No description available.

We sought to determine if compensatory vasodilator and/or pressor responses protect exercising muscle O2 delivery (O2D) under conditions of reduced arterial perfusion pressure, if this is exercise intensity-dependent, and if distinct cardiovascular response phenotypes exist. Ten healthy male subjects (19.5±0.4 years) completed two trials of a ramp protocol forearm isometric handgrip exercise test to exhaustion (2.5 kg increments every 3.5 minutes) in each of forearm above and below heart level (forearm arterial perfusion pressure (FAPP) difference of 29.5±0.97 mmHg). Forearm blood flow ((FBF (ml/min; brachial artery Doppler and echo ultrasound), mean arterial blood pressure (MAP; finger photoplethysmography), and exercising forearm venous effluent (ante-cubital vein catheter) measurements at the end of each work rate (WR) revealed the following. Group level (n=10) Δ FBF was compromised beyond 5 kg WR in above vs. below (P<0.05). There was no evidence of compensatory vasodilator (P=0.21) or pressor (P=0.63) responses. Peak O2D, WR and VO2 were significantly compromised by reduced FAPP (115.6±16.8 vs. 152.0±13.4 mlO2/min, 25.5±1.22 vs. 28.94±1.50 kg and 75.9±5.3 vs. 100.2±8.6 ml/min; P<0.05). In contrast, examination of individual responses revealed distinct cardiovascular response groups with (n=6) vs. without (n=4) compensatory vasodilation with the former having less compromise to submaximal O2D and peak WR (-94.12±23.42 vs. -223.40±36.01 mlO2/min), P<0.05 and -2.5±0.32 vs. -5.32±0.79 kg, P<0.05). In conclusion, exercising forearm muscle hypoperfusion due to reduced FAPP is not compensated for by pressor responses. However, there appear to be distinct phenotypes in which vasodilatory compensation does vs. does not occur, which in the former partially protects O2D and exercise performance. / Thesis (Master, Kinesiology & Health Studies) -- Queen's University, 2012-09-13 16:42:41.751

Goals of this study were to identify and characterize effects of neurokinin A (NKA) in isolated guinea pig hearts. Bradycardia, augmentation of ventricular contractions, and reduction of perfusion pressure were prominent responses to bolus injections of NKA (0.25-25 nmol). NKA was more potent than substance P (SP) in causing bradycardia but did not differ in potency for lowering perfusion pressure. Doses of SP of 25 nmol or less decreased ventricular force, whereas 100 nmol caused a biphasic response. The percent decrease in heart rate produced by 25 nmol NKA was reduced from 58.0 ± 4.8 to 39.6 ± 3.5% in the presence of μM atropine (n = 5). The positive inotropic response to 25 nmol of NKA in spontaneously beating hearts was replaced by a negative inotropic response during pacing (22.5 ± 3.3% increase vs. 11.7 ± 1.7% decrease, n = 5). Reserpine pretreatment did not affect the positive inotropic response to NKA. Specific binding sites for (125)I-labeled NKA were localized to intracardiac ganglia and coronary arteries but not to myocardium. It was concluded that 1) negative chronotropic responses to NKA involve cholinergic and noncholinergic mechanisms, and 2) the positive inotropic response is an indirect action.

The adaptations of vessel diameter represented by vascular conductance (VC), muscle blood flow (MBF) and oxygen delivery (DO2est) were investigated during rest and exercise using the effects of gravity to manipulate muscle perfusion pressure (MPP) by placing the heart above (head-up tilt) and below (head-down tilt) the level of the muscle. This experimental paradigm was used to explore VC and MBF regulation and related control mechanisms during rest and exercise. Study 1 tested the repeatability of Doppler ultra- sound measurements of muscle blood flow velocity (MBV), arterial diameter, MBF and VC. The adaptations in VC and MBF (Study 2) and changes in anterograde and retro- grade MBV patterns (Study 3) were investigated during postural challenges at rest. Study 4, determined the peak VC and its fractional recruitment during transitions from rest to lower (LPO) and higher power output (HPO) calf muscle exercise in HDT and HUT. Study 5 investigated the combined effects of altered MPP and hypoxia during exercise. During rest-HDT, increases in VC compensated for the MPP reduction to maintain MBF, while in rest-HUT, MBF was reduced. Following the start of LPO and HPO exercises, MBF and VC responses were delayed in HDT and accelerated in HUT. During LPO, MBF steady- state was reduced in HUT compared to horizontal (HOR), while the greater increase in VC during HDT maintained MBF at a similar level as HUT. Post-exercise MBF recovered rapidly in all positions after LPO exercise but did not after HPOHDT. During HPOHDT, MBF was reduced despite the increase in VC, while in HPOHUT MBF was similar to that in HPOHOR. The hypoxic challenge added in exercise was met during LPOHDT by in- creased VC to compensate reduced MPP and O2 availability such that MBF maintained DO2est. However, during HPOHDT in hypoxia, VC reached maximal vasodilatory capacity, compromising MBF and DO2est. Together, these findings indicate that LPOHDT in nor- moxia or hypoxia VC increased to maintain MBF and DO2est, but during HPO functional limitation for recruitment of VC constrained MBF and DO2 in normoxia and hypoxia. Elevated muscle electromyograpic signals in HPOHDT were consistent with challenged aer- obic metabolism. MPP reduction in HDT caused slower adaptation of MBF limiting O2 availability would result in a greater O2 deficit that could contribute to an increase in the relative stress of the exercise challenge and advance the onset of muscle fatigue.

No description available.

The adaptations of vessel diameter represented by vascular conductance (VC), muscle blood flow (MBF) and oxygen delivery (DO2est) were investigated during rest and exercise using the effects of gravity to manipulate muscle perfusion pressure (MPP) by placing the heart above (head-up tilt) and below (head-down tilt) the level of the muscle. This experimental paradigm was used to explore VC and MBF regulation and related control mechanisms during rest and exercise. Study 1 tested the repeatability of Doppler ultra- sound measurements of muscle blood flow velocity (MBV), arterial diameter, MBF and VC. The adaptations in VC and MBF (Study 2) and changes in anterograde and retro- grade MBV patterns (Study 3) were investigated during postural challenges at rest. Study 4, determined the peak VC and its fractional recruitment during transitions from rest to lower (LPO) and higher power output (HPO) calf muscle exercise in HDT and HUT. Study 5 investigated the combined effects of altered MPP and hypoxia during exercise. During rest-HDT, increases in VC compensated for the MPP reduction to maintain MBF, while in rest-HUT, MBF was reduced. Following the start of LPO and HPO exercises, MBF and VC responses were delayed in HDT and accelerated in HUT. During LPO, MBF steady- state was reduced in HUT compared to horizontal (HOR), while the greater increase in VC during HDT maintained MBF at a similar level as HUT. Post-exercise MBF recovered rapidly in all positions after LPO exercise but did not after HPOHDT. During HPOHDT, MBF was reduced despite the increase in VC, while in HPOHUT MBF was similar to that in HPOHOR. The hypoxic challenge added in exercise was met during LPOHDT by in- creased VC to compensate reduced MPP and O2 availability such that MBF maintained DO2est. However, during HPOHDT in hypoxia, VC reached maximal vasodilatory capacity, compromising MBF and DO2est. Together, these findings indicate that LPOHDT in nor- moxia or hypoxia VC increased to maintain MBF and DO2est, but during HPO functional limitation for recruitment of VC constrained MBF and DO2 in normoxia and hypoxia. Elevated muscle electromyograpic signals in HPOHDT were consistent with challenged aer- obic metabolism. MPP reduction in HDT caused slower adaptation of MBF limiting O2 availability would result in a greater O2 deficit that could contribute to an increase in the relative stress of the exercise challenge and advance the onset of muscle fatigue.

Background: Previously, we had shown that elevation of cerebral perfusion pressure, using pressors, improved short-term outcomes after traumatic brain injury and hemorrhagic shock in swine. The current study evaluates outcomes after resuscitation with diaspirin cross-linked hemoglobin (DCLHb)-a hemoglobin-based oxygen carrier with pressor activity-in the same swine model of traumatic brain injury and hemorrhagic shock. Methods: Anesthetized and ventilated swine received traumatic brain injury via cortical fluid percussion (6-8 atm) followed by 45% blood volume hemorrhage. One hour later, animals were randomized to either a control group (SAL) resuscitated with normal saline equal to three times shed blood volume or to one of two experimental groups resuscitated with DCLHb. The two experimental groups consisted of a low-dose group, resuscitated with 250 mL of DCLHb (Hb1), and a high-dose group, resuscitated with 500 mL of DCLHb (Hb2). Animals were observed for 210 minutes postresuscitation. Outcomes evaluated were cerebral oxygenation by measuring partial pressure and saturation of oxygen in cerebrovenous blood; cerebral function by evaluating the preservation and magnitude of cerebrovascular carbon dioxide reactivity; and brain structural damage by semiquantitatively assessing beta amyloid precursor protein positive axons. Results: Postresuscitation, cerebral perfusion pressure was higher in the DCLHb groups (p < 0.05, Hb1 and Hb2 vs. SAL), and intracranial pressure was lower in the Hb2 group (p < 0.05 vs. SAL). Cerebrovenous oxygen level was similar in all groups (p > 0.05). At baseline, 5% carbon dioxide evoked a 16 ± 1% increase in cerebrovenous oxygen saturation, indicating vasodilatation. At 210 minutes, this response was nearly absent in SAL (4 ± 4%) (p < 0.05 vs. baseline) and Hb1 (1 ± 5%), but was partially preserved in Hb2 (9 ± 5%). There was no intergroup difference in beta amyloid precursor protein positive axons. Five of 20 SAL and 0 of 13 DCLHb animals developed brain death (flat electroencephalogram) (p = 0.05, SAL vs. DCLhb). Postresuscitation, DCLHb animals maintained higher mean pulmonary arterial pressure (28 ± 1 mm Hg, SAL; 42 ± mm Hg, Hb1; 45 ± 1 mm Hg, Hb2) (p < 0.05, Hb1 and Hb2 vs. SAL) and lower cardiac output (3.9 ± 1.6 L/min, SAL; 2.6 ± 0.1 L/min, Hb1; 2.7 ± 0.1 L/min, Hb2) (p < 0.05, Hb1 and Hb2 vs. SAL). Three Hb2 animals died as a result of cardiac failure, and one SAL animal died as a result of irreversible shock. Conclusion: In this swine model of traumatic brain injury and hemorrhagic shock, resuscitation with DCLHb maintained a higher cerebral perfusion pressure. Low-dose DCLHb (minimal increase in oxygen carriage) failed to significantly improve short-term outcome. With high-dose DCLHb (significant improvement in oxygen carriage), intracranial pressure was lower and cerebrovascular carbon dioxide reactivity was partially preserved; however, this was at the cost of poorer cardiac performance secondary to high afterload.

<p>During brain activity neurons release the major excitatory transmitter glutamate, which is taken up by astrocytes and converted to glutamine. Glutamine returns to neurons for re-conversion to glutamate. This glutamate-glutamine cycle is energy demanding. Glutamate turnover in injured brain was studied using an animal iron-induced posttraumatic epilepsy model and using neurointensive care data from 33 patients with spontaneous subarachnoid hemorrhage (SAH). Immunoblotting revealed that the functional form of the major astrocytic glutamate uptake protein GLT-1 was decreased 1-5 days following a cortical epileptogenic iron-injection, presumably due to oxidation-induced aggregation. Using microdialysis it was shown that the GLT-1 decrease was associated with increased interstitial glutamate levels and decreased interstitial glutamine levels. The results indicate a possible posttraumatic and post-stroke epileptogenic mechanism. Analysing 3600 microdialysis hours from patients it was found that the interstitial lactate/pyruvate (L/P) ratio correlate with the glutamine/glutamate ratio (r =-0.66). This correlation was as strong as the correlation between L/P and glutamate (r=0.68) and between lactate and glutamate (r=0.65). Pyruvate and glutamine correlated linearly (r=0.52). Energy failure periods, defined as L/P>40, were associated with high interstitial glutamate levels. Glutamine increased or decreased during energy failure periods depending on pyruvate. Energy failure periods were clinically associated with delayed ischemic neurological deficits (DIND) or development of radiologically verified infarcts, confirming that L/P>40 is a pathological microdialysis pattern that can predict ischemic deterioration after SAH. DIND-associated microdialysis patterns were L/P elevations and surges in interstitial glutamine. Glutamine and pyruvate correlated with the cerebral perfusion pressure (r=0.25, r=0.24). Glutamine and the glutamine/glutamate ratio correlated with the intracranial pressure (r=-0.29, r=0.40). Glutamine surges appeared upon substantial lowering of the intracranial pressure by increased cerebrospinal fluid drainage. Increased interstitial glutamine and pyruvate levels may reflect augmented astrocytic glycolysis in recovering brain tissue with increased energy demand due to a high glutamate-glutamine turnover.</p>

The neurological wake-up test, NWT, is a clinical monitoring tool that can be used to evaluate the level of consciousness in patients with traumatic brain injury (TBI) and subarachnoid haemorrhage (SAH) during neurocritical care (NCC). Since patients with severe TBI or SAH are often treated with mechanical ventilation and sedation, the NWT requires that the continuous sedation is interrupted. However, interruption of continuous sedation may induce a stress response and the use of the NWT in NCC is controversial. The effects of the NWT on intracranial pressure (ICP) and cerebral perfusion pressure (CPP) were evaluated in 21 patients with TBI or SAH. Compared to baseline when the patients were sedated with continuous propofol sedation, the NWT resulted in increased ICP and CPP (p&lt;0.05). Next, the effects of the NWT on the stress hormones adrenocorticotrophic hormone (ACTH), cortisol, epinephrine and norepinephrine were evaluated in 24 patients. Compared to baseline, the NWT caused a mild stress response resulting in increased levels of all evaluated stress hormones (p&lt;0.05). To compare the use of routine NCC monitoring tools, the choice of sedation and analgesia and the frequency of NWT in Scandinavian NCC units, a questionnaire was used. The results showed that all 16 Scandinavian NCC units routinely use ICP and CPP monitoring and propofol and midazolam were primary choices for patient sedation in an equal number of NCC units. In 2009, the NWT was not routinely used in eight NCC units whereas others used the test up to six times daily. Finally, intracerebral microdialysis (MD), brain tissue oxygenation (PbtiO2) and jugular bulb oxygenation (SjvO2) were used in 17 TBI patients to evaluate the effect of the NWT procedure on focal neurochemistry and cerebral oxygenation. The NWT did not negatively alter interstitial markers of energy metabolism or cerebral oxygenation. In conclusion, the NWT induced a mild stress response in patients with TBI or SAH that did not result in a detectable, significant secondary insult to the injured brain. These results suggest that the NWT may safely be used as a clinical monitoring tool in the NCC of severe TBI and SAH in a majority of patients.

During brain activity neurons release the major excitatory transmitter glutamate, which is taken up by astrocytes and converted to glutamine. Glutamine returns to neurons for re-conversion to glutamate. This glutamate-glutamine cycle is energy demanding. Glutamate turnover in injured brain was studied using an animal iron-induced posttraumatic epilepsy model and using neurointensive care data from 33 patients with spontaneous subarachnoid hemorrhage (SAH). Immunoblotting revealed that the functional form of the major astrocytic glutamate uptake protein GLT-1 was decreased 1-5 days following a cortical epileptogenic iron-injection, presumably due to oxidation-induced aggregation. Using microdialysis it was shown that the GLT-1 decrease was associated with increased interstitial glutamate levels and decreased interstitial glutamine levels. The results indicate a possible posttraumatic and post-stroke epileptogenic mechanism. Analysing 3600 microdialysis hours from patients it was found that the interstitial lactate/pyruvate (L/P) ratio correlate with the glutamine/glutamate ratio (r =-0.66). This correlation was as strong as the correlation between L/P and glutamate (r=0.68) and between lactate and glutamate (r=0.65). Pyruvate and glutamine correlated linearly (r=0.52). Energy failure periods, defined as L/P&gt;40, were associated with high interstitial glutamate levels. Glutamine increased or decreased during energy failure periods depending on pyruvate. Energy failure periods were clinically associated with delayed ischemic neurological deficits (DIND) or development of radiologically verified infarcts, confirming that L/P&gt;40 is a pathological microdialysis pattern that can predict ischemic deterioration after SAH. DIND-associated microdialysis patterns were L/P elevations and surges in interstitial glutamine. Glutamine and pyruvate correlated with the cerebral perfusion pressure (r=0.25, r=0.24). Glutamine and the glutamine/glutamate ratio correlated with the intracranial pressure (r=-0.29, r=0.40). Glutamine surges appeared upon substantial lowering of the intracranial pressure by increased cerebrospinal fluid drainage. Increased interstitial glutamine and pyruvate levels may reflect augmented astrocytic glycolysis in recovering brain tissue with increased energy demand due to a high glutamate-glutamine turnover.