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Biomedical subjects

Philip L Johnson

Publications and source records attributed to Philip L Johnson.

At least 19 recordsLinked to original sources
PubMed2006

Angiotensin-II is a putative neurotransmitter in lactate-induced panic-like responses in rats with disruption of GABAergic inhibition in the dorsomedial hypothalamus.

Intravenous sodium lactate infusions or the noradrenergic agent yohimbine reliably induce panic attacks in humans with panic disorder but not in healthy controls. However, the exact mechanism of lactate eliciting a panic attack is still unknown. In rats with chronic disruption of GABA-mediated inhibition in the dorsomedial hypothalamus (DMH), achieved by chronic microinfusion of the glutamic acid decarboxylase inhibitor L-allylglycine, sodium lactate infusions or yohimbine elicits panic-like responses (i.e., anxiety, tachycardia, hypertension, and tachypnea). In the present study, previous injections of the angiotensin-II (A-II) type 1 receptor antagonist losartan and the nonspecific A-II receptor antagonist saralasin into the DMH of "panic-prone" rats blocked the anxiety-like and physiological components of lactate-induced panic-like responses. In addition, direct injections of A-II into the DMH of these panic-prone rats also elicited panic-like responses that were blocked by pretreatment with saralasin. Microinjections of saralasin into the DMH did not block the panic-like responses elicited by intravenous infusions of the noradrenergic agent yohimbine or by direct injections of NMDA into the DMH. The presence of the A-II type 1 receptors in the region of the DMH was demonstrated using immunohistochemistry. Thus, these results implicate A-II pathways and the A-II receptors in the hypothalamus as putative substrates for sodium lactate-induced panic-like responses in vulnerable subjects.

Angiotensin II↗
PubMed2006

Panic-prone state induced in rats with GABA dysfunction in the dorsomedial hypothalamus is mediated by NMDA receptors.

Rats with chronic inhibition of GABA synthesis and consequently enhanced glutamatergic excitation in the dorsomedial hypothalamus (DMH) develop panic-like responses, defined as tachycardia, tachypnea, hypertension, and increased anxiety as measured by a social interaction (SI) test, after intravenous sodium lactate infusions, a phenomenon similar to patients with panic disorder. Therefore, the present studies tested the role of the postsynaptic NMDA and AMPA type glutamatergic receptors in the lactate-induced panic-like responses in these rats. Rats were fit with femoral arterial and venous catheters and Alzet pumps [filled with the GABA synthesis inhibitor L-allylglycine (L-AG; 3.5 nmol/0.5 microl per hour) or its inactive isomer D-AG] into the DMH. After 4-5 d of recovery only those rats with L-AG pumps exhibited panic-like responses to lactate infusions. Using double immunocytochemistry, we found that rats exhibiting panic-like responses (e.g., L-AG plus lactate) had increased c-Fos immunoreactivity in DMH neurons expressing the NMDA receptor 1 (NR1) subunit, but not those expressing the glutamate receptor 2 and 3 subunits of the AMPA receptors. To confirm this pharmacologically, we tested another group of rats implanted with l-AG pumps with intravenous lactate infusions preceded by injections of either NMDA [aminophosphonopentanoic acid (AP-5) or (+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d]cyclohepten-5,10-imine maleate (MK-801)] or non-NMDA [CNQX or 4-(8-methyl-9H-1,3-dioxolo[4,5-h][2,3]benzodazepin-5-yl)-benzenamine dihydrochloride (GYKI52466)] antagonists into the DMH. Injections of NMDA, but not non-NMDA, antagonists into the DMH resulted in dose-dependent blockade of the tachycardia, tachypnea, hypertension, and SI responses after lactate infusions. These results suggest that NMDA, and not non-NMDA, type glutamate receptors regulate lactate-induced panic-like responses in rats with GABA dysfunction in the DMH.

Allylglycine↗
PubMed2005

Local inhibition of organic cation transporters increases extracellular serotonin in the medial hypothalamus.

In the rat dorsomedial hypothalamus (DMH), serotonin (5-HT) concentrations are altered rapidly in response to acute stressors. The mechanism for rapid changes in 5-HT concentrations in the DMH is not clear. We hypothesize that the mechanism involves corticosteroid-induced alterations in the uptake of 5-HT from extracellular fluid through the action of corticosterone-sensitive organic cation transporters (OCTs). To determine if OCTs affect the clearance of 5-HT from the extracellular fluid compartment within the medial hypothalamus (MH), the OCT blocker, decynium 22 (0, 10, 30, or 100 microM), was perfused into the MH via a microdialysis probe, and dialysate 5-HT concentrations were measured at 20 min intervals. In addition, home cage behavior was measured both before and after drug administration. Inhibition of OCTs in the MH resulted in a reversible dose-dependent increase in extracellular 5-HT concentration. Increases in extracellular 5-HT concentrations were associated with increases in grooming behavior in rats treated with the highest concentration of decynium 22. No other behavioral responses were observed following administration of any concentration of decynium 22. These findings are consistent with the hypothesis that OCTs in the MH play an important role in the regulation of serotonergic neurotransmission and specific behavioral responses. Because the MH plays an important role in the neuroendocrine, autonomic, and behavioral responses to stress-related stimuli, these data lead to new questions regarding the role of interactions between corticosterone and corticosterone-sensitive OCTs in stress-induced 5-HT accumulation within the MH as well as the physiological and behavioral consequences of these interactions.

Analysis of Variance↗
PubMed2005

Are tuberomammillary histaminergic neurons involved in CO2-mediated arousal?

An increase in arousal in response to hypercapnia [elevated arterial PCO2 (partial pressure of CO2) levels] during awake or sleep states is an important component of mechanisms designed to maintain acid-base homeostasis. Since central histaminergic neurons are crucial for maintaining waking states and vigilance, a nonresponsive or dysfunctional histaminergic system could contribute to the lack of arousal in response to hypercapnia in some sleep-related disorders [e.g., sudden infant death syndrome (SIDS) and Ondine's curse]. Therefore, the present study attempted to determine if histaminergic neurons display functional responses to acute exposure to hypercapnic gas (i.e., gas with elevated CO2 concentrations). Healthy adult male rats were placed in flow cages during the light cycle, or inactive phase, and exposed to either atmospheric air or to environmental CO2 concentrations increasing from baseline up to 20% CO2 over a 5-min period. The expression of the protein product of the immediate-early gene c-fos was used as a measure of functional cellular responses within subpopulations of histaminergic neurons. Among the histaminergic subgroups (E1-E5), only the ventral tuberommamillary nucleus (VTMn)/E2 cell group showed significant increases in c-Fos expression following brief exposure to hypercapnic gas. These data are consistent with the hypothesis that histaminergic neuronal cell groups are heterogeneous and are involved in physiological and/or behavioral responses to acute hypercapnic challenge, potentially increasing vigilance during active waking and awakening from sleep during hypercapnic states.

Animals↗
PubMed2005

Decrease in fluoroscopic cardiac silhouette excursion precedes hemodynamic compromise in intraprocedural tamponade.

BACKGROUND: Acute pericardial tamponade is a life-threatening complication of invasive cardiovascular procedures. Survival depends on early recognition and treatment. A diagnostic test to detect pericardial fluid accumulation before a significant fall in blood pressure and without contamination of the sterile field would be valuable. OBJECTIVE: We tested the hypothesis that fluoroscopic excursion of the cardiac silhouette decreases early in the course of acute pericardial tamponade and precedes hemodynamic compromise. METHODS: The pericardial space of seven pigs was accessed by a sub-xiphoid puncture. Tamponade was produced by intrapericardial saline infusion at 20-25 mL/minute until the pericardial pressure equalized with right ventricular end diastolic pressure or the systolic blood pressure reached 40 mmHg. Supine fluoroscopic images were obtained every 2 minutes in the left anterior oblique view with simultaneous echocardiography. The fluoroscopic heart silhouette was digitized, and the maximum excursion during the cardiac cycle was quantified by custom software. The qualitative excursion of the fluoroscopic heart silhouette on randomly selected video images was also graded by two independent observers who were blinded to the time course of the experiment and the hemodynamics. RESULTS: During progressive pericardial fluid accumulation, the cardiac silhouette excursion quantified by the custom software (p < 0.001) and by video rating (p < 0.0001) was significantly reduced within 2 minutes. A statistically significant fall in blood pressure compared with baseline did not occur until 6 minutes (89 +/- 21 vs. 121 +/- 15 mmHg, p < 0.001). The interobserver agreement was very close, with a kappa statistic of 0.78. The reduction in cardiac silhouette excursion was apparent as soon as the effusion was detected by echocardiography. CONCLUSION: Cardiac silhouette excursion becomes reduced early in the course of acute pericardial fluid accumulation. This fluoroscopic observation can be used to detect impending pericardial tamponade before hemodynamic collapse.

Acute Disease↗
PubMed2005

Modulation of anxiety circuits by serotonergic systems.

Anxiety is a complex emotional state associated with sustained heightened autonomic and behavioral arousal and an increase in avoidance behavior. Anxiety-related behavior is a form of risk assessment behavior that is associated with a level of uncertainty or unpredictability regarding the outcome of emotionally salient events, often when both rewarding and aversive outcomes are possible. In this review, we highlight recent advances in our understanding of the neural circuits regulating anxiety states and anxiety-related behavior with an emphasis on the role of brainstem serotonergic systems in modulating anxiety-related circuits. In particular, we explore the possibility that the regulation of anxiety states and anxiety-related behavior by serotonergic systems is dependent on a specific, topographically organized mesolimbocortical serotonergic system that originates in the mid-rostrocaudal and caudal parts of the dorsal raphe nucleus.

Amygdala↗
PubMed2005

Acute hypercarbic gas exposure reveals functionally distinct subpopulations of serotonergic neurons in rats.

Although increasing evidence suggests that anatomically defined subpopulations of serotonergic neurons have unique stress-related functional properties, the topographical distribution of the serotonergic neurons involved in responses to stress-related stimuli have not been well-defined. Inspiration of air containing elevated concentrations of carbon dioxide (CO(2); hypercarbic gas exposure) at high concentrations activates both hypothalamic-pituitary-adrenal axis and sympathetic responses in rats and humans. In order to determine the effects of acute hypercarbic gas exposure on subpopulations of topographically organized serotonergic neurons, conscious adult male rats were placed in flow cages and exposed to either atmospheric air or increasing environmental CO2 concentrations (from baseline concentrations up to 20% CO2) for 5min. The presence of immunoreactivity for the protein product of the immediate-early gene c-fos was used as a measure, at the single cell level, of functional cellular responses within subpopulations of serotonergic, noradrenergic and adrenergic neurons. Rats exposed to hypercarbic gas had increased numbers of c-Fos/tryptophan hydroxylase immunoreactive (ir) and c-Fos/tyrosine hydroxylase-ir neurons in specific topographically organized subdivisions of brainstem nuclei, compared to control rats. Within serotonergic cell groups (B1-B9), the most striking effects occurred in a subpopulation of large, multipolar serotonergic neurons within the ventrolateral periaqueductal grey and ventrolateral part of the dorsal raphe nucleus, a region implicated in serotonin-dependent suppression of stress-induced sympathetic outflow and serotonin-dependent inhibition of 'fight or flight' behaviour. These findings have important implications for understanding the role of serotonergic systems in the modulation of stress-related physiology and behaviour and stress-related neuropsychiatric disorders.

Adrenalectomy↗
PubMed2004

Anatomic and functional topography of the dorsal raphe nucleus.

Serotonergic systems play an important and generalized role in regulation of sleep-wake states and behavioral arousal. Recent in vivo electrophysiologic recording studies in animals suggest that several different subtypes of serotonergic neurons with unique behavioral correlates exist within the brainstem raphe nuclei, raising the possibility that topographically organized subpopulations of serotonergic neurons may have unique behavioral or physiologic correlates and unique functional properties. We have shown that the stress-related and anxiogenic neuropeptide corticotropin-releasing factor can stimulate the in vitro neuronal firing rates of topographically organized subpopulations of serotonergic neurons within the dorsal raphe nucleus (DR). These findings are consistent with a wealth of behavioral studies suggesting that serotonergic systems within the DR are involved in the modulation of ongoing anxiety-related behavior and in behavioral sensitization, a process whereby anxiety- and fear-related behavioral responses are sensitized for a period of up to 24 to 48 h. The dorsomedial subdivision of the DR, particularly its middle and caudal aspects, has attracted considerable attention as a region that may play a critical role in the regulation of acute and chronic anxiety states. Future studies aimed at characterization of the molecular and cellular properties of topographically organized subpopulations of serotonergic neurons are likely to lead to major advances in our understanding of the role of serotonergic systems in stress-related physiology and behavior.

Animals↗
PubMed2004

A functional subset of serotonergic neurons in the rat ventrolateral periaqueductal gray implicated in the inhibition of sympathoexcitation and panic.

The ability of serotonin (5-HT) to facilitate or attenuate autonomic, endocrine, and behavioral responses to stressful stimuli has received much attention. The effects of 5-HT on physiologic and behavioral responses to stressful stimuli seem to depend on the brain region where it is released and the effector system it acts upon. This and the distinct morphology and topographic organization of subpopulations of serotonergic neurons have led to the hypothesis that subpopulations of serotonergic neurons are functionally distinct. Serotonin's role as a modulator of the "fight-or-flight" response is mediated in part by 5-HT release in the dorsolateral periaqueductal gray (DLPAG) and in the rostral ventrolateral medulla (RVLM), an area that contains sympathoexcitatory C1 adrenergic (A) neurons. The release of 5-HT in either region inhibits stress-induced sympathetic activity in part via actions on 5-HT(1A) receptors. In addition, 5-HT release in the DLPAG inhibits fight-or-flight or "Go" behaviors. The origin of endogenous 5-HT in the DLPAG and RVLM seems to be a subpopulation of serotonergic neurons within the ventrolateral PAG, a region implicated in "freezing" or "No Go" behaviors. These serotonergic neurons are located in the lateral "wings" of the dorsal raphe nucleus (DRN) a region also referred to as the ventrolateral DRN. The existence of a functional subpopulation of serotonergic neurons capable of inhibiting sympathoexcitation and fight-or-flight behavioral responses may be clinically relevant for explaining in part the efficacy of serotonergic drugs in the treatment of hypertension and panic attacks in panic disorder patients.

Animals↗
PubMed2003

Adaptive pacing during ventricular fibrillation.

While it has been shown that pacing during ventricular fibrillation (VF) can capture a portion of the epicardium, little is known about the characteristics of the area captured or about whether adaptively changing the pacing rate during VF will increase the area captured. In six open-chested pigs, pacing during VF was performed from the center of a plaque containing 504 electrodes 2 mm apart in a21 x 24 array on the anterior right ventricle. Simultaneous recordings from the 504 electrodes were used to construct activation maps from which the area of epicardium captured by pacing was determined. Four pacing algorithms were examined: (1) fixed rate pacing at 95% of the median VF activation rate, (2 and 3) adaptive pacing in which the pacing timing and/or rate is reset in real time if capture is not obtained, and (4) pacing at a slowly increasing rate after initial capture. Regional capture, defined as control of the myocardium under at least 10 plaque electrodes, was achieved in 71% (92/129) of pacing episodes. The incidence of capture was not significantly different for pacing algorithms 1-3. The maximum area captured for each pacing episode with algorithms 1-3 was 3.8 +/- 2.0 cm2(mean +/- SD). Within each animal, the pattern of capture was similar among all pacing episodes, no matter which algorithm was use dr = 0.85 +/- 0.25). The region of greatest capture extended away from the pacing site along the long axis of the myocardial fibers. However, the area of captured epicardium toward the right ventricular side of the pacing electrode was 9.7 times greater than toward the left ventricular side. This principal direction toward the right ventricular side of the pacing electrode was the same direction traveled by the majority of VF activation fronts before capture occurred. The absence of recorded activations at the pacing site for 20 consecutive stimuli predicted 83% of the time that regional capture was present. With algorithm 4, the pacing rate could be increased 7.1%+/- 4.3%while maintaining capture; however, the area of capture progressively decreased as the pacing rate increased. While pacing from the anterior right ventricular epicardium during VF, the area of capture is repeatable and is markedly asymmetrical with almost 10 times as much epicardium captured on the side of the pacing electrode closest to the acute margin of the right ventricle as on the opposite side. This marked asymmetry is associated both with myofiber orientation and with the direction of spread of activation and hence the direction of dispersion of refractoriness during VF just before pacing is initiated. It is possible to perform adaptive pacing algorithms in real time during VF; however, the two adaptive algorithms tested did not capture significantly more epicardium than a simple fixed-rate pacing algorithm. Although it is possible to maintain capture while increasing the pacing rate during VF, the area of capture decreases.

Algorithms↗
PubMed2003

Emission ratiometry for simultaneous calcium and action potential measurements with coloaded dyes in rabbit hearts: reduction of motion and drift.

INTRODUCTION: Optical measurements of the cardiac calcium transient (Ca) and transmembrane action potential (AP) may be performed simultaneously with emission ratiometry to lessen motion artifacts and photobleaching effects. We examined changes in emission spectrum in perfused rabbit hearts coloaded with Rh237 and a green-emitting Ca dye (Fluo-4 or Oregon Green BAPTA 1) to determine wavelength bands for emission ratiometry and to test whether ratiometry reduces motion artifacts and drift. METHODS AND RESULTS: A 488-nm laser illuminated hearts while a spectrofluorometer collected fluorescence from 489 to 838 nm at 1 kHz. Ratiometry with the Ca- and AP-insensitive emission band 663 to 685 nm (IS) as denominator and the Ca-sensitive band 510 to 532 nm as numerator lessened motion artifacts, which was quantified as a 1.4-fold increase in relative amplitude of the Ca (P < 0.05). Ratiometry with the AP-sensitive band 772 to 794 nm as denominator and the IS as numerator produced a 1.7-fold increase in relative amplitude of the AP (P < 0.05). The ratiometry decreased photobleaching-dependent drift by a factor of 0.6 (P < 0.05) for Ca and 0.45 (P < 0.05) for AP. CONCLUSION: Simultaneous Ca and AP emission ratiometry reduces motion artifacts and drift in hearts with coloaded dyes.

Action Potentials↗
PubMed2003

Stiff guide technique: technical report and illustrative case.

Endovascular techniques are gaining wider acceptance in the treatment of intracranial lesions. Tortuous vasculature is a common reason for failure to treat an intracranial lesion, especially when balloon catheters or stents are used. In these cases, the guiding catheter often buckles into the aorta during an attempt to place the balloon or stent. In our experience, a stiff wire can be used to support the guiding catheter, allowing the balloon catheter or stent to more readily navigate tortuous vessels.

Angioplasty, Balloon↗
PubMed2002

Regional differences in ventricular fibrillation in the open-chest porcine left ventricle.

It has been hypothesized that during ventricular fibrillation (VF), the fastest activating region, the dominant domain, contains a stable reentrant circuit called a mother rotor. This hypothesis postulates that the mother rotor spawns wavefronts that propagate to maintain VF elsewhere and implies that the ratio of wavefronts propagating off a region to those propagating onto it (propoff/propon) should be >1 for the dominant domain but <1 elsewhere. To test this prediction in the left ventricular (LV) epicardium of a large animal, most of the LV free wall was mapped with 1008 electrodes in 7 pigs. VF activation rate was faster in the posterior than in the anterior LV (10.0+/-1.3Hz versus 9.3+/-1.3Hz; P<0.001). The anterior LV had a higher fraction of wavefronts that blocked than did the posterior LV and had a propoff/propon ratio <1 (P<0.001). The mean conduction velocity vectors of the VF wavefronts pointed in the direction from the posterior to the anterior LV. Although these findings favor a dominant domain in the posterior LV, the facts that the anterior LV had a higher incidence of reentry than did the posterior LV and that the posterior LV did not have propoff/propon significantly different from 1 do not. Thus, quantitative regional differences are present over the porcine LV epicardium during VF. Although these differences are not totally consistent with the presence of a dominant domain within the LV free wall, the mean conduction velocity vector is consistent with one in the septum.

Animals↗
PubMed2002

GABAergic drugs alter hypothalamic serotonin release and lordosis in estrogen-primed rats.

The effects of muscimol, a GABA(A) agonist, and phaclofen, a GABA(B) antagonist, on serotonin (5HT) release in the mediobasal hypothalamus and lordosis behavior were studied in freely moving rats using in vivo microdialysis. Two days after implantation of bilateral guide cannulae directed towards the ventromedial nucleus of the hypothalamus (VMH), ovariectomized rats were primed with estradiol (E(2)). The rats were implanted with microdialysis probes 24 h later. Following a pretest for lordosis, perfusate 5HT was measured at 20-min intervals until the baseline was stable. The rats were treated with 10, 30 or 100 microM muscimol or 30 and 100 microM phaclofen in artificial CSF delivered via reverse dialysis for 40 min. Control animals were continuously perfused with artificial CSF. Behavior was tested 20, 60 and 180 min after introduction of the drug. Decreased hypothalamic 5HT (40-60% of baseline) and marked facilitation of lordosis were present 20 min after administration of either drug. The effects of 10 and 30 microM muscimol and 30 microM phaclofen on both 5HT and lordosis were reversed after 180 min. Reversal of the behavioral and neurochemical effects were not evident in either the 100 microM muscimol or 100 microM phaclofen groups at the time-points tested. Proceptive responses were observed in phaclofen-treated rats but not in rats treated with muscimol. Levels of hypothalamic 5HT and lordosis quotients in control rats did not significantly differ from initial values. These results suggest that GABAergic effects on lordosis may be mediated through an interaction with 5HT in the mediobasal hypothalamus.

Animals↗
PubMed2002

Imaging of abdominal aortic aneurysms.

Given the high rate of morbidity and mortality associated with abdominal aortic aneurysms (AAAs), accurate diagnosis and preoperative evaluation are essential for improved patient outcomes. Ultrasonography is the standard method of screening and monitoring AAAs that have not ruptured. In the past, aortography was commonly used for preoperative planning in the repair of AAAs. More recently, computed tomography (CT) has largely replaced older, more invasive methods. Recent advances in CT imaging technology, such as helical CT and CT angiography, offer significant advantages over traditional CT. These methods allow for more rapid scans and can produce three-dimensional images of the AAA and important adjacent vascular structures. Use of endovascular stent grafts has increased recently and is less invasive for the repair of AAAs in selected cases. Aortography and CT angiography can precisely determine the size and surrounding anatomy of the AAA to identify appropriate candidates for the use of endovascular stent grafts. Helical CT and CT angiography represent an exciting future in the preoperative evaluation of AAAs. However, this technology is not the standard of care because of the lack of widespread availability, the cost associated with obtaining new equipment, and the lack of universal protocols necessary for acquisition and reconstruction of these images.

Aortic Aneurysm, Abdominal↗
PubMed2002

Imaging of acquired cerebral herniations.

The consequences of cerebral herniation are compression of the brain, cranial nerves, and blood vessels that may result in serious neurologic morbidity, coma, and even death. A thorough understanding of the various patterns of cerebral herniation is essential, and it is important to remember that many of these patterns of herniation overlap. CT and MR imaging are effective at establishing the diagnosis of cerebral herniation, which will guide important decisions regarding therapeutic options and prognosis.

Brain↗
PubMed2002

Intelligent multichannel stimulator for the study of cardiac arrhythmias.

An intelligent multichannel stimulator (IMS) has been designed and built for use in a cardiac research environment. The device is capable of measuring and responding to cardiac electrophysiological phenomena in real time with carefully timed and placed electrical stimuli. The system consists of 16 channels of sense/stimulation electronics controlled by a digital signal processor (DSP) data acquisition card and a host computer and can be expanded to include more channels. The DSP allows for powerful and flexible algorithms to be implemented for real-time interaction with the cardiac tissue. Although a number of possible uses can be conceived for such a device, the initial motivation was to improve upon attempts to terminate fibrillation by pacing. The IMS was tested in an open-chest animal model, both in sinus rhythm and during fibrillation. It was shown to be an effective research tool by demonstrating the ability to measure and respond to cardiac activations in real time using complex numerical algorithms and appropriately timed stimuli.

Algorithms↗