social stress

10.1101/2021.09.14.459024 ◽

2021 ◽

Author(s):

Dionnet L Bhatti ◽

Lucian Medrihan ◽

Michelle X Chen ◽

Junghee Jin ◽

Kathryn McCabe ◽

...

Keyword(s):

Neuronal Activity ◽

Affinity Purification ◽

Behavioral Outcomes ◽

Behavioral Responses ◽

Specific Gene ◽

Mrna Levels ◽

Cell Type ◽

Stress Resilience ◽

Cell Type Specific ◽

Stress Susceptibility

BACKGROUND: Behavioral responses to stress are, in part, mediated by the hippocampus and Parvalbumin (PV)-expressing neurons. However, whether chronic stress induces molecular and cellular adaptations in hippocampal PV neurons contribute to stress-induced behavioral outcomes remains elusive. METHOD: Using chronic social defeat stress (CSDS), we investigated the role of neuronal activity and gene expression in hippocampal PV neurons in mediating stress-resilience and -susceptibility. We first used in vivo high-density silicon probe recordings and chemogenetics to test whether the activity of PV neurons in ventral dentate gyrus (PVvDG) is associated with particular behavioral outcomes. To find critical molecular pathways associated with stress-resilience and -susceptibility, we used PV-neuron-selective translating ribosome affinity purification and RNAseq. We used immunoblotting, RNAscope, and region- or cell type-specific gene deletion to determine whether Ahnak, a molecule regulating depression-like behavior, was necessary for behavioral divergence after CSDS. RESULTS: We find CSDS modulates neuronal activity in vDG. Notably, stress-susceptibility is associated with an increase of PVvDG firing, which we find is necessary and sufficient for susceptibility. Additionally, genes involved in mitochondrial function, protein synthesis and synaptogenesis are differentially expressed in hippocampal PV neurons of stress-resilient and -susceptible mice. Interestingly, protein and mRNA levels of Ahnak, an endogenous regulator of L-type calcium channels are associated with susceptibility after CSDS. vDG- and PV cell type-specific deletions reveal that Ahnak is required for stress-susceptibility to CSDS. CONCLUSIONS: These findings indicate that CSDS-induced molecular and cellular adaptations in hippocampal PV neurons mediate behavioral consequences, proposing a mechanism underlying individual differences in stress vulnerability.

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Ovine fetal adrenal gland and cardiovascular function

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1988.254.4.r706 ◽

1988 ◽

Vol 254 (4) ◽

pp. R706-R710 ◽

Cited By ~ 2

Author(s):

N. D. Ray ◽

C. S. Turner ◽

N. M. Rawashdeh ◽

J. C. Rose

Keyword(s):

Heart Rate ◽

Adrenal Gland ◽

Arterial Pressure ◽

Blood Volume ◽

Cardiovascular Function ◽

Late Gestation ◽

Arterial Blood ◽

Significant Difference ◽

Ovine Fetus ◽

Ovine Fetal

Given the necessity of the adrenal gland in maintaining cardiovascular function in adults of various species, these experiments were conducted to determine if fetal bilateral adrenalectomy results in altered resting heart rate, hypotension, and decreased basal blood volume as well as a diminished ability of the fetus to maintain arterial pressure and restore blood volume in response to hemorrhage. We studied heart rate, arterial blood pressure, and blood volume changes in response to hemorrhage of 20% of blood volume at 2%/min in seven adrenalectomized and six intact chronically cannulated unanesthetized lambs between 119 and 133 days of gestation. Blood volumes and percent restitution of shed volume were determined using 51Cr-tagged red blood cells and changes in hematocrit. There was no significant difference between groups in basal heart rate, mean arterial pressure, hematocrit, and blood volume. The two groups were similar to hemorrhage-induced changes in these and restitution of volume. Therefore, fetal adrenal glands are not necessary for basal cardiovascular function or regulation subsequent to moderate hemorrhage in the late gestation ovine fetus.

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Acute effects of electronic cigarettes on arterial pressure and peripheral sympathetic activity in young non-smokers

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00448.2020 ◽

2020 ◽

Author(s):

Joshua Eric Gonzalez ◽

William Harold Cooke

Keyword(s):

Arterial Pressure ◽

Health Risks ◽

Sympathetic Activity ◽

Sympathetic Nerve Activity ◽

Electronic Cigarettes ◽

Muscle Sympathetic Nerve Activity ◽

Crossover Design ◽

Acute Effects ◽

Nerve Activity ◽

Peripheral Sympathetic Activity

E-cigarettes like the JUUL are marketed as an alternative to smoking for those who want to decrease the health risks of tobacco. Tobacco cigarettes increase heart rate (HR) and arterial pressure (AP), while reducing muscle sympathetic nerve activity (MSNA) through sympathetic baroreflex inhibition. The acute effects of e-cigarettes on AP and MSNA have not been reported: our purpose was to clarify this issue. Using a randomized crossover design, participants inhaled on a JUUL containing nicotine (59 mg/ml) and a similar placebo e-cigarette (0 mg/ml). Experiments were separated by ~1 month. We recorded baseline ECG, AP (n=15), and MSNA (n=10). Subjects rested for 10 min, (BASE) and then inhaled once every 30 s on an e-cigarette that contained nicotine or placebo (VAPE) for 10 min followed by a 10-min recovery (REC). Data were expressed as Δmeans±SE from BASE. HR increased in the nicotine condition during VAPE and returned to BASE values in REC (5.0±1.3 nicotine vs 0.1±0.8 b/min placebo, during VAPE P<.01). AP increased in the nicotine condition during VAPE and remained elevated during REC. (6.5±1.6 nicotine vs 2.6±1 mmHg placebo, during VAPE and 4.6.0±1.7 nicotine vs 1.4±1.4 mmHg placebo during REC; p<.05). MSNA decreased from BASE to VAPE and did not restore during REC (-7.1±1.6 nicotine vs 2.6±2 bursts/min placebo during VAPE and -5.8±1.7 nicotine vs 0.5±1.4 placebo during REC; p<.05). Our results show that acute e-cigarette usage increases mean arterial pressure leading to a baroreflex mediated inhibition of MSNA.

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Acute resetting of baroreceptor reflex in rabbits: a central component

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1986.250.5.h866 ◽

1986 ◽

Vol 250 (5) ◽

pp. H866-H870 ◽

Cited By ~ 5

Author(s):

D. L. Kunze

Keyword(s):

Arterial Pressure ◽

Test Stimulus ◽

Nerve Stimulation ◽

Sympathetic Activity ◽

Constant Stimulus ◽

Baroreceptor Reflex ◽

Pressure Response ◽

Stimulus Period ◽

Aortic Nerve ◽

Stimulation Of

Electrical stimulation of the aortic nerve of the anesthetized rabbit was used to determine whether there is a central nervous system component to acute resetting of the baroreceptor reflex. After stimulation of the aortic nerve for 5 min at 10 Hz, a ramp test stimulus to the nerve produced a reflex arterial pressure response that was attenuated as compared with that produced by the same ramp prior to the five-min stimulation period. Renal sympathetic nerve activity was recorded simultaneously to determine whether a reduction in the magnitude of the reflex inhibition of sympathetic activity produced by the depressor nerve stimulation could account for the attenuated arterial pressure response. Renal activity during the test ramp was reduced to the same value both before and after the constant stimulus period and thus did not correlate with the attenuated pressure response. There was, however, prolonged inhibition of tonic sympathetic activity after the 5-min stimulus period such that during the test stimulus there was less sympathetic activity to inhibit. The results were similar when sympathetic activity was recorded from branches of the sciatic nerve and from thoracic postganglionic nerves. In these nerves the period of prolonged inhibition after aortic nerve stimulation was up to 5 min. The attenuated pressure response to baroreceptor nerve stimulation after a constant stimulus appears to reflect the reduced change in sympathetic activity rather than the value to which the sympathetic activity falls.

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Arterial pressure and muscle sympathetic nerve activity are increased after two hours of sustained but not cyclic hypoxia in healthy humans

Journal of Applied Physiology ◽

10.1152/japplphysiol.00495.2004 ◽

2005 ◽

Vol 98 (1) ◽

pp. 343-349 ◽

Cited By ~ 31

Author(s):

Renaud Tamisier ◽

Amit Anand ◽

Luz M. Nieto ◽

David Cunnington ◽

J. Woodrow Weiss

Keyword(s):

Blood Pressure ◽

Arterial Pressure ◽

Sympathetic Nerve ◽

Sympathetic Activity ◽

Sympathetic Nerve Activity ◽

Muscle Sympathetic Nerve Activity ◽

Arterial Oxygen ◽

Nerve Activity ◽

Arterial Blood ◽

Sustained Hypoxia

Sustained and episodic hypoxic exposures lead, by two different mechanisms, to an increase in ventilation after the exposure is terminated. Our aim was to investigate whether the pattern of hypoxia, cyclic or sustained, influences sympathetic activity and hemodynamics in the postexposure period. We measured sympathetic activity (peroneal microneurography), hemodynamics [plethysmographic forearm blood flow (FBF), arterial pressure, heart rate], and peripheral chemosensitivity in normal volunteers on two occasions during and after 2 h of either exposure. By design, mean arterial oxygen saturation was lower during sustained relative to cyclic hypoxia. Baseline to recovery muscle sympathetic nerve activity and blood pressure went from 15.7 ± 1.2 to 22.6 ± 1.9 bursts/min ( P < 0.01) and from 85.6 ± 3.2 to 96.1 ± 3.3 mmHg ( P < 0.05) after sustained hypoxia, respectively, but did not exhibit significant change from 13.6 ± 1.5 to 17.3 ± 2.5 bursts/min and 84.9 ± 2.8 to 89.8 ± 2.5 mmHg after cyclic hypoxia. A significant increase in FBF occurred after sustained, but not cyclic, hypoxia, from 2.3 ± 0.2 to 3.29 ± 0.4 and from 2.2 ± 0.1 to 3.1 ± 0.5 ml·min−1·100 g of tissue−1, respectively. Neither exposure altered the ventilatory response to progressive isocapnic hypoxia. Two hours of sustained hypoxia increased not only muscle sympathetic nerve activity but also arterial blood pressure. In contrast, cyclic hypoxia produced slight but not significant changes in hemodynamics and sympathetic activity. These findings suggest the cardiovascular response to acute hypoxia may depend on the intensity, rather than the pattern, of the hypoxic exposure.

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